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Therapeutic drug monitoring of itraconazole and the relevance of pharmacokinetic interactions
REVIEW Therapeutic drug monitoring of itraconazole and the relevance of pharmacokinetic interactions A. Domı´nguez-Gil Hurle´, A. Sa´nchez Navarro and M. J. Garcı´a Sa´nchez Servicio de Farmacia, Hospital Universitario de Salamanca, Dpto. de Farmacia y Tecnologı´a Farmace´utica, Facultad de Farmacia, Universidad de Salamanca, Spain
ABSTRACT A review of the pharmacological aspects of greatest relevance in relation to the monitoring of itraconazole serum levels is presented in this article. The main causes of pharmacokinetic variability, e.g., poor aqueous solubility, the presystemic first-pass effect with the involvement of transporters such as P-glycoprotein, the high extent of metabolism mediated by the CYP450 system and a high probability of pharmacological interactions, are documented and discussed. The pharmacokinetic–pharmacodynamic criteria used to optimise antibiotic therapy, as well as their application to antifungal drugs, are also discussed. Data concerning the breakpoints established for the minimum serum concentrations of itraconazole are included, and the most relevant justifications for drug monitoring are cited. Keywords
Drug interactions, itraconazole, therapeutic drug monitoring
Clin Microbiol Infect 2006; 12 (suppl 7): 97–106
INTRODUCTION It is known that the intrinsic activity is a characteristic required for a product to become a drug. Nevertheless, the activity of a drug does not sufficiently guarantee its safety and efficacy for pharmacological treatments. In the particular field of anti-infective therapy, many chemical products showing high or even very high activity (potency) against several pathogens of clinical interest also present serious difficulties in their use as therapeutic agents in clinical practice. The physicochemical or biological properties related to their kinetic or safety profiles, and problems related to industrial manufacturing, are among the several limitations [1]. Regardless of the clinical circumstances affecting the patient, the outcome of a treatment depends on both the pharmacokinetics and pharmacodynamics of the anti-infective drug administered, the former being conditioned by absorption, distribution, metabolism and Corresponding author and reprint requests: M. J. Garcia Sanchez, Servicio de Farmacia, Hospital Universitario de Salamanca, Dpto. de Farmacia y Tecnologı´a Farmace´utica, Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain 37007 E-mail:[email protected]
excretion processes. Characterisation of the kinetic profile of a drug is one of the main goals during the clinical development of new molecules, and this type of information is essential in establishing the pharmaceutical form, the administration route and the dosage schedules. Changes affecting the pharmacokinetic processes lead to variations in plasma concentrations as well as in the exposure of the target site to the drug; consequently, these modifications may finally affect the safety and efficacy of the treatment. Pharmacodynamics relate to the intrinsic activity and potency of the product against a particular organism, the minimum inhibitory concentration (MIC) being the parameter most widely used as the pharmacodynamic variable, although additional concepts, e.g., the post-antibiotic effect, the post-b-lactamase inhibitor effect or the margin for selection of resistance, have recently been incorporated in studies performed with anti-infective agents [2–4]. In recent years, pharmacokinetic–pharmacodynamic (PK–PD) analysis applied to infectious diseases has undergone important advances, leading to the consideration of some PK–PD parameters as response surrogate variables. This type of analysis combines both pharmacokinetic and pharmacodynamic information about the antimicrobial agent. The area under the
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concentration–time curve (AUC), being the most representative parameter of exposure to a drug, the maximum plasma concentration (Cmax) and the fraction of dosage interval for which drug levels remain above the MIC are the three pharmacokinetic parameters most widely used, the MIC being the only pharmacodynamic parameter currently used for this purpose. Although PK–PD analysis is being undertaken to improve pharmacological treatment with several groups of antibiotics, e.g., aminoglycosides, fluoroquinolones, b-lactams and glycopeptides, this strategy is rarely applied to antifungal agents [5]. The clinical response observed with a drug after the administration of a particular dose may be very different among different patients and may even differ in the same patient during treatment. Thus, a given dose might lead to inefficacy, therapeutic effect or toxicity when used in clinical practice, particularly for drugs with a narrow therapeutic window. This inter- and intra-individual variability is caused by several factors affecting the relationship between the dose administered and the intensity or duration of pharmacological effects. Such variability has both pharmacokinetic and pharmacodynamic components, the latter being the most difficult to characterise [6]. Regarding pharmacokinetics, inter-individual variability has long been recognised and justifies the use of different dosage patterns in different population groups, e.g., paediatric, geriatric or renal-impaired patients, among others. Intra-individual variability, however, is less well-understood and is often ignored as being responsible for unexpected modifications during a given therapeutic regimen. Systematic monitoring of serum concentrations performed in hospital centres for several drugs has revealed the significance of these modifications, which may lead to erratic effects on some occasions [7]. Genetic factors related to drug receptors, binding enzymes, biological transporters (MDR1, P-glycoprotein, etc.) or enzymic systems involved in drug metabolism, together with the pharmacological interactions and physiological or pathological factors, mainly explain the differences observed in the pharmacokinetic profile of a drug. All these factors may affect the absorption, distribution, metabolism and excretion processes [8], eliciting changes in the amount and ⁄ or absorption rate (bioavailability), body access (distribution volume) or elimination capacity (plasma clearance).
Fig. 1. Kinetic profiles simulated for a single dose of a given anti-infective drug in two hypothetical patients showing different drug clearance levels (100 and 50 mL ⁄ min). The differences in the AUC values observed for the two cases will lead to different responses to the same treatment.
Fig. 1 illustrates the influence of changes in drug clearance produced by some of the above factors on the pharmacological response. The graph includes the kinetic profiles simulated for a particular anti-infective drug in two hypothetical patients showing different drug clearance (100 and 50 mL ⁄ min). A wider systemic exposure to the antimicrobial agent (higher AUC value) is observed in the case of lower drug clearance. Since the AUC ⁄ MIC is correlated with clinical response (microbiological cure, clinical outcome, etc.), the differences in the AUC values observed for the two cases will lead to different responses to the same treatment. Pharmacological interactions are another relevant source of pharmacokinetic or pharmacodynamic variability, and the consequences may be inefficacy or toxicity in the case of drugs with a narrow therapeutic window [9]. The adverse reactions caused by pharmacological interactions may result from the drug’s side-effects appearance at a higher incidence and severity or may be new adverse effects not related to the drug when used alone. The former are likely to be due to alterations in any particular pharmacokinetic process that leads to a significant increase of drug levels in serum and body tissues, causing effects similar to those produced by acute or chronic intoxication as a consequence of overdosing. A different situation appears when the associated drugs bind to the same receptors or biological systems, in which case pharmacodynamic interactions will be more likely to occur.
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Interactions related to the enzymic systems involved in drug metabolism, mainly CYP2C9, CYP3A4, CYP2D6 and CYP2C19, are among the most relevant pharmacokinetic interactions. The enzymic inhibition that appears when two or more drugs with affinity for the same system are associated is dose-dependent, with a high degree of selectivity, and it is generally reversible. Most reversible inhibitors are molecules that have nitrogen, imidazole, pyridine or quinolone groups in their chemical structure. Molecules of this type bind to the prosthetic group and the lipophilic region of the enzyme to block enzymic activity. This explains why the potency of inhibitors is dependent on their lipophilicity and the intensity of binding to the prosthetic group on the enzymic system [10–13]. The clinical relevance of enzymic inhibition depends on different factors, the therapeutic margin of the drug involved being the most important. For example, patients receiving anticoagulants, antidepressants and immunosuppressive or cardiovascular agents have a higher risk of side-effects than those receiving drugs with a broader therapeutic range. Despite pharmacological interactions being well-controlled in most cases, they may lead to life-threatening conditions on some occasions. In order to make a proper prediction of the consequences of interactions related to the metabolism of a drug, it is necessary to identify the enzymic routes involved in the process and to establish the contribution of each enzymic system. In some cases, the same enzyme produces several metabolic transformations, while in other cases, several enzymic systems may be involved in a single reaction [14–17]. Adverse reactions produced by pharmacological interactions should be carefully considered, and strategies such as monitoring of drug levels and dosage individualisation should be implemented in order to avoid these unwanted effects. A wide knowledge of the pharmacological characteristics of the drug and close control of the patient are essential in reaching this goal. PHARMACOKINETICS OF ITRACONAZOLE The pharmacokinetics of itraconazole have been extensively studied and are well-documented in several reviews [18–24]. Only the most relevant
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points in relation to therapeutic drug monitoring (TDM) are addressed here. Itraconazole is a highly lipophilic molecule. It is a slightly acidic salt (pKa ¼ 3.7), and hence is ionisable only at very low pH values. It is also poorly soluble in water, with an aqueous solubility close to 1 ng ⁄ mL at pH 7 and slightly higher than 4 ng ⁄ mL at pH 1. These characteristics make the oral absorption of itraconazole difficult when it is administered as capsules. For this type of formulation, reduced bioavailability was observed when the drug was administered under fasting conditions, particularly in patients showing low gastric acidity. These findings were associated with the low solubility of itraconazole, which is the aspect limiting the absorption process. The administration of capsules together with food, as well as the co-administration of acidic fluids such as cola drinks, were strategies used to overcome the problem [25,26]. Gastrointestinal absorption is limited by solubility (responsible for the concentration of drug able to pass through membranes and also for the rate of dissolved molecules appearing at the absorption site), by the acidic ⁄ basic character (determining the ionised fraction in solution at a given pH), by the lipophilicity (controlling the partition coefficient between the aqueous and lipophilic phases of body tissues) and by the permeability (determining the ability of molecules to pass through membranes). The Biopharmaceutical Classification System proposed by Amidon et al. [27] groups drugs according to their aqueous solubility and their permeability. This classification was first accepted by the FDA, and then by the European Agency for the Evaluation of Medical products (EMEA) in 1998, and it is now being used efficiently, not only during the preclinical development of new drugs, but also for the planning of bioavailability assays according to the in-vitro ⁄ in-vivo data relationships, and for the design of new therapeutic forms. According to the Biopharmaceutical Classification System, itraconazole belongs to class II, which includes molecules with low solubility and high permeability, for which the dissolution rate is the factor limiting absorption. In this situation, changes in the molecular structure leading to chemical species with higher water solubility or modifications in the pharmaceutical dosage form are the most frequent strategies for
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increasing drug bioavailability, the formation of complexes being one method that can be used for this purpose. Complex formation may be defined as the reversible association of substrate and ligand molecules to form a new chemical species known as a complex, with a defined molecular ratio, which has physico-chemical properties that in many cases may be very different from those of their components (substrates). Among the different types of complexes, it is worth mentioning the so-called inclusion complexes, which are produced by an interaction at the molecular level between two types of compound; one of them acts as the ‘host’, being able to take into its structure another compound called the ‘guest’ [28]. Cyclodextrins (CDs) are among the host compounds, and are currently the most widely used for this purpose, due to their favourable characteristics, which include adequate size, good stability and reduced side-effects. When the CD–drug complex comes into contact with an aqueous medium, the complex dissociates and the guest molecule is released. The dissociation rate constant of the complex determines the amount of free drug, and hence, the absorption rate is limited by this factor [29]. Moreover, the CD–drug complex may have higher chemical stability, solubility and bioavailability than the free drug [29]. An inclusion complex formed by itraconazole and a particular type of CD (2-hydroxypropylb-cyclodextrin) at a molecular ratio of 1:3 significantly modifies the solubility of the antifungal agent, producing an increase in the oral bioavailability of the drug [30]. The synthesis of this inclusion complex facilitates the formulation of itraconazole as an oral solution, as well as a parenteral preparation for intravenous administration [19,31]. The oral solution of itraconazole has a more favourable bioavailability than the capsule form [22]. A comparative study revealed a 37% increase in the relative bioavailability of the former formulation as compared to the latter. More recent studies have shown that the absorption of the oral solution of CD–itraconazole is increased in the absence of food, providing an additional advantage for at-risk patients. Pharmacokinetic assays have revealed that administration of the oral solution with no food leads to an increase in the AUC as well as in the Cmax values. In sum, the administration of the oral solution containing the CD–itraconazole complex under fasting conditions produces a 30% increase
in absorption, compared to administration of this formulation with food [32]. Although tolerance to CDs is high, it must be taken into account that these compounds may accumulate in renalimpaired patients because of their renal excretion [19]. Itraconazole is widely distributed throughout the body, this process being highly dependent on the physico-chemical properties of the drug, with a reported apparent distribution volume of 10.7 L ⁄ kg. It is highly bound to serum proteins, mainly to serum albumin, and it has a bound fraction of 99.8%. In some body tissues, e.g., skin, lungs, muscle and liver, very high concentrations of itraconazole and ⁄ or its metabolites are found [19,20,22,26,33]. Data concerning the disposition of the drug after inhalation have confirmed that the parent drug and its hydroxy metabolite reach tissue concentrations higher than simultaneous plasma levels [34]. Itraconazole is extensively biotransformed in the organism and more than 30 metabolites have been identified. The major metabolic route is mediated by the CYP450 system, the main isoenzymes involved in the metabolism of the azoletype antifungal agents being the following: CYP3A4 (itraconazole, ketoconazole, voriconazole, fluconazole) and CYP2C9 or CYP2C19 (fluconazole, ketoconazole, voriconazole). For itraconazole, the major metabolite is the hydroxy derivative, which shows an antifungal activity similar to that of the parent drug according to in-vitro studies. The concentrations of this derivative are about 1.5–2 times the corresponding levels of the parent drug [19,22]. An elimination half-life of 20 h has been reported for itraconazole after its administration as a single dose of 200 mg. Nevertheless, this parameter increases to 30 h under steady-state conditions as a consequence of saturation of the metabolic processes [35]. The pharmacokinetics of itraconazole have been studied in different population groups. No significant modification of the pharmacokinetic processes has been found in renal-impaired patients. Accordingly, modifications in the dosage schedules would not be necessary in this type of patient, although administration of the drug is not recommended for individuals with a creatinine clearance under 30 mL ⁄ min, probably because of the impaired renal excretion of metabolites and CD, with the corresponding accumulation in this
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situation [36,37]. Modifications in the absorption and elimination of itraconazole, however, have been observed in cirrhotic patients, and dosage individualisation is recommended for this population group [38]. Itraconazole is a potent enzymic inhibitor [18,39,40] and therefore some precautions have to be taken when it is associated with other drugs. Clearance alterations due to enzymic inhibition or induction directly affect serum plasma levels, the AUC value and even bioavailability when enzymic systems are involved in the absorption process. Fig. 2 includes the serum concentration profiles simulated for a drug undergoing metabolism administered alone and associated with an enzymic inhibitor. As a consequence of the decrease in clearance, an increase in serum levels above the maximum tolerated concentrations may occur for drugs with a narrow therapeutic window [40,41]. In the case of itraconazole being administered in association with other drugs with a capacity for enzymic induction or inhibition, the interaction may affect the serum concentrations of the antifungal agent. Accordingly, rifampicin, rifabutin, diphenylhydantoin and carbamazepine, all well-known as enzymic inducers, reduce the serum levels of itraconazole, while inhibitor drugs such as clarithromycin, erythromycin, ritonavir and indinavir lead to an increase in itraconazole levels [20,42]. The potential effects of itraconazole on other drugs, as a consequence of its high enzymic inhibitory capacity, should also be borne in mind, particularly for immunosuppressive agents, oral anticoagulants, statins, and anti-retroviral or
Fig. 2. Serum concentration profiles simulated for a multiple dosage regimen for a drug administered alone and in association with an enzymic inhibitor. MTC, maximum tolerated concentration.
cytotoxic products [43–45]. Data from our laboratory confirm this statement, since it was found that the half-life of sirolimus was increased from 62 to 602 h when it was associated with itraconazole. Also, cyclosporin undergoes a relevant interaction with itraconazole, and its association with this drug was incorporated as a categorical co-variable to estimate the clearance of the immunosuppressive agent in a population model for cyclosporin in transplant recipients [47]. Additionally, itraconazole and several other products that inhibit the liver CYP450 system or P-glycoprotein (fluconazole, voriconazole nifedipine, etc.) undergo interactions with vincristine and cyclophosphamide that affect their metabolism and lead to an increase in the toxicity of these compounds [47–49]. TDM should be supported by analytical, PK– PD, clinical and pharmaco-economic criteria. The monitoring of serum concentrations of some drugs has constituted routine practice in many hospitals for the last 25 years, although, in fact, this practice was initiated much earlier (1960) in some centres. The initial aim of TDM was to individualise dosage schedules with a view to improving clinical outcomes, but improvements in the safety profiles of drugs showing potential toxicity, e.g., aminoglycosides, glycopeptides or antiepileptic drugs, rapidly became the main goal of TDM. Accordingly, this procedure provides an excellent tool for control of pharmacological treatments, patient protection and improvement in the safety of drugs [41]. Currently, the development of TDM programmes is restricted to situations fulfilling several requirements related to analytical, pharmacological, clinical and economic issues. The implementation of a TDM programme first requires the existence of an analytical technique that shows the appropriate criteria of accuracy, specificity, sensibility and efficiency. In recent years, several techniques for the quantification of itraconazole that fulfil the above requirements have been developed and reported [50]. Most of them are techniques involving chromatography, capillary electrophoresis and mass spectrophotometry, all of these being complicated for implementation in the clinical setting. Prompted by the interest in monitoring itraconazole, we have developed a chromatographic technique using fluorescence detection. This analytical method has been validated and it allows us to accurately
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determine serum concentrations of itraconazole and its hydroxy metabolite within a run time of less than 8 min, with quantification limits of 50 and 25 ng ⁄ mL for the parent drug and metabolite, respectively. In brief, the analytical method is as follows: serum samples (500 L) are subjected to a single liquid–liquid extraction process with diethyl ether in basic medium. The extractive phase is mixed with the eluent phase (acetonitrile ⁄ water, 55:45, with tri-ethanol amine adjusted to pH 3 with orthophosphoric acid). Following this, it is injected into the chromatographic equipment (Hewlett Packard 1050; fluorescence detector Shimadzu RF-10AXL; kexc ¼ 260 nm; kemiss ¼ 365 nm) at a flow rate of 1.5 mL ⁄ min. It is important to make sure that the analytical procedure has been properly validated, and interference with additional drugs used in polytherapy has to be avoided. Regarding PK–PD criteria, antifungal agents may be assembled using the same classification system as that used for antibiotics [51]. Accordingly, they can be allocated to class I, II or III, depending on their killing mechanism pattern. Class I would include drugs showing a concentration-dependent pattern together with a relevant post-antifungal effect such as amphotericin B and caspofungin. For this group, the Cmax ⁄ MIC and AUC ⁄ MIC are the response surrogate variables. Flucytosine would be included within class II, which includes products with a time-dependent antifungal effect and reduced post-antifungal effect, the surrogate variables being, in this case, T>MIC and AUC ⁄ MIC. Finally, class III would include the azole-type antifungal agents, itraconazole being among them. For this group, a time-dependent effect, together with a variable post-antifungal effect, is observed. As for class II, AUC ⁄ MIC and T>MIC seem to be the parameters best related to response. According to these considerations, the time needed for minimum serum concentrations (Cmin) to be reached has been selected as the sampling time for monitoring itraconazole levels. This means that blood should be withdrawn immediately before administration of the next dose (at the end of a dosage interval). In order to achieve maximum efficacy with itraconazole treatments, the concentration at this sampling time must be above the MIC value established for the infecting pathogen. The existence of a well-defined therapeutic range is another essential requirement for
performing TDM. This is necessary for decisionmaking and optimisation of dosage schedules. In the particular case of itraconazole, early studies performed in vitro and with laboratory animals, to define the relationship between serum concentrations and antifungal activity, revealed that more than 99.6% of 750 strains of dermatophytes were inhibited by concentrations of 1000 ng ⁄ mL [52]. Data from another study [53] using an experimental model with infection produced by Aspergillus fumigatus showed a sigmoid relationship between serum concentrations of itraconazole and antifungal activity. Cmin values above 600 ng ⁄ mL were related to maximum inhibitory activity, and Cmin values lower than this were linked to lower activity. Several clinical studies have established a breakpoint for Cmin of 500 ng ⁄ mL, which is related to a lower incidence of massive fungal invasion [24,54,55]. Nevertheless, other clinical studies failed to reach the same conclusion, probably due to the difficulty of setting up homogeneous study groups [54,56,57]. A meta-analysis was performed in order to establish the relationship between the efficacy of itraconazole for the prophylaxis of fungal infections in neutropenic patients and the dose [58]. The authors, however, did not use the dose administered but what they called the bioavailable daily dose (BDD), which was defined as the product of the dose administered (D) and the absolute bioavailability of the formulation (F). Patients were divided into two groups according to the F value of the formulation administered (F ¼ 22% for capsules and F ¼ 55% for oral solution). The group receiving a BDD of 200 mg (oral solution) showed a lower incidence of fungal infections than the group receiving a BDD of 100 mg (capsules). These results agree with data from the above-mentioned studies, relating better efficacy to higher Cmin values. The authors of the meta-analysis suggested a breakpoint for the BDD of 200 mg, which is equivalent to 400 mg of itraconazole administered as an oral solution [58]. Nonetheless, the current data concerning itraconazole are insufficient to define a therapeutic window for this drug, although a value of 500 ng ⁄ mL for Cmin has been accepted as the efficacy breakpoint for this drug. As the active hydroxy metabolite is present in serum at concentrations of 1.5–2-fold the corresponding levels of the parent drug, Cmin values of itraconazole
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above the selected breakpoint mean that the Cmin for total active compounds (parent drug plus active metabolite) is higher than the MIC values for pathogens responsible for most fungal infections [59,60]. Some dosage schedules based on the administration of a loading dose have been reported to achieve steady-state levels within the first days of treatment with itraconazole. Nevertheless, TDM could offer an additional strategy for attaining the optimum dosage schedule in the shortest period of time. The dosage patterns established for steady-state levels to be reached rapidly are as follows. For the intravenous route, 200 mg ⁄ 12 h should be administered for 2 days, followed by a maintenance dose of 200 mg daily. When the oral route is chosen, 200 mg ⁄ 12 h of the oral solution should be administered, followed by monitoring of serum levels on day 7 of treatment. If the concentration measured has the recommended value, the same treatment can be maintained. In the case of the desirability of achieving steadystate levels within the first 48 h by oral administration because the intravenous route is not indicated, the treatment should be initiated with the oral solution at 800 mg ⁄ 12–24 h for 2 days (loading dose), followed by 200 mg ⁄ 12 h. TDM of itraconazole is of particular interest in the following cases: when new drugs are associated with it, in the event of possible unknown pharmacokinetic interactions; when non-compliance with the prescribed treatment is suspected; or in cases of a high probability of low bioavailability. This clinical practice is also recommended during chemotherapy cycles and immediately after the end of such treatments [60]. When serum levels of itraconazole are monitored, modifications to the dosage schedule are recommended in the following situations. 1. When the Cmin determined after 3 days of treatment with 200 mg ⁄ 12 h is above 500 ng ⁄ mL but lower than 2000 ng ⁄ mL, the dosage interval should be extended to 24 h. 2. When the Cmin determined after 3 days of treatment with 200 mg ⁄ 12 h is above 2000 ng ⁄ mL, intravenous administration should be stopped and the oral route must be used, if tolerated by the patient. 3. When the Cmin determined after 3 days of treatment with 200 mg ⁄ 12 h is below 500 ng ⁄ mL, the same intravenous pattern should be maintained.
As mentioned above, we have implemented a TDM program for itraconazole, with a total of 54 patients and 122 serum determinations being included to date. The mean values of Cmin deermined for itraconazole and its hydoxy metabolite are 1237.57 ± 990.07 ng ⁄ mL and 2087.49 ± 1542.35 ng ⁄ mL, respectively (unpublished data). The high variability in these values and also the low percentage (54.1%) of the Cmin values within the 500–2000 ng ⁄ mL range should be noted. Among the rest, 25.4% are below 500 ng ⁄ mL and 20.5% above 2000 ng ⁄ mL. Although the data available are too limited for definitive conclusions to be drawn, this preliminary information points to a significant number of patients with Cmin values below the recommended breakpoints when they receive the standard doses. These findings support the interest in TDM for optimising treatment with itraconazole. In summary, the most relevant justifications for the monitoring of serum concentrations of itraconazole are: 1. Low and erratic bioavailability. Like other drugs with poor water solubility, itraconazole is not well-absorbed after oral administration, leading to highly variable absorption extent and rates and, consequently, to differences in serum levels as well as AUC values. The involvement of P-glycoprotein in the oral absorption of itraconazole may be another reason for the high variability observed in the bioavailability of this drug, since this determines the presystemic first-pass effect [61]. Although the new oral solution improves absorption and reduces variability, the bioavailability of itraconazole cannot be considered to be optimal. 2. Absorption processes being influenced by several factors such as pathologies and chemotherapy. Many clinical circumstances modify the permeability of gastrointestinal membranes and lead to changes in the amount and rate of drug absorption. Neutropenic status in AIDS patients or transplant recipients are two examples of factors affecting the oral bioavailability of itraconazole. 3. Dose-dependent pharmacokinetics. In the case of itraconazole, non-linear kinetics have been reported and documented [20]. Consequently, increases in dosage do not produce proportional increases in serum concentrations. This has been attributed to the limited metabolic
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4.
5.
6.
7.
capacity of the organism [35] and also to the involvement of biological transporters such as P-glycoprotein in the presystemic first-pass effect [61]. Poor correlation between the dose administered and serum levels. Because of the high variability in the values of pharmacokinetic parameters, the same dose may lead to very different concentration–time profiles in different patients, and even to differences during the treatment of a single patient. High probability of interactions with other drugs that are substrates of CYP450. Inhibitors or inducers of this enzymic system may affect the metabolism of itraconazole and hence increase or decrease, respectively, the serum levels of the antifungal agent. It should be noted that itraconazole, as a potent enzymic inhibitor, might also modify the serum profile of co-administered drugs that are metabolised through the above-mentioned CYP450 system, particularly when these drugs have a narrow therapeutic window. Additional strategy for compliance control among patients receiving oral treatment. Although the oral route is more convenient for patients at home, the risk of non-compliance is still high and TDM may be a method for gaining insight into patient compliance. The serum concentration ⁄ dose ratio is used as a measure of the degree of compliance. Optimisation of hospital public health resources. Nowadays, implementation of health technologies and ⁄ or strategies should be supported by efficiency and efficacy criteria. Pharmaco-economic studies include analysis and evaluation of benefits ⁄ risk vs. the costs of health interventions in which the use of drugs is involved. Cost-efficiency studies provide the proper support for decisionmaking about the selection of drugs and other different health-oriented procedures. Recent assays have shown that the cost of invasive fungal infections may lie between 22 197 and 31 200 US$ per episode, while the cost of the oral drug (400 mg ⁄ day) is only about 16 US$ per day. Additional pharmaco-economic studies would be necessary to evaluate the global economic impact of the prophylaxis of fungal infections on public health-related costs. Recently, Buchkowsky et al. have reported
the interest in and possible limitations of TDM of itraconozole, highlighting the relevance of this clinical strategy for immunosuppressed patients [60]. CONCLUSIONS Itraconazole is an antifungal agent with an interesting pharmacodynamic profile. Its clinical usefulness in the prophylaxis and treatment of fungal infections has been proven and welldocumented. However, owing to its pharmacokinetic profile, careful control of patients receiving treatment with this drug is recommended. The new oral solution, based on the CD inclusion complex, improves the bioavailability and facilitates patient compliance with treatment outside hospital because of the possibility of once-daily administration. Since the drug is metabolised by the CYP450 enzymic system, there is a high probability of interactions with other drugs that use the same metabolic route. Additionally, itraconazole is a potent enzymic inhibitor and may therefore modify the kinetic profile of co-administered drugs that are substrates of the CYP450 system. The pharmacokinetic variability of itraconazole and its clinical consequences may be controlled by the implementation of a proper TDM programme. REFERENCES 1. Testa B, Waterbeemd HV, Folkers G, Gue R, eds. Pharmacokinetic optimization in drug research. Biological, physicochemical, and computational strategies. Zurich: Wiley-VCH, 2001. 2. Thorburn CE, Molesworth SJ, Sutherland R, Tittenhouse S. Postantibiotic and post-b-lactamase inhibitor effects of amoxicillin plus clavulanate. Antimicrob Agents Chemother 1996; 40: 2796–2801. 3. Ambrose PG, Owens RC, Grasela D. Antimicrobial pharmacodynamics. Med Clin North Am 2000; 84: 1431–1436. 4. Firsov AA, Vostrov SN, Lubenko Y, Drlica K, Portonoy YA, Zinner SH. In vitro pharmacodynamic evaluation of the mutant selection window hypothesis using four fluoroquinolones against Staphylococcus aureus. Antimicrob Agents Chemother 2003; 47: 1604–1613. 5. Wong-Beringer A, Kriengkauykiat J. Systemic antifungal therapy: new options, new challenges. Pharmacotherapy 2003; 23: 1441–1462. 6. Ensom MHH, Davis GA, Cropp CD et al. Clinical pharmacokinetics in the 21st century. Does the evidence support definitive outcomes? Clin Pharmacokinet 1998; 34: 265–279. 7. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005; 26: 2211– 2221.
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8. Poirier JM, Berlioz F, Isnard F et al. Marked intra- and inter-patient variability of itraconazole steady state plasma concentrations. Therapie 1996; 51: 163–167. 9. Hansten PD. Understanding drug–drug interactions. Sci Am Sci Med 1998; 5: 15–25. 10. Preskorn SH. Reducing the risk of drug–drug interactions: a goal of rational drug development. J Clin Psychiatry 1996; 57 (suppl 1): 3–6. 11. Lin JH, Lu AYH. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 1998; 35: 361–390. 12. Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Phamacokinet Biop 1996; 24: 475–490. 13. Preskorn SH, Magnus RD. Inhibition of hepatic P-450 isoenzymes by serotonin selective reuptake inhibitors: in vitro and in vivo findings and their implications for patient care. Psychopharmacol Bull 1994; 30: 251–259. 14. Watkins PB, Turgeon DK, Saenger P et al. Comparison of urinary 6-b-cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity. Clin Pharmacol Ther 1992; 52: 265–273. 15. Lown KS, Thummel KE, Benedict PE. The erythromycin breath test predicts the clearance of midazolam. Clin Pharmacol Ther 1995; 57: 16–24. 16. Cheng CL, Smith DE, Cox SR et al. Correlation between ERMBT and oral exposure to delavirdine mesylate in HIVpositive patients. Pharm Res 1995; 12: S374. 17. Tateishi T, Graham SG, Krivoruk Y, Wood AJ. Omeprazole does not affect measured CYP3A4 activity using the erythromycin breath test (letter). Br J Clin Pharmacol 1995; 40: 411–412. 18. Maertens J, Boogaerts M. The place for itraconazole in treatment. J Antimicrob Chemother 2005; 56 (suppl S1): i33– i38. 19. Willems L, van der Geest R, de Beule K. Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics. J Clin Pharm Ther 2001; 26: 159–169. 20. Prentice AG, Glasmacher A. Making sense of itraconazole pharmacokinetics. J Antimicrob Chemother 2005; 56 (suppl S1): i17–i22. 21. Hardin TC, Graybill JR, Fetchick R, Woestenborghs R, Rinaldi M, Kuhn JG. Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob Agents Chemother 1998; 32: 1310–1313. 22. Koks H, Meenhorst PL, Bult A et al. Itraconazole solution: summary of pharmacokinetic features and review of activity in the treatment of fluconazole-resistant oral candidosis in HIV-infected persons. Pharmacol Res 2002; 46: 195–201. 23. Mohr JF, Finkel KW, Rex JH, Rodrı´guez JR, Leitz GJ, Ostrosky-Zeichner L. Pharmacokinetics of intravenous itraconazole in stable hemodialysis patients. Antimicrob Agents Chemother 2004; 48: 3151–3153. 24. Winston DJ, Maziarz RT, Chandrasekar PH et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomised trial. Ann Intern Med 2003; 138: 705–713. 25. Lohitnavy M, Lohitnavy O, Thangkeattiyanon O, Srichai W. Reduced oral itraconazole bioavailability by antacid suspension. J Clin Pharm Ther 2005; 30: 201–206.
26. de Beule K, Van Gestel J. Farmacologı´a de itraconazol. Drugs 2001; 61 (suppl 1): 29–40. 27. Amidon GL, Lennerna¨s H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995; 12: 413–420. 28. Uekama K. Cyclodextrins in drug delivery system. Adv Drug Deliv Rev 1999; 36: 1–2. 29. Stella VJ, Rao VM, Zannou EA, Zia V. Mechanisms of drug release from cyclodextrin complexes. Adv Drug Deliv Rev 1999; 36(1): 3–16. 30. Stevens DA. Itraconazole in cyclodextrin solution. Pharmacotherapy 1999; 19: 603–611. 31. Saag M. Itraconazole oral solution: pharmacokinetics and absorption. AIDS Patient Care STDS 1997; 11 (suppl 1): S16–S17. 32. Van de Velde VJS, Van Peer AP, Heykants JJP et al. Effect of food on the pharmacokinetics of a new hydroxypropylbeta-cyclodextrin formulation of itraconazole. Pharmacotherapy 1996; 16: 424–428. 33. Heykants J, Van Peer A, Van de Velde V et al. The clinical pharmacokinetics of itraconazole: an overview. Mycoses 1989; 32: 67–88. 34. Conte JE, Golden JA, Kipps J, McIver M, Zurlinden E. Intrapulmonary pharmacokinetics and pharmacodynamics of itraconazole and 14-hydroxyitraconazole at steady state. Antimicrob Agents Chemother 2004; 48: 3823–3827. 35. Grant SM, Clissold SP. Itraconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 1989; 37: 310–344. 36. Boelaert J, Schurgers M, Mathys E et al. Itraconazole pharmacokinetics in patients with renal dysfunction. Antimicrob Agents Chemother 1998; 32: 1595–1597. 37. Rajewski RA, Traijer G, Bresnahan J, Jaberaboansari P, Stella VJ, Thompson DO. Preliminary safety evaluation of parenterally administered sulfoalkyl ether beta-cyclodextrin derivatives. J Pharm Sci 1995; 84: 927–932. 38. Girois SB, Chapuis F, Decullier E, Revol BGP. Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis. Eur J Clin Microbiol Infect Dis 2005; 24: 119–130. 39. Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE. Role of itraconazole metabolites in CYP3A4 inhibition. Drug Metab Disp 2004; 32: 1121–1131. 40. Wilke RA, Moore JH, Burmester JK. Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage. Pharmacogenet Genom 2005; 15: 415–421. 41. Potter M. Strategies for managing systemic fungal infection and the place of itraconazole. J Antimicrob Chemother 2005; 56 (suppl 1): 49–54. 42. Yu DT, Peterson JF, Seger DL, Gerth WC, Bates DW. Frequency of potential azole drug–drug interactions and consequences of potential fluconazole drug interactions. Pharmacoepide Miol Drug Saf 2005; 14: 755–777. 43. Florea NR, Capitano B, Nightingale CH, Hull D, Leitz GJ, Nicolau DP. Beneficial pharmacokinetic interaction between cyclosporine and itraconazole in renal transplant recipients. Transplant Proc 2003; 35: 2873–7287. 44. Molden E, Garcia BH, Braathen P, Eggen AE. Co-prescription of cytochrome P450 2D6 ⁄ 3A4 inhibitor–substrate pairs in clinical practice. A retrospective analysis of data
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54. Winston DJ, Busuttil RW. Randomized controlled trial of oral itraconazole solution versus intravenous ⁄ oral fluconazole for prevention of fungal infections in liver transplant recipients. Transplantation 2002; 74: 688–695. 55. Glasmacher A, Hahn C, Leutner C et al. Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole. Mycoses 1999; 42: 443–451. 56. Boogaerts M, Winston DJ, Bjow EJ et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial. Ann Intern Med 2001; 135: 412–422. 57. Berenguer J, Ali NM, Allende MC et al. Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporine A, and correlation between therapeutic response and itraconazole concentrations in plasma. Antimicrob Agents Chemother 1994; 38: 1303–1308. 58. Glasmacher A, Prentice A, Gorschluter M et al. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients. J Clin Oncol 2003; 21: 4615–4626. 59. Poirier JM, Cheymol G. Optimisation of itraconazole therapy using target drug concentrations. Clin Pharmacokinet 1998; 35: 461–473. 60. Buchkowsky SS, Partovi N, Ensom MH. Clinical pharmacokinetic monitoring of itraconazole is warranted in only a subset of patients. Ther Drug Monit 2005; 27: 322–333. 61. Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW. Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother 2002; 46: 160–165.
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ABSTRACT A review of the pharmacological aspects of greatest relevance in relation to the monitoring of itraconazole serum levels is presented in this article. The main causes of pharmacokinetic variability, e.g., poor aqueous solubility, the presystemic first-pass effect with the involvement of transporters such as P-glycoprotein, the high extent of metabolism mediated by the CYP450 system and a high probability of pharmacological interactions, are documented and discussed. The pharmacokinetic–pharmacodynamic criteria used to optimise antibiotic therapy, as well as their application to antifungal drugs, are also discussed. Data concerning the breakpoints established for the minimum serum concentrations of itraconazole are included, and the most relevant justifications for drug monitoring are cited. Keywords
Drug interactions, itraconazole, therapeutic drug monitoring
Clin Microbiol Infect 2006; 12 (suppl 7): 97–106
INTRODUCTION It is known that the intrinsic activity is a characteristic required for a product to become a drug. Nevertheless, the activity of a drug does not sufficiently guarantee its safety and efficacy for pharmacological treatments. In the particular field of anti-infective therapy, many chemical products showing high or even very high activity (potency) against several pathogens of clinical interest also present serious difficulties in their use as therapeutic agents in clinical practice. The physicochemical or biological properties related to their kinetic or safety profiles, and problems related to industrial manufacturing, are among the several limitations [1]. Regardless of the clinical circumstances affecting the patient, the outcome of a treatment depends on both the pharmacokinetics and pharmacodynamics of the anti-infective drug administered, the former being conditioned by absorption, distribution, metabolism and Corresponding author and reprint requests: M. J. Garcia Sanchez, Servicio de Farmacia, Hospital Universitario de Salamanca, Dpto. de Farmacia y Tecnologı´a Farmace´utica, Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain 37007 E-mail:[email protected]
excretion processes. Characterisation of the kinetic profile of a drug is one of the main goals during the clinical development of new molecules, and this type of information is essential in establishing the pharmaceutical form, the administration route and the dosage schedules. Changes affecting the pharmacokinetic processes lead to variations in plasma concentrations as well as in the exposure of the target site to the drug; consequently, these modifications may finally affect the safety and efficacy of the treatment. Pharmacodynamics relate to the intrinsic activity and potency of the product against a particular organism, the minimum inhibitory concentration (MIC) being the parameter most widely used as the pharmacodynamic variable, although additional concepts, e.g., the post-antibiotic effect, the post-b-lactamase inhibitor effect or the margin for selection of resistance, have recently been incorporated in studies performed with anti-infective agents [2–4]. In recent years, pharmacokinetic–pharmacodynamic (PK–PD) analysis applied to infectious diseases has undergone important advances, leading to the consideration of some PK–PD parameters as response surrogate variables. This type of analysis combines both pharmacokinetic and pharmacodynamic information about the antimicrobial agent. The area under the
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concentration–time curve (AUC), being the most representative parameter of exposure to a drug, the maximum plasma concentration (Cmax) and the fraction of dosage interval for which drug levels remain above the MIC are the three pharmacokinetic parameters most widely used, the MIC being the only pharmacodynamic parameter currently used for this purpose. Although PK–PD analysis is being undertaken to improve pharmacological treatment with several groups of antibiotics, e.g., aminoglycosides, fluoroquinolones, b-lactams and glycopeptides, this strategy is rarely applied to antifungal agents [5]. The clinical response observed with a drug after the administration of a particular dose may be very different among different patients and may even differ in the same patient during treatment. Thus, a given dose might lead to inefficacy, therapeutic effect or toxicity when used in clinical practice, particularly for drugs with a narrow therapeutic window. This inter- and intra-individual variability is caused by several factors affecting the relationship between the dose administered and the intensity or duration of pharmacological effects. Such variability has both pharmacokinetic and pharmacodynamic components, the latter being the most difficult to characterise [6]. Regarding pharmacokinetics, inter-individual variability has long been recognised and justifies the use of different dosage patterns in different population groups, e.g., paediatric, geriatric or renal-impaired patients, among others. Intra-individual variability, however, is less well-understood and is often ignored as being responsible for unexpected modifications during a given therapeutic regimen. Systematic monitoring of serum concentrations performed in hospital centres for several drugs has revealed the significance of these modifications, which may lead to erratic effects on some occasions [7]. Genetic factors related to drug receptors, binding enzymes, biological transporters (MDR1, P-glycoprotein, etc.) or enzymic systems involved in drug metabolism, together with the pharmacological interactions and physiological or pathological factors, mainly explain the differences observed in the pharmacokinetic profile of a drug. All these factors may affect the absorption, distribution, metabolism and excretion processes [8], eliciting changes in the amount and ⁄ or absorption rate (bioavailability), body access (distribution volume) or elimination capacity (plasma clearance).
Fig. 1. Kinetic profiles simulated for a single dose of a given anti-infective drug in two hypothetical patients showing different drug clearance levels (100 and 50 mL ⁄ min). The differences in the AUC values observed for the two cases will lead to different responses to the same treatment.
Fig. 1 illustrates the influence of changes in drug clearance produced by some of the above factors on the pharmacological response. The graph includes the kinetic profiles simulated for a particular anti-infective drug in two hypothetical patients showing different drug clearance (100 and 50 mL ⁄ min). A wider systemic exposure to the antimicrobial agent (higher AUC value) is observed in the case of lower drug clearance. Since the AUC ⁄ MIC is correlated with clinical response (microbiological cure, clinical outcome, etc.), the differences in the AUC values observed for the two cases will lead to different responses to the same treatment. Pharmacological interactions are another relevant source of pharmacokinetic or pharmacodynamic variability, and the consequences may be inefficacy or toxicity in the case of drugs with a narrow therapeutic window [9]. The adverse reactions caused by pharmacological interactions may result from the drug’s side-effects appearance at a higher incidence and severity or may be new adverse effects not related to the drug when used alone. The former are likely to be due to alterations in any particular pharmacokinetic process that leads to a significant increase of drug levels in serum and body tissues, causing effects similar to those produced by acute or chronic intoxication as a consequence of overdosing. A different situation appears when the associated drugs bind to the same receptors or biological systems, in which case pharmacodynamic interactions will be more likely to occur.
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Interactions related to the enzymic systems involved in drug metabolism, mainly CYP2C9, CYP3A4, CYP2D6 and CYP2C19, are among the most relevant pharmacokinetic interactions. The enzymic inhibition that appears when two or more drugs with affinity for the same system are associated is dose-dependent, with a high degree of selectivity, and it is generally reversible. Most reversible inhibitors are molecules that have nitrogen, imidazole, pyridine or quinolone groups in their chemical structure. Molecules of this type bind to the prosthetic group and the lipophilic region of the enzyme to block enzymic activity. This explains why the potency of inhibitors is dependent on their lipophilicity and the intensity of binding to the prosthetic group on the enzymic system [10–13]. The clinical relevance of enzymic inhibition depends on different factors, the therapeutic margin of the drug involved being the most important. For example, patients receiving anticoagulants, antidepressants and immunosuppressive or cardiovascular agents have a higher risk of side-effects than those receiving drugs with a broader therapeutic range. Despite pharmacological interactions being well-controlled in most cases, they may lead to life-threatening conditions on some occasions. In order to make a proper prediction of the consequences of interactions related to the metabolism of a drug, it is necessary to identify the enzymic routes involved in the process and to establish the contribution of each enzymic system. In some cases, the same enzyme produces several metabolic transformations, while in other cases, several enzymic systems may be involved in a single reaction [14–17]. Adverse reactions produced by pharmacological interactions should be carefully considered, and strategies such as monitoring of drug levels and dosage individualisation should be implemented in order to avoid these unwanted effects. A wide knowledge of the pharmacological characteristics of the drug and close control of the patient are essential in reaching this goal. PHARMACOKINETICS OF ITRACONAZOLE The pharmacokinetics of itraconazole have been extensively studied and are well-documented in several reviews [18–24]. Only the most relevant
Therapeutic drug monitoring of itraconazole 99
points in relation to therapeutic drug monitoring (TDM) are addressed here. Itraconazole is a highly lipophilic molecule. It is a slightly acidic salt (pKa ¼ 3.7), and hence is ionisable only at very low pH values. It is also poorly soluble in water, with an aqueous solubility close to 1 ng ⁄ mL at pH 7 and slightly higher than 4 ng ⁄ mL at pH 1. These characteristics make the oral absorption of itraconazole difficult when it is administered as capsules. For this type of formulation, reduced bioavailability was observed when the drug was administered under fasting conditions, particularly in patients showing low gastric acidity. These findings were associated with the low solubility of itraconazole, which is the aspect limiting the absorption process. The administration of capsules together with food, as well as the co-administration of acidic fluids such as cola drinks, were strategies used to overcome the problem [25,26]. Gastrointestinal absorption is limited by solubility (responsible for the concentration of drug able to pass through membranes and also for the rate of dissolved molecules appearing at the absorption site), by the acidic ⁄ basic character (determining the ionised fraction in solution at a given pH), by the lipophilicity (controlling the partition coefficient between the aqueous and lipophilic phases of body tissues) and by the permeability (determining the ability of molecules to pass through membranes). The Biopharmaceutical Classification System proposed by Amidon et al. [27] groups drugs according to their aqueous solubility and their permeability. This classification was first accepted by the FDA, and then by the European Agency for the Evaluation of Medical products (EMEA) in 1998, and it is now being used efficiently, not only during the preclinical development of new drugs, but also for the planning of bioavailability assays according to the in-vitro ⁄ in-vivo data relationships, and for the design of new therapeutic forms. According to the Biopharmaceutical Classification System, itraconazole belongs to class II, which includes molecules with low solubility and high permeability, for which the dissolution rate is the factor limiting absorption. In this situation, changes in the molecular structure leading to chemical species with higher water solubility or modifications in the pharmaceutical dosage form are the most frequent strategies for
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increasing drug bioavailability, the formation of complexes being one method that can be used for this purpose. Complex formation may be defined as the reversible association of substrate and ligand molecules to form a new chemical species known as a complex, with a defined molecular ratio, which has physico-chemical properties that in many cases may be very different from those of their components (substrates). Among the different types of complexes, it is worth mentioning the so-called inclusion complexes, which are produced by an interaction at the molecular level between two types of compound; one of them acts as the ‘host’, being able to take into its structure another compound called the ‘guest’ [28]. Cyclodextrins (CDs) are among the host compounds, and are currently the most widely used for this purpose, due to their favourable characteristics, which include adequate size, good stability and reduced side-effects. When the CD–drug complex comes into contact with an aqueous medium, the complex dissociates and the guest molecule is released. The dissociation rate constant of the complex determines the amount of free drug, and hence, the absorption rate is limited by this factor [29]. Moreover, the CD–drug complex may have higher chemical stability, solubility and bioavailability than the free drug [29]. An inclusion complex formed by itraconazole and a particular type of CD (2-hydroxypropylb-cyclodextrin) at a molecular ratio of 1:3 significantly modifies the solubility of the antifungal agent, producing an increase in the oral bioavailability of the drug [30]. The synthesis of this inclusion complex facilitates the formulation of itraconazole as an oral solution, as well as a parenteral preparation for intravenous administration [19,31]. The oral solution of itraconazole has a more favourable bioavailability than the capsule form [22]. A comparative study revealed a 37% increase in the relative bioavailability of the former formulation as compared to the latter. More recent studies have shown that the absorption of the oral solution of CD–itraconazole is increased in the absence of food, providing an additional advantage for at-risk patients. Pharmacokinetic assays have revealed that administration of the oral solution with no food leads to an increase in the AUC as well as in the Cmax values. In sum, the administration of the oral solution containing the CD–itraconazole complex under fasting conditions produces a 30% increase
in absorption, compared to administration of this formulation with food [32]. Although tolerance to CDs is high, it must be taken into account that these compounds may accumulate in renalimpaired patients because of their renal excretion [19]. Itraconazole is widely distributed throughout the body, this process being highly dependent on the physico-chemical properties of the drug, with a reported apparent distribution volume of 10.7 L ⁄ kg. It is highly bound to serum proteins, mainly to serum albumin, and it has a bound fraction of 99.8%. In some body tissues, e.g., skin, lungs, muscle and liver, very high concentrations of itraconazole and ⁄ or its metabolites are found [19,20,22,26,33]. Data concerning the disposition of the drug after inhalation have confirmed that the parent drug and its hydroxy metabolite reach tissue concentrations higher than simultaneous plasma levels [34]. Itraconazole is extensively biotransformed in the organism and more than 30 metabolites have been identified. The major metabolic route is mediated by the CYP450 system, the main isoenzymes involved in the metabolism of the azoletype antifungal agents being the following: CYP3A4 (itraconazole, ketoconazole, voriconazole, fluconazole) and CYP2C9 or CYP2C19 (fluconazole, ketoconazole, voriconazole). For itraconazole, the major metabolite is the hydroxy derivative, which shows an antifungal activity similar to that of the parent drug according to in-vitro studies. The concentrations of this derivative are about 1.5–2 times the corresponding levels of the parent drug [19,22]. An elimination half-life of 20 h has been reported for itraconazole after its administration as a single dose of 200 mg. Nevertheless, this parameter increases to 30 h under steady-state conditions as a consequence of saturation of the metabolic processes [35]. The pharmacokinetics of itraconazole have been studied in different population groups. No significant modification of the pharmacokinetic processes has been found in renal-impaired patients. Accordingly, modifications in the dosage schedules would not be necessary in this type of patient, although administration of the drug is not recommended for individuals with a creatinine clearance under 30 mL ⁄ min, probably because of the impaired renal excretion of metabolites and CD, with the corresponding accumulation in this
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situation [36,37]. Modifications in the absorption and elimination of itraconazole, however, have been observed in cirrhotic patients, and dosage individualisation is recommended for this population group [38]. Itraconazole is a potent enzymic inhibitor [18,39,40] and therefore some precautions have to be taken when it is associated with other drugs. Clearance alterations due to enzymic inhibition or induction directly affect serum plasma levels, the AUC value and even bioavailability when enzymic systems are involved in the absorption process. Fig. 2 includes the serum concentration profiles simulated for a drug undergoing metabolism administered alone and associated with an enzymic inhibitor. As a consequence of the decrease in clearance, an increase in serum levels above the maximum tolerated concentrations may occur for drugs with a narrow therapeutic window [40,41]. In the case of itraconazole being administered in association with other drugs with a capacity for enzymic induction or inhibition, the interaction may affect the serum concentrations of the antifungal agent. Accordingly, rifampicin, rifabutin, diphenylhydantoin and carbamazepine, all well-known as enzymic inducers, reduce the serum levels of itraconazole, while inhibitor drugs such as clarithromycin, erythromycin, ritonavir and indinavir lead to an increase in itraconazole levels [20,42]. The potential effects of itraconazole on other drugs, as a consequence of its high enzymic inhibitory capacity, should also be borne in mind, particularly for immunosuppressive agents, oral anticoagulants, statins, and anti-retroviral or
Fig. 2. Serum concentration profiles simulated for a multiple dosage regimen for a drug administered alone and in association with an enzymic inhibitor. MTC, maximum tolerated concentration.
cytotoxic products [43–45]. Data from our laboratory confirm this statement, since it was found that the half-life of sirolimus was increased from 62 to 602 h when it was associated with itraconazole. Also, cyclosporin undergoes a relevant interaction with itraconazole, and its association with this drug was incorporated as a categorical co-variable to estimate the clearance of the immunosuppressive agent in a population model for cyclosporin in transplant recipients [47]. Additionally, itraconazole and several other products that inhibit the liver CYP450 system or P-glycoprotein (fluconazole, voriconazole nifedipine, etc.) undergo interactions with vincristine and cyclophosphamide that affect their metabolism and lead to an increase in the toxicity of these compounds [47–49]. TDM should be supported by analytical, PK– PD, clinical and pharmaco-economic criteria. The monitoring of serum concentrations of some drugs has constituted routine practice in many hospitals for the last 25 years, although, in fact, this practice was initiated much earlier (1960) in some centres. The initial aim of TDM was to individualise dosage schedules with a view to improving clinical outcomes, but improvements in the safety profiles of drugs showing potential toxicity, e.g., aminoglycosides, glycopeptides or antiepileptic drugs, rapidly became the main goal of TDM. Accordingly, this procedure provides an excellent tool for control of pharmacological treatments, patient protection and improvement in the safety of drugs [41]. Currently, the development of TDM programmes is restricted to situations fulfilling several requirements related to analytical, pharmacological, clinical and economic issues. The implementation of a TDM programme first requires the existence of an analytical technique that shows the appropriate criteria of accuracy, specificity, sensibility and efficiency. In recent years, several techniques for the quantification of itraconazole that fulfil the above requirements have been developed and reported [50]. Most of them are techniques involving chromatography, capillary electrophoresis and mass spectrophotometry, all of these being complicated for implementation in the clinical setting. Prompted by the interest in monitoring itraconazole, we have developed a chromatographic technique using fluorescence detection. This analytical method has been validated and it allows us to accurately
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determine serum concentrations of itraconazole and its hydroxy metabolite within a run time of less than 8 min, with quantification limits of 50 and 25 ng ⁄ mL for the parent drug and metabolite, respectively. In brief, the analytical method is as follows: serum samples (500 L) are subjected to a single liquid–liquid extraction process with diethyl ether in basic medium. The extractive phase is mixed with the eluent phase (acetonitrile ⁄ water, 55:45, with tri-ethanol amine adjusted to pH 3 with orthophosphoric acid). Following this, it is injected into the chromatographic equipment (Hewlett Packard 1050; fluorescence detector Shimadzu RF-10AXL; kexc ¼ 260 nm; kemiss ¼ 365 nm) at a flow rate of 1.5 mL ⁄ min. It is important to make sure that the analytical procedure has been properly validated, and interference with additional drugs used in polytherapy has to be avoided. Regarding PK–PD criteria, antifungal agents may be assembled using the same classification system as that used for antibiotics [51]. Accordingly, they can be allocated to class I, II or III, depending on their killing mechanism pattern. Class I would include drugs showing a concentration-dependent pattern together with a relevant post-antifungal effect such as amphotericin B and caspofungin. For this group, the Cmax ⁄ MIC and AUC ⁄ MIC are the response surrogate variables. Flucytosine would be included within class II, which includes products with a time-dependent antifungal effect and reduced post-antifungal effect, the surrogate variables being, in this case, T>MIC and AUC ⁄ MIC. Finally, class III would include the azole-type antifungal agents, itraconazole being among them. For this group, a time-dependent effect, together with a variable post-antifungal effect, is observed. As for class II, AUC ⁄ MIC and T>MIC seem to be the parameters best related to response. According to these considerations, the time needed for minimum serum concentrations (Cmin) to be reached has been selected as the sampling time for monitoring itraconazole levels. This means that blood should be withdrawn immediately before administration of the next dose (at the end of a dosage interval). In order to achieve maximum efficacy with itraconazole treatments, the concentration at this sampling time must be above the MIC value established for the infecting pathogen. The existence of a well-defined therapeutic range is another essential requirement for
performing TDM. This is necessary for decisionmaking and optimisation of dosage schedules. In the particular case of itraconazole, early studies performed in vitro and with laboratory animals, to define the relationship between serum concentrations and antifungal activity, revealed that more than 99.6% of 750 strains of dermatophytes were inhibited by concentrations of 1000 ng ⁄ mL [52]. Data from another study [53] using an experimental model with infection produced by Aspergillus fumigatus showed a sigmoid relationship between serum concentrations of itraconazole and antifungal activity. Cmin values above 600 ng ⁄ mL were related to maximum inhibitory activity, and Cmin values lower than this were linked to lower activity. Several clinical studies have established a breakpoint for Cmin of 500 ng ⁄ mL, which is related to a lower incidence of massive fungal invasion [24,54,55]. Nevertheless, other clinical studies failed to reach the same conclusion, probably due to the difficulty of setting up homogeneous study groups [54,56,57]. A meta-analysis was performed in order to establish the relationship between the efficacy of itraconazole for the prophylaxis of fungal infections in neutropenic patients and the dose [58]. The authors, however, did not use the dose administered but what they called the bioavailable daily dose (BDD), which was defined as the product of the dose administered (D) and the absolute bioavailability of the formulation (F). Patients were divided into two groups according to the F value of the formulation administered (F ¼ 22% for capsules and F ¼ 55% for oral solution). The group receiving a BDD of 200 mg (oral solution) showed a lower incidence of fungal infections than the group receiving a BDD of 100 mg (capsules). These results agree with data from the above-mentioned studies, relating better efficacy to higher Cmin values. The authors of the meta-analysis suggested a breakpoint for the BDD of 200 mg, which is equivalent to 400 mg of itraconazole administered as an oral solution [58]. Nonetheless, the current data concerning itraconazole are insufficient to define a therapeutic window for this drug, although a value of 500 ng ⁄ mL for Cmin has been accepted as the efficacy breakpoint for this drug. As the active hydroxy metabolite is present in serum at concentrations of 1.5–2-fold the corresponding levels of the parent drug, Cmin values of itraconazole
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above the selected breakpoint mean that the Cmin for total active compounds (parent drug plus active metabolite) is higher than the MIC values for pathogens responsible for most fungal infections [59,60]. Some dosage schedules based on the administration of a loading dose have been reported to achieve steady-state levels within the first days of treatment with itraconazole. Nevertheless, TDM could offer an additional strategy for attaining the optimum dosage schedule in the shortest period of time. The dosage patterns established for steady-state levels to be reached rapidly are as follows. For the intravenous route, 200 mg ⁄ 12 h should be administered for 2 days, followed by a maintenance dose of 200 mg daily. When the oral route is chosen, 200 mg ⁄ 12 h of the oral solution should be administered, followed by monitoring of serum levels on day 7 of treatment. If the concentration measured has the recommended value, the same treatment can be maintained. In the case of the desirability of achieving steadystate levels within the first 48 h by oral administration because the intravenous route is not indicated, the treatment should be initiated with the oral solution at 800 mg ⁄ 12–24 h for 2 days (loading dose), followed by 200 mg ⁄ 12 h. TDM of itraconazole is of particular interest in the following cases: when new drugs are associated with it, in the event of possible unknown pharmacokinetic interactions; when non-compliance with the prescribed treatment is suspected; or in cases of a high probability of low bioavailability. This clinical practice is also recommended during chemotherapy cycles and immediately after the end of such treatments [60]. When serum levels of itraconazole are monitored, modifications to the dosage schedule are recommended in the following situations. 1. When the Cmin determined after 3 days of treatment with 200 mg ⁄ 12 h is above 500 ng ⁄ mL but lower than 2000 ng ⁄ mL, the dosage interval should be extended to 24 h. 2. When the Cmin determined after 3 days of treatment with 200 mg ⁄ 12 h is above 2000 ng ⁄ mL, intravenous administration should be stopped and the oral route must be used, if tolerated by the patient. 3. When the Cmin determined after 3 days of treatment with 200 mg ⁄ 12 h is below 500 ng ⁄ mL, the same intravenous pattern should be maintained.
As mentioned above, we have implemented a TDM program for itraconazole, with a total of 54 patients and 122 serum determinations being included to date. The mean values of Cmin deermined for itraconazole and its hydoxy metabolite are 1237.57 ± 990.07 ng ⁄ mL and 2087.49 ± 1542.35 ng ⁄ mL, respectively (unpublished data). The high variability in these values and also the low percentage (54.1%) of the Cmin values within the 500–2000 ng ⁄ mL range should be noted. Among the rest, 25.4% are below 500 ng ⁄ mL and 20.5% above 2000 ng ⁄ mL. Although the data available are too limited for definitive conclusions to be drawn, this preliminary information points to a significant number of patients with Cmin values below the recommended breakpoints when they receive the standard doses. These findings support the interest in TDM for optimising treatment with itraconazole. In summary, the most relevant justifications for the monitoring of serum concentrations of itraconazole are: 1. Low and erratic bioavailability. Like other drugs with poor water solubility, itraconazole is not well-absorbed after oral administration, leading to highly variable absorption extent and rates and, consequently, to differences in serum levels as well as AUC values. The involvement of P-glycoprotein in the oral absorption of itraconazole may be another reason for the high variability observed in the bioavailability of this drug, since this determines the presystemic first-pass effect [61]. Although the new oral solution improves absorption and reduces variability, the bioavailability of itraconazole cannot be considered to be optimal. 2. Absorption processes being influenced by several factors such as pathologies and chemotherapy. Many clinical circumstances modify the permeability of gastrointestinal membranes and lead to changes in the amount and rate of drug absorption. Neutropenic status in AIDS patients or transplant recipients are two examples of factors affecting the oral bioavailability of itraconazole. 3. Dose-dependent pharmacokinetics. In the case of itraconazole, non-linear kinetics have been reported and documented [20]. Consequently, increases in dosage do not produce proportional increases in serum concentrations. This has been attributed to the limited metabolic
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4.
5.
6.
7.
capacity of the organism [35] and also to the involvement of biological transporters such as P-glycoprotein in the presystemic first-pass effect [61]. Poor correlation between the dose administered and serum levels. Because of the high variability in the values of pharmacokinetic parameters, the same dose may lead to very different concentration–time profiles in different patients, and even to differences during the treatment of a single patient. High probability of interactions with other drugs that are substrates of CYP450. Inhibitors or inducers of this enzymic system may affect the metabolism of itraconazole and hence increase or decrease, respectively, the serum levels of the antifungal agent. It should be noted that itraconazole, as a potent enzymic inhibitor, might also modify the serum profile of co-administered drugs that are metabolised through the above-mentioned CYP450 system, particularly when these drugs have a narrow therapeutic window. Additional strategy for compliance control among patients receiving oral treatment. Although the oral route is more convenient for patients at home, the risk of non-compliance is still high and TDM may be a method for gaining insight into patient compliance. The serum concentration ⁄ dose ratio is used as a measure of the degree of compliance. Optimisation of hospital public health resources. Nowadays, implementation of health technologies and ⁄ or strategies should be supported by efficiency and efficacy criteria. Pharmaco-economic studies include analysis and evaluation of benefits ⁄ risk vs. the costs of health interventions in which the use of drugs is involved. Cost-efficiency studies provide the proper support for decisionmaking about the selection of drugs and other different health-oriented procedures. Recent assays have shown that the cost of invasive fungal infections may lie between 22 197 and 31 200 US$ per episode, while the cost of the oral drug (400 mg ⁄ day) is only about 16 US$ per day. Additional pharmaco-economic studies would be necessary to evaluate the global economic impact of the prophylaxis of fungal infections on public health-related costs. Recently, Buchkowsky et al. have reported
the interest in and possible limitations of TDM of itraconozole, highlighting the relevance of this clinical strategy for immunosuppressed patients [60]. CONCLUSIONS Itraconazole is an antifungal agent with an interesting pharmacodynamic profile. Its clinical usefulness in the prophylaxis and treatment of fungal infections has been proven and welldocumented. However, owing to its pharmacokinetic profile, careful control of patients receiving treatment with this drug is recommended. The new oral solution, based on the CD inclusion complex, improves the bioavailability and facilitates patient compliance with treatment outside hospital because of the possibility of once-daily administration. Since the drug is metabolised by the CYP450 enzymic system, there is a high probability of interactions with other drugs that use the same metabolic route. Additionally, itraconazole is a potent enzymic inhibitor and may therefore modify the kinetic profile of co-administered drugs that are substrates of the CYP450 system. The pharmacokinetic variability of itraconazole and its clinical consequences may be controlled by the implementation of a proper TDM programme. REFERENCES 1. Testa B, Waterbeemd HV, Folkers G, Gue R, eds. Pharmacokinetic optimization in drug research. Biological, physicochemical, and computational strategies. Zurich: Wiley-VCH, 2001. 2. Thorburn CE, Molesworth SJ, Sutherland R, Tittenhouse S. Postantibiotic and post-b-lactamase inhibitor effects of amoxicillin plus clavulanate. Antimicrob Agents Chemother 1996; 40: 2796–2801. 3. Ambrose PG, Owens RC, Grasela D. Antimicrobial pharmacodynamics. Med Clin North Am 2000; 84: 1431–1436. 4. Firsov AA, Vostrov SN, Lubenko Y, Drlica K, Portonoy YA, Zinner SH. In vitro pharmacodynamic evaluation of the mutant selection window hypothesis using four fluoroquinolones against Staphylococcus aureus. Antimicrob Agents Chemother 2003; 47: 1604–1613. 5. Wong-Beringer A, Kriengkauykiat J. Systemic antifungal therapy: new options, new challenges. Pharmacotherapy 2003; 23: 1441–1462. 6. Ensom MHH, Davis GA, Cropp CD et al. Clinical pharmacokinetics in the 21st century. Does the evidence support definitive outcomes? Clin Pharmacokinet 1998; 34: 265–279. 7. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005; 26: 2211– 2221.
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