Pharmacodynamic aspects of sustained release preparations

Advanced Drug Delivery Reviews 33 (1998) 185–199

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Pharmacodynamic aspects of sustained release preparations Amnon Hoffman* Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120, Israel Received 1 September 1997; received in revised form 7 November 1997; accepted 15 February 1998

Abstract The sustained release (SR) mode of drug administration has certain features that have an important impact on the magnitude of the pharmacologic response: (a) it minimizes fluctuation in blood drug concentrations (i.e. between peak and trough). However, due to the pronounced non-linear relationship between drug concentration and pharmacologic effect (i.e. pharmacodynamics) the impact of this property differs considerably as a function of the shape of the pharmacodynamic profile and the position of the specific range of concentrations on the curve of this profile; (b) it produces a slow input rate which tends to minimize the body’s counteraction to the drug’s intervening effect on regulated physiological processes; and (c) it provides a continuous mode of drug administration. This important pharmacodynamic characteristic may produce, in certain cases, an opposite clinical effect than that attained by an intermittent (pulsatile) mode of administration of the same drug. For many drugs with non-concentration-dependent pharmacodynamics, the exposure time, rather than the AUC, is the relevant parameter and it can therefore be optimized by SR preparations. The slow input function may minimize hysteresis in cases where the site of action is not in a rapid equilibrium with the blood circulation. The pharmacodynamics of the desired effect(s) and / or adverse effect(s) may also be influenced by the site of administration, especially in cases where the drug is delivered directly to its site of action. These factors demonstrate the important influence of the mode of administration on the pharmacological and clinical outcomes. In addition, they highlight the need to include these pharmacodynamic considerations in all stages from drug development to the optimization of their clinical use.  1998 Elsevier Science B.V. All rights reserved. Keywords: Pharmacodynamics; Pharmacokinetics; Administration rate; Drug delivery; Sustained release; Pharmacologic response; Exposure time; Adverse effect; Drug development

Contents 1. Introduction ............................................................................................................................................................................ 2. The correlation between the therapeutic concentration range, the pharmacodynamic profile and the magnitude of effect ................. 2.1. Different pharmacodynamic zones along the concentration–effect curve .............................................................................. 2.2. The effect of the shape factor on the relationship between DC and DE ................................................................... 2.3. Implications of the sigmoidicity of the pharmacodynamic profile on the preferred delivery rate ............................................. 2.4. Drugs with relatively low CEmax ................................................................................................................. 2.4.1. The b-lactam antibiotics example ............................................................................................................................ 2.4.2. The erythropoietin example..................................................................................................................................... *Tel.: 1972-2-675-8667; fax: 1972-2-643-6246; e-mail: [email protected] 0169-409X / 98 / $ – see front matter  1998 Elsevier Science B.V. All rights reserved. PII: S0169-409X( 98 )00027-1

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3. The effect of narrowing magnitude of fluctuation on reducing adverse reactions .......................................................................... 3.1. Prevention of adverse effects ............................................................................................................................................ 3.2. Selectivity of pharmacologic response ............................................................................................................................... 3.3. Implications for drug development .................................................................................................................................... 4. The impact of the rate of administration on the magnitude of pharmacologic effect ...................................................................... 4.1. Rapid vs. slow nifedipine administration............................................................................................................................ 4.2. Rapid vs. slow prazocin administration .............................................................................................................................. 4.3. Rapid vs. slow rates of loop diuretics administration........................................................................................................... 4.4. Rebound activity following abrupt termination of drug input ............................................................................................... 4.5. The impact of high Cmax of analgesics ............................................................................................................................... 5. Pulsatile vs. continuous mode of administration......................................................................................................................... 6. The impact of the site of administration on the magnitude of the pharmacologic response............................................................. 7. The relationship between the location of the site of action, rate of delivery and magnitude of response .......................................... 8. The pharmacodynamic impact of exposure time ........................................................................................................................ 9. Circadian variation in drug response ......................................................................................................................................... 10. Individualized DDS ............................................................................................................................................................... 11. Conclusions .......................................................................................................................................................................... References ..................................................................................................................................................................................

1. Introduction The basic rationale for the development of controlled drug delivery is to modulate the magnitude and duration of drug action(s), and to dissociate it from the inherent properties of the drug molecule. To enable optimal design of controlled release systems, a thorough understanding of the pharmacokinetics and pharmacodynamics of the drug is necessary. While the pharmacokinetic consequences of controlled release dosage forms are generally well understood and taken into consideration [1], the pharmacodynamic aspects, (i.e. the relationship between drug concentration and magnitude of pharmacologic effect) are less well studied. The lack of a well defined relationship between blood concentration and therapeutic effect, and hence the required drug input rate for optimal response, is the major factor currently limiting the wider application of controlled drug delivery [2]. In many cases, the development of sustained release (SR) dosage forms is somewhat empirical. It is often based on the sole objective of reducing the dosing frequency or fluctuation between peak and trough plasma concentrations (Cmax and Cmin , respectively) associated with conventional tablet or capsule formulations. The development process tends to be based on an intuitive pharmacodynamic rationale assuming that the magnitude of response elicited by the drug is closely related to changes in its plasma concentration [3]. This is an overly simplified as-

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sumption, in view of the fact that in the majority of cases the relationship between drug concentration in the systemic blood circulation and magnitude of effect is non-linear. Thus, similar magnitude of fluctuations in drug concentration (DC) at different concentration ranges are likely to cause dissimilar fluctuations in the magnitude of response [4]. In addition to reduced DC, SR formulations provide other important aspects that affect the magnitude of effect, including: the (slow) rate of input and the continuous (vs. intermittent) mode of drug administration. These formulation-dependent parameters, together with the individual pharmacodynamic characteristics of the patient (e.g. the level of endogenous agonist / antagonist compounds) produce the overall pharmacodynamic pattern of the drug action that is commonly defined as ‘what the drug does to the body’.

2. The correlation between the therapeutic concentration range, the pharmacodynamic profile and the magnitude of effect Sustained release formulations are aimed at reducing DC. However, due to the non-linear nature of the pharmacodynamic profile the impact of certain size of DC on the magnitude of response varies according to the specific shape of the pharmacodynamic profile (of the examined response) at the relevant range of

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drug concentrations that is attained by the SR formulation. It is widely accepted that the sigmoidal Emax model (Eq. (1)) (which is strictly empirical) can be used in many cases to describe the mathematical correlation between drug concentration (C) and the intensity of effect (E), where E0 is the baseline effect (i.e. the magnitude of the measured parameter representing effect, with no drug), Emax is the maximal effect, and EC 50 is the drug concentration that elicits 50% of the maximal effect. Emax ? C n ]]] E 5 E0 6 EC 50 1 C n

(1)

The operational shape factor n, which determines the slope of the curve, is used to provide a better fit of data to the model [5]. Although the shape factor has no clear physiological meaning it is thought to evolve from the distribution function of the individual effector units and their inherent concentrationresponse properties [6]. Several other pharmacodynamic models have been derived from this fundamental equation [7].

2.1. Different pharmacodynamic zones along the concentration–effect curve The introduction of the shape factor enables a better description of the concentration–effect rela-

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tionship of many pharmacological responses, either efficacious, toxic or both. In order to describe the relationship between the impact of the fluctuation in drug concentrations (DC) and the corresponding magnitude of fluctuation in pharmacologic response (DE), different zones of concentration ranges along the pharmacodynamic profile may be defined (Fig. 1): the E0 zone where the drug concentrations are too low to cause measurable pharmacologic response; low E zone, for those concentrations below EC 50 that elicit measurable effect; the EC 50 zone; the Emax zone that includes any concentration that is greater than the minimal concentration required to produce Emax (CEmax ); and the high E zone that lies between EC 50 zone and Emax zone. The magnitude of DE elicited by a certain degree of DC depends on the pharmacodynamic characteristics of the specific concentration-zone.

2.2. The effect of the shape factor on the relationship between DC and DE As was shown already in 1972 by Levy [4], where n51, a twofold fluctuation in drug concentration (i.e. Cmin is 50% of Cmax ) may produce different values of DE according to the proximity of the specific concentration to EC 50 . While at low E zone DE is |80%, at the EC 50 zone it is 46% and at high E zone only 10%. The relationship between DC and

Fig. 1. Illustration of distinct zones of concentration ranges along the pharmacodynamic profile.

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DE, is not only a function of the respective zone but is also affected by the sigmoidicity of the specific pharmacodynamic profile. The correlation between DC and DE as a function of the different zones and n values is illustrated in Fig. 2 and Fig. 3. As n increases the corresponding DE for a particular DC is considerably larger than for lower n values at the EC 50 zone, while at low n values the magnitude of DE is very modest at all the pharmacodynamic zones. Minimizing DC by using a SR DDS lessen in general the magnitude of DE, albeit not to the same degree at the different pharmacodynamic zones. As shown in Fig. 2 and Fig. 3 in many cases even a 100% difference between Cmin and Cmax contributes only a minor change of DE which tends to be clinically insignificant. Thus, in order to determine the optimal input function of a drug, and thereby the preferred DDS design, all these factors should be taken into consideration.

2.3. Implications of the sigmoidicity of the pharmacodynamic profile on the preferred delivery rate When n,1 the pharmacodynamic profile is relatively shallow, which indicates that for this pharmacologic response only very modest attenuation in magnitude of effect is expected even for large degrees of DC. Thus, in such cases there is no pharmacodynamic rationale to develop SR formulations. On the other hand, for those pharmacodynamic profiles which are described by n.1, the slope of the pharmacodynamic curve in the region of EC 50 is steeper; thus, the affectability of response intensity to a change in drug concentration increases. For pharmacologic effects that are characterized by n.5 (e.g. the neuromuscular blocking activity of vecuronium and pancuronium [8]) the pharmacodynamic profile is very steep. In this case, the range of drug blood

Fig. 2. The effect of the shape factor (n) value on the magnitude of fluctuation in pharmacologic response (DE) at different zones of concentration ranges along the pharmacodynamic profile, for a twofold fluctuation in drug concentration DC. (EC 50 is 50 mg / ml and Emax is 100, DE is calculated as the difference in the magnitude of effect elicited by the peak and trough concentrations, normalized by the response to the trough.)

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Fig. 3. The effect of the degree of fluctuations in drug concentration (DC) on the corresponding magnitude of fluctuation in pharmacologic response (DE) when the shape factor (n) of the sigmoidal Emax model is 2, EC 50 is 50 mg / ml and Emax is 100.

concentrations required to elicit any magnitude of response between E0 and Emax is relatively very small, and can be referred to as a ‘critical concentration’, that is, nearly the EC 50 concentration. This type of pharmacodynamic profile represents an all-or-none phenomenon, which means that the delivery system has to provide concentrations that exceed the critical concentration in order to produce a measurable effect. If during the elimination phase the drug concentration falls below the ‘critical concentration’, the pharmacologic response drops abruptly. An example for this case is the clinical response of Parkinisonian patients to levodopa [9]. The pharmacodynamic profile of this response is characterized by a high n value, as long as the drug concentrations remain above EC 50 (i.e. the ‘critical concentration’) the response is essentially independent of the fluctuation in plasma concentration (as described above (Section 2.1) for Emax zone); however, a rapid deterioration occurs when the effect site concentration falls below the EC 50 . This occurrence is a contributing factor to the on / off phenomenon typi-

cally described for the response of these patients to levodopa.

2.4. Drugs with relatively low CEmax For drugs having a significant portion of the dosing interval systemic concentrations well above CEmax , there is no additional contribution of the concentration above CEmax to the magnitude of response (since the maximal response is already obtained). Thus, the most efficient and favorable mode of administration in such cases would be a constant rate of drug input to maintain the drug concentration somewhat above CEmax . For example, the pharmacodynamic profile of ranitidine’s effect on gastric suppression of acid secretion in ulcer patients has been characterized according to the sigmoidal Emax model, and the following parameters were determined: EC 50 ¯45 ng / ml, CEmax ¯100 ng / ml and the value of n¯6 [10]. As can be seen in Fig. 4, bolus administration of the drug (by both a low and a high dose) produces serum concentrations that are

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Fig. 4. Mean plasma concentrations 6S.E.M. following administration of ranitidine dose of 50 mg (triangles and dotted lines) and 100 mg (triangles and solid lines) as i.v. bolus treatments and during continuous infusion regimens of 6.25 mg / h (circles and dotted lines) and 10 mg / h (circles and solid lines). The shaded area illustrates the range of concentrations that produce magnitude of effect (elevation of gastric pH) below Emax (from ref. [10] with permission).

much larger than CEmax for part of the dosing interval (4 h and 7 h, for the low and high bolus dose, respectively). Whereas, during the rest of the dosing interval the serum concentrations are below the critical concentration. On the other hand, the much lower serum ranitidine concentration produced by the continuous infusion exceeds the CEmax and thereby produces the maximal effect throughout the dosing interval. Thus, constant rate infusion with a lower total daily dose than intravenous bolus administration results in a comparable acid suppression.

2.4.1. The b -lactam antibiotics example The pharmacodynamics of b-lactam antibiotic antimicrobial activity are not concentration-dependent [11]. If, for the sake of simplicity, the time dimension (of microorganism exposure to the drug) is disregarded, the concentration–antimicrobial activity of these medications can be theoretically described according to the sigmoidal Emax model with E0 being the antimicrobial effect of the immune system, and an n value that is expected to be high (i.e. n.5), thus constructs a steep concentration effect profile, as illustrated in Fig. 5. The perception in this case that the n value is high is based on the following considerations: (a) for these drugs the

Fig. 5. Theoretical pharmacodynamic profile of beta-lactam antibiotics against susceptible pathogens. The scheme illustrates the relative narrow margins between drug concentrations that do not contribute antimicrobial effect (less than MIC) and the concentration required to achieve maximal activity (Emax ) (From ref. [12] with permission).

concentration range between the minimal effective concentration (MIC) and CEmax (that is up to 43 MIC) is relatively narrow; (b) the relationship between concentration and bactericidal effect of each individual effector unit (i.e. each microorganism) has an all-or-none pattern; therefore, since the variability in degree of sensitivity to the drug within the microorganism population is expected to be low, n value has to be high [6]. In this case EC 50 has a concentration slightly above MIC (or more accurately, above the minimal bactericidal concentration (MBC)). The high concentrations exceeding CEmax , that are typically achieved following bolus parenteral administration of these drugs (as well as following administration of immediate release (IR) preparations) [12] do not provide any additional therapeutic effect. As b-lactam antibiotics do not exhibit postantibiotic effect (or only a very short effect) against susceptible microorganisms such as Enterobacteriaceae or Pseudomonas species, bacterial regrowth occurs rapidly after these antibiotic concentrations fall below the bacterial MIC [13,14]. Therefore, the most important pharmacodynamic parameter for these drugs has been shown to be the time above the CEmax . Accordingly, it was found that continuous infusion of these drugs produced significantly better therapeutic outcomes than intermittent dosing [15]. These pharmacodynamic principles were utilized recently to produce an oral SR amoxi-

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cillin preparation [12] that was shown to maintain active serum drug concentrations against susceptible pathogens for a longer time period than the conventional IR gelatin capsule formulation. In this approach even though the bioavailability (i.e. AUC) following administration of SR formulation is lower than the IR preparation, the SR formulation is clinically advantageous due to the pharmacodynamic considerations.

2.4.2. The erythropoietin example Another example demonstrating the advantages of continuous administration over intermittent dosing when the range of drug concentrations attained following bolus administration is well above the CEmax (i.e. the Emax zone) was reported for recombinant human erythropoietin (r-HuEPO) [16]. In this example there is enhanced activity of r-HuEPO on hematological parameters (e.g. elevated red blood cell count and hematocrit levels) following continuous administration of the recombinant hormone to anaemic rats in comparison to daily bolus administrations of the same daily dose for 5 days. These results were also found to be in agreement with the clinical outcome following slow absorption of rHuEPO from the subcutaneous site of administration in comparison to intravenous administration of the hormone [17].

3. The effect of narrowing magnitude of fluctuation on reducing adverse reactions

3.1. Prevention of adverse effects In general, almost all drugs cause side effects or have extraneous activity in addition to their primary therapeutic function. An important principle in the design of a proper delivery system for a drug is the consideration that each of the pharmacologic effects of the drug has its own pharmacodynamic profile (e.g. the antihistaminic-effect of H 1 blocking agents and their sedative activity follow different pharmacodynamic profiles). Furthermore, while a certain pharmacological effect is considered as a therapeutic response, larger intensities of the same effect are regarded as undesired (and possibly toxic). Thus, an important advantage of SR formulations is that by

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narrowing the range of drug concentrations (especially, by reducing Cmax levels) the delivery system enables the minimization of the adverse effects associated with elevated drug concentrations. This pharmacodynamic principle has been widely applied as a means to improve drug therapy. There are numerous examples to demonstrate modulation of adverse effect by SR formulations [18,19]. This consideration has been utilized especially for drugs with a ‘narrow therapeutic index’ such as theophylline. Until the appearance of SR theophylline preparations, the clinical use of this drug was problematic due to toxicity manifestations associated with the large fluctuation in serum theophylline concentration produced by immediate release (IR) preparations and solutions (or elixirs).

3.2. Selectivity of pharmacologic response Minimization of fluctuations in drug concentration also makes it possible to obtain a certain selectivity in the elicited pharmacological effect. This is especially true when the drug activates different types of receptors at different concentrations. For example, the relative b 1 -selective b-blockers such as metoprolol, used extensively to treat hypertension and angina, have a tendency to lose their selectivity of action at higher plasma concentrations. Thus, SR formulations with lower Cmax are favorable for these drugs since the adverse effects on respiratory function, peripheral vascular disease and glucose homeostasis result from the blockade of b 2 -receptors [20]. Similarly, clonidine at low concentrations activates a 2 -receptors which leads to an inhibition of neuronal activity of the noradrenergic neurons. Higher concentrations activate a 1 -receptors, yielding a functional response similar to increased noradrenergic response [21]. Thereby, at low concentrations the drug reduces blood pressure, while at higher concentrations it elevates blood pressure. In a like manner, low doses of scopolamine elevate heart rate variability (HRV) while higher doses reduce HRV [22]. The pharmacodynamic profile may have more complex patterns such as U-shape [23], or inverse U-shape (i.e. bell-shaped curves) [24]. This pharmacodynamic characteristic occurs apparently due to activation of two opposing pharmacological responses. By minimizing fluctuation in drug con-

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centrations with SR preparations, it is possible to achieve the required response without activation of the antagonistic activity.

3.3. Implications for drug development Minimized fluctuation in drug concentration also has an important role in drug development. Many potentially important drugs are screened out during the initial evaluation process due to an improper mode of administration. For instance, preclinical assessments of activity vs. toxicity ratio are commonly performed by a bolus parenteral administration of a daily dose of the examined compound. In this evaluation strategy, the animals are exposed to high Cmax concentrations that are substantially higher than would be therapeutically required. Thus, drugs that could be potentially useful if administered in SR formulations, are rejected out of hand in the screening process. Valproic acid embryotoxicity is an example of this phenomenon. A reduction in the embryotoxicity of valproic acid follows SR administration of the drug to laboratory animals, whereas the same daily dose causes pronounced embryotoxicity when given in bolus injections [25].

occurs, most probably, due to a buffering counterregulatory process (aimed at preserving serum calcium levels within the homeostatic range) which is triggered by the higher calcitonin dose and / or by rapid decrease in serum calcium levels. Although the regulation of serum calcium levels involves several feedback loops between parathyroid hormone (PTH), vitamin D, calcitonin, serum phosphate levels and gastrin [27], it is known that an abrupt fall in serum calcium by as little as 0.05 mM (0.2 mg%) stimulates PTH secretion, which in turn, by a negative feedback loop, reduces the fall in serum calcium concentrations. It was shown [26] that following administration of the same doses to thyroid-parathyroidectomized rats, the nadir time and extent for maximal hypocalcemic effect of the two calcitonin doses were identical. This finding confirms the involvement of thyroid / parathyroid hormone counter feedback action in the generation of this non-linear pharmacodynamic phenomenon. This example illustrates the point that by exposing the body to drastic changes in homeostatic conditions a counter-secretion of antagonistic compounds could be activated and thereby reducing the overall effects.

4.1. Rapid vs. slow nifedipine administration 4. The impact of the rate of administration on the magnitude of pharmacologic effect In order to maintain homeostasis, the living body regulates most of its biochemical and physiological processes by complex feedback loop systems. In many cases the pharmacologic response, which intervenes with the natural physiologic processes, provokes a rebound activity of the body in a way that minimizes the activity of the drug. For example, we have found that when a high dose of human calcitonin (200 U / kg) was administered to rats, the nadir (greatest hypocalcemic effect) was similar to the nadir obtained following a much lower dose of 0.8 U / kg. Furthermore, the nadir following the higher dose appeared significantly later (6 h vs. 2 h P,0.0001) [26]. This finding contradicts the expectation from ordinary dose-response behavior where a larger dose (over 200 times higher) is expected to induce a greater pharmacologic response after a shorter time period. This atypical response

The rate by which the drug is administered to the body has an important impact on the magnitude of the apparent effect. While a bolus administration may provoke counter activity, slow presentation of the drug may affect the body without triggering balanced endogenous activity. A classic example that illustrates the role of input rate on the magnitude of effect is nifedipine. This calcium channel blocker has been used for several years in the treatment of angina pectoris and hypertension. The drug was originally marketed in an immediate release (IR) capsule formulation and later on in a sustained release tablet formulation that had comparable bioavailability (50%). However, while the capsule produces rapid and relatively high peak concentrations, the SR tablet gives a flat plasma concentration profile. It was found that the increase in heart rate (side effect) was far less with the SR tablets than with the IR capsules, whereas with both preparations a slight blood pressure lowering effect was achieved in the normotensive subjects that were examined [28]. This finding

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led to the realization that the rate-of-increase in nifedipine plasma concentration (rather than the absolute concentration) is a determining factor for the drug’s hemodynamic effects. Clear evidence for this explanation was obtained in a study in which nifedipine was given by two i.v. regimens designed to produce the same steady state concentration by a rapid vs. gradual infusion rate. No increase in heart rate occurred with the slow regimen, whereas a substantial and long lasting increase was seen with the rapid regimen [29]. On the other hand, a gradual decrease in blood pressure was observed following the slow input while blood pressure was minimally affected. This outcome clarifies that the concentration–effect relationship of the blood pressure lowering effect of nifedipine is shifted to the left and is steeper following a slow input than with a rapid input rate as obtained following the administration of an IR formulation. It has been proposed that following slow input, the activation of the compensatory responses produced by high levels of endogenous agents such as catecholamines [30] is limited. Therefore, the tolerability of an SR formulation is likely to be enhanced. There is evidence that the rate of input of nisoldipine plays a major role in its hemodynamic profile [31], and it seems likely to be true for some other calcium antagonists as well [32].

4.2. Rapid vs. slow prazocin administration Similarly, when the blood pressure lowering effect of prazocin following administration of either SR dosage form or IR formulation of the drug was compared, it was found that at any given concentration the slow administration produced a much greater response [33]. It is likely that the augmented response is due to the reduced degree of activation of counteracting physiological mechanisms when the drug was administered at a slow input rate [34].

4.3. Rapid vs. slow rates of loop diuretics administration The impact of the rate of administration of loop diuretics, such as furosemide and bumetanide, on the magnitude of the diuretic response is also of interest. For instance, infusion of 20 mg of furosemide to dogs over infusion times ranging from 10 s to 8 h

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demonstrated that the 8-h infusion produced significantly greater urine output and urine excretion of sodium than the 10-s, 30-min, or 2-h infusion, without any increase in the total amount of urinary furosemide recovery [35]. Similarly, while no direct correlation was found between the extent of furosemide absorption and the magnitude of response [36,37], a clear correlation was shown between the slow rate of drug excretion and elevated diuretic efficiency. Furthermore, it was found that continuous administration of loop diuretics improves diuresis in critically ill patients who require prompt, controllable diuresis, or who demonstrate ‘diuretic tolerance’ to conventional administration regimens [38]. The pharmacodynamic reasoning for this seems to involve two mechanisms: (a) the amount of drug molecules (at the receptor site) required to produce the maximal effect is relatively low, and a slow delivery rate (indicated by the rate of drug excretion) is sufficient to attain it; (b) rapid introduction of the drug (e.g. following administration of an IR formulation) causes intervention in the homeostatic mechanisms influencing fluid and electrolyte balance which activate the sympathetic nervous system and the renin angiotensin–aldosterone system [39]. This counteraction shifts the concentration effect profile to the right. Similar results were reported for bumetanide given to critically ill patients [40], where elevation in bumetanide dose caused parallel increase in urine flow and electrolyte excretion rates up to a bumetanide excretion rate of |7 mg / kg / h and either plateaued (urine flow rate) or declined at higher bumetanide excretion rates.

4.4. Rebound activity following abrupt termination of drug input In addition to the counter activity provoked by rapid drug administration, the rebound activity following abrupt termination of drug input (‘the off response’) should also be taken into account. For instance, when nitroglycerin infusion to rats with congestive heart failure was abruptly terminated it caused rebound elevations of left ventricular enddiastolic pressure to about 25% above baseline values, whereas graded withdrawal did not lead to any significant hemodynamic rebound [41].

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4.5. The impact of high Cmax of analgesics The pharmacodynamics of analgesia present another aspect of the impact of the drug input rate on the magnitude of response. It has been suggested by Levy [42] that the rate of decline of clinical analgesia after administration of various narcotic and nonnarcotic analgesics, and even placebos, is essentially the same, and the maximum degree of analgesia and the duration of action is a function of Cmax . Thus, a rapid mode of administration that provides larger Cmax values (that are not associated with significant adverse effects) could provide a longer duration of pain relief than those obtained after a slower-absorbed dosage form.

5. Pulsatile vs. continuous mode of administration There is accumulating evidence that the input function of hormones (and their recombinant analogs) administered as therapeutic agents have a major impact on the response. This phenomenon is attributed mainly to the fact that these hormones are secreted in pulses, including insulin [43,44] somatostatin, c-peptide, growth hormone (GH), PTH and luteinizing hormone (LH). When the delivery system mimics the natural secretory pattern of the hormone, it provides optimal hormone replacement therapy. On the other hand, the continuous administration of large doses may suppress natural hormone secretion by affecting the feedback mechanism in the body. Mazar [45] has clearly described the effect of the input function on the outcome of somatostatin derivative and for gonadotropin-releasing hormone (GnRH). For somatostatin derivatives, optimal suppression of GH secretion, in the treatment of acromegaly, was obtained following a constant rate input. Similarly, if GnRH is given continuously, gonadotropin secretion is suppressed through the mechanism of downregulation, which is used clinically in the treatment of prostate, endometrial and breast cancer [46,47]. On the other hand, pulsatile delivery of GnRH provides optimal response in stimulating pituitary gonadotropin secretion. This particular response occurs because the wave contour is a specific factor in the pharmacodynamic effects of

GnRH on pituitary gonadotropin and the steepness of the rising edge of the GnRH wave contour is a specific determinant of pituitary LH secretion [48]. In a like manner, continuous administration of insulin downregulates the numbers of insulin receptors, a phenomenon that can be minimized by pulsatile insulin secretion [49].

6. The impact of the site of administration on the magnitude of the pharmacologic response In many cases the assessment of the correlation between drug concentration in the systemic blood circulation and the magnitude of effect is irrelevant. This is especially true in most cases of drug ‘targeting’. In these cases the DDS delivers the drug specifically to its site(s) of action while the drug concentrations in other tissues and biological fluids tend to be negligible. This is especially important in cancer chemotherapy and enzyme replacement treatment. There are a variety of strategies to direct the drug to its biophase. The two most common approaches are: (a) chemical modifications of the parent compound to a derivative which is activated only at the target site, and (b) utilizing carriers such as liposomes, microspheres, nanoparticles, antibodies, cellular carriers (erythrocytes and lymphocytes), and macromolecules [1]. Another approach is to administer the drug directly to its site of action. For example, it was shown that intrauterine delivery of progestin during hormone replacement therapy with estrogen to postmenopausal women minimized the estrogen effect in the uterus while it had no impact on the systemic activity of the estrogen [50]. Similarly, we have shown that administration of niacin and bezafibrate by a continuous infusion to the gut produced an elevated hypolipidemic effect as compared to the infusion of the same doses to the jugular vein (Hoffman et al., unpublished data). The antiplatelet aggregation activity of acetylsalicylic acid (aspirin) occurs by irreversible acetylation of the platelet in the portal vein [51]. Therefore, the drug concentration in the systemic circulation, and the concentration of its main metabolite, salicylic acid, provide no clear indication to the magnitude of this important activity in the prevention

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of myocardial infarction. On the other hand, significantly elevated effects of 5-fluorouracil are attained in hepatic carcinoma following direct administration of the drug into the hepatic artery as compared to intravenous administration [52]. Another interesting example is the modified pharmacodynamic profile as a function of the rate of insulin administration. In general, the concentration– effect relationship is not expected to be influenced by the mode of administration. However, comparing the pharmacodynamic parameters (according to the sigmoidal Emax model) following postprandial administration of 10 U of the short acting (regular insulin) and 25 U of NPH insulin (the intermediate-acting insulin) revealed that the sigmoidal curves require markedly different parameter values (EC 50 , and n) to describe the curve [53], and n value is even greater for a more rapid mode of insulin administration (i.e. intravenous bolus) [54]. These examples clearly demonstrate the point that the systemic drug concentration cannot be used in many cases as a sole parameter for predicting magnitude of effect, and in some case does not provide any information at all.

7. The relationship between the location of the site of action, rate of delivery and magnitude of response In many cases the response is delayed in relation to appearance of the drug in the blood since the site of pharmacological action is outside the vasculature, and there appears to be a delay in equilibration between plasma drug concentration and the drug concentration at the effect site [55]. The same occurrence may also result from other factors including production of active metabolites, triggering an indirect effect(s), number of steps between receptor binding and measured effect, etc. These cases represent a non-steady state effect–concentration relationship which takes the shape of an anticlockwise hysteresis loop indicating that there are time-dependent changes in pharmacodynamic parameters. While higher concentrations are required to elicit a certain magnitude of effect following a bolus administration of the drug, much lower concentrations are required to produce the same magnitude of effect once the

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drug is distributed to the biophase. In these cases a slow rate of drug administration minimizes the hysteresis and thus requires lower Cmax concentrations in order to achieve the required response.

8. The pharmacodynamic impact of exposure time Prolonged exposure to a drug may cause sensitization (upregulation) or desensitization (tolerance or downregulation) which alters the concentration–effect relationship as a function of time and adds complexity to the pharmacodynamics of the drug. The administration mode of the drug also affects the magnitude of these time-dependent alterations [56]. This should be taken into consideration during the design of the optimal input function of the drug from a DDS. These issues are addressed elsewhere in this issue [57]. Another aspect of the time dimension is the exposure time of the target organ to the drug and its impact on the overall response. For example, blactam antibiotics would require more than an hour to kill test bacteria, while the bactericidal activity of aminoglycosides is rapid [58]. In accord with this parameter, the preferred mode of b-lactam administration would assure that bactericidal concentrations are present at the infection site for prolonged periods of time (preferably, throughout the dosing interval). On the other hand, due to the pharmacodynamic properties of the aminoglycoside antibiotic drugs (such as gentamycin) that are concentration dependent [59] and require only short time exposures to the bacteriocidal concentration, the preferred mode of administration of these drugs is by an intermittent bolus regimen. The high Cmax attained following bolus administration, even for a very short time period is sufficient to produce its bactericidal activity. The current therapeutic trend adopts a once a day dosing regimen for gentamycin [60,61]. This dosing regimen provides another advantage, reduced nephrotoxicity and autotoxicity. The sites of action of these serious adverse effects are in direct correlation with the trough drug concentrations rather than the Cmax concentrations. Therefore, extended time span between dosing lowers trough concentrations thereby exposing the biophases of the toxic activity of

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gentamycin (in the kidney and the ears) to lower concentrations. Another category of medication where the exposure time has an important role on the overall response is antitumor agents. These drugs can be classified into two groups; cell cycle phase nonspecific (type I) and specific (type II) drugs [62]. The cytotoxic activity of type I drugs depends on the time–concentration product (AUC), whereas that of type II drugs is time-dependent. Therefore, for cycle specific agents the important factor for evaluating the efficiency of any delivery system is the duration of exposure above the minimal cytotoxic level and not the peak concentration (so that the AUC may not be an appropriate measure). For example, for the folate antagonist methotrexate, a 10-fold increase in duration of exposure to concentrations .10 nmol / l gave a 100-fold increase in cytotoxicity, while a 10-fold increase in Cmax caused a threefold increase in cytotoxicity [63].

9. Circadian variation in drug response During the development stages of a new DDS it is much more appropriate to consider the concentration–effect relationship as constant over time. Such a consideration makes it possible to determine a certain range of blood drug concentrations as a ‘therapeutic range’ and to design accordingly an appropriate input function of the drug from the DDS that also takes into consideration the pharmacokinetic properties of the drug. However, in practice the pharmacodynamic function is not fixed and may be influenced by many factors, including psychological mood, posture, physical activity, interactions with drugs or food, etc. One such factor that has received extensive attention is the impact of the circadian rhythm, known as chronotherapeutics. This includes the circadian attenuation of both the severity of the disease state as well as in the concentration– effect relationship. For example, it was found that the response of the airways to beta-agonist aerosol medications during the morning is stronger than evening dosing. Others have shown that administration of 6-mercaptopurine to children with acute lymphoblastic leukemia in the evening led to 2.5fold higher probability of cure compared to morning

dosing. Similarly, the gastric irritation produced by NSADs is more significant in the morning than in the evening. Until now, for most of these cases there has not been enough research or clinical data regarding these considerations to impose modifications in DDS design. For instance, although it is known that the morning increase in blood pressure, heart rate, platelet aggregation and blood coagulation increase cardiac risk at that time, there is not yet data to confirm that releasing an antihypertensive drug in the middle of the night would reduce cardiac events more than if the same drug is administered in the beginning of the day. On the other hand, in order to accommodate the increased risk for asthma attack that is 100-fold greater during nighttime sleep than during daytime activity (nocturnal asthma), an SR, once-a-day formulation was introduced in the US during the 1980s as Uniphyl (Purdue Fredrick Pharmaceutical Co.). This SR formulation is taken in the evening to attain an elevated theophylline level overnight, and maintains lower levels of the medication during the day when the risk of acute asthma episode is reduced. For a comprehensive review of chronotherapeutics see refs. [64–66].

10. Individualized DDS Design of tailor-made DDS for particular patient response characteristics may be justified in those cases where it has been clinically proven to be important. An example of such a case is the development of computerized insulin pumps for prevention of hyperglycemia in diabetic patients [67]. While from a therapeutic point of view an individualized DDS with the specific input function according to the patient’s unique requirements would be ideal, it can not be justified economically since for most drugs it would not be cost-beneficial. This conclusion may change in the future, as the technology of programmable dispensable DDS progresses.

11. Conclusions As specified above the input rate and mode of administration provide added dimensions to the relationship between the dose and its pharmaco-

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logical (and thereby clinical) effect. It would, therefore, be advantageous to assess the impact of variation in these parameters on the effect of both known and novel active agents. This recommendation is relevant as the earlier dose ranging studies, done in immediate release dosage forms, do not reveal the broader spectrum of the dose response relationship and thus jeopardize any attempt at drug optimization. Gross simplifications carried out previously, such as considering a direct relationship between drug concentration and effect, and assuming that flatter concentration vs. time profile is always better, should not be made any more in light of the current knowledge about the complex relationship between pharmacodynamics and mode of administration.

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