Pharmacology of bisphosphonates

Bone 49 (2011) 42–49

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Bone j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b o n e

Review

Pharmacology of bisphosphonates Serge Cremers a,⁎, Socrates Papapoulos b a b

Columbia University Medical Center, New York, NY, USA Leiden University Medical Center, Leiden, The Netherlands

a r t i c l e

i n f o

Article history: Received 23 November 2010 Revised 18 January 2011 Accepted 19 January 2011 Available online 31 January 2011 Edited by: David Burr Keywords: Bisphosphonates Pharmacokinetics Pharmacodynamics Review

a b s t r a c t Four decades of preclinical and clinical research of the pharmacology of bisphosphonates have generated data and concepts that have considerably improved their clinical use. However, despite this progress several pharmacological aspects relevant to bisphosphonate action on bone are still incompletely understood. This is mainly due to the complex, unique pharmacological properties of bisphosphonates. We review here the pharmacokinetic and pharmacodynamic data of bisphosphonates that are relevant for their clinical application and for the potential choice of a given compound, focusing on uncertainties that still exist. This article is part of a Special Issue entitled Bisphosphonates. © 2011 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . Distribution. . . . . . . . . . . . . . . . . . . . . . . . . . Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . Skeletal elimination . . . . . . . . . . . . . . . . . . . . . . Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . Integrated quantitative pharmacokinetics and pharmacodynamics References . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction Bisphosphonates (BPs) are currently the most widely used treatment of common skeletal disorders such as osteoporosis, metastatic bone disease and Paget's disease of bone. BPs have unique pharmacological properties which distinguish them from other therapies, including selective uptake in the skeleton preferentially at sites with increased bone remodeling and slow release from bone. Knowledge of their pharmacology as well as of differences among the various members of the class is essential for optimal clinical outcomes and minimalization of the risk of adverse effects. In theory, the study of the pharmacokinetics and pharmacodynamics can enhance clinical decision making and may lead to the choice of a given BP, its route of

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administration and the dosing in the individual patient. In practice, however, data published so far are rather suboptimal, sometimes difficult to interpret and conclusions formulated are often not fully supported by the data. The pharmacokinetics and pharmacodynamics of BPs, that include absorption, distribution, skeletal retention, elimination from the skeleton, renal excretion and inhibition of osteoclastic activity, have been extensively reviewed in the past [1–3]. We discuss here the pharmacokinetic and pharmacodynamic data generated over a period of 40 years of use of BPs that are relevant for their clinical application and for the potential choice of a given compound focusing on uncertainties that still exist. Absorption

⁎ Corresponding author at: Dept of Medicine, Endocrinology, Columbia University Medical Center, 630 West 168 Street, PH8-West Room 864, New York, NY 10032, USA. E-mail address: [email protected] (S. Cremers). 8756-3282/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2011.01.014

Bisphosphonates are currently administered either orally or intravenously. Oral BPs are absorbed throughout the entire gastrointestinal (GI)

S. Cremers, S. Papapoulos / Bone 49 (2011) 42–49

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Early studies with radio-labeled compounds showed that the BP that is not immediately excreted by the kidney, is taken up primarily by bone but some of it also by soft tissues such as the liver, kidney and spleen [16]. There may be differences in extra-skeletal distribution of BPs but besides potential differences in plasma protein binding and kidney concentrations, studied in relation to renal toxicity, the biodistribution in the circulation and soft tissues has never been investigated as thoroughly as the distribution into bone. Differences in extraskeletal distribution of BPs may be important if reported direct effects of BPs on tumor cells are proven in appropriate studies [17]. Despite the focus on biodistribution of BPs to bone, our knowledge about it in humans is still limited. It has been a challenge to quantify the amount of BP taken up during the first passage by bone, which is a well-perfused organ. In addition, the exact way that a BP is transferred from the circulation to bone is not known though it is generally believed that BPs enter the extracellular space of the bone by paracellular transport and bind to free hydroxyapatite that is available on the surface. However, studies investigating these important steps in the biodistribution of the BPs are lacking. In contrast, the last step in this process, the binding of BP to bone crystals, has been extensively investigated in vitro and in vivo revealing substantial differences in binding affinities among BPs [3,18–21]. Crystallographic, NMR, molecular modeling and dynamic in vitro studies over the years have shown that the phosphonate groups and the R1 and R2 groups play a major role in the binding [3]. As discussed in more detail elsewhere [3] R1 can be H, Cl or OH (with binding affinity in that order) and R2 can range between Cl and complex organic structures,

A Concentration (pmol/g)

Distribution

including the N-containing ones that have also been shown to affect the binding of the BPs to calcium crystals [3]. Binding is weakest for the non N-BPs etidronate, clodronate and tiludronate, and considerably stronger for the N-BPs risedronate, ibandronate, pamidronate, alendronate and zoledronate though the differences among N-BPs are substantially smaller than the differences between N- and non N-BPs as a group. In vitro binding data may not be directly applicable to humans and data generated in different studies and patient populations cannot be used to compare BPs. The only way to adequately compare binding properties of BPs in vivo is to test them in head-tohead studies in a single experimental model or patient population, but such studies are lacking in humans. A bisphosphonate is not distributed evenly throughout skeleton as has been shown with the use of C14-labeled and 99mTc-labeled BPs in animals and humans, respectively. For example, in humans the uptake of BP in the femur shaft is lower than that of the neck of the femur and the spine which shows the highest uptake [22,23]. A recent study, conducted to explore the potential role of biodistribution of BPs to the jaw showed differences in distribution of zoledronate not only among various bones (Fig. 1) [24], but also among the different skeletal envelopes, with high uptake in trabecular bone and less in cortical bone, as well as uptake in other envelopes such as the periosteum (Fig. 2) [24]. In addition, early studies by Masarachia, Azuma and Sato showed preferential (but not exclusive) distribution of BPs to active bone remodeling sites with a high percentage of the BP that is takenup being covered by bone within a period of weeks in rodents [25–27].

Concentration (pmol/g)

tract by paracellular transport with better absorption from segments of the tract with larger surface areas [4]. There are small differences in absorption among bisphosphonates, which is very low, and the most widely used nitrogen-containing BPs (N-BPs), alendronate, risedronate and ibandronate, have an absorption (F) of about 0.7% [2]. BPs without a nitrogen atom in their side chain, such as clodronate and etidronate seem to have a slightly higher F of 2–2.5% [2]. Several attempts to increase the low oral bioavailability of BPs have been unsuccessful. The low oral absorption decreases even further in the presence of food and calcium, magnesium or aluminum containing drinks but may increase in the presence of elevated gastric pH [4–6]. Many of these effects have been extensively investigated leading to the conclusion that oral bioavailability is similar for all compounds and cannot determine the choice of a given BP. However, oral bioavailability should be considered in the choice of generic formulations of different BPs which become increasingly available. In the past, pharmaceutical formulations of tablets were modified by manufacturers mainly to decrease the risk of GI side effects and such modifications were shown to alter also the already low oral bioavailability. For example, three different formulations of oral pamidronate, enteric-coated pellets, enteric-coated tablets and an oral solution, resulted in estimated oral bioavailabilities of 0.74, 0.4 and 0.2%, respectively [7]. Formulations of tablets or capsules are likely to differ among generic BPs and dissolution profiles and bioavailability should be investigated for every one of them and compared with the brand formulations [8,9]. Regulatory requirements for generic formulations include pharmacokinetic studies to demonstrate bioequivalence of the drug. For this purpose, bioequivalence of BPs can be estimated from urinary data only, although an optimal bioequivalence study is considered to be a randomized single and multiple dose cross-over study with both formulations that includes serum and urine measurements of the BP concentrations and an adequate wash-out period [10]. For most generic bisphosphonates adequate studies have been conducted, ensuring similar systemic exposure to the drug. However, tolerability, which may differ among formulations and pharmacodynamic endpoints which are essential for assessing the efficacy of the drug, is not required for the approval of generic formulations [11–15].

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Fig. 1. Tissue concentrations (mean ± S.D., n = 3 dogs) of 14C-zoledronic acid-related radioactivity 96 h after a single 0.15 mg/kg intravenous infusion to dogs (A, calcified tissues; B, noncalcified tissues). Concentrations are based on measurement of total 14 C-radioactivity after dissection; asterisks indicate concentrations below the LOQ. With permission from [24].

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Fig. 2. Autoradioluminograph of the tibia (longitudinal section) at 96 h after a 15-min IV Infusion of 0.15 mg/kg areas correspond to higher levels of radioactivity. With permission from [24].

99m

Tc-labeled BPs are used in human studies due to their relatively short radiation half-life. However, because of this, they can only be used to investigate the uptake rather than the distribution in bone. Following intravenous administration of 99mTc-labeled BPs to humans the bone uptake of BPs is rapid and most of the BP that is not excreted in the urine within 24 h is either bound to bone or is in the extracellular matrix about to bind to bone [28,29]. This specific property of BPs allows the study of the skeletal retention of cold pharmacologically active BPs in patients. The skeletal retention of BPs, or rather the whole body retention of BPs, is determined by measuring the BP in the urine and is calculated by subtracting the amount of BP excreted within a time period of 24 h (or longer) after administration of the drug from the intravenous dose [2]. However, it is still unclear if the adsorption of 99mTc-labeled BPs and cold BPs to bone is the same. In clinical studies, the amount of BP delivered to the skeleton, calculated as whole body retention, shows a very wide range. For example, in patients with Paget's disease the skeletal retention of olpadronate ranged between 10 and 90% of the administered dose [30] while the retention of pamidronate ranged between 47 and 74% in patients with osteoporosis [31], and between 12 and 98% in patients with breast cancer and bone metastases [32]. Similarly, the retention of zoledronate in patients with breast cancer ranged between 25 and 93% [33]. These wide ranges of BP uptake are largely due to differences in renal function and pretreatment rate of bone turnover [30]. However, they also demonstrate that recommended treatment regimens in clinical practice deliver widely different doses to the target organ. If we assume that monthly administration of zoledronate 4 mg to patients with bone metastases will provide 48 mg in one year, individual patients will retain in their skeleton a BP amount ranging between 12 and 45 mg, a three-fold difference. In contrast to this large variability in BP retention among patients, the intra-patient variability during subsequent administrations of BP is low even when the rate of bone turnover has decreased. It was shown, for example, that the intra-patient variability following three subsequent monthly intravenous infusions of zoledronate to cancer patients was only 7% [33] and similar data have been obtained with pamidronate in patients with osteoporosis [2]. The other intriguing observation in these studies is that the mean skeletal retention of a given BP does not seem to be very different among bone disorders with great differences in the rate of bone turnover such as Paget's disease, breast cancer with bone metastases, osteoporosis and rheumatoid arthritis [2]. These observations illustrate the inadequate understanding of the binding of BPs to bone in vivo and there is no reason to believe that the situation is different in patients treated with oral BPs. Clearly the only available experimental tool for such studies, the whole body retention, provides only crude estimates of binding as it cannot account for differences in uptake by different bones as well as within a single bone in which most of the BP will be taken up by the metabolically most active trabecular surfaces. Recent work with fluorescently labeled pharmacologically active BPs has led to re-

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C-zoledronic acid to skeletally mature adult male dogs; whiter

evaluation of the specific binding of BPs to bone. Roelofs et al. showed penetration of BPs into the osteocyte canalicular network [34] suggesting that the binding and possibly also the effects of BPs are not limited to the bone surface. Moreover, the distribution into the osteocyte network appears to differ among BPs with compounds with weaker binding properties showing better penetration into the canalicular network [35]. In addition, uptake of fluorescently labeled BP by bone marrow cells was shown in rabbits, adding to the complexity of distribution of BPs in the skeleton [34]. Thus, despite significant progress in our understanding of the binding properties of BPs to bone over the past four decades, our knowledge is still incomplete and the significance of identified factors influencing the skeletal binding of BPs in selecting a dose regimen for an individual patient is unclear. Elimination Few BPs are metabolized. Only the non N-BPs etidronate and clodronate are metabolized intracellularly to cytotoxic ATP analogs [36]. It is unclear, however, what percentage of the dose is metabolized and how these metabolites are excreted. It is also unknown if these analogs appear in serum or urine of patients. BPs are excreted unchanged in urine, though a very small percentage of parenterally administered BPs is excreted in the bile, as shown in C14-labeled ADME (Absorption, Distribution, Metabolism and Excretion) studies. At pharmacological doses, BPs are excreted by glomerular filtration. At supra-therapeutic doses active tubular secretion of BPs may also play a role, but this has only been shown in rodents [1]. Renal excretion of BPs correlates well with renal function as shown by the relationships between creatinine clearance and renal clearance of pamidronate, risedronate, ibandronate and zoledronate. Because of these relationships dose adjustments can be made based on creatinine clearance, leading to altered Cmax (maximum plasma concentration), AUC (area under the plasma concentration time curve) as well as amount of BP delivered to the skeleton. The relationship between renal clearance and creatinine clearance is comparable among BPs and cannot be used to differentiate the various BPs. For pamidronate the relationship is: Clr (mL/min) = 6.25 + 0.735 ⁎ Clcr (mL/min) [37], for risedronate Clr (mL/min) = 1.38 + 0.811 ⁎ Clcr (mL/min) [38] and for clodronate Clr (mL/min) = 5.5 + 0.92 ⁎ Clcr (mL/min) [39]. while a weaker and flatter relationship was reported for zoledronate [40]. Potential differences in this relationship between BPs have not been investigated in head-to-head studies and all BPs are not indicated for the treatment of patients with Clcr b35 mL/min. Renal handling of BPs together with protein binding has been explored as potential determinants of renal toxicity of some BPs [41]. However, much of published data and interpretations offered are again not derived from head-to-head studies and it is currently difficult to use renal elimination data to make a choice among BPs.

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Fig. 3. Calcified tissue concentrations versus time of 14C-zoledronic acid-related radioactivity (mean ± S.D., n = 3 rats) after intravenous once daily dosing for 16 consecutive days to rats (0.15 mg/kg/day, inset: day 1). Concentrations are based on measurement of total 14C-radioactivity after dissection; concentrations are shown for the following times: 24 h after the 1st dose, 24 h after the 8th dose, and 1, 16, 31, 64, 128, and 240 days after the 16th dose [24].

However, the availability of data linking renal function to renal clearance of a BP allows a more rational adjustment of the dose of a BP in patients with renal impairment.

Skeletal elimination Once BPs attach to the skeleton they are desorbed from the hydroxyapatite during bone resorption and are taken up by osteoclasts, but they can also be taken up again by the skeleton or can be released in the circulation. The amount of BP in the skeleton can be further embedded in the bone during continuing bone formation [42]. It is thought that the BP which is embedded in bone is released only during subsequent resorption, explaining the very slow and long elimination of all BPs from the skeleton. The preferential, but not exclusive, binding of BP to sites with active remodeling, the release of surface bound BP by desorption and resorption, the embedding in bone and long-term release by subsequent resorption, are thought to explain the multiple

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phases of elimination of BP from bone, reflected in their measured concentrations in serum and urine [43]. Studies with C14 labeled BPs have measured the actual concentrations of BPs in the skeleton at various time points after starting or stopping treatment in animals (Fig. 3) [24,44]. Direct measurements of BP concentrations in human bone biopsies are not available. In humans, the amount of BP in bone is inferred from dose, serum and urine concentrations [2,44]. In one of the earliest reports on the long-term skeletal retention and subsequent release of BP in humans, concentrations of alendronate were measured in urines of patients for 1.5 years following intravenous administration of the BP (Fig. 4) [43]. This approach has been validated in animal models and has been repeated by other groups to describe the long-term pharmacokinetics of BPs, which were often described inadequately due to limitations in the sensitivity of assays to measure BPs and/or because of poor study design given the extremely long time elimination of the drugs from the skeleton [2]. Studies with adequate data collection over at least one year and use of sufficiently sensitive assays have confirmed the specific property of BPs to be very slowly released from the skeleton [2]. However, there are no data to allow comparison of long-term pharmacokinetics of a single BP in different bone diseases or of different BPs in the same disease. In addition, there is limited information about factors that may affect the long-term elimination of BPs from bone, such as, for example, the rate of bone turnover. Available information suggests that, perhaps surprisingly, longterm elimination of BPs from the skeleton is not significantly affected by the rate of bone remodeling [45]. There has been only one head-to-head study comparing the elimination of alendronate and risedronate but this has never been published in a peer-reviewed journal [46]. We, therefore, do not know whether there are differences in longterm release of BPs from bone and suggestions derived from in vitro studies, should await confirmation in properly performed human studies. Such suggestions, however, create research hypotheses and the recent studies showing differential distribution of BPs into the canalicular system, which may complicate long-term release from bone even more [35], provide an excellent opportunity for further experimental testing. Long-term head-to-head pharmacokinetic studies with sufficiently sensitive assays and a good study design are, thus, needed to investigate potential differences in long-term release of different BPs from bone. However, it must be also realized that a clinical study with determination only of concentrations of BPs in urine and blood, may not be sensitive enough to detect subtle differences in binding to, distribution in and release from bone between BPs.

Fig. 4. The mean (95% CIs) urinary cumulative excretion (left panel) and skeletal retention (right panel) of alendronate, expressed as a percent of the total administered dose, in 11 patients with postmenopausal osteoporosis. Note the short early phases of elimination followed by a much longer terminal phase [43].

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Pharmacodynamics For the development of appropriate therapeutic regimens with BPs, the difficulties in studying and interpreting their complex pharmacokinetics are balanced by the availability of specific pharmacodynamic information. Such information can be accurately obtained in vivo due to the action of BPs on bone resorption, a pharmacodynamic response that can be readily quantitated in vitro and in vivo. The antiresorptive potency of BPs has been extensively studied in preclinical models which, despite their differences, were generally successful in ranking the potency of the various BPs [42]. In addition, with some models, in vitro potency data could predict in vivo data, demonstrating the importance of pharmacodynamics for clinical application and limiting to some extent the role of pharmacokinetics in explaining differences in antiresorptive potencies between BPs [47,48]. Numerous approaches have been used over the years to assess the effects of BPs on bone resorption and turnover and more recently specific biochemical markers of bone turnover have been extensively used. Accurate pharmacodynamic information in humans was originally obtained during treatment of Paget's disease demonstrating that the early effect of BP treatment is the rapid decrease of bone resorption. This is followed by a progressive slower decrease of bone formation due to the coupling of these two processes. Although bone turnover markers are useful for measuring pharmacodynamics of bisphosphonates, they suffer from a similar problem to BP distribution in that the sources of markers in terms of different parts of the skeleton are not uniform, e.g. in reflecting cortical versus trabecular response. The goal during drug development has for long been the consistent decrease of bone resorption, assessed by biochemical markers, to the low normal range. This approach has been associated

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with long-term remissions in Paget's disease and reduction of bone fragility in osteoporosis. However, the minimum as well as the maximum decrease of bone resorption for optimal efficacy and safety, respectively, is currently unknown. The very frequently discussed hypothesis of “oversuppression of bone turnover”, though theoretically attractive, has not been proven experimentally and the level of bone resorption that may define oversuppression has not been estimated. A number of preclinical studies have demonstrated differences in antiresorptive potencies of BPs but the first clinical study specifically designed to address this question was the FACT study which compared the efficacy of alendronate 70 mg and risedronate 35 mg given once-weekly in women with postmenopausal osteoporosis [49]. In this study, alendronate decreased biochemical markers of bone turnover and increased BMD significantly more than risedronate (Fig. 5). This result contrasts the differences in the magnitude of antiresorptive potencies between the two bisphosphonates in preclinical models and raises question about the importance of the individual pharmacokinetics of the two BPs. In addition, it is unclear whether these changes translate into better clinical efficacy as in different clinical trials the two BPs appear to have similar antifracture efficacy in patients with osteoporosis although no head-to-head studies to support this conclusion are available. They suggest, however, additional effects on bone fragility that are not captured by changes in bone resorption as assessed by biochemical markers. For treatment regimens with drug-free intervals longer than one week, potency and tolerability of BPs will mainly determine the outcome. This has been illustrated by Gasser in ovariectomized rats which received different single intravenous doses of bisphosphonates currently used in the treatment of osteoporosis [50]. He showed that the size and duration of the effect of the BP was dose-dependent and

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high doses of weaker BPs (e.g. alendronate) can be as effective as low doses of very potent BPs (e.g. zoledronate) in the maintenance of the effect. Support for this has been obtained in clinical studies. Intravenous administration of a single 5 mg dose of zoledronate, to osteoporotic patients decreases bone resorption during a period of at least one year [51]. Similar results have, however, been obtained after intravenous administration of alendronate 7.5 mg/d for 4 consecutive days [43]. Zoledronate and alendronate are two of the strongest mineral binders [3]. An additional determinant of the response of biochemical markers of bone resorption to BP is the nature of the bone disease. A single intravenous dose of 75 mg of pamidronate will elicit different responses in patients with Paget's disease, osteoporosis, metastatic bone disease or hypercalcemia or malignancy and the antiresorptive effect would wear off faster in that sequence. The effect will last long in patients with Paget's disease of bone but only a few days in patients with hypercalcemia of malignancy. Although adequate pharmacokinetic studies comparing excretion of a single BP across diseases are missing, there are indications that differences in skeletal binding play a minor role. The overall effect of BPs on biochemical markers of bone resorption depends, therefore, not only on the potency of the BP but also on its pharmacokinetics, the dosing regimen as well as the characteristics of the bone disease to be treated. All these should be considered when comparing the effect of different BPs on bone resorption. To fully understand the increasing number of factors contributing to antiresorptive efficacy of a certain dose regimen of a BP, a quantitative Pharmacokinetic/Pharmacodynamic (PK–PD) or systems biology approach is essential. Integrated quantitative pharmacokinetics and pharmacodynamics Data such as amount and serum and urine concentrations collected over time can be used to calculate pharmacokinetic characteristics of the BPs. These are required to describe and predict serum, urine and bone concentrations in patients during various dose regimens. Such pharmacokinetic characteristics can be non-compartmental pharmacokinetic parameters, which include, area under the serum concentration time curve (AUC), oral bioavailability, volume of distribution, renal and nonrenal clearance, whole body retention, Cmax (maximum plasma concentration) and half-lives. Given the multi-exponential decline of serum and urine concentrations of BPs with time, their pharmacokinetics can also be described using compartmental models, mathematical models consisting of several equations, including differential equations. Parameters included in the equations of a compartmental model are oral bioavailability, volumes of distribution of the different compartments and inter-compartmental clearance or micro-rate constants, which together can be used to calculate parameters such as AUC, Cmax, halflives and whole body retention. Once the parameters of a compartmental model have been established, serum, urine and bone concentrations during various dose regimens can be simulated. Both non-compartmental and compartmental pharmacokinetics are used during various phases of drug development and are important for establishing, for example, initial dose regimens in larger animals and humans from studies of smaller animals by so-called allometric scaling [52]. Noncompartmental and compartmental pharmacokinetics are also used to optimize dose regimens by identifying factors that explain variability in certain pharmacokinetic parameters, such as creatinine clearance, explaining variability in renal clearance. Compartmental pharmacokinetics and the relationship between renal function and renal clearance of a BP were used in the calculation of the dose reduction of zoledronate in patients with metastatic bone disease to prevent renal toxicity [53]. Compartmental pharmacokinetic models have been described for pamidronate, olpadronate, ibandronate, incadronate and zoledronate [30,31,53–56]. However, in the past it has often been difficult to collect reliable information about BP concentrations in vivo, either because the

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observation period of the study was too short or because assays for their measurement in blood and urine were not sensitive enough. Therefore, many of the existing pharmacokinetic models for BPs can only be used to describe short-term pharmacokinetics. The ultimate goal of describing pharmacokinetics is to be able to relate concentration time curves of the drug to its action, or to pharmacodynamics with time. In the case of BPs, the latter would be the pattern of changes of biochemical markers of bone resorption during and after administration of the drug. There have been several attempts to develop integrated PK–PD (Pharmacokinetic–Pharmacodynamic) models for BPs, which, similar to the compartmental pharmacokinetic models, consist of a system of differential equations [31,54,55]. An ideal PK–PD model should describe short- and long-term pharmacokinetics, estimate the amount of BP at the site of action (bone), should be derived from a data set providing serum and urine drug concentrations as well as levels of bone resorption markers in the same patients, and should be validated prospectively in a separate data set. None of the PK–PD models reported in the literature meets these requirements. Several calculation methods exist to develop PK–PD models, ranging from relatively simple pooled data analysis to more sophisticated nonlinear mixed effect modeling [57]. A PK–PD model for intravenous pamidronate in osteoporosis, calculated using pooled data analysis, describes short- and longterm pharmacokinetics, and uses the amount of BP on bone as the driver of the level of the marker of bone resorption. However, the pharmacokinetic and pharmacodynamic data used to develop this model were obtained in different studies and, the model was never prospectively validated [31]. The best prospectively validated model has been described for ibandronate [54,58]. The model, calculated using sophisticated nonlinear mixed effect modeling, described serum and urine CTX data in patients with osteoporosis. An original model used the BP on bone as driver of the CTX levels, but due to limited long-term serum and urine ibandronate concentration data, further development of a full PK–PD model encountered many numerical and computer runtime problems [54]. The pharmacokinetic part of the model was, therefore, simplified from a multi-compartment model describing renal excretion and amount of BP on bone to a so-called Kinetic–Pharmacodynamic model (K–PD), which basically describes the dose of the drug as the driving force of changes in bone resorption levels [54]. Although the model was subsequently validated, its general validity is questioned because key characteristics of BP pharmacology, predominantly the amount of BP on bone, are missing from the pharmacokinetics part of it. This model can be used, however, for a dose interval similar to the period of collection of the pharmacodynamic parameters that formed the basis of the calculations or when the dose interval does not exceed two to three remodeling cycles, in line with the concept of Bauss et al. that the total dose rather than the frequency of administration of BP determines the response within a given period [59]. Despite the legitimate caveats this K–PD model helped in the clinical development of ibandronate. It predicted the fluctuating CTX pattern during intermittent intravenous ibandronate leading to suboptimal antifracture efficacy of low doses of this BP, as well as the pattern of CTX changes during monthly oral administration (Fig. 6) [58]. Pharmacokinetic and integrated PK–PD models of BPs are not used in patient care but are predominantly used to give advice in drug development. If applied to patient care it is in the disguised form of a dosing table such as that used to advice on decreases of the dose of zoledronate in renal dysfunction (see insert for Zometa). The availability of pharmacokinetic and integrated PK–PD models for BPs plays, therefore, seldom a role in selecting a given BP for an individual patient. However, PK and integrated PK–PD models for BPs in different bone diseases are becoming increasingly relevant for clinical practice when physicians adjust the dose or the dose frequency of a BP because of fear of potentially dose-related side effects. Using these models one could at least obtain information

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Fig. 6. Median CTX change from baseline during oral daily 2.5 mg and monthly 150 mg of ibandronate according to K–PD model [58].

about serum, urine and bone concentrations of the BP during an altered dosing regimen, as well as of the changes of biochemical markers of bone resorption. Such simulations could be done for a population, but also for an individual patient using Bayesian statistics combining population pharmacokinetic and pharmacodynamic data with individual serum and urine concentrations of the BP and biochemical markers of bone resorption. The adequate prediction of the speed of reversibility of the antiresorptive effect of BPs is also very important not only for exploring potential differences among BPs but also in the decision of discontinuing long-term treatment, an approach used commonly in clinical practice. Although there is data suggesting that in osteoporosis the reversibility of the effect may be faster for some BPs (e.g. risedronate) these data are difficult to interpret due to lack of head-tohead studies [60,61]. In cancer it is also important to be able to predict the reversibility of the antiresorptive effect of BPs for reduction of the frequency of administration in patients with stable disease [62]. These aspects are currently investigated in the Optimize-2 trial and a clinical pharmacology sub-study of this trial with intravenous zoledronate in patients with cancer metastatic to the bone (Clinicaltrials.gov). PK–PD models may be further employed to optimize treatment regimens of BPs targeting cells other than osteoclasts such as tumor cells or osteocytes [17,34]. In such case the pharmacokinetics of the drug will not change but the pharmacodynamic response, changes in markers other than biochemical markers of bone resorption, should

be built in the model. The new data on biodistribution of BPs in bone have created interest in reconsidering pharmacokinetic (and PK–PD) models for BPs. This is nowadays easier with available sensitive assays for BPs, such as mass spectrometric assays. With the availability of new bone-active drugs, pharmacodynamic models are becoming increasingly complex and there have been attempts to build into the calculations other factors involved in bone metabolism and response such as, for example, calcium, phosphate, vitamin D metabolites, PTH, RANKL or intracellular signaling factors [63]. Such models allow a more comprehensive analysis and simulation of relevant factors that are affected by drugs which may translate to more accurate, comprehensive predictions of their effects on bone (Fig. 7) [63]. Such complex models currently used for the development of new therapeutics e.g. new antiresorptive and anabolic drugs can also be applied in the further development of BPs. In addition to describing more biochemical and molecular pharmacodynamic factors, these models are also expanding to include other factors which are relevant for clinical outcome such as bone mineral density, or finite element modeling of QCT data [64]. In summary, quantitative description of pharmacokinetics and pharmacodynamics of BPs has been successfully used and continues to be used in the further understanding of the pharmacology of these drugs as well as in the development of other bone-active drugs. PK– PD models themselves are becoming, however, increasingly complex, due to increasing knowledge of the actual biodistribution and actions of the BPs. The use of these models is currently confined to drug development, although they can also be used in patient care, such as the disguised form of dosing tables. Further refinement of these models may help to optimize therapy of the individual patient. References [1] Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996;18(2):75–85. [2] Cremers SC, Pillai G, Papapoulos SE. Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet 2005;44(6):551–70. [3] Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008;19(6):733–59. [4] Porras AG, Holland SD, Gertz BJ. Pharmacokinetics of alendronate. Clin Pharmacokinet 1999;36(5):315–28. [5] Dunn CJ, Goa KL. Risedronate: a review of its pharmacological properties and clinical use in resorptive bone disease. Drugs 2001;61(5):685–712. [6] Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Freeman A, Quan H, et al. Studies of the oral bioavailability of alendronate. Clin Pharmacol Ther 1995;58(3):288–98. [7] Cheung WK, Honc F, Schoenfeld S, Knight R, Seaman J, Bowen AT, et al. A singledose bioavailability study of pamidronate disodium after oral administration as

Fig. 7. Percent of baseline (%) following RANKL inhibition (60 mg denosumab every 6-month administration) for (A) plasma calcium (dashed line) and phosphate (solid line), (B) plasma PTH (dashed line) and calcitriol (solid line), and (C) bone-related osteoclast (dashed line) and osteoblast (solid line) function. A horizontal reference (dotted line) is included on each figure at the baseline value of 100%. Circles (○) represent observed plasma calcium (A), PTH (B) and serum c-telopeptide (C). Triangles (Δ) represent observed bone-specific alkaline phosphatase (C). Observed values were reproduced from [63,65].

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