Review Maraviroc: pharmacokinetics and drug interactions

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1 Antiviral Therapy 14: Review Maraviroc: pharmacokinetics and drug interactions Samantha Abel 1,2, David J Back 3 and Manoli Vourvahis 4 * 1 Pfizer Global Research and Development, Sandwich, UK 2 Present address: Valley Writing Solutions, Ltd, Barham, UK 3 Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK 4 Pfizer Global Research and Development, New London, CT, USA *Corresponding author: manoli.vourvahis@pfizer.com Maraviroc is a potent selective CCR5 antagonist and is the first of this new class of oral agents to be approved for the treatment of CCR5-tropic HIV type-1. Maraviroc is extensively metabolized by CYP3A4, with renal clearance accounting for approximately 23% of total clearance. The half-life of maraviroc is approximately 16 h. Maraviroc does not inhibit any of the major CYP450 enzymes at clinically relevant doses and it has not shown any clinically relevant effects on plasma concentrations of other agents; hence, no dose adjustments of coadministered agents are required. Maraviroc exposure is altered by agents that modulate the activity of CYP3A4 and, in some circumstances, maraviroc dose adjustment is necessary. This article aims to review all pharmacokinetic and drug interaction data available for maraviroc, and to provide a comprehensive summary of the dose adjustment recommendations for maraviroc when coadministered with agents from all classes of antiretroviral therapy as well as other commonly co administered agents. Introduction According to the 2008 UNAIDS/WHO AIDS epidemic report [1], there were an estimated 33 million people worldwide infected with HIV in 2007, including 2.7 million newly-infected people. Over 2 million people were estimated to have died from AIDS that year. Although currently available antiretroviral agents have markedly improved the health and life expectancy of HIV-infected patients, new and improved agents with better side effect profiles, reduced potential for resistance and simpler dosing regimens are still needed. For many years, the primary targets for antiretroviral therapy were inhibitors of the viral protease and reverse transcriptase enzymes. More recently, therapies designed to prevent viral entry or integration of HIV into human cells have been developed. Maraviroc is the first in a new class of entry inhibitors called CCR5 antagonists and is currently the only antiretroviral agent to target a human receptor. Maraviroc prevents the binding of HIV type-1 (HIV-1) gp160 to CCR5, which in turn prevents the virus fusing with the human cell membrane [2]. Maraviroc is orally bioavailable and has been shown to be safe and effective in treatment-experienced and treatment-naive patients with CCR5-tropic HIV-1 [3 7]. This article reviews the current knowledge of the pharmacokinetics and drug interaction profile of maraviroc on the basis of comprehensive in vitro and clinical studies presented and/or published before 31 December The pharmacokinetics of maraviroc in specific populations are reviewed and guidance is provided on the dose adjustments required when maraviroc is coadministered with all classes of antiretroviral agents, as well as other commonly coadministered agents. Physical/chemical properties Maraviroc (4,4-difluoro-N-{(1S)-3-[exo-3-(3-isopropyl- 5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1] oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide) is a moderately lipophilic (log D ) and basic (pk a 7.3) compound with a molecular weight of 514 [8]. The molecular formula of maraviroc is C 29 H 41 F 2 N 5 O and the structure of maraviroc is shown in Figure 1. Maraviroc is highly soluble across the physiological ph range of [9]. Maraviroc pharmacokinetics Absorption Maraviroc (as assessed in Caco-2 monolayers in vitro) has limited apical to basolateral permeability, but markedly higher permeability in the opposite direction. This polarized transport (efflux ratio >10) is indicative 2009 International Medical Press (print) (online) 607

2 S Abel et al. of transporter-mediated efflux. P-glycoprotein (P-gp) inhibitors markedly reduced the efflux ratio of maraviroc. Also, maraviroc exposure was higher in P-gp knockout mice compared with wild-type mice (maximum concentration [C max ] and area under the curve [AUC] were increased by 108% and 183%, respectively), providing further evidence of the involvement of transporters, such as P-gp, in the absorption of maraviroc [8]. Clinical studies in healthy volunteers have shown that oral maraviroc is rapidly absorbed with the time to maximum concentration (T max ) typically occurring Figure 1. Chemical structure of maraviroc F F O NH N N N N h post-dose (Figure 2). Maraviroc exhibits non-proportional oral pharmacokinetics, although the degree of non-proportionality is most marked at oral doses <100 mg. The clinical dose of maraviroc (in the absence of potent CYP3A4 modulators) is 300 mg twice daily, and around this dose the degree of nonproportionality is small [10]. Maraviroc has been shown to have linear pharmacokinetics when dosed intravenously. Comparison of maraviroc AUC following oral and intravenous (IV) dosing demonstrated that the absolute bioavailability of a 100 mg dose of maraviroc is 23% [11]. A mass-balance model was developed to describe the disposition of maraviroc and predicted that the absorption of maraviroc at 300 mg was approximately 84%. Given the good aqueous solubility of maraviroc, absorption is not considered likely to be solubility-limited. The predicted absolute bioavailability at 300 mg is 33%. Effect of food Administration of maraviroc immediately after a highfat meal leads to a dose-dependent reduction in maraviroc exposure compared with administration in fasted conditions. The effect of food is reduced as maraviroc dose increases. At oral doses of 300 mg and 600 mg, food reduces maraviroc AUC by approximately 33 37% Figure 2. Mean plasma concentration time profiles of maraviroc at steady state following once- or twice-daily dosing 1,100 Maraviroc plasma concentration, ng/ml 1, mg twice daily 100 mg twice daily 300 mg twice daily 600 mg once daily Time post-dose, h International Medical Press

3 Maraviroc: pharmacokinetics and drug interactions [9,12,13]. A study in HIV-1-infected patients comparing 10 days of maraviroc monotherapy administered with food to that administered in the fasted state ( 2 h after or 1 h prior to food) demonstrated no apparent difference in the reduction in viral load [14]. In addition, in Phase III studies, maraviroc was dosed without regard to food intake and shown to be an effective treatment [5]. The effect of food was investigated in treatmentnaive patients receiving maraviroc 300 mg twice daily and was shown to have only a small effect (<11%) on maraviroc average plasma concentrations (C av ) [15]. Distribution Maraviroc is bound (76%) to human plasma proteins (as determined in vitro by equilibrium dialysis) and has moderate affinity for both albumin and α1-acid glycoprotein [8,9]. The volume of distribution of maraviroc is 194 l, as determined after IV administration in healthy volunteers [11]. Maraviroc appears largely confined to plasma with minimal penetration of erythrocytes, as demonstrated by blood/plasma partitioning ratios of approximately 0.6 both in vitro (by spiking [ 14 C]- maraviroc into human whole blood [8]) and ex vivo (scintillation analysis of blood and plasma from healthy volunteers administered with [ 14 C]-maraviroc [11]). A study in healthy female volunteers demonstrated that maraviroc is present in cervicovaginal fluid and vaginal tissue biopsies at concentrations approximately fourfold and twofold higher than in plasma, respectively [16]. Metabolism A study in three healthy male volunteers, who received a single oral dose of maraviroc (300 mg) containing nominally 48 µci [ 14 C]-maraviroc, showed that unchanged maraviroc was the major circulating component in plasma (40 42%) and was also the major excreted component (33%). The major metabolic routes for maraviroc involve oxidation and N-dealkylation. The most abundant circulating metabolite accounted for 22% of circulating radioactivity and has no significant pharmacological activity [9,11]. A mass-balance model for oral maraviroc predicts that the first pass extraction of maraviroc is 60%. Studies in human liver microsomes and microsomes prepared from cells expressing individual recombinant cytochrome P450s (CYP450s) have confirmed that maraviroc is primarily metabolized by CYP3A4 with no significant involvement of any other CYP450s [17]. Elimination The total clearance of maraviroc, determined after IV dosing in healthy volunteers, was approximately 44 l/h. Renal clearance accounts for 23% of total clearance and is unaffected by dose. Non-renal clearance accounts for 77% of total clearance and is thought to be predominantly metabolic [11]. Exposure in specific populations Age No specific studies have been conducted to assess the effect of age on the pharmacokinetics of maraviroc; however, data from both healthy volunteers and HIV-infected populations included in the Phase I/IIa programmes (n=413) and the HIV-infected patients from the Phase III programmes (929 treatment-experienced patients and 512 treatment-naive patients) have been subjected to extensive population pharmacokinetic analyses, including covariate analysis [12,15,18]. The age range in the healthy volunteers was limited to years, whereas in HIV-infected patients, the ages ranged from 16 to 75 years (treatment-experienced) and 20 to 70 years (treatment- naive). Although some of the analyses demonstrated a statistically significant effect of age on intrinsic clearance and/or hepatic extraction parameters within the models, age was found to have no clinically relevant effect on exposure parameters. Hence, there is no need to adjust maraviroc dose on the basis of age. Gender Females represented 23% of the Phase I/IIa programme, 11% of the treatment-experienced population and 26% of the treatment-naive population [12,15,18]. None of the covariate analyses demonstrated a clinically relevant effect of gender on the pharmacokinetics of maraviroc. Race A number of maraviroc Phase I studies were conducted in Singapore, consequently, Asian individuals represented 23% of the Phase I/IIa population [12]. Caucasian individuals accounted for 73%, Black individuals accounted for 3% and the remaining <1% of individuals were classed as other [12]. Population meta-analysis of the Phase I/IIa data suggested that Asians typically had maraviroc AUCs that were 26% higher than non-asians. This difference is not considered clinically relevant. In addition, a specific study designed to compare the pharmacokinetics of maraviroc in Asian and non-asian healthy volunteers demonstrated no differences [19]. Black patients represented 15% of the treatmentexperienced population and 27% of the treatment-naive population in the Phase III programmes [15,18]. Population pharmacokinetic analyses of the treatment-naive population showed a statistically significantly higher exposure (17.5%) in Black (n=140) and other (n=35) patients combined, when compared with Caucasians (n=327) and Asians (n=10) combined. Because this Antiviral Therapy

4 S Abel et al. difference is not considered to be clinically relevant, no dose adjustment on the basis of race is required [15,18]. Hepatic impairment Maraviroc is extensively metabolized, hence patients with hepatic impairment might be at increased risk of increased maraviroc plasma concentrations. A study in patients with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment demonstrated that modest increases in C max (11% and 32%, respectively) and AUC (25% and 46%, respectively) were observed in both groups compared with patients with normal hepatic function [20]. There is currently no information on the pharmacokinetics of maraviroc in patients with severe hepatic impairment. Although no dose adjustment is currently indicated in patients with hepatic impairment, maraviroc should be used with caution in this patient population [9,13,20]. Renal impairment A study to investigate the effect of renal impairment on maraviroc pharmacokinetics is currently ongoing and will be reported separately. Drug interactions The treatment of HIV/AIDS is based on combinations of antiretroviral agents. Current guidelines recommend that, where possible, HIV-infected patients receive at least two and preferably three active agents from multiple drug classes [21]. In addition, HIV infection is associated with many comorbidities, which themselves require drug treatment. As many of the existing antiretroviral agents and other commonly coadministered agents are known to affect the pharmacokinetics of other drugs, a thorough understanding of the drug drug interaction potential of these agents is essential to appropriate selection of drug combinations and doses. Effects of maraviroc on coadministered drugs In vitro studies with human liver microsomes and using standard probe substrates for seven of the major CYP450s has established that maraviroc is a weak inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 (50% inhibitory concentration [IC 50 ]>30 µm) [17]. Mean total C max following 1,200 mg maraviroc administered to healthy volunteers was 2,807 ng/ml, which equates to 5.5 µm [10]. As such, it is considered unlikely that maraviroc, at clinically relevant doses, will affect the pharmacokinetics of other coadministered CYP substrates. Data from several clinical studies investigating the effect of maraviroc on the pharmacokinetics of commonly coadministered agents or probe substrates are consistent with this view [22]. Protease inhibitors Maraviroc (150 mg twice daily) has no effect on the pharmacokinetics of the protease inhibitors (PIs) darunavir and ritonavir (600/100 mg twice daily) when given in combination with etravirine (200 mg twice daily) [23], or on the pharmacokinetics of ritonavir (100 mg once daily) when given in combination with elvitegravir (150 mg once daily) [24]. Two further studies designed primarily to investigate the effect of PIs (darunavir/ritonavir and tipranavir/ritonavir) on maraviroc pharmacokinetics [25,26], also noted that darunavir, tipranavir and ritonavir exposures in the presence of maraviroc (150 mg twice daily) were similar to historical controls, suggesting that there are no clinically relevant effects of maraviroc and that no dose adjustments of coadministered PIs are required. Non-nucleoside/nucleotide reverse transcriptase inhibitors Maraviroc (300 mg and 150 mg twice daily) has no effect on the pharmacokinetics of etravirine (200 mg twice daily) either when administered alone or in combination with darunavir/ritonavir (600/100 mg twice daily) [23]. No formal studies have been conducted with the other non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs); however, as they are all primarily metabolized by CYP450s [27], maraviroc is not expected to affect their pharmacokinetics, and hence no dose adjustments of coadministered NNRTIs are required. Nucleoside/nucleotide reverse transcriptase inhibitors Maraviroc (300 mg twice daily) has no effect on the pharmacokinetics of lamivudine (150 mg twice daily) and zidovudine (300 mg twice daily) [22]. As the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are primarily either renally cleared or metabolized by non-cyp450s [21,28], maraviroc is not expected to affect their pharmacokinetics, and hence no dose adjustments of coadministered NRTIs are required. Integrase inhibitors The AUC τ (where t is the dosing interval) and concentration at 12 h (C 12 ) of raltegravir (400 mg twice daily) were reduced by an average of 37% and 28%, respectively, when coadministered with maraviroc (300 mg twice daily) compared with raltegravir alone [29]. A mean decrease in raltegravir C 12 of <60% is not considered to be clinically relevant [30] and hence no raltegravir dose adjustment is recommended. Maraviroc (150 mg twice daily) has no effect on the pharmacokinetics of elvitegravir (150 mg once daily) International Medical Press

5 Maraviroc: pharmacokinetics and drug interactions when coadministered with ritonavir (100 mg once daily) [24]. No dose adjustments of coadministered integrase inhibitors are required. Other drugs that are CYP450 substrates Maraviroc (300 mg twice daily) is considered to have no clinically relevant effect on the pharmacokinetics of midazolam (7.5 mg), a commonly used CYP3A4 probe substrate [22]. In addition, maraviroc (at doses up to 300 mg twice daily and 600 mg once daily) had no apparent effect on endogenous urinary 6β-hydroxycortisol/cortisol ratios [10]. These data are consistent with maraviroc not inhibiting or inducing CYP3A4 at clinically relevant doses. At doses up to 300 mg twice daily, maraviroc did not affect CYP2D6 activity, as assessed by debrisoquine metabolic ratio (DMR), although the DMR was higher in the presence of maraviroc 600 mg once daily, suggesting that maraviroc has weak potential for CYP2D6 inhibition at this dose [10]. However, none of the volunteers DMRs rose above 12.6, which is considered to be the value above which individuals are classed as CYP2D6 poor metabolizers [31,32]. In addition, recent in vitro data demonstrated that maraviroc has an IC 50 value for CYP2D6 inhibition of >100 µm [9]. Given the current dosing recommendations for maraviroc, which are aimed at targeting C av within the range expected for a 300 mg twice-daily dose, maraviroc is considered unlikely to affect the pharmacokinetics of any coadministered CYP450 substrates. Other drugs that are P-gp substrates In vitro data suggest that maraviroc could inhibit P-gp in the gut [9] and might thus affect the bioavailability of certain drugs. The clinical relevance of this data is currently unclear as no clinical studies have been conducted with P-gp substrates. Oral contraceptives Maraviroc (100 mg twice daily) has no effect on the pharmacokinetics of the oral contraceptive steroids ethinylestradiol and levonorgestrel [22]. Although the dose of maraviroc used in this study was lower than the recommended clinical dose, the results are expected to be relevant given the preclinical and clinical data at higher exposures, suggesting that maraviroc has minimal potential to inhibit CYP450. Summary of effects of maraviroc on coadministered drugs In summary, maraviroc does not appear to affect the pharmacokinetics of coadministered agents and hence no dose-adjustments of coadministered agents are required. No agents are contraindicated with maraviroc [9,13]. Effects of coadministered drugs on maraviroc Because maraviroc is a CYP3A4 and P-gp substrate, agents that modulate the activity of this enzyme/transporter have the potential to affect maraviroc pharmacokinetics. Many of the antiretroviral drugs currently used to treat HIV are potent inhibitors and/or inducers of CYP3A4 and/or P-gp and hence a thorough drug interaction programme was undertaken to determine the magnitude of any interaction and whether any maraviroc dose adjustments are required. All of the formal drug interaction studies were conducted in healthy volunteers. In addition, a study to assess the effect of several antiretroviral combinations on maraviroc pharmacokinetics was conducted in HIV-infected patients with comparison to historical controls receiving maraviroc monotherapy [33]. A summary of the drug interaction data is provided in Table 1. Data from these formal drug interaction studies were used to define the dose adjustment criteria that were used in the Phase III MOTIVATE studies in treatment-experienced patients. In all individuals for whom a significant increase in maraviroc exposure was observed, the effect on maraviroc C max was generally less (approximately twofold) than the effect on AUC. The dose-limiting adverse event associated with maraviroc (postural hypotension) appears to be associated with the C max [10], whereas efficacy appears to be more closely associated with the C av [34]. As such, the downward dose adjustment criteria for maraviroc were based on an attempt to maintain a maraviroc C max that was consistent with that observed with 300 mg twice daily maraviroc alone, whilst accepting that total maraviroc exposure (AUC) might be higher than that seen with 300 mg twice daily maraviroc alone. This potential increase in exposure was felt to be acceptable and assumed that maximal efficacy would be maintained without an associated increase in adverse events. This assumption appears to be valid given the safety and efficacy data from the MOTIVATE studies [5,6]. Subsequently, a population pharmacokinetic co variate analysis of maraviroc was conducted on data from the MOTIVATE studies [18]. As these studies involved treatment-experienced patients, the majority of whom had background therapies that included PIs and NNRTIs, the appropriateness of the dose adjustment recommendations for many of these agents was assessed. The median C av from the Phase IIa studies with maraviroc 300 mg twice-daily monotherapy (131 ng/ml) was taken to be the target exposure for this assessment [18]. Protease inhibitors The majority of the PIs are classed as moderate or strong CYP3A4 and/or P-gp inhibitors [35] and hence Antiviral Therapy

6 S Abel et al. have the potential to increase maraviroc exposure. The effects of many of the commonly used PIs on the pharmacokinetics of maraviroc have been formally assessed in drug interaction studies in healthy volunteers. These include atazanavir with or without ritonavir, darunavir/ritonavir, lopinavir/ritonavir, ritonavir, saquinavir with or without ritonavir and tipranavir/ritonavir. In some instances, the effect of these agents in combination with efavirenz or etravirine were also investigated. Data from these studies as well as the findings of the population pharmacokinetics analyses are discussed. Atazanavir with or without ritonavir The effect of atazanavir (400 mg once daily) and atazanavir/ritonavir (300/100 mg once daily) on the pharmacokinetics of maraviroc (300 mg twice daily) was assessed [26]. In both cases, maraviroc exposure was significantly increased, although the effect of atazanavir/ ritonavir was greater than that of atazanavir alone. Maraviroc C max increased by 2.7- and 4.9-fold (atazanavir/ritonavir), and 2.1- and 3.6-fold (atazanavir), respectively. It is recommended that maraviroc 150 mg twice daily is given when in combination with atazanavir with or without ritonavir. The population pharmacokinetic analysis of the MOTIVATE data confirmed that 150 mg twice-daily maraviroc when coadministered with atazanavir/ritonavir achieved a median C av (202 ng/ ml) that was in excess of the target [18]. Darunavir/ritonavir The effect of darunavir/ritonavir (600/100 mg twice daily) on the pharmacokinetics of maraviroc (150 mg twice daily) was assessed [25]. Darunavir/ritonavir increased maraviroc C max by 2.3- and 4.1- fold, respectively. A separate study demonstrated that maraviroc (150 mg twice daily) exposure was also Table 1. Effect of coadministered drugs on maraviroc pharmacokinetics Ratio (90% CI) of maraviroc pharmacokinetics Dose of with or without coadministered drug a Coadministered drug coadministered drug Dose of maraviroc Subjects, n C max AUC Protease inhibitors Atazanavir 400 mg once daily 300 mg twice daily ( ) 3.57 ( ) Atazanavir/ritonavir 300/100 mg once daily 300 mg twice daily ( ) 4.88 ( ) Darunavir/ritonavir 600/100 mg twice daily 150 mg twice daily ( ) 4.05 ( ) Lopinavir/ritonavir 400/100 mg twice daily 300 mg twice daily ( ) 3.95 ( ) Ritonavir 100 mg twice daily 100 mg twice daily ( ) 2.61 ( ) Saquinavir 1,200 mg thrice daily 100 mg twice daily ( ) 4.25 ( ) Saquinavir/ritonavir 1,000/100 mg twice daily 100 mg twice daily ( ) 9.77 ( ) Tipranavir/ritonavir 500/200 mg twice daily 150 mg twice daily ( ) 1.02 ( ) NNRTIs Efavirenz 600 mg once daily 100 mg twice daily ( ) 0.55 ( ) Etravirine 200 mg twice daily 300 mg twice daily ( ) 0.47 ( ) Nevirapine 200 mg twice daily 300 mg single dose ( ) b 1.01 ( ) b Protease inhibitors plus NNRTIs Darunavir/ritonavir 600/100 mg twice daily 150 mg twice daily ( ) 3.10 ( ) plus etravirine plus 200 mg twice daily Lopinavir/ritonavir 400/100 mg twice daily 300 mg twice daily ( ) 2.53 ( ) plus efavirenz plus 600 mg once daily Saquinavir/ritonavir 1,000/100 mg twice daily 100 mg twice daily ( ) 5.00 ( ) plus efavirenz plus 600 mg once daily NRTI Tenofovir 300 mg twice daily 300 mg twice daily ( ) 1.03 ( ) Integrase inhibitors Elvitegravir/ritonavir 150/100 mg once daily 150 mg twice daily ( ) 2.86 ( ) Raltegravir 400 mg twice daily 300 mg twice daily ( ) 0.85 ( ) Anti-infective agents Ketoconazole 400 mg once daily 100 mg twice daily ( ) 5.00 ( ) Rifampicin 600 mg once daily 100 mg twice daily ( ) 0.37 ( ) Sulfamethoxazole/ 800/160 mg twice daily 300 mg twice daily ( ) 1.11 ( ) trimethoprim (cotrimoxazole) a No effect=1.00. b In HIV-infected patients compared with historical controls. AUC, area under the curve; CI, confidence interval; C max, maximum concentration; NNRTIs, non-nucleoside/nucleotide reverse transcriptase inhibitors; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor International Medical Press

7 Maraviroc: pharmacokinetics and drug interactions increased, albeit to a lesser extent, when coadministered with darunavir/ritonavir in the presence of etravirine (200 mg twice daily), a known CYP3A4 inducer [23]. In this instance, maraviroc C max were increased by 1.8- and 3.1-fold, respectively. It is recommended that maraviroc 150 mg twice daily is administered when dosed in combination with darunavir/ritonavir. Darunavir was not allowed as part of optimized background therapy in the blinded portion of the MOTIVATE studies. Therefore, the effects of darunavir/ritonavir on maraviroc pharmacokinetics in treatment-experienced patients could not be assessed. Fosamprenavir No formal drug interaction studies have been conducted with maraviroc and fosamprenavir. There is currently conflicting advice as to the dose recommendation for maraviroc when coadministered with fosamprenavir/ritonavir. The current US label implies that maraviroc dose should be reduced to 150 mg twice daily [9], whereas the EU label states that maraviroc should be dosed at 300 mg twice daily with fosamprenavir/ritonavir [13]. The population pharmacokinetic analysis of the MOTIVATE data showed that 150 mg twice-daily maraviroc coadministered with fosamprenavir/ritonavir achieved a similar median C av (129 ng/ ml) to the target [18]. However, it also demonstrated that fosamprenavir/ritonavir was the weakest of the PIs studied in terms of effects on maraviroc exposure. The population pharmacokinetic analysis suggests that maraviroc 150 mg twice daily provides acceptable exposures when dosed with fosamprenavir/ritonavir; however, equally, it is likely that maraviroc 300 mg twice daily (plus fosamprenavir/ritonavir) exposures would be within the range seen when it is coadministered with other PIs, thus this dose is also acceptable. Indinavir No formal drug interaction studies have been conducted with maraviroc and indinavir. However, the MOTI- VATE population pharmacokinetic analyses showed that 150 mg twice daily maraviroc when coadministered with indinavir/ritonavir achieved a median C av (389 ng/ml) that was in excess of the target [18]. Lopinavir/ritonavir The effect of lopinavir/ritonavir on the pharmacokinetics of maraviroc has been assessed in several studies [26,36]. Initially, the effect of lopinavir/ritonavir (400/100 mg twice daily) on the pharmacokinetics of maraviroc (100 mg twice daily) was investigated and was found to increase maraviroc C max by 1.6- and 3.8-fold, respectively [26]. In the same study, subsequent halving of the maraviroc dose (to 50 mg twice daily in the presence of lopinavir/ritonavir) appeared to adequately compensate for the interaction with C max being 0.5- and 1.6-fold, respectively, compared with maraviroc 100 mg twice daily alone. A subsequent study investigated the effect of lopinavir/ritonavir (400/100 mg twice daily) on the pharmacokinetics of maraviroc (300 mg twice daily) and demonstrated similar increases in C max (approximately two- and fourfold, respectively) as the previous study [36]. In addition, the effect of coadministering lopinavir/ritonavir with efavirenz was investigated and it was noted that although the magnitude of interaction was reduced, the net effect was still an increase in maraviroc exposure (C max increased by 1.3- and 2.5-fold, respectively). A study in HIV-infected patients demonstrated that the C max and AUC of maraviroc (300 mg single dose) were 1.8- and 2.7-fold higher, respectively, in patients receiving lopinavir/ritonavir, stavudine and lamivudine compared with maraviroc alone (historical controls) [33]. The MOTIVATE population pharmacokinetics analysis showed that 150 mg twice daily maraviroc coadministered with lopinavir/ ritonavir achieved a median C av (282 ng/ml) that was in excess of the target [18]. Ritonavir As ritonavir is now commonly used at subtherapeutic doses to increase exposure of other antiretroviral agents (for example, PIs and elvitegravir), the effect of ritonavir (100 mg twice daily) on the pharmacokinetics of maraviroc (100 mg twice daily) was investigated [26]. Ritonavir was shown to increase maraviroc C max and AUC by 1.3- and 2.6-fold, respectively. In the same study, subsequent halving of the maraviroc dose (to 50 mg twice daily), appeared to adequately compensate for the interaction with C max being 0.4- and 0.9-fold, respectively, compared with maraviroc 100 mg twice daily alone. Saquinavir with or without ritonavir The effect of saquinavir (Fortovase ) with or without ritonavir on the pharmacokinetics of maraviroc has been investigated in several studies [26,36]. In the first study, saquinavir (1,200 mg thrice daily) was shown to increase maraviroc (100 mg twice daily) C max by 3.3- and 4.3-fold, respectively [26]. Two further studies demonstrated that saquinavir/ritonavir (1,000/100 mg twice daily) had a markedly larger effect than saquinavir alone, with the studies showing an increase in maraviroc (100 mg twice daily) C max of 4.3- and 4.8-fold, and an increase in AUC τ of 8.3- and 9.8-fold, respectively [26,36]. In one of these studies, reducing the dose of maraviroc to 25 mg twice daily compensated for the interaction, with C max being 0.6- and 1.4- fold, respectively, compared with maraviroc 100 mg twice daily alone [26]. The MOTIVATE population Antiviral Therapy

8 S Abel et al. pharmacokinetic analysis showed that 150 mg twice daily maraviroc coadministered with saquinavir/ritonavir achieved a median C av (307 ng/ml) that was in excess of the target [18]. Tipranavir/ritonavir Tipranavir/ritonavir (500/200 mg twice daily) was considered to have no clinically relevant effect on the pharmacokinetics of steady state maraviroc (150 mg twice daily) in healthy volunteers [26]. This is further supported by the MOTIVATE population pharmacokinetic analysis, which demonstrated that maraviroc exposure in treatment-experienced patients taking tipranavir/ritonavir was similar to that without tipranavir/ritonavir [18]. It is postulated that this apparent lack of interaction is caused by opposing effects of CYP3A4 inhibition and P-gp induction when tipranavir/ritonavir are coadministered [37,38]. NNRTIs The NNRTIs are all metabolized by CYP450s and are generally modulators of CYP3A4 activity [27]. Efavirenz [39] and etravirine [40] are CYP3A4 inducers, whereas delavirdine is a CYP3A4 inhibitor [27]. Data on nevirapine are conflicting with some studies suggesting CYP3A4 induction [41,42] and others suggesting no effect on CYP3A4 activity [43]. Given the potential to affect the pharmacokinetics of maraviroc, the results of formal drug interaction studies and data from the population pharmacokinetic analysis of the Phase III studies are discussed. Efavirenz As expected with a CYP3A4 inducer, efavirenz (600 mg once daily) reduced maraviroc (100 mg twice daily) C max by 56% and 51%, respectively, in healthy volunteers [36]. However, doubling the dose of maraviroc to 200 mg twice daily compensated for the induction with maraviroc C max values returning to 116% and 109%, respectively, of the values for maraviroc 100 mg twice daily alone. A further study evaluated the effect of efavirenz on maraviroc pharmacokinetics when given with boosted PIs (lopinavir/ritonavir and saquinavir/ritonavir). In both cases, although efavirenz reduced the effect of the PIs, the net interaction was still inhibition with a marked increase in maraviroc exposure [36]. The MOTIVATE population pharmacokinetic analysis confirmed that the net effect is inhibition when efavirenz is coadministered with CYP3A4 inhibitors (PIs or delavirdine) [18]. There were insufficient patients receiving efavirenz in the absence of CYP3A4 inhibitors in the MOTIVATE studies to assess its independent effects on maraviroc pharmacokinetics in HIV-infected patients. Etravirine Etravirine (200 mg twice daily) alone decreased maraviroc (300 mg twice daily) C max by 60% and 53%, respectively, in healthy volunteers [23]. However, when coadministered with darunavir/ritonavir (600/100 mg twice daily), maraviroc (150 mg twice daily) C max was increased by 1.8- and 3.1- fold, respectively, suggesting that inhibition predominates as seen previously with other combinations of CYP3A4 inducers and inhibitors. Nevirapine Only limited data are available on the effect of nevirapine on the pharmacokinetics of maraviroc. A study in HIV-infected patients receiving antiretroviral therapy including nevirapine, lamivudine and tenofovir disoproxil fumurate compared the pharmacokinetics of maraviroc (300 mg single dose) to historical data in HIV-infected patients receiving maraviroc monotherapy [33]. In this study, the antiretroviral combination appeared to have no affect on maraviroc AUC from 0 to 12 h, but did increase C max by 1.5-fold. It is assumed that this increase was caused by nevirapine because tenofovir disoproxil fumurate has been demonstrated to have no effect on maraviroc pharmacokinetics [44] and it is considered unlikely that lamivudine would have any effect. The relevance of the increase in C max of a single maraviroc dose is unclear, but no dose adjustment is recommended when coadministered with nevirapine. Delavirdine No formal drug interaction studies have been performed with maraviroc and delavirdine. However, given that it is a known CYP3A4 inhibitor [45], a dose reduction of maraviroc (to 150 mg twice daily) was recommended for the MOTIVATE studies when maraviroc and delavirdine were coadministered. Although data on delavirdine in the absence of a PI in the MOTIVATE studies were limited (n=10), the population pharmacokinetic analysis suggested that maraviroc (150 mg twice daily) exposures in the presence of delavirdine were similar to those seen with 300 mg twice-daily monotherapy [18]. NRTIs The NRTIs are predominantly cleared by renal excretion or by non-p450 metabolism (for example, alcohol dehydrogenase and/or glucuronyltransferases) [28]. As maraviroc is extensively metabolized by CYP3A4, metabolismbased interactions with NRTIs are considered unlikely. However, maraviroc does undergo some renal clearance, probably involving active processes, hence there is a theoretical potential for a drug interaction. Tenofovir disoproxil fumurate does interact with other renally cleared agents, via competition for organic anion transporters, International Medical Press

9 Maraviroc: pharmacokinetics and drug interactions and possibly via direct action on renal function [46 48]. A drug interaction study demonstrated that tenofovir disoproxil fumurate (300 mg once daily) had no effect on the pharmacokinetics of maraviroc (300 mg twice daily) [44]. Given this lack of interaction, formal interaction studies with other NRTIs and maraviroc have not been conducted and no dose adjustments of coadministered NRTIs are required. Integrase inhibitors Raltegravir (400 mg twice daily) was considered to have no clinically relevant effects on the pharmacokinetics of maraviroc (300 mg twice daily) and hence no dose adjustments are required [29]. A study that investigated the effects of elvitegravir in combination with ritonavir (150/100 mg once daily) on the pharmacokinetics of maraviroc (150 mg twice daily) demonstrated that maraviroc C max were increased 2.2-fold and 2.9-fold, respectively [24]. It is anticipated that elvitegravir will always be coadministered with a boosted PI, hence, when maraviroc and elvitegravir are dosed together, maraviroc dose should be adjusted according to the recommendations for the coadministered PI. Drug interactions with non-antiretroviral agents Potent CYP3A4 inhibitors Ketoconazole (400 mg once daily) has been shown to increase maraviroc (100 mg twice daily) C max Table 2. Dosing guidance for maraviroc when coadministered with other agents Coadministered agents Dosage Antiretroviral Anti-infectives Other 150 mg twice-daily Protease inhibitors with Clarithromycin; itraconazole; Nefazodone. maraviroc when or without ritonavir ketoconazole; and coadministered with (except tipranavir/ritonavir): telithromycin. potent CYP3A4 amprenavir/ritonavir, inhibitors atazanavir, atazanavir/ ritonavir, darunavir/ ritonavir, fosamprenavir/ ritonavir (USA), indinavir, nelfinavir, lopinavir/ritonavir, saquinavir and saquinavir/ ritonavir; delavirdine; and elvitegravir/ritonavir a. 600 mg twice-daily Efavirenz; etravirine. Rifampicin/rifampin. Anticonvulsants: carbamazepine, oxycarbazepine, maraviroc when phenobarbital and phenytoin. coadministered with potent CYP3A4 inducers (without a potent CYP3A4 inhibitor). 300 mg twice-daily NRTIs: abacavir, didanosine, Antibacterials or Benzodiazepines: alprazolam, clonazepam, diazepam, maraviroc when emtricitabine, lamivudine, antifungals: azithromycin, lorazepam, midazolam and oxazepam; coadministered with stavudine, tenofovir and clotrimazole, erythromycin, endocrine/oral contraceptive agents: desogestrel, other medications zidovudine; enfuvirtide; fluconazole, cotrimoxazole ethinylestradiol, levonorgestrel, megestrol acetate, (without potent CYP3A4 nevirapine; raltegravir; and voriconazole; norethindrone, norgestimate and norgestrel; inhibitors or inducers). tipranavir/ritonavir; and antiprotozoals: atovaquone histamine H2 antagonists: cimetidine, famotidine and fosamprenavir/ritonavir (EU). and pentamidine; ranitidine; opioids: buprenorphine, codeine, antitubercular agents: hydrocodone and methadone; PDE-5 inhibitors: isoniazid and rifabutin; sildenafil, tadalafil and vardenafil; proton pump antivirals: acyclovir, ganciclovir, inhibitors: esomeprazole, lansoprazole, omeprazole, pegylated interferon, ribavirin, pantoprazole and rabeprazole; SSRIs: citalopram, valacyclovir and valganciclovir; escitalopram, fluoxetine, fluvoxamine, norfluoxetine, and leprostatic agents: dapsone. paroxetine and sertraline; and statins: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin. Agents that were specifically studied with maraviroc are in bold; all other agents listed were not specifically evaluated with maraviroc, but might be coadministered in HIV-infected patients. a If elvitegravir is coadministered with a ritonavir-boosted protease inhibitor then the maraviroc dose should be adjusted based on maraviroc dosing recommendations for coadministration with that particular ritonavir-boosted protease inhibitor. NNRTIs, non-nucleoside/nucleotide reverse transcriptase inhibitors; NRTIs, nucleoside/nucleotide reverse transcriptase inhibitors; SSRIs, selective serotonin reuptake inhibitors; PDE-5, phosphodiesterase type-5. Antiviral Therapy

10 S Abel et al. by 3.4- and 5.0-fold, respectively [26]. As such, it is recommended that the dose of maraviroc is reduced to 150 mg twice daily when coadministered with ketoconazole. Given these data and the data from the drug interaction studies with PIs, the dose of maraviroc should be reduced to 150 mg twice daily when it is coadministered with any potent CYP3A4 inhibitor. Potent CYP3A4 inhibitors include clarithromycin, itraconazole, ketoconazole, nefazodone and telithromycin, as well as the PIs (except tipranavir/ ritonavir [globally] and fosamprenavir/ ritonavir [in Europe]). Fluconazole and voriconazole are considered to be moderate inhibitors [35] and hence no maraviroc dose adjustment is recommended when they are coadministered. CYP3A4 inducers Rifampicin is a potent CYP3A4 inducer and decreased both maraviroc (100 mg twice daily) C max by 66% and 63%, respectively [36]. Doubling the dose of maraviroc (to 200 mg twice daily in the presence of rifampicin) was shown to compensate for the interaction, with C max returning to 97% and 116%, respectively, of the values seen following 100 mg twice daily maraviroc alone. Although this study was conducted at a lower dose than is clinically recommended, it is considered that a similar finding would be observed at higher doses. Therefore, it is recommended that the dose of maraviroc is doubled to 600 mg twice daily when coadministered with potent CYP3A4 inducers, which include carbamazepine, efavirenz, phenobarbital, phenytoin and rifampicin [36,39,49 51]. Rifabutin is a weaker inducer of CYP3A4 [51], thus no maraviroc dose adjustment is recommended when they are coadministered. Cotrimoxazole Cotrimoxazole (trimethoprim and sulfamethoxazole) is commonly used to treat or prevent HIV-associated Pneumocystis jiroveci infections. Competition for organic cation transporters has been implicated in the decreased renal tubular secretion of zidovudine and lamivudine when coadministered with trimethoprim [52,53]. At high concentrations, both trimethoprim and sulfamethoxazole have been shown to inhibit CYP3A4 in vitro [54]. However, cotrimoxazole had no effect on the pharmacokinetics of maraviroc and hence no dose adjustment is recommended [44]. Summary Maraviroc, as the first of a new class of oral antiretroviral agents, is a significant addition to the armamentarium of treatments available, particularly to treatment-experienced HIV-1-infected patients. The pharmacokinetics and drug interaction potential of maraviroc have been thoroughly investigated during its development and have enabled clear guidance to be available to the prescriber (Table 2). Unlike many other HIV treatments, maraviroc does not affect the pharmacokinetics of any coadministered agent. In addition, although other agents do affect maraviroc pharmacokinetics, the ability to perform simple and logical maraviroc dose adjustments means that maraviroc can be used with any otherwise compatible antiretroviral regimen. This provides ultimate flexibility and maximizes the potential for patients to receive the most effective regimen, thereby reducing the likelihood of virological failure and resistance. Disclosure statement SA was formerly employed by Pfizer Global Research and Development (PGRD; Sandwich, UK) during the development of maraviroc, is currently a paid consultant to PGRD (New London, CT, USA) and is now a Director of Valley Writing Solutions, Ltd (UK). Valley Writing Solutions, Ltd received funding from Pfizer Inc. for editorial assistance with manuscript. MV is an employee of PGRD. DJB is on the advisory boards for Bristol Myers Squibb, Boehringer Ingelheim, Tibotec, Pfizer, GlaxoSmithKline and Delphic Diagnostics Ltd. DJB is also on the speakers bureau for Abbott Laboratories, Bristol Myers Squibb, Boehringer Ingelheim, Tibotec, Gilead and GlaxoSmithKline. Unrestricted educational grants have been provided by Abbott Laboratories, Bristol Myers Squibb, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche and Tibotec. References 1. Joint United Nations Programme on HIV/AIDS Report on the global AIDS epidemic. (Accessed 27 October 2008.) Available from KnowledgeCentre/HIVData/GlobalReport/2008/ 2. Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 2005; 49: Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of maraviroc (MVC) plus optimized background therapy (OBT) in viremic, antiretroviral treatment experienced patients infected with CCR5-tropic HIV-1: 24-week results of a Phase 2b/3 study in the USA and Canada. 14th Conference on Retroviruses and Opportunistic Infections February 2007, Los Angeles, CA, USA. Abstract 104bLB. 4. Nelson M, Fatkenheuer G, Konourina I, et al. Efficacy and safety of maraviroc (MVC) plus optimized background therapy (OBT) in viremic, antiretroviral treatment experienced patients infected with CCR5-tropic (R5) HIV-1 in Europe, Australia and North America: 24 week results. 14th Conference on Retroviruses and Opportunistic Infections February 2007, Los Angeles, CA, USA. Abstract 104aLB. 5. Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008; 359: International Medical Press

11 Maraviroc: pharmacokinetics and drug interactions 6. Hardy WD, Gulick R, Mayer H, et al. Efficacy and safety of maraviroc in treatment-experienced (TE) patients infected with R5 HIV-1: 96-week combined analysis of the MOTIVATE 1 & 2 studies. 9th International Congress on drug therapy in HIV infection November 2008, Glasgow, UK. 7. Saag M, Heera J, Goodrich J, et al. Reanalysis of the MERIT Study with the Enhanced Trofile Assay (MERIT-ES). 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America October 2008, Washington, DC, USA. Poster H-1232a. 8. Walker DK, Abel S, Comby P, Muirhead GJ, Nedderman AN, Smith DA. Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV. Drug Metab Dispos 2005; 33: Pfizer, Inc. Selzentry (maraviroc) tablets: US prescribing information. (Accessed 19 December 2008.) Available from Abel S, van der Ryst E, Rosario MC, et al. Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers. Br J Clin Pharmacol 2008; 65 Suppl 1: Abel S, Russell D, Whitlock LA, et al. Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects. Br J Clin Pharmacol 2008; 65 Suppl 1: Chan PLS, Weatherley B, McFadyen L. A population pharmacokinetic meta-analysis of maraviroc in healthy volunteers and asymptomatic HIV-infected subjects. Br J Clin Pharmacol 2008; 65 Suppl 1: Pfizer, Ltd. Celsentri (maraviroc). Summary of product characteristics. (Accessed 27 October 2008.) Available from celsentri/celsentri.htm 14. Fätkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 2005; 11: Weatherley B, McFadyen L, Chan PLS, Marshall S. 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Poster 17A. 19. Russell D, Ridgway C, Taylor-Worth R, Weissgerber G, Tan Y, Muirhead G. Comparison of the pharmacokinetics of maraviroc (UK-427,857) in healthy Asian and Caucasian subjects. 6th International Workshop on Clinical Pharmacology of HIV Therapy April 2005, Quebec City, QC, Canada. Poster Abel S, Ridgway C, Hamlin J, Davis J. An open, parallel group study to compare the pharmacokinetics, safety and toleration of a single oral dose of maraviroc in subjects with mild and moderate hepatic impairment with subjects with normal hepatic function. 8th International Workshop on Clinical Pharmacology of HIV Therapy April 2007, Budapest, Hungary. Poster Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; (Accessed 27 October 2008.) Available from nih.gov/contentfiles/adultandadolescentgl.pdf 22. 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Reduced enzyme activity and evaluation of metabolic correlation of CYP2D6 probe drugs. Eur J Clin Pharmacol 1996; 51: Pozniak AL, Boffito M, Russell D, Ridgway CE, Muirhead GJ. A novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of maraviroc in HIV-positive subjects. Br J Clin Pharmacol 2008; 65 Suppl 1: McFadyen L, Jacqmin P, Wade JR, Weatherley B, Chan P. Maraviroc (MVC) exposure-efficacy relationship in treatment-experienced HIV-1-infected patients. 11th European AIDS Conference (EACS) October 2007, Madrid, Spain. Abstract P4.1/06. Antiviral Therapy