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J Antimicrob Chemother doi:10.1093/jac/dkt006 Pharmacokinetic profile and safety of 150 mg of maraviroc dosed with 800/100 mg of darunavir/ritonavir all once daily, with and without nucleoside analogues, in HIV-infected subjects Borja Mora-Peris1*, Adam Croucher2, Laura J. Else3, Jaime H. Vera1,2, Saye Khoo3, George Scullard2, David Back3 and Alan Winston1,2 1 Department of Medicine, Faculty of Medicine, Imperial College London, St Mary’s Hospital Campus, Norfolk Place, London W2 1PG, UK; 2 Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust, St Mary’s Hospital, Praed Street, London W2 1NY, UK; 3Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK *Corresponding author. Clinical Trials, Winston Churchill Wing, St Mary’s Hospital, Imperial College London, Praed Street, London W2 1NY, UK. Tel/Fax: +44-203-312-6738/6123; E-mail: [email protected] Received 8 October 2012; returned 22 November 2012; revised 14 December 2012; accepted 31 December 2012 Background: Once-daily nucleoside-sparing combination antiretroviral therapy regimens are attractive options for the treatment of HIV infection. However, the pharmacokinetic profiles of such regimens are often not established. Methods: HIV-infected subjects receiving 245/200 mg of tenofovir/emtricitabine plus 800/100 mg of darunavir/ ritonavir once daily with plasma HIV RNA ,50 copies/mL were eligible. On day 1 (period 1), 150 mg of maraviroc daily was added and on day 11 (period 2), tenofovir/emtricitabine discontinued. At steady-state (days 10 and 20), intensive pharmacokinetic sampling was undertaken. We assessed (i) the number of subjects with trough (Ctrough) and average (Cavg) maraviroc concentrations ,25 and ,75 ng/mL, respectively; (ii) geometric mean (GM) ratios for pharmacokinetic parameters for period 2 versus period 1; and (iii) factors associated with total maraviroc exposure. Results: Eleven subjects completed the study procedures (mean age 49 years; range 35 –59 years). In three subjects, maraviroc Ctrough and Cavg were ,25 and ,75 ng/mL, respectively (Cavg, 68 ng/mL and Ctrough, 14 and 21 ng/mL). Although not statistically significant, a trend was observed towards lower maraviroc, darunavir and ritonavir concentrations in period 2 versus period 1; total maraviroc exposure was 3579 ng. h/mL (95% CI: 2983 –4294) and 2996 ng. h/mL (95% CI: 2374–3782) in periods 1 and 2, respectively, and the GM ratio was 0.84 (95% CI: 0.67 –1.05). Only total ritonavir exposure was significantly associated with total maraviroc exposure (P ¼ 0.049; 95% CI: 0.01– 0.91). No clinical safety concerns were observed. Conclusions: Within this novel nucleoside-sparing regimen, maraviroc exposure is dependent on ritonavir exposure, which was slightly reduced in the absence of tenofovir/emtricitabine. Keywords: antiretroviral therapy, HIV, HIV antiviral pharmacology, nucleoside sparing Introduction Modern combination antiretroviral therapy (cART) for HIV infection is one of the major medical advances of recent years. By preventing HIV disease progression, cART has transformed HIV infection into a chronic manageable medical condition.1 – 3 Despite this success, antiretroviral therapy is lifelong and strategies are urgently needed to overcome the ensuing toxicities of such long-term therapy. One such strategy is nucleoside-sparing antiretroviral therapy, where the long-term side effects of nucleoside reverse transcriptase inhibitors may be avoided.4 – 6 However, often the pharmacokinetic profiles of such regimens are not well described. An attractive, potential nucleoside-sparing cART regimen is maraviroc, darunavir and ritonavir, all dosed once daily. Maraviroc is a CCR5 receptor antagonist approved for use in the treatment of HIV-1.7,8 It is metabolized in the liver by the CYP3A4 pathway.9,10 Darunavir, an HIV-protease inhibitor, is also primarily metabolized in the liver by the CYP3A4 isoenzyme. The metabolism of both of these agents is inhibited by ritonavir, a CYP3A inhibitor,11 increasing their plasma exposure. For example, the # The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected] 1348 JAC Maraviroc/darunavir pharmacokinetic study total and maximum plasma exposure of maraviroc are increased by 4.1- and 2.3-fold, respectively, when maraviroc is dosed with 600/100 mg of darunavir/ritonavir twice daily compared with maraviroc alone.12 This raises the possibility of utilizing a oncedaily maraviroc dosing schedule in combination with a ritonavirboosted protease inhibitor. Clinical data support this approach. In highly treatment-experienced HIV-infected subjects receiving either once- or twice-daily maraviroc (150 mg) in combination with boosted protease inhibitors, similar virological responses have been described with both maraviroc doses.8,13 The objective of this study was to assess the safety, tolerability and steady-state pharmacokinetic profile of 800/100/150 mg of darunavir/ritonavir/maraviroc all dosed once daily, with and without 245/200 mg of tenofovir/emtricitabine, in HIV-infected subjects receiving stable antiretroviral therapy. Methods Study design This prospective pharmacokinetic study was conducted at Imperial College Healthcare NHS Trust (St Mary’s Hospital, London, UK) between October 2011 and January 2012. Adult subjects on stable once-daily antiretroviral therapy comprising 245 mg of tenofovir, 200 mg of emtricitabine, 800 mg of darunavir and 100 mg of ritonavir were eligible to participate. Exclusion criteria included current alcohol abuse or drug dependence, positive urine for drug of abuse at screening (InstallertTM ; Innovacon Inc., San Diego, CA, USA), pregnancy, active opportunistic infection or significant comorbidities, such as hepatitis B or C infection, and the use of concomitant medication with known interaction potential. Additional inclusion criteria included the following: CCR5-tropic HIV based on a genotypic tropism assay [by sequencing of the V3 region of the env and submission to the Geno2pheno algorithm (clonal analysis, 5.75% false positive rate cut-off)] from either a stored plasma sample, where available, or fresh plasma; plasma HIV RNA ,50 copies/mL (Quantiplex assayTM ; Bayer, Emeryville, CA, USA) at screening and on at least one other occasion over the last 3 months; normal screening laboratory testing parameters; and a body mass index between 18 and 32 kg/m2. This study was registered in the European Clinical Trials Database (EudraCT number 2009-014924-42) and local ethical approval was granted prior to recruiting participants. All patients were required to sign an informed consent prior to entering screening. Study procedures During study period 1 (days 1 –10), 150 mg of maraviroc once daily was added to the current cART and in study period 2 (day 11– 20), tenofovir/ emtricitabine was discontinued (Figure S1, available as Supplementary data at JAC Online). Treatment compliance was assessed on days 10 and 20 by study staff through a pill count. The study treatment ceased and subjects recommenced their pre-study, usual antiretroviral regimen on day 21. A urine drug screen for illegal substances, CD4+ lymphocyte count, haematology and chemistry panels were undertaken throughout the study period. HIV RNA was measured at screening, baseline, day 10, day 20 and the follow-up visit at days 30–35. Pharmacokinetic analysis Intensive pharmacokinetic sampling was performed on days 10 and 20 when steady-state had been achieved. Blood samples for darunavir, ritonavir and maraviroc were collected 10 min prior to dosing and 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dosing. Dosing took place at a fed state after a standardized breakfast. Darunavir, ritonavir and maraviroc concentrations were determined using HPLC– tandem mass spectrometry as previously described.14 The lower limits of quantification for darunavir, ritonavir and maraviroc were 16, 5 and 5 ng/mL, respectively. Inter- and intra-assay precision did not exceed 10% for any compound. Statistical analysis Pharmacokinetic parameters were calculated using non-compartmental methods (WinNonlin; Pharsight Corporation, Mountain View, CA, USA). The 95% CIs were constructed for the ratio of geometric means (GMs) of the AUC (AUC0 – 24), average plasma concentration (Cavg; defined as the AUC0 – 24/24), maximum plasma concentration (defined as the maximum observed concentration, Cmax) and trough plasma concentration (defined as the concentration at 24 h after the observed dose, Ctrough) for each of maraviroc, darunavir and ritonavir for both study periods. All statistical calculations were performed and analysed using SPSS (version 19.0; SPSS Inc., Chicago, IL, USA). Within-subject changes in the assessed pharmacokinetic parameters between days 10 and 20 were evaluated by assessment of GM ratios (GMR) and the corresponding 95% CIs. The CIs were determined using logarithms of the individual GM values; the calculated values were then expressed as linear values. Changes in the pharmacokinetic parameters were considered significant when the 95% CI did not cross one. Interpatient variability in the pharmacokinetic parameters was expressed as a coefficient of variation (CV) [(standard deviation/mean)×100]. The number of subjects with maraviroc Ctrough and Cavg ,25 and ,75 ng/mL (concentrations previously associated with near-maximal virological responses9,15) were assessed, as was the number of individuals with maraviroc Cmax .1000 ng/mL (concentration associated with increased risk for postural hypotension16,17). Subject characteristics and laboratory parameters were described. Associations between total maraviroc plasma exposure (log10 transformed) and both patient characteristics and total ritonavir and darunavir exposure were investigated using linear regression modelling. The CIs were then expressed as linear values. All univariate associations with P values ,0.1 were included in the multivariate analyses, where values ,0.05 were considered statistically significant. Results Patient characteristics and drug tolerability Of 19 subjects screened, 13 were enrolled. The presence of CXCR4 HIV strains was the predominant reason for subjects failing study screening procedures. Of the 13 enrolled subjects, 1 subject underwent early termination due to poor compliance with the study therapy and another subject discontinued due to a concurrent seasonal viral illness, leaving 11 individuals who completed both study periods (Figure S1). The patients’ baseline characteristics are described in Table 1. The study medications were well tolerated and no safety or laboratory concerns were observed. All 11 patients reported 100% adherence to the therapy. During the study and follow-up periods, the plasma HIV RNA of all patients remained undetectable. Pharmacokinetic parameters over study periods The pharmacokinetic parameters for maraviroc, darunavir and ritonavir are shown in Table 2. Three separate individuals had maraviroc concentrations (Cavg or Ctrough) below the levels associated with near-maximal efficacy as follows: one individual had a maraviroc Cavg ,75 ng/mL in study period 2 (68 ng/mL) 1349 Mora-Peris et al. (Figure 1a), one subject had a maraviroc Ctrough ,25 ng/mL in period 1 (14 ng/mL) and another in period 2 (21 ng/mL) (Figure 1b). No individual had a documented maraviroc Cmax .1000 ng/mL. Table 1. Patient demographics and clinical characteristics Factors associated with maraviroc plasma exposure Parameter Number of participants Age (years), mean (SD) Male, n (%) 11 47.9 (8.8) 9 (82) Ethnicity, n (%) Caucasian black Baseline CD4+ count (cells/mL), mean (SD) HIV RNA ,50 copies/mL for .3 months, n (%) 8 (73) 3 (27) 558 (271) 11 (100) HIV subtype, n (%) not available B D A/D Current smoker, n (%) Antiretroviral therapy of emtricitabine/ tenofovir+darunavir/ritonavir at screening, n (%) Duration of darunavir/ritonavir therapy prior to study entry (months), mean (SD) Patients on first-line therapy or having started therapy with a protease inhibitor as third agent, n (%) Time under virological success (months), median (IQR) Although no statistically significant differences in pharmacokinetic parameters were observed between periods 2 and 1 for maraviroc, darunavir or ritonavir, slight reductions in Ctrough, Cavg and AUC0 – 24 were observed in period 2 compared with period 1. 4 (36.4) 5 (45.6) 1 (9) 1 (9) 3 (27) 11 (100) 16.4 (14.7) 9 (81.8) 39 (65) On day 20, although several factors were associated with total maraviroc exposure in a univariate model, in a multivariate analysis only total ritonavir exposure was significantly associated with total maraviroc exposure (P ¼ 0.049; 95% CI: 0.01 –0.91) (Table S1, available as Supplementary data at JAC Online). Discussion In this study assessing a nucleoside-sparing antiretroviral regimen comprising 800/100/150 mg of darunavir/ritonavir/maraviroc all dosed once daily, no short-term efficacy or safety concerns were observed. Interestingly, we observed small reductions in maraviroc, darunavir and ritonavir total plasma exposure when dosed without tenofovir/emtricitabine, although these changes were not statistically significant. During the study period, plasma maraviroc concentrations were below concentrations associated with near-maximal efficacy (75 and 25 ng/mL for Cavg and Ctrough, respectively9,15) in three subjects (Ctrough of 14 ng/mL in one subject in period 1 and 21 ng/mL in one subject in period 2 and Cavg of 68 ng/mL in one subject in period 2). Despite this, no evidence of loss of HIV virological control was observed, with several possible explanations for this. Firstly, recruited subjects had no evidence of HIV strains harbouring drug resistance-associated mutations and Table 2. Pharmacokinetic parameters results for maraviroc, darunavir and ritonavir (n¼11) Day 10, GM value (95% CI) Maraviroc Ctrough (ng/mL) Cmax (ng/mL) Cavg (ng/mL) AUC0 – 24 (ng . h/mL) t12 (h) Darunavir Ctrough (ng/mL) Cmax (ng/mL) Cavg (ng/mL) AUC0 – 24 (ng . h/mL) t12 (h) Ritonavir Ctrough (ng/mL) Cmax (ng/mL) Cavg (ng/mL) AUC0 – 24 (ng . h/mL) t12 (h) 1350 48.8 (32.8–72.6) 415 (341–504) 149 (124–179) 3579 (2983– 4294) 9.6 (6.9–13.5) 1465 (906–2368) 5861 (4692– 7321) 2799 (2271– 3450) 67177 (54506– 82794) 19.2 (10.7–34.6) 47.6 (33.4–67.8) 409 (311–537) 176 (135–231) 4235 (3236– 5541) 6.6 (5.2–8.5) Day 20, GM CV% 51 27 26 26 50 59 30 30 30 106 46 35 31 31 33 value (95% CI) 44.9 (35.7– 56.3) 413 (311– 547) 125 (99 –158) 2996 (2374–3782) 10.9 (8.6 –13.9) 1563 (1166–2094) 5534 (4431–6912) 2542 (1998–3234) 61002 (47 941–77621) 20.7 (14.6– 29.4) 49.6 (34.2– 71.9) 353 (271– 462) 161 (128– 204) 3873 (3064–4896) 7.7 (5.4 –10.9) CV% GMR day 20/day 10 (95% CI) 30 42 33 33 38 0.92 (0.55–1.54) 0.99 (0.79–1.25) 0.84 (0.67–1.05) 0.84 (0.67–1.05) 1.13 (0.76–1.69) 46 37 37 37 64 1.07 (0.63–1.81) 0.94 (0.79–1.13) 0.91 (0.78–1.06) 0.91 (0.78–1.06) 1.09 (0.48–2.44) 42 37 31 31 68 1.04 (0.62–1.75) 0.86 (0.70–1.07) 0.91 (0.81–1.03) 0.91 (0.81–1.03) 1.16 (0.77–1.75) JAC Maraviroc/darunavir pharmacokinetic study MVC Cavg MVC Cavg (ng/mL) (a) 250 225 200 175 150 125 100 75 50 25 0 GMR day 20/day 10 (95% CI) : 0.84 (0.67–1.05) Cavg=75 ng/mL # Day 10 Day 20 Study periods MVC Ctrough (ng/mL) (b) 150 MVC Ctrough GMR day 20/day 10 (95% CI): 0.92 (0.55–1.54) 125 100 75 50 25 ** C * trough=25 ng/mL 0 Day 10 Day 20 Study periods Figure 1. (a) Maraviroc average plasma concentration levels (MVC Cavg) during periods 1 and 2 of the study. Filled triangles, individual subjects; #, subject 2. (b) Maraviroc trough plasma concentration levels (MVC Ctrough) during periods 1 and 2 of the study. Filled triangles, individual subjects; *, subject 10; **, subject 6. remained on darunavir/ritonavir throughout the study period. Darunavir/ritonavir alone is likely to provide sufficient antiretroviral activity to maintain suppression of HIV viraemia in such subjects.18,19 Furthermore, within the short study time frame, rebound of viraemia may not have been observed. Secondly, the proposed optimal lower maraviroc Ctrough is ≥24-fold higher than the serum-adjusted EC90 of 0.57 ng/mL (0.06 –10.7), based on laboratory testing from 43 primary HIV-1 clinical isolates;20 hence, lower concentrations of maraviroc are likely to provide antiretroviral activity. Additionally, variability in maraviroc Ctrough in our study was generally high, which may limit the clinical relevance of this pharmacokinetic parameter. Pharmacokinetic data from a cohort study assessing differing maraviroc dosing schedules being utilized in clinical practice, reported similar maraviroc Ctrough exposure of 43 ng/mL (IQR 35 –55) to that seen in our study in the group receiving the same antiretroviral regimen.21 Within this cohort, when higher doses of maraviroc were utilized in clinical practice, such as 300 mg once daily, as expected, greater plasma exposure of maraviroc was observed. Although no clinical cases of toxicity (postural hypotension) were observed with higher doses of maraviroc in this cohort study, 9% (6/66) of subjects had a peak maraviroc concentration of .1000 ng/mL, which may be associated with an increased risk for postural hypotension. Furthermore, due to sparse pharmacokinetic sampling, this may be an under-representation of the true peak concentrations, as sampling near the time of maximal exposure may have been missed in many subjects. However, we did not observe any peak maraviroc concentration .1000 ng/mL and can be confident not to have missed maximum plasma exposure in our study, as all subjects completed all of the intensive pharmacokinetic measurements as per the study protocol. Similar studies have been carried out to assess the combination of darunavir/ritonavir and maraviroc twice daily, which showed good tolerability and favourable pharmacokinetic profiles.22 Although our study findings suggest that with the dosing regimen we studied, maximum maraviroc plasma exposure is unlikely to reach concentrations associated with risk for postural hypotension, on the converse, minimum exposure of maraviroc is near the lower proposed therapeutic threshold and studies assessing the virological efficacy of this regimen are required. Indeed, such a study is underway. The MODERN study is assessing 150/800/100 mg of maraviroc/darunavir/ritonavir alone, all once daily, in a prospective, randomized, double-blind study, as a therapeutic option for therapy-naive HIV-infected individuals.23 Here, the clinical efficacy of the novel regimen we have studied will be tested against standard antiretroviral therapy including nucleoside analogues. Examining this novel regimen in this challenging treatment scenario, namely assessing virological response in subjects commencing antiretroviral therapy for the first time, allows one of the ultimate tests of efficacy in HIV therapeutics. Interestingly, general reductions in the total plasma exposure of all drugs were observed on discontinuation of tenofovir/emtricitabine, although these reductions were not of statistical significance. A previous study has reported small reductions in darunavir exposure24 on discontinuation of tenofovir/emtricitabine, but no change in ritonavir exposure. With regard to other HIV-protease inhibitors, no changes in saquinavir concentrations are reported when administered with or without tenofovir25 and reductions in atazanavir exposure have been reported when administered with tenofovir,26,27 although the clinical relevance of this interaction remains disputed.28 To our knowledge, no interactions between emtricitabine itself and other antiretrovirals have been reported.29,30 Maraviroc is a substrate of the ABCB1 (P-glycoprotein) efflux transporter and the CYP3A isoenzyme.9,10 Tenofovir does not undergo CYP3A or hepatic metabolism31 and, historically, no significant pharmacokinetic interactions with maraviroc have been described.32 We believe the reductions in darunavir and maraviroc exposure we observed are likely related to the slight reduction in ritonavir exposure observed in period 2. However, the mechanism underpinning the slight decrease in ritonavir exposure during this study period remains elusive. Regarding other factors that could affect the metabolism of maraviroc, the lack of genotype testing in our study made it impossible to assess the correlation of OATP1B1 polymorphisms observed in vitro with plasma concentrations of maraviroc as a substrate of this transporter.10 In this study, maraviroc concentrations in the CSF were not assessed and this could be critical in the activity of maraviroc against CCR5-using strains, common in the brain. Recent 1351 Mora-Peris et al. studies have evaluated the concentration of unbound maraviroc in plasma as a research tool to estimate penetration in the CNS.33 However, total concentrations were measured in this study and no estimation of the concentration in the CSF is possible. Other studies have reported higher maraviroc concentrations at trough in subjects of black ethnicity.21 Such a trend was also present in our study but there was a lack of statistical significance of this association due to the small number of subjects, especially those of black ethnicity. With an ageing HIV-infected population and the need for lifelong effective antiretroviral therapy, novel, once-daily, antiretroviral treatment strategies, avoiding the long-term toxicities associated with nucleoside analogues, are urgently required. Unfortunately, studies in recent years have reported disappointing efficacy results when utilizing such nucleoside-sparing treatment regimens.34 – 36 This lack of efficacy may for some regimens be associated with pharmacokinetic concerns,37 highlighting the need for the detailed pharmacokinetic profiles of such regimens to be determined in the population where such regimens will be utilized. Our results, describing the pharmacokinetic profile of 800/100/150 mg of darunavir/ritonavir/maraviroc dosed once daily without nucleoside analogues in HIV-infected subjects, add to the growing knowledge in this field, with the results of clinical efficacy studies awaited. Acknowledgements We are grateful to the NIHR Biomedical Facility at Imperial College London for infrastructure support. We are grateful to Simon Portsmouth (Pfizer) and Manoli Vourvahis (Pfizer) for their assistance in interpreting some of the pharmacokinetic results. We would like to thank all the study participants, the nursing and pharmacy staff and the Clinical Trials Centre, Imperial College London (St Mary’s Campus), UK (Ken Legg, Ngaire Latch, Kanta Jhalli, Ling-Jun Chen, Scott Mullaney, Siobhan McKenna, Nadia Naous and Rosy Weston). References 1 Antiretroviral Therapy Cohort Collaboration. 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