Pharmacokinetic profile of maraviroc 150 mg dosed with darunavir/ritonavir once daily, with and without nucleoside analogues, in HIV‐infected subjects

• Published in: Journal of the International AIDS Society Vol. 15; no. S4; pp. 1 - 2
• Main Authors: Mora‐Peris, B, Croucher, A, Else, L, Khoo, S, Vera, J, Back, D, Winston, A
• Format: Journal Article
• Language: English
• Published: Geneva International AIDS Society 01.11.2012; John Wiley & Sons, Inc
• Subjects: Acquired immune deficiency syndrome; AIDS; Antiretroviral agents; Antiretroviral drugs; Antiviral drugs; Confidence intervals; Exposure; HIV; Human immunodeficiency virus; Pharmacokinetics; Ritonavir
• ISSN: 1758-2652; 1758-2652
• DOI: 10.7448/IAS.15.6.18332

Background Once‐daily nucleoside‐sparing combination antiretroviral therapy (cART) regimens, such as maraviroc/darunavir/ritonavir, may be attractive therapeutic options. However, the pharmacokinetic (PK) profiles of such regimens have not been established. Methods HIV‐1‐infected subjects on stable cART comprising of tenofovir/emtricitabine (TDF/FTC) 245/200 mg plus darunavir/ritonavir 800/100 mg once daily with plasma HIV‐1 RNA <50 copies/mL were eligible to enter this phase I, open‐label, prospective, two‐period PK study. On day 1 (period 1) maraviroc 150 mg daily was added to subjects cART regimen and on day 11 (period 2) TDF/FTC discontinued. At steady state (days 10 and 20) intensive PK sampling was undertaken. Geometric mean (GM) ratios for PK parameters between periods 2 versus 1 were calculated. In addition the number of subjects with trough (Ctrough) and average (Cave) maraviroc concentrations below 25 and 75 ng/mL (values previously associated with optimal virological response) were calculated and factors associated with total maraviroc exposure assessed. Results Eleven subjects completed study procedures with a mean age 49 years (range 35–59 years), 82% male and 27% and 73% of black and Caucasian ethnicity, respectively. Maraviroc GM (95% confidence interval [CI]) Ctrough and Cave concentrations in both study periods (see Table) were > 25 and > 75 ng/mL (concentrations associated with near maximal efficacy). No individual subjects had a maraviroc Cave below 75 ng/mL in either study period. One subject had a maraviroc Ctrough concentration below 25 ng/mL in period 1 (14 ng/mL) and one other subject in period 2 (21 ng/mL). Although no statistically significant differences in PK parameters were observed between period 2 and period 1 for any drug (see Table), a trend was observed towards lower maraviroc, darunavir and ritonavir concentrations in period 2 (TDF/FTC discontinued) versus period 1. Period 1 Period 2 GM (95% CI) GM (95% CI) GMR Period 2/1 (95% CI) Maraviroc Ctrough ng/mL 47.65 (33.18–68.42) 44.86 (35.75–56.31) 0.92 (0.55–1.54) Cave ng/mL 149 (126–175) 125 (99–157) 0.84 (0.67–1.05) AUC0–24 ng.h/mL 3567 (3027–4205) 2996 (2374–3781) 0.84 (0.67–1.05) Darunavir Ctrough ng/mL 1445 (936–2232) 1563 (1166–2094) 1.07 (0.63–1.81) Cave ng/mL 2891 (2364–3537) 2542 (1997–3234) 0.91 (0.78–1.06) AUC0–24 ng.h/mL 69395 (56726–84893) 61001 (47941–77621) 0.91 (0.78–1.06) Ritonavir Ctrough ng/mL 46 (33–64) 50 (34–72) 1.04 (0.62–1.75) Cave ng/mL 175 (137–223) 161 (128–204) 0.91 (0.81–1.03) AUC0–24ng.h/mL 4208 (3301–5365) 3873 (3064–4896) 0.91 (0.81–1.03) AUC, area under the plasma concentration‐time curve; CI, confidence interval; GMR, geometic mean ratio. On day 20, in a multivariate model, only total ritonavir exposure (AUC0–24) was statistically significantly associated with total maraviroc exposure (AUC0–24) at day 20 (p = 0.045; 95% CI: 0.01–0.89). No clinically relevant safety concerns were observed. Conclusions The PK profile of maraviroc/darunavir/ritonavir 150/800/100 mg all once daily appears favourable. Maraviroc exposure is dependent on ritonavir exposure which was slightly reduced in the absence of TDF/FTC.