Pharmacokinetic profile of maraviroc 150 mg dosed with darunavir/ritonavir once daily, with and without nucleoside analogues, in HIV‐infected subjects
Authors: Mora‐Peris B , Croucher A , Else L , Khoo S , Vera J , Back D , Winston A 
Published: November 2012

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.