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.
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 (C(trough)) and average (C(avg)) 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 C(trough) and C(avg) were <25 and <75 ng/mL, respectively (C(avg), 68 ng/mL and C(trough), 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=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.
Department of Medicine, Faculty of Medicine, Imperial College London, St Mary's Hospital Campus, Norfolk Place, London W2 1PG, UK. b.mora-peris@imperial.ac.uk
Borja
B
Mora-Peris
Adam
A
Croucher
Laura J
LJ
Else
Jaime H
JH
Vera
Saye
S
Khoo
George
G
Scullard
David
D
Back
Alan
A
Winston
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D019540:Area Under Curve; D018791:CD4 Lymphocyte Count; D003510:Cyclohexanes / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000069454:Darunavir; D004359:Drug Therapy, Combination; D005260:Female; D023581:HIV Fusion Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D014230:Triazoles / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use
D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D013449:Sulfonamides; D014230:Triazoles; D000077592:Maraviroc; D019438:Ritonavir; D000069454:Darunavir
HIV; HIV antiviral pharmacology; antiretroviral therapy; nucleoside sparing