The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjects

• Published in: British journal of clinical pharmacology Vol. 62; no. 3; pp. 336 - 344
• Main Authors: Adkison, Kimberly K., Shachoy‐Clark, Anne, Fang, Lei, Lou, Yu, Otto, Vicky R., Berrey, M. Michelle, Piscitelli, Stephen C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2006; Blackwell Science
• Subjects: Adolescent; Adult; Animals; aplaviroc; Benzoates - pharmacokinetics; Biological and medical sciences; CCR5; CCR5 Receptor Antagonists; Drug Combinations; drug interaction; Drug Interactions; Female; HIV Infections - drug therapy; Humans; Lopinavir; Male; Medical sciences; Mice; Middle Aged; Pharmacology. Drug treatments; Piperazines - pharmacokinetics; Pyrimidinones - pharmacology; Pyrimidinones - therapeutic use; Rats; ritonavir; Ritonavir - pharmacology; Ritonavir - therapeutic use; Spiro Compounds - pharmacokinetics; Human; Antiretroviral agent; Healthy subject; Enzyme; Ritonavir; Lopinavir; aplaviroc; Enzyme inhibitor; Chemokine receptor; CC chemokine; CCR5 chemokine receptor; Peptidases; Hydrolases; Antiviral; Drug interaction; Antagonist; Pharmacokinetics; CCR5; Protease inhibitor
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2006.02661.x

Aims This study assessed the effects of the CYP3A inhibitors lopinavir/ritonavir (LPV/r) on the steady‐state pharmacokinetics (PK) of aplaviroc (APL), a CYP3A4 substrate, in healthy subjects. Methods In Part 1, APL PK was determined in eight subjects who received a single oral 50‐mg APL test dose with/without a single dose of 100 mg ritonavir (RTV). Part 2 was conducted as an open‐label, single‐sequence, three‐period repeat dose study in a cohort of 24 subjects. Subjects received APL 400 mg every 12 h (b.i.d.) for 7 days (Period 1), LPV/r 400/100 mg b.i.d. for 14 days (Period 2) and APL 400 mg + LPV/r 400/100 mg b.i.d. for 7 days (Period 3). All doses were administered with a moderate fat meal. PK sampling occurred on day 7 of Periods 1 and 3 and day 14 of Period 2. Results In Part 1, a single RTV dose increased the APL AUC0–∞ by 2.1‐fold [90% confidence interval (CI) 1.9, 2.4]. Repeat dose coadministration of APL with LPV/r increased APL exposures to a greater extent with the geometric least squares mean ratios (90% CI) being 7.7 (6.4, 9.3), 6.2 (4.8, 8.1) and 7.1 (5.6, 9.0) for the APL AUC, Cmax, and Cmin, respectively. No change in LPV AUC or Cmax and a small increase in RTV AUC and Cmax (28% and 32%) were observed. The combination of APL and LPV/r was well tolerated and adverse events were mild in severity with self‐limiting gastrointestinal complaints most commonly reported. Conclusions Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations.