The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjects.
OBJECTIVE
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 AUC(0-infinity) 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, C(max), and C(min), respectively. No change in LPV AUC or C(max) and a small increase in RTV AUC and C(max) (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.
Adkison
Kimberly K
KK
GlaxoSmithKline, Research Triangle Park, NC, USA.
Shachoy-Clark
Anne
A
Fang
Lei
L
Lou
Yu
Y
Otto
Vicky R
VR
Berrey
M Michelle
MM
Piscitelli
Stephen C
SC
D000293:Adolescent; D000328:Adult; D000818:Animals; D001565:Benzoates / Q000493:pharmacokinetics; D065100:CCR5 Receptor Antagonists; D054659:Diketopiperazines; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D061466:Lopinavir; D008297:Male; D051379:Mice; D008875:Middle Aged; D010879:Piperazines / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D019438:Ritonavir / Q000494:pharmacology* / Q000627:therapeutic use; D013141:Spiro Compounds / Q000493:pharmacokinetics
D001565:Benzoates; D065100:CCR5 Receptor Antagonists; D054659:Diketopiperazines; D004338:Drug Combinations; D010879:Piperazines; D011744:Pyrimidinones; D013141:Spiro Compounds; D061466:Lopinavir; C499671:aplaviroc; D019438:Ritonavir