pyrimidinones and aplaviroc

This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral-naïve patients harbouring R5- or R5X4-tropic virus.. A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed.. This study was terminated prematurely because of APL-associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent-to-treat (M-ITT) population]; of these, 133 completed the 12-week treatment phase. The proportion of subjects in the M-ITT population with HIV-1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4-tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability.. While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.

Topics: Adult; Aged; Benzoates; Diketopiperazines; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Piperazines; Pyrimidinones; Receptors, CCR5; Ritonavir; RNA, Viral; Spiro Compounds; Young Adult

The CCR100136 (EPIC) study evaluated the antiviral activity of the novel CCR5 entry inhibitor aplaviroc in combination with lopinavir-ritonavir in drug-naïve human immunodeficiency virus type 1-infected subjects. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, 11 subjects met the protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, aplaviroc susceptibility, and env sequencing were performed on plasma at day 1 and at the time of virologic failure. Molecular evolutionary analyses were also performed. Treatment-emergent resistance to aplaviroc or lopinavir-ritonavir was not observed at the population level. However, aplaviroc resistance was detected prior to therapy at both the clonal and population levels in one subject with virologic failure and in six subjects in a minority (<50%) of clones at day 1 or at the time of virologic failure. Reduced aplaviroc susceptibility manifested as a 50% inhibitory concentration curve shift and/or a plateau. Sequence changes in the clones with aplaviroc resistance were unique to each subject and scattered across the envelope coding region. Clones at day 1 and at the time of virologic failure were not phylogenetically distinct. Two subjects with virologic failure had a population tropism change from CCR5- to dual/mixed-tropic during treatment. Virologic failure during a regimen of aplaviroc and lopinavir-ritonavir may be associated with aplaviroc resistance, only at the clonal level, and/or, infrequently, tropism changes.

Topics: Anti-HIV Agents; Benzoates; Clinical Trials as Topic; Diketopiperazines; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; env Gene Products, Human Immunodeficiency Virus; Evolution, Molecular; HIV Protease Inhibitors; Humans; Inhibitory Concentration 50; Lopinavir; Piperazines; Pyrimidinones; Ritonavir; Spiro Compounds; Treatment Failure; Tropism

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.. 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.. 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.. Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations.

Topics: Adolescent; Adult; Animals; Benzoates; CCR5 Receptor Antagonists; Diketopiperazines; Drug Combinations; Drug Interactions; Female; HIV Infections; Humans; Lopinavir; Male; Mice; Middle Aged; Piperazines; Pyrimidinones; Rats; Ritonavir; Spiro Compounds