Hepatotoxicity observed in clinical trials of aplaviroc (GW873140).
Aplaviroc (APL) was a new CCR5 antagonist that was investigated in two dose-ranging studies with antiretroviral therapy-naïve, human immunodeficiency virus-infected adults: ASCENT, in which 147 subjects were randomized 2:2:1 to receive zidovudine-lamivudine (ZDV-3TC) plus APL 600 mg twice a day (BID), APL 800 mg BID, or efavirenz (EFV), respectively, and EPIC, in which 195 subjects were randomized 2:2:2:1 to receive lopinavir-ritonavir (LPV-RTV) plus APL 200 mg BID, APL 400 mg BID, APL 800 mg once a day, or ZDV-3TC BID, respectively. Both studies (and, ultimately, the clinical development of APL) were discontinued after a mean of 14 weeks of therapy because of higher than anticipated severe liver toxicity; grade 2 or higher treatment-emergent elevations in alanine aminotransferase (ALT) levels were observed in 17/281 (6.0%) APL recipients but only 2/55 (3.6%) control recipients, while grade 2 or higher elevations in total bilirubin levels occurred in 29/281 (10.3%) APL recipients but only 4/55 (7.3%) controls. Two APL recipients developed grade 3 or higher treatment-emergent elevations in both ALT and total bilirubin levels, and one of these individuals had a severe case of hepatic cytolysis that was attributed to APL. Despite the high intersubject variability in APL plasma exposures, a Pearson correlation analysis of the combined study data did not reveal any significant associations between plasma concentrations and the liver enzyme elevations observed during the study. The mechanism for the idiosyncratic hepatotoxicity observed in the clinical trials of APL is unknown but is likely intrinsic to the molecule rather than its novel mechanism of action.
Nichols
W G
WG
Infectious Diseases Medicine Development Centre, GlaxoSmithKline, 881-995 Greenford Road, Greenford, Middlesex UB6 0HE, United Kingdom. garrett.x.nichols@gsk.com.
Steel
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Bonny
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Adkison
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Curtis
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Millard
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Kabeya
K
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Clumeck
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D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D001565:Benzoates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D054659:Diketopiperazines; D004311:Double-Blind Method; D005260:Female; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D013141:Spiro Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology
D001565:Benzoates; D054659:Diketopiperazines; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D013141:Spiro Compounds; C499671:aplaviroc; D000410:Alanine Transaminase; D001663:Bilirubin