title: Ritonavir 100 mg does not cause QTc prolongation in healthy subjects: a possible role as CYP3A inhibitor in thorough QTc studies.
abstract: To assess the QTc prolongation by ritonavir (RTV) 100 mg and explore its potential use as CYP3A inhibitor in thorough QTc (TQT) studies. Randomized, crossover study of single-dose RTV 100 mg, placebo, and moxifloxacin (MFLX) 400 mg in 65 healthy subjects with serial triplicate electrocardiograms obtained for 12 h post-dose. Largest mean placebo-adjusted QTcF increase from baseline (90% confidence interval (CI)) for RTV 100 mg was noninferior to placebo (0.16 ms (-1.38, 1.69)). Study sensitivity was validated by detecting the largest mean placebo-adjusted QTcF increase from baseline (90% CI) for MFLX of 8.31 ms (6.44, 10.18). A single dose of RTV 100 mg does not cause QTc prolongation in healthy subjects. Based on the potent CYP3A4 inhibition, lack of QTc effect and better safety profile, RTV 100 mg could replace ketoconazole as the CYP3A4 inhibitor in TQT studies.
authors.affiliation: Clinical Pharmacology, Pfizer Global R&D, San Diego, California, USA. nenadsarapa@yahoo.com
authors.forename: N
authors.initials: N
authors.lastname: Sarapa
authors.forename: D J
authors.initials: DJ
authors.lastname: Nickens
authors.forename: S R
authors.initials: SR
authors.lastname: Raber
authors.forename: R R
authors.initials: RR
authors.lastname: Reynolds
authors.forename: M A
authors.initials: MA
authors.lastname: Amantea
mesh_terms: D000328:Adult; D001372:Aza Compounds / Q000494:pharmacology; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000494:pharmacology; D012016:Reference Values; D015203:Reproducibility of Results; D012107:Research Design; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D019438:Ritonavir / Q000009:adverse effects* / Q000493:pharmacokinetics; D013457:Sulfur Compounds / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D001372:Aza Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D024841:Fluoroquinolones; D017320:HIV Protease Inhibitors; D007093:Imidazoles; D011804:Quinolines; D018894:Reverse Transcriptase Inhibitors; D013457:Sulfur Compounds; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D007654:Ketoconazole; D000077266:Moxifloxacin; C433874:capravirine