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Effect of a Single Supratherapeutic Dose of Dolutegravir on Cardiac Repolarization
Author(s) -
Chen Shuguang,
Min Sherene S.,
Peppercorn Amanda,
Borland Julie,
Lou Yu,
Song Ivy,
Fujiwara Tamio,
Piscitelli Stephen C.
Publication year - 2012
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/j.1875-9114.2012.01033.x
Subject(s) - dolutegravir , qt interval , moxifloxacin , medicine , placebo , pharmacokinetics , crossover study , pharmacodynamics , confidence interval , anesthesia , randomized controlled trial , pharmacology , viral load , antibiotics , alternative medicine , family medicine , pathology , human immunodeficiency virus (hiv) , antiretroviral therapy , microbiology and biotechnology , biology
Study Objective To assess the effect of a supratherapeutic dose of the integrase inhibitor dolutegravir on the QT and corrected QT ( QT c) interval. Design Randomized, partial‐blind, placebo‐controlled, single‐dose, 3‐period, balanced crossover study. Setting Clinical research unit. Subjects Forty‐two healthy subjects were randomized; of these subjects, 38 completed the study, three withdrew early because of protocol violations, and one was lost to follow‐up. Intervention Subjects were randomized to receive three single doses of the following treatments: dolutegravir 250‐mg suspension, moxifloxacin 400‐mg tablet, and placebo suspension; each treatment was separated by a 14‐day washout period. Treatment with the dolutegravir and placebo suspension was blinded, whereas treatment with moxifloxacin was open label. Measurements and Main Results The pharmacokinetic exposure at a supratherapeutic dose of dolutegravir 250 mg was 2–4 times higher than the pharmacokinetic exposure at clinically relevant dosages (50 mg once or twice/day). The upper limit of the 90% confidence interval ( CI ) for the placebo‐adjusted mean change from baseline of the QT c interval (ΔΔ QT cF) using Fridericia's formula was less than 10 msec at all time points. The sensitivity of the study to detect modest increases in QT interval was established with moxifloxacin, a positive control for QT ‐interval prolongation. The maximum ΔΔ QT cF values for dolutegravir and moxifloxacin were observed at 4 hours: 1.99 msec (90% CI −0.55–4.53 msec) and 9.58 msec (90% CI 7.05–12.11 msec), respectively. Conclusion This pharmacokinetic‐pharmacodynamic model demonstrates no relationship between dolutegravir plasma concentration and ΔΔ QT cF. Furthermore, a supratherapeutic dose of dolutegravir was generally well tolerated without any serious or severe adverse events. As such, dolutegravir does not affect cardiac repolarization.