Document Detail


Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization.
MedLine Citation:
PMID:  22422361     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
STUDY OBJECTIVE: To assess the effect of a supratherapeutic dose of the integrase inhibitor dolutegravir on the QT and corrected QT (QTc) 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 QTc interval (ΔΔQTcF) 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 ΔΔQTcF 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 ΔΔQTcF. 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.
Authors:
Shuguang Chen; Sherene S Min; Amanda Peppercorn; Julie Borland; Yu Lou; Ivy Song; Tamio Fujiwara; Stephen C Piscitelli
Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2012-03-15
Journal Detail:
Title:  Pharmacotherapy     Volume:  32     ISSN:  1875-9114     ISO Abbreviation:  Pharmacotherapy     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-30     Completed Date:  2012-07-24     Revised Date:  2013-08-15    
Medline Journal Info:
Nlm Unique ID:  8111305     Medline TA:  Pharmacotherapy     Country:  United States    
Other Details:
Languages:  eng     Pagination:  333-9     Citation Subset:  IM    
Copyright Information:
© 2012 Pharmacotherapy Publications, Inc.
Affiliation:
Infectious Diseases Medicines Discovery and Development, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Anti-Bacterial Agents / adverse effects
Aza Compounds / adverse effects
Confidence Intervals
Cross-Over Studies
Double-Blind Method
Electrocardiography / drug effects*
Female
Follow-Up Studies
HIV Integrase Inhibitors / administration & dosage,  adverse effects*,  pharmacokinetics
Heart Conduction System
Heterocyclic Compounds, 3-Ring / administration & dosage,  adverse effects*,  pharmacokinetics
Humans
Long QT Syndrome / chemically induced*,  physiopathology
Male
Middle Aged
Quinolines / adverse effects
Socioeconomic Factors
Young Adult
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Aza Compounds; 0/HIV Integrase Inhibitors; 0/Heterocyclic Compounds, 3-Ring; 0/Quinolines; DKO1W9H7M1/dolutegravir; U188XYD42P/moxifloxacin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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