title: Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects.
abstract: A randomized, partial-blind, repeat-dose, 3-period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open-label 400-mg dose of the positive control moxifloxacin, with a 21-day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day -1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3-fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2-sided 90% confidence intervals for ΔΔQTcF (difference in time-matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization.
authors.affiliation: Parexel International, Research Triangle Park, Durham, NC, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.affiliation: ViiV Healthcare, Research Triangle Park, Durham, NC, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Buchanan
authors.affiliation: GlaxoSmithKline, Upper Providence, PA, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Parexel International, Research Triangle Park, Durham, NC, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ford
authors.affiliation: Chimerix, Research Triangle Park, Durham, NC, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gould
authors.affiliation: ViiV Healthcare, Research Triangle Park, Durham, NC, USA.
authors.forename: David
authors.initials: D
authors.lastname: Margolis
authors.affiliation: ViiV Healthcare, Research Triangle Park, Durham, NC, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Spreen
authors.affiliation: ViiV Healthcare, Research Triangle Park, Durham, NC, USA.
authors.forename: Parul
authors.initials: P
authors.lastname: Patel
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D064368:Healthy Volunteers; D006321:Heart / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011728:Pyridones / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult; D054659:Diketopiperazines
chemical_list: D019380:Anti-HIV Agents; D024841:Fluoroquinolones; D000077266:Moxifloxacin; D011728:Pyridones; C584914:cabotegravir; D054659:Diketopiperazines
keywords: GSK1265744; HIV-1; QT interval; cabotegravir; cardiac conduction; integrase inhibitor