title: Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval.
abstract: Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC(95) = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C(max) of approximately 20 muM raltegravir was attained, approximately 4-fold higher than the C(max) at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.
authors.affiliation: Merck & Co, Inc, RY34-A500, PO Box 2000, Rahway, NJ 07065-0900, USA. marian_iwamoto@merck.com
authors.forename: M
authors.initials: M
authors.lastname: Iwamoto
authors.forename: J T
authors.initials: JT
authors.lastname: Kost
authors.forename: G C
authors.initials: GC
authors.lastname: Mistry
authors.forename: L A
authors.initials: LA
authors.lastname: Wenning
authors.forename: S A
authors.initials: SA
authors.lastname: Breidinger
authors.forename: T C
authors.initials: TC
authors.lastname: Marbury
authors.forename: J A
authors.initials: JA
authors.lastname: Stone
authors.forename: K M
authors.initials: KM
authors.lastname: Gottesdiener
authors.forename: D M
authors.initials: DM
authors.lastname: Bloomfield
authors.forename: J A
authors.initials: JA
authors.lastname: Wagner
mesh_terms: D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects; D001372:Aza Compounds / Q000009:adverse effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D019428:HIV Integrase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011760:Pyrrolidinones / Q000009:adverse effects* / Q000493:pharmacokinetics; D011804:Quinolines / Q000009:adverse effects; D000068898:Raltegravir Potassium; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D011804:Quinolines; D000068898:Raltegravir Potassium; D000077266:Moxifloxacin