Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval.
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.
Iwamoto
M
M
Merck & Co, Inc, RY34-A500, PO Box 2000, Rahway, NJ 07065-0900, USA. marian_iwamoto@merck.com
Kost
J T
JT
Mistry
G C
GC
Wenning
L A
LA
Breidinger
S A
SA
Marbury
T C
TC
Stone
J A
JA
Gottesdiener
K M
KM
Bloomfield
D M
DM
Wagner
J A
JA
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
D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D011804:Quinolines; D000068898:Raltegravir Potassium; D000077266:Moxifloxacin