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Raltegravir Thorough QT/QTc Study: A Single Supratherapeutic Dose of Raltegravir Does Not Prolong the QTcF Interval

From Merck & Co, Inc, Whitehouse Station, New Jersey (Dr Iwamoto, Dr Kost, G. C. Mistry, Dr Wenning, S. A. Breidinger, Dr Stone, Dr Gottesdiener, Dr Bloomfield, Dr Wagner) and Orlando Clinical Research Center, Orlando, Florida (Dr Marbury).

Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC₉₅ = 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 20 µM raltegravir was attained, 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.

Key Words: Raltegravir • HIV-1 integrase inhibitor • QTc interval • thorough QT • ECG

Address for reprints: Marian Iwamoto, MD, PhD, Merck & Co, Inc, RY34-A500, PO Box 2000, Rahway, NJ 07065-0900; e-mail: marian_iwamoto{at}merck.com.

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