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Lack of a Pharmacokinetic Effect of Raltegravir on Midazolam: In Vitro/In Vivo Correlation

From Merck & Co, Inc, Whitehouse Station, New Jersey (Dr Iwamoto, Dr Kassahun, Dr Troyer, Dr Hanley, Ms Lu, Ms Rhoton, Ms Petry, Dr Ghosh, Mr Mangin, Dr Wenning, Dr Stone, Dr Gottesdiener, Dr Wagner) and Healthcare Discoveries, Inc, San Antonio, Texas (Dr DeNoia).

Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (95% inhibitory concentration = 33 nM in 50% human serum). In vitro characterization of raltegravir inhibition potential was assessed against a panel of cytochrome P450 (CYP) enzymes. An open-label, 2-period study was conducted to assess the effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP 3A4 probe substrate: period 1, 2.0 mg of midazolam; period 2, 400 mg of raltegravir every 12 hours for 14 days with 2.0 mg of midazolam on day 14. There was no meaningful in vitro effect of raltegravir on inhibition of a panel of CYP enzymes and induction of CYP 3A4. In the presence of raltegravir, midazolam area under the curve extrapolated to infinity (AUC_0-) and maximum plasma concentration (C_max) geometric mean ratios were similar (geometric mean ratios and 90% confidence intervals: 0.92 [0.82, 1.03] (P = .208) and 1.03 [0.87, 1.22] (P = .751), respectively). No substantial differences were observed in T_max (P = .750) or apparent half-life (P = .533) of midazolam. Plasma levels of midazolam were not substantially affected by raltegravir, which implies that raltegravir is not a clinically important inducer or inhibitor of CYP 3A4 and that raltegravir would not be expected to affect the pharmacokinetics of other drugs metabolized by CYP 3A4 to a clinically meaningful extent.

Key Words: Raltegravir • HIV-1 integrase inhibitor • pharmacokinetics • midazolam • drug interaction

Address for correspondence: Marian Iwamoto, MD, PhD, Merck & Co, Inc, RY34-A500, PO Box 2000, Rahway, NJ 07065-0900.

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