Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir.
Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration = 31 nM in 50% human serum). The possible effects of ritonavir and efavirenz on raltegravir pharmacokinetics were separately examined. Two clinical studies of healthy subjects were conducted: for ritonavir plus raltegravir, period 1, 400 mg raltegravir; period 2, 100 mg ritonavir every 12 h for 16 days with 400 mg raltegravir on day 14; for efavirenz plus raltegravir, period 1, 400 mg raltegravir; period 2, 600 mg efavirenz once daily for 14 days with 400 mg raltegravir on day 12. In the presence of ritonavir, raltegravir pharmacokinetics were weakly affected: the plasma concentration at 12 h (C(12 h)) geometric mean ratio (GMR) (90% confidence interval [CI]) was 0.99 (0.70, 1.40), area under the concentration-time curve from zero to infinity (AUC(0-infinity)) was 0.84 (0.70, 1.01), and maximum concentration of drug in serum (C(max)) was 0.76 (0.55, 1.04). In the presence of efavirenz, raltegravir pharmacokinetics were moderately to weakly reduced: C(12 h) GMR (90% CI) was 0.79 (0.49, 1.28); AUC(0-infinity) was 0.64 (0.52, 0.80); and C(max) was 0.64 (0.41, 0.98). There were no substantial differences in the time to maximum concentration of drug in plasma or the half-life. Plasma concentrations of raltegravir were not substantially affected by ritonavir. Though plasma concentrations of raltegravir were moderately to weakly reduced by efavirenz, the degree of this reduction was not clinically meaningful. No dose adjustment is required for raltegravir with coadministration with ritonavir or efavirenz.
Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065-0900, USA. marian_iwamoto@merck.com
Marian
M
Iwamoto
Larissa A
LA
Wenning
Amelia S
AS
Petry
Martine
M
Laethem
Marina
M
De Smet
James T
JT
Kost
Sheila A
SA
Breidinger
Eric C
EC
Mangin
Neal
N
Azrolan
Howard E
HE
Greenberg
Wouter
W
Haazen
Julie A
JA
Stone
Keith M
KM
Gottesdiener
John A
JA
Wagner
D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D048588:Benzoxazines / Q000008:administration & dosage*; D003521:Cyclopropanes; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D019438:Ritonavir / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D011760:Pyrrolidinones; D018894:Reverse Transcriptase Inhibitors; D000068898:Raltegravir Potassium; C098320:efavirenz; D019438:Ritonavir