Effect of tipranavir-ritonavir on pharmacokinetics of raltegravir.
Raltegravir (RAL) is a novel and potent human immunodeficiency virus type 1 integrase inhibitor that is predominantly metabolized via glucuronidation. The protease inhibitor combination tipranavir (TPV) at 500 mg and ritonavir (RTV) at 200 mg (TPV-RTV) has inhibitory and inductive effects on metabolic enzymes, which includes the potential to induce glucuronosyltransferase. Because RAL may be coadministered with TPV-RTV, there is the potential for the induction of RAL metabolism. Consequently, we assessed the effect of TPV-RTV on the pharmacokinetics of RAL and the safety and tolerability of this combination. Eighteen healthy adults were enrolled in this open-label study. The participants received RAL at 400 mg twice daily for 4 days (period 1) and TPV-RTV twice daily for 7 days (period 2), followed immediately by 400 mg RAL with TPV-RTV twice daily for 4 days (period 3). Under steady-state conditions, the RAL concentration at 12 h (C(12)) was decreased when RAL was administered with TPV-RTV (geometric mean ratio [GMR], 0.45; 90% confidence interval [CI] 0.31, 0.66; P = 0.0021); however, the area under the concentration-time curve from time zero to 12 h (GMR, 0.76; 90% CI, 0.49, 1.19; P = 0.2997) and the maximum concentration in serum (GMR, 0.82; 90% CI, 0.46, 1.46; P = 0.5506) were not substantially affected. There were no serious adverse experiences or discontinuations due to study drug-related adverse experiences, and RAL coadministered with TPV-RTV was generally well tolerated. Although the RAL C(12) was decreased with TPV-RTV in this study, favorable efficacy data collected in phase III studies substantiate that TPV-RTV may be coadministered with RAL without dose adjustment.
Hanley
William D
WD
Merck & Co., Inc., Whitehouse Station, New Jersey, USA. william_hanley@merck.com
Wenning
Larissa A
LA
Moreau
Allison
A
Kost
James T
JT
Mangin
Eric
E
Shamp
Trisha
T
Stone
Julie A
JA
Gottesdiener
Keith M
KM
Wagner
John A
JA
Iwamoto
Marian
M
D000293:Adolescent; D000328:Adult; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000097:blood / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides; D055815:Young Adult
D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D011760:Pyrrolidinones; D013449:Sulfonamides; D000068898:Raltegravir Potassium; D019438:Ritonavir; C107201:tipranavir