Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects.
Raltegravir is a novel human immunodeficiency virus-1 integrase inhibitor with potent in vitro activity (95% inhibitory concentration (IC95)=33 nM in 50% human serum). Three double-blind, randomized, placebo-controlled, pharmacokinetic, safety, and tolerability studies were conducted: (1) single-dose escalation study (10-1,600 mg), (2) multiple-dose escalation study (100-800 mg q12 h x 10 days), and (3) single-dose female study (400 mg). Raltegravir was rapidly absorbed with a terminal half-life (t1/2) approximately 7-12 h. Approximately 7-14% of raltegravir was excreted unchanged in urine. Area under the curve (AUC)(0-infinity) was similar between male and female subjects. After multiple-dose administration, steady state was achieved within 2 days; there was little to modest accumulation of raltegravir. Trough levels were >33 nM for dose levels of 100 mg and greater. Raltegravir is generally well tolerated at doses of up to 1,600 mg/day given for up to 10 days and exhibits a pharmacokinetic profile supportive of twice-daily dosing with multiple doses of 100 mg and greater achieving trough levels >33 nM.
Iwamoto
M
M
Department of Clinical Pharmacology, Merck Research Laboratories, a division of Merck & Co., Inc., Whitehouse Station, NJ, USA. marian_iwamoto@merck.com
Wenning
L A
LA
Petry
A S
AS
Laethem
M
M
De Smet
M
M
Kost
J T
JT
Merschman
S A
SA
Strohmaier
K M
KM
Ramael
S
S
Lasseter
K C
KC
Stone
J A
JA
Gottesdiener
K M
KM
Wagner
J A
JA
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D009930:Organic Chemicals / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D012016:Reference Values
D019428:HIV Integrase Inhibitors; D009930:Organic Chemicals; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium