Pharmacokinetics of tenofovir disoproxil fumarate and ritonavir-boosted saquinavir mesylate administered alone or in combination at steady state.
A phase I study was conducted to formally evaluate the steady-state pharmacokinetics (PK) of tenofovir disoproxil fumarate (TDF) and ritonavir (RTV)-boosted saquinavir mesylate (SQV) when coadministered in healthy volunteers. Forty subjects received multiple doses of TDF (300 mg, once daily) and SQV/RTV (1,000 mg/100 mg, twice daily) alone and together under steady-state conditions in an open-label, fixed sequence design. Blood samples for tenofovir (TFV) and SQV/RTV PK were drawn over respective 24- and 12-h dosing intervals, and drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety was assessed periodically by clinical and laboratory monitoring. Thirty-two subjects completed the study and were fully evaluable; three subjects discontinued participation in the study due to adverse events, three subjects withdrew for personal reasons, and two subjects withdrew because of inadequate venous access for blood sampling. Steady-state TFV PK were not significantly altered upon coadministration with SQV/RTV. Steady-state SQV (administered as SQV/RTV) AUCtau, Cmax, and Ctau increased 29, 22, and 47%, respectively, upon coadministration with TDF, and all subjects achieved a Ctau of >100 ng/ml. These modestly increased SQV exposures are not clinically meaningful given its clinical use with RTV already results in >10-fold-higher SQV levels. Steady-state RTV AUCtau and Cmax levels were not significantly altered, whereas Ctau was 23% higher upon coadministration of SQV/RTV and TDF. Thus, no clinically relevant interactions between TDF and RTV-boosted SQV were observed under conditions simulating clinical practice.
Gilead Sciences, Inc., Department of Clinical Pharmacology and Pharmacokinetics, 4 University Place, 4611 University Dr., Durham, NC 27707, USA.
Gregory E
GE
Chittick
Jian
J
Zong
M Robert
MR
Blum
Jeffrey J
JJ
Sorbel
John A
JA
Begley
Nathalie
N
Adda
Brian P
BP
Kearney
D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000493:pharmacokinetics*; D019258:Saquinavir / Q000493:pharmacokinetics*; D000068698:Tenofovir
D019380:Anti-HIV Agents; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine; D019258:Saquinavir; D019438:Ritonavir