Lack of a pharmacokinetic interaction between steady-state tipranavir/ritonavir and single-dose valacyclovir in healthy volunteers.
OBJECTIVE
This study assessed the single-dose pharmacokinetics of the herpes antiviral acyclovir (administered as the pro-drug valacyclovir) alone and in combination with twice-daily 200 mg ritonavir-boosted tipranavir (500 mg) at steady state.


METHODS
The study was an open label, one-sequence cross-over pharmacokinetic study in HIV-negative adults. Plasma drug concentrations were measured by validated LC/MS/MS assays; pharmacokinetics (AUC, C(max)) were determined using noncompartmental methods. The geometric mean ratio and 90% confidence interval [GMR, 90% CI] were used to evaluate the drug interaction.


RESULTS
Twenty-six of 29 subjects completed the trial. With steady-state tipranavir/ritonavir, acyclovir C(max) decreased 4.9% [0.95, 0.88-1.02] and AUC increased 6.6% [1.07, 1.04-1.09]. The majority of subjects experienced at least one adverse event, most of which were mild gastrointestinal disorders. Three subjects discontinued tipranavir/ritonavir treatment as a result of drug-related increases in ALT/AST, including one subject who experienced mild upper abdominal pain. All subjects recovered without sequelae.


CONCLUSIONS
When administered as a single dose of valacyclovir with steady-state tipranavir/ritonavir, there were no clinically important changes in acyclovir pharmacokinetics. This result indicates that valacyclovir can be co-administered safely with no dose adjustments.
Sabo
John P
JP
Boehringer Ingelheim Pharmaceuticals, Inc., R&D, 900 Ridgebury Road, Ridgefield, CT 06877, USA.
Cong
Xiuyu Julie
XJ
Kraft
Michael-Friedrich
MF
Wallace
Lacey
L
Castles
Mark A
MA
Mauss
Stefan
S
MacGregor
Thomas R
TR
D000212:Acyclovir / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011355:Prodrugs; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011753:Pyrones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013449:Sulfonamides; D053719:Tandem Mass Spectrometry; D000077483:Valacyclovir; D014633:Valine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D011355:Prodrugs; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D014633:Valine; D000077483:Valacyclovir; D019438:Ritonavir; D000212:Acyclovir; C107201:tipranavir