Pharmacokinetic characterization of different dose combinations of coadministered tipranavir and ritonavir in healthy volunteers.
OBJECTIVE
To characterize the steady-state pharmacokinetic combination of the nonpeptidic protease inhibitor tipranavir (TPV) with ritonavir (RTV) in 95 healthy adult volunteers, a phase 1, single-center, open-label, randomized, parallel-group trial was conducted.


METHODS
Participants received 250-mg self-emulsifying drug delivery system (SEDDS) capsules of TPV at doses between 250 mg and 1250 mg twice daily for 11 days, then received one or two RTV 100-mg SEDDS capsules, in addition to the TPV capsules, for the next 21 days.


RESULTS
Coadministration of TPV and RTV (TPV/r) resulted in a greater than 20-fold increase in steady-state TPV trough concentrations (Cssmin) as compared with TPV at steady state alone. Mean TPV Cssmin was above a preliminary target threshold of 20 microM with all but one of the RTV-boosted doses; without boosting, none of the TPV-alone doses exceeded the threshold. The average steady-state Cssmin for TPV 500 mg and 750 mg with RTV 100 mg or 200 mg were 20 to 57 times the protein-adjusted TPV IC90R49\CCR418569) for protease inhibitor-resistant HIV-1. An erythromycin breath test, a surrogate marker for cytochrome P450 isoenzyme 3A4 activity, indicated that all TPV/r combinations given provided net inhibition of this isoenzyme. The most frequent treatment-related adverse events were mild gastrointestinal symptoms.


CONCLUSIONS
This phase 1 study demonstrated that RTV-boosted TPV achieves concentrations that are expected to be effective in treating drug-experienced patients.
MacGregor
Thomas R
TR
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA. tmacgreg@rdg.boehringer-ingelheim.com
Sabo
John P
JP
Norris
Stephen H
SH
Johnson
Philip
P
Galitz
Lawrence
L
McCallister
Scott
S
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002214:Capsules; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004655:Emulsions; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011753:Pyrones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides
D002214:Capsules; D004655:Emulsions; D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D019438:Ritonavir; C107201:tipranavir