Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers.
OBJECTIVE
To evaluate the safety and pharmacokinetic interaction between GW433908, ritonavir (RTV), and efavirenz (EFV).


METHODS
In period 1, subjects received either a once daily (QD) regimen of GW433908 1395 mg + RTV 200 mg (Study 1) or a twice daily (bid) regimen of GW433908 700 mg + RTV 100 mg (Study 2) for 14 days. In period 2, subjects received EFV 600 mg QD with either the same GW433908 + RTV regimen as in period 1 (arm 1) or with a GW433908 + RTV regimen that included an additional 100 mg of RTV (arm 2) for 14 days. Amprenavir (APV) pharmacokinetic sampling and safety assessments were performed on the last day of each period.


RESULTS
Plasma APV exposure was not significantly altered when EFV was coadministered with GW433908 700 mg twice daily (BID) + RTV 100 mg BID. Plasma APV exposure was decreased when EFV was coadministered with GW433908 1395 mg QD + RTV 200 mg QD. However, administration of EFV with GW433908 1395 mg QD + RTV 300 mg QD (i.e., adding an extra 100 mg of RTV) was able to negate this interaction. Adverse events were consistent with prior data for each of the separate agents.


CONCLUSIONS
When EFV is coadministered with the GW433908 700 mg + RTV 100 mg BID regimen, no dosage adjustment is recommended. However, when EFV is coadministered with the GW433908 1400 mg + RTV 200 mg QD regimen, an increase to RTV 300 mg QD is needed to maintain plasma APV exposure.
Wire
Mary Beth
MB
GlaxoSmithKline, Five Moore Drive, 17.2231.2B, Research Triangle Park, NC 27709, USA.
Ballow
Charles
C
Preston
Sandra L
SL
Hendrix
Craig W
CW
Piliero
Peter J
PJ
Lou
Yu
Y
Stein
Daniel S
DS
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood; D019540:Area Under Curve; D048588:Benzoxazines; D002219:Carbamates; D002784:Cholesterol / Q000097:blood; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005663:Furans; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010755:Organophosphates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010078:Oxazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014280:Triglycerides / Q000097:blood
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D002219:Carbamates; D003521:Cyclopropanes; D005663:Furans; D010755:Organophosphates; D010078:Oxazines; D011355:Prodrugs; D013449:Sulfonamides; D014280:Triglycerides; C095108:amprenavir; D002784:Cholesterol; C098320:efavirenz; D019438:Ritonavir; C426859:fosamprenavir