Evaluation of steady-state pharmacokinetic interactions between ritonavir-boosted BILR 355, a non-nucleoside reverse transcriptase inhibitor, and lamivudine/zidovudine in healthy subjects.
OBJECTIVE
BILR 355 is a second generation non-nucleoside reverse transcriptase inhibitor. It has shown promising in vitro anti-HIV-1 activities and favourable human pharmacokinetic properties after co-administration with ritonavir (RTV). Lamivudine (3TC) is a nucleoside reverse transcriptase inhibitor. It is excreted predominantly in urine by a transporter-mediated pathway. These two drugs are likely to be given together to HIV-infected patients. The objective of this study was to investigate any steady-state pharmacokinetic interactions between RTV-boosted BILR 355 and 3TC/zidovudine (ZDV).


METHODS
This was a randomized, open label, prospective study. In group A, 39 healthy subjects were given 3TC/ZDV (150 mg/300 mg) twice daily (b.i.d.) for 7 days, and then BILR 355 and RTV (BILR 355/r, 150 mg/100 mg) were co-administered with this regimen for an additional 7 days. Intensive blood samples were taken on days 7 and 14 for pharmacokinetic assessments. In group B, 12 healthy subjects were given BILR 355/r (150 mg/100 mg) b.i.d. for 7 days. The pharmacokinetic data from group B were pooled with data from group B subjects in other similar studies performed in parallel (BILR 355 alone group in BILR 355 drug-drug interaction studies with tipranavir, lopinavir/RTV, and emtricitabine/tenofovir DF; BILR 355 regimen was the same).


CONCLUSIONS
After co-administration with BILR 355/r, the AUC(12,ss) and C(max,ss) of 3TC increased by 45% and 24%, respectively; the elimination half-life (t(1/2) ,ss) of 3TC was significantly increased. However, the pharmacokinetics of ZDV was unchanged. Co-administration with 3TC/ZDV resulted in a 22% decrease in AUC(12,ss) and a 20% decrease in C(max,ss) for BILR 355. The observed increase in exposure and prolongation of t(1/2,ss) of 3TC is potentially related to inhibition of OCT-mediated urinary excretion of 3TC.


CONCLUSIONS
Concomitant administration of BILR 355 with 3TC/ZDV resulted in a modest decrease in exposure to BILR 355 and a 45% increase in exposure to 3TC.
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877-0368, USA. fenglei.huang@boehringer-ingelheim.com
F
F
Huang
L
L
Allen
D B
DB
Huang
F
F
Moy
R
R
Vinisko
T
T
Nguyen
L
L
Rowland
T R
TR
MacGregor
M A
MA
Castles
P
P
Robinson
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult; D015215:Zidovudine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
C548654:5,11-dihydro-11-ethyl-5-methyl-8-(2-(1-oxido-4-quinolinyl)ethyl)-6H-dipyrido(3,2-B,2',3'-E)(1,4)diazepin-6-one; D019380:Anti-HIV Agents; D001381:Azepines; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; C109078:lamivudine, zidovudine drug combination; D019259:Lamivudine; D015215:Zidovudine; D019438:Ritonavir