Mutual pharmacokinetic interactions between bosentan and lopinavir/ritonavir in healthy participants.
BACKGROUND
We aimed to investigate the extent of pharmacokinetic drug interactions between bosentan and a fixed combination of lopinavir/ritonavir.


METHODS
This was a three-way crossover study in 12 healthy male participants treated with bosentan (125 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily) alone or in combination for 9.5 days.


RESULTS
Combination treatment resulted in slightly lower area under the concentration-time curve during the 12 h dosing interval under steady-state conditions (AUC(tau,ss)) values of both lopinavir and ritonavir with geometric mean ratios (GMRs; 90% confidence intervals [CIs]) of 0.86 (0.74-0.99) for lopinavir and 0.83 (0.76-0.92) for ritonavir. The maximum concentration in steady state (C(max,ss)) of lopinavir and ritonavir remained unchanged with a GMR of 0.95 and 1.01, respectively, and the 90% CIs were within the range of 0.8-1.25. The observed effects of bosentan on lopinavir and ritonavir pharmacokinetics were considered to be not clinically relevant. The pharmacokinetics of bosentan were strongly affected by coadministration. Bosentan concentration increased up to 48-fold during the first 4 days of coadministration with lopinavir/ritonavir. At steady state, the GMR for AUC(tau,ss) was 5.22 (3.84-7.10) and for C(max,ss) was 6.12 (4.24-8.82). The increased exposure to bosentan was reflected in an increase in adverse events attributed to bosentan, that is, mainly headache, but not in liver enzyme abnormalities.


CONCLUSIONS
Bosentan does not affect lopinavir and ritonavir exposure to a clinically relevant extent, but tolerability of bosentan should be monitored in HIV patients under antiretroviral therapy with lopinavir/ritonavir. It is anticipated that all ritonavir-boosted protease inhibitors will have a similar effect on bosentan pharmacokinetics.
Dingemanse
Jasper
J
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. jasper.dingemanse@actelion.com
van Giersbergen
Paul L M
PL
Patat
Alain
A
Nilsson
Per N
PN
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000077300:Bosentan; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D061466:Lopinavir; D008297:Male; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D019380:Anti-HIV Agents; D000959:Antihypertensive Agents; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D013449:Sulfonamides; D061466:Lopinavir; D019438:Ritonavir; D000077300:Bosentan