Coadministration of Lopinavir/Ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction

Lopinavir/ritonavir (LPV/RTV) is a CYP3A4 inhibitor and substrate; it also may induce cytocbrome P-450 (CYP) isozymes. Phenytoin (PHT) is a CYP3A4 inducer and CYP2C9/CYP2C 19 substrate. This study quantified the pharmacokinctic (PK) drug interaction between LPV/RTV and PHT. Open-label, randomized, multiple-dose, PK study in healthy volunteers. Subjects in arm A (n = 12) received LPV/RTV 400/100 mg twice daily (BID) (days 1-10), followed by LPV/RTV 400/100 mg BID + PHT 300 mg once daily (QD) (days 11-22). Arm B (n = 12) received PHT 300 mg QD (days 1-11), followed by PHT 300 mg QD + LPV/RTV 400/100 mg BID (days 12-23). Plasma samples were collected on day I I and day 22; PK parameters were compared by geometric mean ratio (GMR, day 22:day 11). P values <0.05 were considered significant. Following PHT addition, LPV area under the concentration-time curve (AUC(0-12h)) decreased from 70.9 +/- 37.0 to 49.6 +/- 25.1 mug-h/mL (GMR 0.67, P= 0.011) and C-0h, decreased from 6.0 +/- 3.2 to 3.6 +/- 2.3 mu/mL (GMR 0.54, P = 0.001). Following LPV/RTV addition, PHT AUC(0-24h), decreased from 191.0 +/- 89.2 to 147.8 +/- 104.5 mug(.)h/mL (GMR 0.69, P = 0.009) and C-0h, decreased from 7.0 +/- 4.0 to 5.3 +/- 4.1 mug/mL (GMR 0.66, P = 0.033). Concomitant LPV/RTV and PHT use results in a 2-way drug interaction. Phenytoin appears to increase LPV clearance via CYP3A4 induction, which is not offset by the presence of low-dose RTV. LPV/RTV may increase PHT clearance via CYP2C9 induction. Management should be individualized to each patient; dosage or medication adjustments may be necessary.