Background: Lopinavir/Ritonavir (LPV/r) inhibits CYP3A4 and Phenytoin (PHT) is a substrate for CYP2C9 and CYP2C19; both drugs are CYP450-inducers. The purpose of this study was to assess the multiple-dose pharmacokinetic (PK) interaction between LPV/r and PHT.

Methods: An open-label, randomized, 2-period crossover, steady-state PK study in healthy volunteers was performed. Arm A (n = 12) received: Day (D) 1–10: LPV/r 400/100mg BID; D 11–22: LPV/r 400/100mg BID + PHT 300mg QD and Arm B (n = 12) received: D1–11: PHT 300mg QD; D 12–23: PHT 300mg QD + LPV/r 400/100mg BID. In Arm A, 7 LPV/r plasma samples were collected over 12h on D 11 and D 22. In Arm B, 6 PHT plasma samples were collected over 24 hrs beginning on D 11 and D 22. Genotyping was performed for CYP2C9 and CYP2C19. Samples were analyzed by LC/MS/MS and PK parameters calculated by non-compartmental methods.

Results: Twnety-four (24) subjects enrolled (92% male, mean age 25 yrs, weight 87 kg). Four (4) did not complete Arm B. No prolonged adverse events ³ Grade II occurred. CYP2C9 genotypes in Arm B were *1*1 (n = 3), *1*2 (n = 3), *1*3 (n = 2); CYP2C19 genotypes were *1*1 (n = 6), *1*2 (n = 2). PK parameters (mean ± SD) are summarized below (C_0h in mg/mL, AUC in mg×hr/mL). C_max, C_12h, and C_24h followed similar trends. Although subjects with CYP2C9*1*2 or *1*3 had higher PHT AUC_0-24h and C_0h than CYP2C9*1*1 subjects, genotype did not appear to predict magnitude of interaction.

 

	D11	D22	Ratio of Geometric Means (D22 : D11) [90% CI]	p-value (paired t-test)
LPV AUC0-12h	70.89 ± 36.96	49.61 ± 25.09	0.67 [0.53 – 0.85]	0.011
LPV C0h	5.97 ± 3.17	3.55 ± 2.31	0.54 [0.42 – 0.70]	0.001
RTV AUC0-12h	3.08 ± 2.79	1.99 ± 1.09	0.72 [0.54 – 0.97]	0.074
RTV C0h	0.28 ± 0.33	0.14 ± 0.15	0.53 [0.36 – 0.78]	0.013
PHT AUC0-24h	191.00 ± 89.21	147.75 ± 104.54	0.69 [0.57 – 0.84]	0.009
PHT C0h	7.04 ± 4.02	5.31 ± 4.05	0.66 [0.49 – 0.89]	0.033

 

Conclusion: Co-administration of LPV/r and PHT results in a 2-way drug interaction whereby both LPV/r and PHT concentrations are decreased. PHT appears to increase LPV clearance, which is not offset by ritonavir present in the formulation. LPV/r appears to induce metabolism of PHT. This 2-way drug interaction is likely to be clinically significant, particularly for those with reduced viral susceptibility to LPV. Dosage or medication regimen adjustments may be necessary for optimal management.