Background: At clinically relevant concentration, the HIV-protease inhibitor lopinavir/ritonavir (LPV/r) inhibits CYP3A in vitro and in vivo, but is predicted to be a very weak inhibitor of CYP2D6 from LPV/r in vitro and previous ritonavir in vivo data. The purpose was to confirm that LPV/r 400/100-mg BID would minimally affect the pharmacokinetics (PK) of the CYP2D6 probe, desipramine (DMI).

Methods: This was an open-label sequential study in 16 healthy males and females; 15 completed the study. Subjects were given a single 100-mg dose of DMI on days 1 and 16. LPV/r 400/100-mg BID was given on days 6-20. Plasma samples were collected for 120-h after each DMI dose; LPV/r samples were obtained over 12-h on day 16. DMI, 2-OH DMI and LPV/r were measured by LC/MS/MS; noncompartmental methods were used for PK. Effect of LPV/r on DMI was assessed by paired t-test; 90% confidence intervals (CI) for the bioavailability of the combination regimen relative to DMI alone were obtained for DMI log-transformed Cmax and AUC.

Results:

Mean (± SD) Point Estimates and 90% CI of Cmax and AUC_¥ for DMI + LPV/r (day 16) vs DMI Alone (day 1)

 

* Ratio of geometric means.

The 90% CI for DMI Cmax and AUC were within 0.80 to 1.25, suggesting no significant effect of LPV/r on DMI bioavailability. DMI half-life was similar on days 16 and 1 (22.9 vs 21.2-h) and Tmax occurred slightly later on day 16 (8.5 vs 6.9-h, p=0.034). The 2-OH DMI metabolite Cmax decreased by 34% (19.6 ± 8.7 vs 29. 8 ± 12.5 ng/mL, p<0.001) and AUC_¥ decreased by 25% (606 ± 197 vs 808 ± 245-ng•h/mL, p<0.001). Since there was no effect on DMI PK, the slight reduction in 2-OH DMI AUC is likely due to induction of glucuronidation by LPV/r, rather than inhibition of CYP2D6-mediated formation from DMI. Concentration of LPV/r were within the expected range.

Conclusions: Consistent with predictions, LPV/r does not inhibit CYP2D6-mediated metabolism at clinically relevant concentrations.