Impact of Ritonavir on Protease Concentrations

• Ritonavir can ? PI exposure by one or more of the following mechanisms:

  • P-glycoprotein inhibition
    • ? absorption
  • CYP3A4 inhibition (GI, liver)
    • ? first-pass effect
    • ? drug clearance

• Different effects on PK profile, depending upon the protease inhibitor

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It appears that ritonavir can have differential effects on the kinetic profile of different protease inhibitors.

• a) Cmax boosting: Saquinavir, nelfinavir and lopinavir are highly susceptible to P-gp degradation in the intestinal tract and/or first pass metabolism; thus the primary effect of ritonavir coadministration will be to enhance bioavailability. This allows for use of lower protease dosages.

• b) Half-life boosting: On the other hand, with amprenavir and indinavir, the primary effect of ritonavir is to decrease drug clearance and prolong half-life. This may allow for decreased dosing frequency.

It should be noted that the overall effect on protease inhibitor disposition is often a combination of these two mechanisms.

Reference:

Hoetelmans RMV, Piscitelli SC, Hill AM. A Guide to Protease Inhibitor Boosting. Copyright F.Hoffmann-LaRoche, April 2001.