Dual Protease Combinations

• Combining 2 protease inhibitors at therapeutic doses

  • Saquinavir 400 mg + ritonavir 400 mg BID: 50-fold ? saquinavir
  • Saquinavir 1200 mg + nelfinavir 1250 mg BID: 392% ? saquinavir
  • Indinavir 400 mg + ritonavir 400 mg BID: 3-fold ? Cmin, 62% ? Cmax indinavir
  • other examples

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• Dual protease combinations are often a desirable therapeutic option. Besides additive or synergistic antiviral activity, the pharmacokinetic profile of one or both agents may be enhanced.

A) Increased drug concentrations
• For instance, the hard-gel capsule formulation of saquinavir has a low oral bioavailability of approximately 4%. Since a dose-related antiviral effect has been observed with saquinavir, saquinavir may be combined with other protease inhibitors such as ritonavir or nelfinavir, in order to enhance saquinavir exposure.

B) Improved pharmacokinetic profile
• The pharmacokinetics of indinavir may vary by up to 2-fold between individuals. When indinavir is combined with ritonavir, the interpatient variability of indinavir is minimized, and more consistent drug concentrations may be expected.

C) Simplified dosing regimen
• In addition, when protease inhibitors are co-administered, the resulting interaction may allow for few dosing times (e.g., BID vs. TID), or less pills to take.