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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir.

OBJECTIVE: To assess the pharmacokinetic interaction between ritonavir and saquinavir. METHODS: Ritonavir and saquinavir were administered in single doses to six groups of healthy volunteers in a two-way (saquinavir alone and ritonavir plus saquinavir for groups I through V) and a three-way (ritonavir alone, saquinavir alone, and ritonavir plus saquinavir for group VI) crossover manner with the following doses: group I, 200 mg saquinavir and 300 mg ritonavir; group II, 200 mg saquinavir and 600 mg ritonavir; group III, 400 mg saquinavir and 300 mg ritonavir; group IV, 400 mg saquinavir and 600 mg ritonavir; group V; 600 mg saquinavir and 200 mg ritonavir; group VI, 600 mg saquinavir and 600 mg ritonavir. RESULTS: Coadministration of ritonavir markedly increased the area under the plasma concentration-time curve (AUC) and peak concentration of saquinavir (> 50-fold and 22-fold, respectively). For a constant ritonavir dose, the pharmacokinetics of saquinavir were relatively proportional to dose. For a constant saquinavir dose, the increase in saquinavir concentration tended to be less than proportional to ritonavir dose. Ritonavir reduced intersubject variability in the saquinavir AUC from 60% to 28%. The in vivo inhibition constant was 0.025 +/- 0.020 micrograms/ml with noncompartmental estimation and 0.0164 +/- 0.0004 micrograms/ml with nonlinear mixed-effects model compartmental analysis. Saquinavir showed no clinically significant effect on the pharmacokinetics of ritonavir (+6.4% in AUC). The regimens were well tolerated. CONCLUSIONS: The large effect of ritonavir on the pharmacokinetics of saquinavir is consistent with a large reduction of saquinavir first-pass metabolism and postabsorptive clearance. Given the limited bioavailability of saquinavir given in the hard gelatin capsule formulation, this drug interaction is expected to have implications in the use of protease inhibitors in the management of human immunodeficiency virus infection.[1]

References

  1. Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir. Hsu, A., Granneman, G.R., Cao, G., Carothers, L., el-Shourbagy, T., Baroldi, P., Erdman, K., Brown, F., Sun, E., Leonard, J.M. Clin. Pharmacol. Ther. (1998) [Pubmed]
 
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