Pharmacokinetics and pharmacodynamics of saquinavir in pediatric patients with human immunodeficiency virus infection.

Objective: Our objective was to investigate the clinical pharmacologic characteristics of saquinavir given as a soft gelatin capsule, either alone or in combination with nelfinavir, to children and adolescents with human immunodeficiency virus infection.

Methods: The pharmacokinetics of 50 mg/kg saquinavir 3 times a day (tid) alone versus 33 mg/kg saquinavir tid plus 30 mg/kg nelfinavir tid was assessed after single-dose administration and after short- and long-term administration. The single-dose pharmacokinetics of fixed (1200 mg) versus unrestricted weight-adjusted dosing (50 mg/kg) was also investigated.

Results: Saquinavir as the sole protease inhibitor resulted in lower saquinavir exposure in children (steady-state geometric mean area under the concentration-time curve from time zero to 24 hours [AUC (0-24 h)], 5790 ng x h/ml; steady-state concentration 8 hours after drug administration [C(8h,SS)], 65 ng/ml) and adolescents [steady-state geometric mean AUC(0-24 h), 5914 ng x h/ml] than that reported in adults treated with 1200 mg tid [steady-state geometric mean AUC(0-24 h), 21,700 ng x h/ml; C(8h,SS), 223 ng/ml]. This finding appeared to be attributable to markedly higher apparent oral clearance, potentially as a result of increased systemic clearance and reduced oral bioavailability. Nelfinavir combined with saquinavir reduced apparent oral clearance, increasing saquinavir exposure in children [steady-state geometric mean AUC(0-24 h), 11,070 ng x h/ml; C(8h,SS), 380 ng/ml] to levels that approach those observed in adults. A significant correlation between average trough concentration and sustained viral load suppression was observed in children. The apparent threshold for maintaining viral load suppression was a mean trough saquinavir concentration above 200 ng/ml.

Conclusions: The pharmacokinetics of saquinavir in children is different from that of adults, and administration of saquinavir alone will not give consistently efficacious plasma levels. The best way of improving saquinavir exposure in children is through combination therapy with other protease inhibitors that inhibit saquinavir metabolism.