728   Pharmacokinetics of Saquinavir (SQV) with Nelfinavir (NFV) or Ritonavir (RTV) in HIV- Infected Children.

R. C. Brundage¹, M. W. Kline², J. Lindsey³, T. Fenton³, and C. V. Fletcher¹for the PACTG 397 Team.
¹Univ. of Minnesota, Minneapolis;²Baylor Coll. of Med., Houston TX; and³Harvard Sch. of Publ. Health, Boston, MA.

Background:Dual protease inhibitor therapy is increasingly accepted either for direct therapeutic effect or as a pharmacokinetic (PK) booster to increase exposure and simplify regimens. PACTG 397 is a clinical trial of SQV- containing regimens in HIV-infected children. The study initially used, in combination with 1 or 2 NRTIs (Cohort 1), SQV 50 mg/kg (max 1200 mg) TID (Arm 1) or SQV 50 mg/kg (max 1200 mg) BID plus NFV 55 mg/kg BID (Arm 2). Due to concerns about low SQV concentrations, the protocol was amended (Cohort 1a) to evaluate 2 strategies to increase SQV exposure. Only subjects in Cohort 1 were allowed to roll over into 1a. Arm 1 was dosed at SQV 50 mg/kg (max 1200 mg) plus RTV 100 mg/m²

and Arm 2 was dosed at SQV 50 mg/kg (max 1600 mg) plus NFV 55 mg/kg; all doses were administered BID. The objective of this PK study was to characterize SQV, NFV and RTV exposures during SQV/RTV and SQV/ NFV therapy.

Methods:12-hr AUCs were obtained for SQV, NFV and RTV at week 4. PK data were available from 11 and 8 subjects in Arms 1 and 2, respectively. 4 of these subjects also provided AUCs in Cohort 1 Arm 2.

Results:The median (range) SQV AUC in the Cohort 1 SQV/NFV arm was 3.1 (0.63—37.4) mg × hr/L and was used as the base for comparison of 1a AUCs. Upon increasing the maximum SQV dose to 1600 mg, the Cohort 1a SQV/NFV arm produced a SQV AUC of 9.5 (2.6—22.1) mg × hr/L. Although nominally greater, this difference was not significant (P > 0.2). In the SQV/RTV arm, the SQV AUC was significantly increased to 19.6 (4.9—46.2) mg × hr/L (P = 0.01). These SQV AUCs can be referenced to historical controls of 3.5 (0.89—10.7) mg × hr/L following SQV 800 mg TID without the addition of NFV or RTV. NFV AUCs were 30.7 (13.3—75.1) and 41.9 (11.1—99.8) mg × hr/L in Cohorts 1 and 1a, respectively; this difference was not significant (P > 0.1). The RTV AUC was 12.1 (3.9—29.2) mg × hr/L.

Conclusions:.Increasing the maximum SQV dose from 1,200 to 1,600 mg BID co-administered with NFV did increase the median AUC, but the difference was not significant. However, SQV AUCs were significantly greater when dosed with RTV. Low-dose RTV is a more effective PK booster than therapeutic doses of NFV in pediatric patients.