Background:  SPD754 is a potent NRTI with linear plasma pharmacokinetics following single (up to 1600 mg) and multiple doses (up to 800 mg twice daily).

Methods:  63 HIV⁺ patients were randomized to receive either placebo (n = 11), or 1 of 6 regimens of SPD754:  200 mg twice daily (n = 11), 400 mg twice daily (n = 6), 600 mg twice daily (n = 9), 800 mg twice daily (n = 12), 800 mg once daily (n = 6), 1200 mg once daily (n = 5) as monotherapy for 10 days. Peripheral blood mononuclear cells (PBMC) were collected prior to dosing and at 2, 4, 8, 12, and 24 hours after the morning dose on day 8. Samples were assayed for SPD754-TP concentrations by a validated LC/MS method. Concurrent blood samples were drawn to allow investigation of the relationship between plasma SPD754 concentrations (analysed by non-compartmental methods) and intracellular triphosphate concentrations. Adverse events were collected throughout the dosing period and at post treatment follow-up.

Results:  Maximum observed intracellular SPD754-triphosphate concentrations were typically achieved at approximately 4 hours after dosing. Mean (SD) Cmax increased with dose both for the bid and qd regimens and was 1.65 (0.67), 2.90 (1.60), 3.73 (2.32), 5.55 (1.94), 2.79 (1.34), 6.10 (2.49) pmol/10⁶ cells for the 200 mg twice daily, 400 twice daily, 600 mg twice daily, 800 mg twice daily, 800 mg once daily, and 1200 mg once daily regimens, respectively. Mean (SD) SPD754-tri-phosphate AUC0-tau also increased with dose and was 13.2 (5.2), 25.2 (14.7), 31.9 (21.0), 47.9 (17.7), 35.0 (21.1), and 68.7 (33.7) hour×pmol/10⁶ cells for the 200 mg twice daily, 400 mg twice daily, 600 mg twice daily, 800 mg twice daily, 800 mg once daily, and 1200 mg once daily regimens, respectively. The intracellular half-life of SPD754-triphosphate was approximately 6 to 7 hours. Preliminary analyses in a subset of patients (n = 14) indicate that, with the current formulation, intracellular SPD754-triphosphate concentrations are related to plasma concentrations of SPD754, the correlation coefficients for AUC0-tau and Cmax being 0.84 and 0.72, respectively. All doses of SPD754 were well tolerated and there was no apparent difference between the twice daily and once daily regimens in the incidence or profile of adverse events observed.

Conclusions:  The was some evidence of intracellular accumulation of SPD754-triphosphate with twice daily dosing which was well tolerated and associated with sustained intracellular concentrations of SPD754-triphosphate. These results indicate that twice daily dosing is suitable for further clinical trials. Although the once daily regimens were also well tolerated, the forgiveness of once daily dosing requires further investigation.

Keywords: SPD754; Triphosphate; Pharmacokinetics