Background:  A once-daily (qd) formulation of d4T (XR) (stavudine extended release capsules/prolonged release capsules) was developed to simplify HIV treatment. This study assessed the PK of a d4T XR formulation given qd compared to the currently available d4T (IR) capsule formulation dosed BID. Each was given in combination with lamivudine (3TC) BID and efavirenz (EFV) qd as part of a larger phase II, 48-week study. 

Methods:  This PK substudy included 16 antiretroviral-naïve, HIV‑infected individuals and was conducted during the first 14 days of the larger trial.  In the larger phase II study, the 2 treatment groups received either d4T XR 100 mg qd + d4T IR placebo BID + 3TC 150 mg BID + EFV 600 mg QD or d4T XR placebo qd + d4T IR 40 mg BID + 3TC 150 mg BID + EFV 600 mg qd.  EFV and 3TC were given open-label, while d4T IR and XR were blinded.  The PK substudy included determination of full plasma concentration-time profiles on day 1 (single-dose) and day 14 (steady-state). Serial blood samples were collected at selected times over a 24‑hour period on days 1 and 14.  Plasma concentrations were determined by a validated LC/MS/MS analytical method, and the resulting concentration-time data were subjected to a non-compartmental PK analysis.  PK parameters determined included Cmax, Tmax, AUC(∞), AUC(TAU), AUC(0‑24), T-Half; Accumulation Index (the ratio of AUC [TAU] on day 14 vs day 1), and Fluctuation Index ([Cmax-Cmin]/Average Css). 

Results:  For both XR and IR formulations, Cmax, Tmax, and AUC (TAU) were similar on days 1 and 14. Geometric mean Cmax (ng/mL) for d4T XR (day 1, 187.3; day 14, 237.5) however, was approximately 50% lower than d4T IR (day 1, 522.6; day 14, 520.2), but the geometric mean total daily exposure of d4T XR (AUC [0-24] ng·h/mL, day 1, 1834.7; day 14, 1746.9) was reasonably similar to the IR formulation (day 1, 2418.8; day 14, 2533.0).  Geometric mean Cmin was 5.5 times higher for d4T XR than for the IR formulation.  For either formulation, the mean accumulation index on day 14 was approximately 1 (XR, 1.08; IR, 1.03), suggesting that there was a lack of accumulation of d4T XR or IR following multiple dosing.  The d4T XR formulation reduced the mean fluctuation index by almost 2-fold (2.36) compared to the IR formulation (4.23).

Conclusions:  The d4T XR formulation given qd exhibited drug exposure that was reasonably similar to the IR formulation.  The PK profile of d4T XR supports qd dosing.