Background: A once daily (qd) formulation of d4T (XR) (stavudine extended release capsules/prolonged release capsules) was developed to simplify HIV treatment.  This study was designed to assess single- and multiple-dose PK and the safety and tolerability of d4T XR following oral administration of a 100-mg dose in asymptomatic HIV-infected subjects.

Methods:  This was a single-center, open‑label, multiple-dose study. Subjects received a single daily oral dose of 100-mg d4T XR on days 1 through 9 in the morning following an overnight fast of 8 hours.  Subjects currently taking immediate-release d4T (IR) and AZT were restricted from taking these NRTIs from day 1 until discharge. Serial blood samples were collected at selected times over a 24‑hour period on days 1, 7, and 9; and samples were collected at 30, 36, 42, and 48 hours post-dose following the day 9 dose. Additionally, samples for trough levels were collected on days 4, 5, and 6. 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. Estimates of the intrasubject variability of Cmax and AUC were obtained from an ANOVA with subject and day (day 7 and 9) as factors in the model.  Cmax and AUC were log transformed.  Clinical safety evaluations, including clinical laboratory tests, were performed during screening and prior to discharge from the study.

Results: A total of 16 subjects were enrolled, but 1 subject discontinued after day 7 for personal reasons.  The plasma d4T XR concentration-versus-time profiles were comparable following single and multiple dosing.  The inter- and intrasubject variability was: Cmax, 26.5% and 9.7%; AUC, 31.2% and 8.3%.  Accumulation index was ~1, indicating a lack of accumulation after multiple dosing and that steady state was achieved by the second dose. The fluctuation index was 2.5 ± 0.8.  There were no deaths or serious adverse events (AEs). The most frequently reported treatment-emergent AE was headache (3 subjects). No AEs led to therapy discontinuation.

Conclusions:  The d4T XR formulation sustained plasma concentrations in the therapeutic range over a 24-h dosing interval, with low inter- and intra-subject variability, and was well tolerated in these HIV-infected patients. The PK profile of d4T XR supports qd dosing.