Effect of Food on the Bioavailability of Stavudine in Subjects with Human Immunodeficiency Virus Infection

Abstract

A randomized, three-way crossover study was carried out to determine the effects of food ingestion on the pharmacokinetics of stavudine (d4T). Fifteen subjects with human immunodeficiency virus (HIV) infection and CD4+ cell counts of ≥200/μl received 70 mg of d4T in a fasting state or 1 h before or 5 min after a standardized high-fat breakfast. A 7- to 15-day washout period was included between treatments. Blood and urine were collected before and for 10 h after dosing, and plasma and urine d4T concentrations were determined with a validated radioimmunoassay. Plasma drug concentration-time data were analyzed with a noncompartmental model. The mean maximum plasma drug concentration (C max) and the time toC max (T max) for administration of d4T after a meal were significantly lower and longer (P = 0.0001 for both measures) than those observed in the fasting state, although the area under the concentration-time curve from time zero to infinity (AUC0–∞) was not significantly different. Neither of these parameters was significantly altered when d4T was taken 1 h before a meal. The bioavailability of d4T taken after a meal was 95% of that observed in the fasting state, and it was 97% when d4T was administered before a meal (P > 0.05 for both comparisons with the fasting state). The results of this study indicate that (i) ingestion of food does not affect the bioavailability of d4T and that patients with HIV infection can take it without regard to meals, and (ii) absorption is essentially complete within 1 h when d4T is administered in the fasted state.

Effect of reducing the paediatric stavudine dose by half: A physiologically-based pharmacokinetic model

“…The resulting exposure parameter, the area under the concentration–time curve (AUC), was compared with the literature values from in vivo studies [8,18–21]. The model qualification was measured by the slope (β) of the regression line: …”

“…The 500 simulations of 30, 40 and 70 mg b.i.d. in a virtual adult population were compared with literature that reported stavudine exposure with these three doses [8,18–21]. The paediatric simulations consisted of 0.61 mg/kg b.i.d.…”

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Stavudine

“…The pharmacokinetics of d4T is well described by a linear two‐compartment open model with first‐order absorption and elimination 28. Plasma concentrations in patients with asymptomatic HIV infections reach a mean peak drug plasma concentration ( C max ) of approximately 1.4 µg/mL within 1 h after oral administration of d4T (70 mg) as a single dose 29. The mean BA of oral d4T in HIV‐infected patients is over the range 86%–100% and is not affected by administration of food 11,28–34.…”

“…Plasma concentrations in patients with asymptomatic HIV infections reach a mean peak drug plasma concentration ( C max ) of approximately 1.4 µg/mL within 1 h after oral administration of d4T (70 mg) as a single dose 29. The mean BA of oral d4T in HIV‐infected patients is over the range 86%–100% and is not affected by administration of food 11,28–34. Also, the systemic exposure is the same regardless of capsule or solution administration 11.…”

Effects of Food on Drug Absorption

“…For patients' compliance, drug administration without restriction on food intake is ideal, especially in chronic use. Gemifloxacin for bacterial infections and stavudine therapy for human immunodeficiency virus (HIV)-infected patients are good examples of drugs administered without food restriction (Kaul et al ., 1998;Allen et al ., 2000). However, there are exceptions; rufinamide exhibits higher fluctuations in the fed state when compared with the fasted state, and, yet, it is recommended to be administered, with supervision, in the fed state owing to the attainment of higher plasma concentrations (Cardot et al ., 1998).…”