Pharmacokinetics of single-dose oral stavudine in subjects with renal impairment and in subjects requiring hemodialysis

Two open-label studies assessed the pharmacokinetics of single orally administered doses of 30 mg of stavudine in subjects with renal impairment. In one study (study I), 15 subjects with selected degrees of renal impairment, but not requiring hemodialysis, were stratified into three groups of five subjects each according to creatinine clearance (CLCR) normalized by body surface area (ml/min/1.73 m(2)): mild (CLCR, 60 to 80), moderate (30 to 50), and severe (less than or equal to 20) renal impairment. Five healthy subjects (CLCR greater than or equal to 90) were also enrolled. The stavudine area under the curve from 0 h to infinity (AUC(0-infinity)) increased nonlinearly with declining renal function: 1,863, 2,215, 3,609, and 5,928 ng . h/ml for normal renal function and for mild, moderate, and severe renal impairment, respectively (P = 0.0001 between renal impairment groups). The following stavudine dosage recommendations for renal impairment were proposed for subjects weighing greater than or equal to 60 kg: CLCR of >50 ml/min/1.73 m(2), 40 mg every 12 h; CLCR of 21 to 50 ml/min/1.73 m(2), 20 mg every 12 h; and CLCR of 10 to 20 mi/min/1.73 m(2), 20 mg every 24 h. For subjects weighing <60 kg, the proposed doses were 30, 15, and 15 mg, respectively, with the same dosing intervals specified above. In a second study (study II), 12 subjects with end-stage renal disease requiring hemodialysis three times a week were enrolled in a randomized, open-label crossover study (dialysis 2 h after dosing and lasting 4 h or dosing without dialysis). There were no statistically significant differences for AUG(0-infinity), AUG(2-6), time to maximum concentration of drug in serum, half-life, or apparent oral clearance when the two treatment dosage regimens were compared. As a result of study II, the recommended dosing rate for subjects requiring hemodialysis was the same as that proposed for those with severe renal impairment not requiring hemodialysis; however, dosing was recommended to follow hemodialysis and to occur at the same time each day.