Penetration of stavudine into the cerebrospinal fluid (CSF) was studied in healthy humans. In this open, randomized study, a single oral dose of 40 mg of stavudine was given to 12 fasting volunteers > or = 18 years of age. Subjects were divided into three groups based on the time of CSF sampling (i.e., 0.75-1.25, 2-3, or 4-5 hours after dosing). Blood samples were collected over an 8-hour period after dosing and included a sample simultaneous with CSF collection to permit an estimate of CSF : plasma ratios. Stavudine concentrations in plasma and CSF were determined by a validated high-performance liquid chromatography method. Repeated measurements of vital signs, physical examination, and clinical laboratory tests indicated that the stavudine dose was well tolerated. CSF levels were not detected 0.75 to 1.25 hours after dosing. Thereafter, levels were detected in the CSF of five subjects; the mean concentration was 61 ng/ml. The mean CSF: plasma ratio increased with time, from 0.16 at 2 to 3 hours postdose in one subject to 0.40 at 4 to 5 hours postdose in four subjects. In conclusion, the mean stavudine concentration of 61 ng/ml achieved in the CSF of five subjects exceeds the ED50 of clinical isolates of HIV (230 nM, 52 ng/ml).

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.

Modest increases in Cmax and AUC0-infinity are not anticipated to have a negative effect on the outcome of therapy in hepatically impaired subjects, nor are they anticipated to result in adverse drug reactions. Patients with moderate to severe (Child-Pugh grade B or C) hepatic dysfunction do not require gatifloxacin dose adjustments. In addition, the similarity in half-life (t1/2) for the groups (8.9 hrs for hepatically impaired subjects, 9.3 hrs for controls) suggests that no difference would be anticipated in the extent of drug accumulation after multiple doses. The overall safety and tolerability of a single oral dose of gatifloxacin 400 mg were excellent in both healthy subjects and those with hepatic impairment.

This open-label study enrolled five subjects with biopsy-proven cirrhosis and moderate to severe hepatic impairment (Child-Pugh classification grade B or C) and five age- and gender-matched controls. All subjects received a single 40-mg oral dose of stavudine (d4T). Stavudine pharmacokinetics in subjects with hepatic impairment were similar to those in age- and gender-matched control subjects and were not substantially different from those previously observed in human immunodeficiency virus-infected patients. Based on these findings, stavudine use does not require modification of the dose or dosing interval for patients with liver disease.