PHARMACOKINETICS OF 2-FLUORODIDEOXYCYTIDINE (2FDDC) IN PATIENTS INFECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS

1 The aim of this study was to estimate an oral dosage regimen of 2FddC giving peak plasma drug concentrations close to the antiretroviral IC50 of 150 ng ml-1. 2 A total of 55 doses (40 intravenous infusions and 15 oral solutions) were given to 21 patients. One group (n = 6-11) received single doses of 0.01 mg kg-1 intravenously (i.v.), 0.1 mg kg-1 i.v. and 0.1 mg kg-1 orally (p.o.) in that order. The other group (n = 8-10) received single doses of 0.03 mg kg-1 i.v., 0.3 mg kg-1 i.v. and 0.3 mg kg-1 p.o. in that order. Blood and urine samples were collected up to 24 h after each dose for drug assay by h.p.l.c.-u.v. 3 The peak plasma concentrations of 2FddC were proportional to dosage across the range 0.03 to 0.3 mg kg-1. After intravenous dosing, the mean (%CV) volume of distribution was 60 (28) 1 and the mean (CV%) plasma clearance was 23 (23) 1 h-1. On average, 71% of the dose was recovered unchanged in urine and renal clearance exceeded concurrent creatinine clearance. 4 Plasma concentrations reached mean peaks of 37 and 96 ng ml-1 after oral doses of 0.1 and 0.3 mg kg-1 respectively. The mean absolute bioavailability was 50% within a 95% confidence interval of 20 to 80%. 5 The adverse events were usually mild or moderate in severity and were generally attributed to the disease rather than the drug. 6 It is predicted that an oral dosage of 30 mg 8-hourly would result in little or no drug accumulation and that plasma drug concentrations would be close to 150 ng ml-1 at peak.