Plasma and cerebrospinal fluid pharmacokinetics of 3′-azido-3′-deoxythymidine: A Novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases

We investigated the clinical pharmacokinetics of azidothymidine (N3TdR) as part of a phase I/II trial in the treatment of acquired immunodeficiency syndrome and related diseases. During the 6-week course of therapy, drug levels in plasma, cerebrospinal fluid, and urine were determined by HLPC. The plasma half-life of N3TdR was 1.1 hour. The total body clearance was 1.3 L/kg/hr. At intravenous doses of 5 mg/kg or oral doses of 10 mg/kg, plasma levels were continuously maintained above the target level of 1 mumol/L. Oral bioavailability was 63% +/- 13%. Substantial penetration of N3TdR into cerebrospinal fluid was demonstrated. At doses of 5 mg/kg intravenously or 10 mg/kg orally, cerebrospinal fluid drug levels exceeded and were maintained close to 1 mumol/L. Nineteen percent of the administered dose was excreted unchanged into the urine. Renal clearance was 0.23 L/kg/hr. N3TdR possesses pharmacokinetic properties that would facilitate the long-term treatment of patients with acquired immunodeficiency syndrome: it can be given orally and it penetrates the central nervous system.