Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome—related complex

Abstract

The pharmacokinetics of didanosine (2',3'-dideoxyinosine) after intravenous and oral administration were evaluated in an open, escalating-dose phase I study in patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex. Didanosine was administered twice a day for 2 weeks as an intravenous infusion of 60 minutes duration at doses ranging from 0.4 to 16.5 mg/kg, followed by 4 weeks of oral treatment at twice the intravenous dose. Serial blood and urine samples were obtained on the first and final day of intravenous administration and after the first oral dose, as well as at steady state. Didanosine demonstrated linear pharmacokinetic behavior over the dose ranges of 0.4 to 16.5 mg/kg intravenously and 0.8 to 10.2 mg/kg orally. There was no indication of significant changes in pharmacokinetic parameters with repeated administration. The apparent elimination half-life after oral administration was approximately 1.4 hour. Renal clearance values exceeded the glomerular filtration rate, indicating that active tubular secretion of didanosine occurs. Bioavailability of didanosine when administered as a solution with an antacid was approximately 43% for doses from 0.8 to 10.2 mg/kg in patients with AIDS and advanced AIDS-related complex. Bioavailability of didanosine from the citrate-phosphate-buffered solution, the formulation currently used in phase II and expanded access studies, was comparable to the formulation used in the phase I trials.

Effect of fluconazole on pharmacokinetics of 2',3'-dideoxyinosine in persons seropositive for human immunodeficiency virus

“…Of the quantity that reaches systemic circulation, 30 to 50% appears in urine as an unchanged drug; the remainder is excreted as various metabolites, which appear to be products of xanthine oxidase or other purine metabolic pathways (11,14). In dogs that receive ddI under conditions that mimic those in humans, the bioavailability and t 1/2 of ddI are similar to (10a).…”

“…The commercial formulations of ddI (tablets and buffered powder) differ in bioavailability (3a, 14, 20), and all dosage forms include buffers to increase stability in gastric fluids. Systemic availability appears to be further compromised by a rate-limited absorption step (8,12,14), leading to recommendations that ddI be taken BID instead of once a day (3a, 8). With the ddI formulations used in this trial (taken BID under fasting conditions), mean systemic bioavailability has been reported to range from 33 to 41% (8,14,15,18,22).…”

“…Systemic availability appears to be further compromised by a rate-limited absorption step (8,12,14), leading to recommendations that ddI be taken BID instead of once a day (3a, 8). With the ddI formulations used in this trial (taken BID under fasting conditions), mean systemic bioavailability has been reported to range from 33 to 41% (8,14,15,18,22). Since the AUC of ddI has been shown to correlate with both suppression of p24 antigen and the frequency of adverse effects (7,8,22), a prospective study to evaluate whether monitoring concentrations in serum improves response or reduces toxicity may be beneficial.…”

“…Prior to analysis, all serum samples were incubated at 58 to 60ЊC for 30 min in order to inactivate HIV. Incubation at 56ЊC for up to 3 h does not alter ddI concentrations (14). Concentrations of ddI were determined by validated radioimmunoassay with commercially available reagents (Sigma Chemical Co., St. Louis, Mo.).…”

Lack of pharmacokinetic interaction between intravenous 2',3'-dideoxyinosine and 3'-azido-3'-deoxythymidine in rats

“…Between 8 and 10 a.m. the rats received a dose of ddI and/or AZT by intravenous injection. In patients, the concentrations in plasma are less than 10 to 20 ,ug/ml for AZT (9) and ddl (10). In this study, we used a dose of 40 mg/kg to give maximal concentrations in plasma of approximately 100 ,ug/ml for both drugs, because pharmacokinetic interactions such as inhibition of drug metabolism are expected to be more pronounced in the presence of higher concentrations in plasma.…”