A pharmacokinetic interaction study of didanosine coadministered with trimethoprim and/or sulphamethoxazole in HIV seropositive asymptomatic male patients.
1. The pharmacokinetics of didanosine, trimethoprim, and sulphamethoxazole were evaluated in ten HIV seropositive asymptomatic patients as single agents and upon coadministration of single doses. 2. Using a randomized, balanced incomplete block crossover study with at least a 1-week washout period between successive treatments, each patient under fasting conditions received four of the following five treatments: 200 mg didanosine as a single agent; 200 mg trimethoprim + 1000 mg sulphamethoxazole; 200 mg trimethoprim + 200 mg didanosine; 1000 mg sulphamethoxazole + 200 mg of didanosine and; 200 mg trimethoprim + 1000 mg sulphamethoxazole + 200 mg didanosine. 3. Serial blood and urine samples were collected following the administration of each treatment. Plasma and urine samples were analyzed using high-pressure liquid chromatography (h.p.l.c.)/ultraviolet assays specific for unchanged didanosine, trimethoprim and/or sulphamethoxazole. 4. Percent urinary recovery (%UR) and renal clearance (CLR) emerged as consistently affected parameters, being decreased in the case of didanosine (35%, P = 0.016) and trimethoprim (32%, P = 0.019) and increased in the case of sulphamethoxazole (39%, P = 0.079), when all three agents were coadministered. The magnitude of the changes in didanosine CLR and %UR values was no greater when both trimethoprim and sulphamethoxazole were coadministered vs when each single agent was given with didanosine, suggesting that any effect was not additive. 5. Other key parameters such as Cmax, AUC, and t1/2 for didanosine (1309.9 ng ml-1, 1796.9 ng ml-1 h, and 1.61 h, respectively), trimethoprim (1.96 micrograms ml-1, 22.86 micrograms ml-1 h, and 9.03 h, respectively) or sulphamethoxazole (58.62 micrograms ml-1, 799.7 micrograms ml-1 h and 9.84 h, respectively) were not affected when didanosine was coadministered with either trimethoprim (didanosine: 1751.9 ng ml-1, 2158.0 ng ml-1 h, and 1.28 h; trimethoprim: 1.81 micrograms ml-1, 28.89 micrograms ml-1 h, and 11.4 h), sulphamethoxazole (didanosine: 1279.3 ng ml-1, 1793.2 ng ml-1 h, and 1.61 h; sulphamethoxazole: 53.57 micrograms ml-1, 732.1 micrograms ml-1 h, and 8.95 h), or the combination of trimethoprim and sulphamethoxazole (didanosine: 1283.7 ng ml-1, 1941.8 ng ml-1 h, and 1.38 h; trimethoprim: 1.59 micrograms ml-1, 26.68 micrograms ml-1 h, and 11.3 h; sulphamethoxazole: 59.48 micrograms ml-1, 760.9 micrograms ml-1 h, and 9.47 h). 6. Because the observed differences in CLR and %UR are small and not considered to be clinically relevant, it is not necessary to alter the dosing regimens of didanosine, trimethoprim or sulphamethoxazole when administered in combination to HIV seropositive patients.
Srinivas
N R
NR
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Knupp
C A
CA
Batteiger
B
B
Smith
R A
RA
Barbhaiya
R H
RH
D000328:Adult; D016049:Didanosine / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination; D006679:HIV Seropositivity / Q000378:metabolism*; D006801:Humans; D008297:Male; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000493:pharmacokinetics*
D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D016049:Didanosine