A PHARMACOKINETIC INTERACTION STUDY OF DIDANOSINE COADMINISTERED WITHTRIMETHOPRIM AND OR SULFAMETHOXAZOLE IN HIV-SEROPOSITIVE ASYMPTOMATICMALE-PATIENTS/

1 The pharmacokinetics of didanosine, trimethoprim, and sulphamethoxaz ole were evaluated in ten HIV seropositive asymptomatic patients as si ngle agents and upon coadministration of single doses. 2 Using a rando mized, balanced incomplete block crossover study with at least a 1-wee k washout period between successive treatments, each patient under fas ting conditions received four of the following five treatments: 200 mg didanosine as agent; 200 mg trimethoprim+1000 mg sulphamethoxazole; t rimethoprim+200 mg didanosine; 1000 mg sulphamethoxazole+200 mg of did anosine and; 200 mg trimethoprim+1000 mg sulphamethoxazole+200 mg dida nosine. 3 Serial blood and urine samples were collected following the administration of each treatment. Plasma and urine samples were analyz ed using high-pressure liquid chromatography (h.p.l.c.)/ultraviolet as says specific for unchanged didanosine, trimethoprim and/or sulphameth oxazole. 4 Percent urinary recovery (%UR) and renal clearance (CL(R)) emerged as consistently affected parameters, being decreased in the ca se of didanosine (35%, P=0.016) and trimethoprim (32%, P=0.019) and in creased in the case of sulphamethoxazole (39%, P=0.079), when all thre e agents were coadministered. The magnitude of the changes in didanosi ne CL(R) and %UR values was no greater when both trimethoprim and sulp hamethoxazole were coadministered vs when each single agent was given with didanosine, suggesting that any effect was not additive. 5 Other key parameters such as C-max, AUC, and t(1/2) for didanosine (1309.9 n g ml(-1), 1796.9 ng ml(-1) h, and 1.61 h, respectively), trimethoprim (1.96 mu g ml(-1), 22.86 mu g ml(-1) h, and 9.03 h, respectively) or s ulphamethoxazole (58.62 mu g ml(-1), 799.7 mu g ml(-1) h and 9.84 h, r espectively) 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 mu g ml(-1), 28.89 mu g ml(-1) h, and 11.4 h), sulphamethoxazole (didanosine: 1279.3 ng ml(-1), 1793.2 ng m l(-1) h, and 1.61 h; sulphamethoxazole: 53.57 mu g ml(-1), 732.1 mu g ml(-1) h, and 8.95 h), or the combination of trimethoprim and sulphame thoxazole (didanosine: 1283.7 ng ml(-1), 1941.8 ng ml(-1) h, and 1.38 h; trimethoprim: 1.59 mu g ml(-1), 26.68 mu g ml(-1) h, and 11.3 h; su lphamethoxazole: 59.48 mu g ml(-1), 760.9 mu g ml(-1) h, and 9.47 h). 6 Because the observed differences in CL(R) 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.