A pharmacokinetic interaction study of didanosine coadministered with trimethoprim and/or sulphamethoxazole in HIV seropositive asymptomatic male patients

Abstract

R. A. SMITH3 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 pg ml‐1, 22.86 μg ml‐1 h, and 9.03 h, respectively) or sulphamethoxazole (58.62 μg ml‐1, 799.7 μg 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 μg ml‐1, 28.89 μg 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 μg ml‐1, 732.1 μg ml‐1 h, and 8.95 h), or the combination of trimethoprim and sulphamethoxazole (didanosine: 1283.7 μg ml‐1, 1941.8 ng ml‐1 h, and 1.38 h; trimethoprim: 1.59 μg ml‐1, 26.68 μg ml‐1 h, and 11.3 h; sulphamethoxazole: 59.48 μg ml‐1, 760.9 μg 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.

Effects of Trimethoprim on the Clearance of Apricitabine, a Deoxycytidine Analog Reverse Transcriptase Inhibitor, and Lamivudine in the Isolated Perfused Rat Kidney

“…Because the half-life of trimethoprim is approximately 9 to 12 h (Odlind et al, 1984;Hutt et al, 1988;Srinivas et al, 1996), it seems likely that trimethoprim concentrations above the IC 50 would be sustained throughout the day in clinical practice. However, a recent pharmacokinetic study in healthy volunteers found that the magnitude of the interaction between ATC and trimethoprim was modest compared with IPK findings.…”

Renal excretion of emtricitabine II. Effect of trimethoprim on emtricitabine excretion: In vitro and in vivo studies

“…Typical TMP plasma concentrations in HIV‐infected patients treated for PJP are in the range of 5–14 µg/mL,17–19 which is well in excess of the IC 50 value generated in the IPK (1.86 µg/mL, 90% confidence interval 1.10–2.60). The elimination t ½ of TMP is approximately 9–14 h 17, 20–23. Thus, plasma concentrations of TMP would decline by roughly 50% within the usual 12 h dosage interval.…”

Medicinal Chemistry of Antiviral/Anticancer Prodrugs Subjected to Phosphate Conjugation

“…Zalcitabine (50) inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Half life is 2 h. Zalcitabine (50) is phosphorylated into zalciatbine-5'-triphosphate (51), that competes with dGTP for incorporation into viral DNA. Zalcitabine-5'-triphosphate (51) inhibits the HIV reverse transcriptase enzyme competitively, and acts as chain terminator of DNA synthesis, as lack of 3'-OH group in the incorporated nucleoside analogue prevents the formation of 5'-to 3'-linkage.…”

“…Half life is 2 h. Zalcitabine (50) is phosphorylated into zalciatbine-5'-triphosphate (51), that competes with dGTP for incorporation into viral DNA. Zalcitabine-5'-triphosphate (51) inhibits the HIV reverse transcriptase enzyme competitively, and acts as chain terminator of DNA synthesis, as lack of 3'-OH group in the incorporated nucleoside analogue prevents the formation of 5'-to 3'-linkage. FDA approval for the treatment of HIV infection was achieved in 1992 [55] in 1996 in combination with zidovudine (52).…”