PHARMACOKINETICS OF LAMIVUDINE ADMINISTERED ALONE AND WITH TRIMETHOPRIMSULFAMETHOXAZOLE

Objective: To determine the effect of multiple dosing of combined sulf amethoxazole and trimethoprim on the single-dose pharmacokinetics of l amivudine. Methods: Fourteen subjects with human immunodeficiency viru s who had CD4+ cells greater than or equal to 200/mm(3) received two s ingle doses of 300 mg lamivudine, separated by 7 to 14 days, in a rand omized two-way crossover study, Treatment consisted of lamivudine alon e versus trimethoprim-sulfamethoxazole (160/800 mg) daily on days 1 th rough 4 followed by lamivudine plus trimethoprim-sulfamethoxazole on d ay 5. Blood and urine were collected over 24 to 32 hours to determine lamivudine, trimethoprim, sulfamethoxazole, and N-4-acetylsulfamethoxa zole concentrations. Results: Coadministration of a single dose of lam ivudine and trimethoprim-sulfamethoxazole after daily dosing for 5 day s altered the pharmacokinetics of lamivudine, A 43% increase in area u nder the concentration-time curve (AUC(infinity)) and a 35% decrease i n renal clearance (CL(R)) were observed when lamivudine was coadminist ered with trimethoprim-sulfamethoxazole compared with lamivudine alone . The geometric least-squares mean (95% confidence intervals) for the parameters of lamivudine alone and when given concurrently with trimet hoprim-sulfamethoxazole were as follows: AUC(infinity), 10,124 (9,432- 10,866) and 14,448 (13,461-15,508) ng . hr/ml, respectively; CL(R) 16. 6 (14.1-19.4) and 10.8 (9.5-12.6) L/hr, respectively, Coadministration did not significantly alter the pharmacokinetics of trimethoprim or s ulfamethoxazole. Conclusions: Coadministration of lamivudine with trim ethoprim-sulfamethoxazole resulted in an increased AUC(infinity) and a decreased CL(R) of lamivudine, However, given the favorable safety pr ofile of lamivudine, it is unlikely that this interaction will result in a significant increase in concentration-related toxicity at the dos es studied.