Pharmacokinetics and Tolerance of a Single Twelve-Tablet Dose of Trimethoprim (960 mg)-Sulfamethoxazole (4,800 mg)

Abstract

To evaluate the potential usefulness of a single large oral dose of trimethoprim-sulfamethoxazole (TMP-SMZ) for the treatment of uncomplicated genitourinary gonorrhea, the pharmacokinetics of a 12-tablet dose containing 960 mg of TMP and 4,800 mg of SMZ were studied in 15 male volunteers, and the tolerance of this regimen was compared to that of a placebo in a double-blind crossover study. Both TMP and SMZ were rapidly absorbed. Peak mean serum concentrations (± standard deviation) ofTMP, total SMZ, and free SMZ were 9.2 + 2.2, 259.4 ± 40.9, and 233.7 + 33.6 ,g/ml, respectively. Elimination half-lives were 16.7, 14.6, and 12.9 h, respectively. When results were compared to data from similar studies after smaller doses, peak mean serum concentrations were proportional to dose, but elimination half-lives were longer after larger doses. Urinary concentrations ofTMP, total SMZ, and free SMZ were many-fold higher than serum concentrations. Percents recovery (+ standard deviation) in urine were 60.6 + 10.6, 80.2 + 7.8, and 37.4 ± 6.5%, respectively, during the 48 h after administration. The incidence of severe headache and of objective transient oliguria was significantly higher after TMP-SMZ than after placebo. Although the observed serum concentrations of TMP and SMZ surpassed concentrations necessary to inhibit clinical isolates ofNeisseria gonorrhoeae in vitro for longer than 24 h, the adverse reactions associated with a 12-tablet dose of TMP-SMZ would preclude the clinical usefulness of such a therapeutic regimen.Multidose regimens of trimethoprim-sulfamethoxazole (TMP-SMZ) have been well tolerated but have had varying degrees of efficacy in the treatment of uncomplicated genitourinary gonorrhea. In studies (1,2,9,15,17) that compared various treatment regimens, using a total of 16 to 20 tablets (each containing 80 mg of TMP and 400 mg of SMZ), cure rates were consistently higher (92 to 100%) when four-to sixtablet doses were administered than were cure rates (80 to 95%) when one-to three-tablet doses were administered. The higher cure rates observed with the former were attributed to the presumably higher serum and tissue concentrations, which were achieved despite the smaller number of doses.Because of the apparent efficacy of relatively short-term, high-dose therapy with multidose regimens of TMP-SMZ and the desirability of using a single-dose regimen for the treatment of uncomplicated genitourinary gonorrhea, the efficacy of single doses consisting of 8 to 12 tablets has also been studied (4, 7, 9, 10, 13;

Drug monitoring during the treatment of AIDS-associated Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole

“…treatment of 23 patients with Pneumocystis carinii pneumonia, the mean trimethoprim plasma concentration was 7·7±3 μg/ml (sulfamethoxazole 198±74 μg/ml). As described by others ( 6, 16), oral and i.v. administration of co‐trimoxazole produces comparable mean plasma concentrations.…”

Relationship of Sulfamethoxazole Therapeutic Drug Monitoring to Clinical Efficacy and Toxicity

“…20 This study included peak levels drawn up to 5 hours after dosing, which was extrapolated from earlier studies that showed peak concentrations of TMP/SMX vary from 1-6 hours after administration. [27][28][29] This methodology was further supported by a large retrospective study that showed no difference in median peak SMX levels between a strict peak cohort (level attainment up to 3 hours after dosing) and a modified peak cohort (level attainment up to 5 hours after dosing). 22 Another possible source of variability in the peak serum levels is the great number of ICU-status patients included in the study.…”

A Physiologically-Based Pharmacokinetic Model of Trimethoprim for MATE1, OCT1, OCT2, and CYP2C8 Drug–Drug–Gene Interaction Predictions

“… Trimethoprim in plasma and urine. Population predictions of trimethoprim ( a – f ) plasma concentration–time profiles and ( g – i ) fraction excreted unchanged in urine profiles compared to observed data [ 43 , 54 , 55 , 57 , 58 ] of representative intravenous and oral studies. Population prediction arithmetic means are shown as lines; the shaded areas illustrate the 68% population prediction intervals.…”

“…The solid line marks the line of identity and dotted lines indicate 1.25-fold and dashed lines indicate 2-fold deviation. Data are shown as triangles (training dataset) or dots (test dataset) [ 30 , 31 , 33 , 37 , 41 , 43 , 46 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. Details on the predicted clinical studies and the individual fraction excreted unchanged in urine values are provided in the Supplementary Materials .…”