Kinetic effects of trimethoprim-sulfamethoxazole in children with biliary atresia: a new dosing regimen.
Pharmacokinetics for combination trimethoprim/ sulfamethoxazole (TMP/SMX) was studied in only four patients with biliary atresia (BA): three girls, 6.2,8.0 and 8.2 years of age and one boy 8.4 years of age, as this is an uncommon obstructive anomaly of the extrahepatic biliary system and has been described as having a poor prognosis. These four patients are the survivors of 27 initial children who were operated on previously. They have been receiving 2.3 +/- 0.5 mg/kg TMP, and 11.5 +/- 2.6 mg/kg SMX every 12 h since 2 weeks after surgical treatment for biliary atresia performed at 2-2.5 months of age. The patients have suffered some episodes of cholangitis during their short lives, most of them after interrupting temporally the chemotherapy. Nevertheless, they have achieved a favorable quality of life. TMP/SMX disposition was well characterized by a one compartment open pharmacokinetic model. Wide interpatient variability was observed for all pharmacokinetic parameters with coefficients of variation for t1/2 el, ClT, and Vd of 33.2, 49.6, and 26.3%, respectively, for SMX and 108.9, 52.1, and 71.0%, respectively, for TMP. A marked difference in the pharmacokinetics of TMP and SMX was observed, for example; (ClT: mean +/- SD; 90.3 +/- 47.0 ml/kg/g for TMP and 13.7 +/- 6.8 ml/kg/h for SMX), (t1/2 el with 7.93 +/- 8.64 h for TMP and 10.51 +/- 3.49 h for SMX). In order to develop dosage schedules that would reliably achieve peak serum concentrations of TMP/SMX in the therapeutic range, we found that established dose leads to high fluctuations at steady state between C(max), ss and C(min), ss, without maintaining therapeutic levels. Recommended maintenance dose varied from 8 to 30 mg/kg for SMX with a mean of 21.9 +/- 10.89 mg/kg/12 h, and from 0.8 to 4.5 mg/kg/12 h with a mean of 3.2 +/- 1.7 mg/kg/12 h. The present study illustrates the need for pharmacokinetic studies for the individualization of drug dosing in patients with BA.
Lares-Asseff
I
I
Division de Medicina Experimental, Unidad de Investigación en Salud Infantil del Instituto Nacional de Pediatría, México, DF.
Villegas
F
F
Pérez
G
G
Toledo
A
A
Camacho
A
A
López
D C
DC
D001656:Biliary Atresia / Q000188:drug therapy* / Q000378:metabolism; D002648:Child; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D013420:Sulfamethoxazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014295:Trimethoprim / Q000008:administration & dosage / Q000493:pharmacokinetics*
D014295:Trimethoprim; D013420:Sulfamethoxazole