Joaquín Cravioto

Pharmacokinetics of metronidazole in severely malnourished and nutritionally rehabilitated children

A comparison of the pharmacokinetics of oral metronidazole, after a single dose of 30 mg/kg body weight, was done in two groups of subjects: group I consisted of 10 severely malnourished children, aged 4 to 43 months; group II consisted of 10 children, aged 3 to 25 months, who were studied after nutritional rehabilitation. The biologic half‐life of elimination was significantly longer (p< 0.01) in severely malnourished children (median, 10.21 hours; range, 4.89 to 22.93 hours) than in rehabilitated children (median, 5.09 hours; range, 2.61 to 8.75 hours). Metabolic clearance of metronidazole was significantly lower in group I (p< 0.01; median, 0.077 L/kg/hr; range, 0.033 to 0.192 L/kg/hr) than in nutritionally rehabilitated children (median, 0.166 L/kg/hr; range, 0.105 to 0.300 L/kg/hr). Volume of distribution was not different between groups I and II, although both showed higher values than the values reported for children who were not malnourished. These findings suggest that the dose of metronidazole should be reduced in malnourished children, and the therapeutic regimen should be individualized for each patient.

A New Dosing Regimen for Metronidazole in Malnourished Children

The use of metronidazole for the treatment of intestinal parasitosis has increased markedly, particularly in developing countries, where the association of malnutrition and parasitosis is very common. Since biotransformation of metronidazole is significantly affected by severe malnutrition, and undesirable effects of the drug seem to be related to its plasma concentration, it was decided to carry out a study to establish a dosing-regimen of metronidazole in severely malnourished children. A single dose of 30 mg/kg body weight, and computer simulation of a steady-state was studied in 10 malnourished and in 10 patients undergoing nutritional rehabilitation. Due to ethical considerations (refusal of parents to allow a second dose of metronidazole) acute malnourished children and rehabilitated patients are 2 distinct groups. The results indicate that a predicted drug cumulation would occur in malnourished children with the ordinary dosage regimen (30 mg/kg/day). Based on the clearance data, daily maintenance doses for pediatric patients with severe malnutrition should be 12.0 mg/kg/day, corresponding to a 60% reduction of the common dose calculated to achieve and maintain a plasma concentration of 6.0 micrograms/ml of metronidazole. The study illustrates the need for pharmacokinetic data to establish the individual dose of a drug particularly under conditions that alter biotransformation processes.

Pharmacokinetics of cyclosporine as a function of energy--protein deficiency in children with chronic renal failure.

The present study was conducted to determine whether malnutrition in patients with chronic renal failure requiring cyclosporine therapy for renal transplantation has some effect on the clinical pharmacokinetics of cyclosporine. Eleven pediatric patients were enrolled in this study before renal transplantation and divided into two groups (group I: six well-nourished patients with a deficit in weight/height ratio < or = 7%; group II: five malnourished patients with a deficit in weight/height > 8%). The patients received a single oral dose of cyclosporine (3.0 mg/kg). Blood samples were collected for a 26-hour period, and serum concentrations of cyclosporine were measured using fluorescence-polarization immunoassay technology. The results suggest that, when malnutrition is present, the median Cmax of cyclosporine decreases by almost threefold (from 387.5 ng/mL in group I to 136.1 ng/mL in group II). An observed 52% reduction in AUC0-infinity (from 2,856.0 ng/mL/hr in group I to 1,481.4 ng/mL/hr in group II) was caused by the increased volume of distribution (from 4.6 L/kg in group I to 11.1 L/kg in group II). The elimination half-life (t1/2) was longer in group II compared with that of group I (12.4 hr for group II; range, 7.8-13.5 hr versus 8.9 hr for group I; range, 5.2-16.0 hr). Differences in t1/2 were not statistically significant at 5% confidence intervals. The effects of energy malnutrition on the pharmacokinetics of cyclosporine could explain in part some of the interindividual variability. This study provides pharmacokinetic guidelines for the use of cyclosporine.

Pharmacokinetic Changes of Cyclosporine (CsA) by Effect of Malnutrition in Children with Chronic Renal Failure

Clinical Pharmacology & Therapeutics (1996) 59, 203–203; doi: 10.1038/sj.clpt.1996.312