Population Pharmacokinetics of Intravenous Colistin in Pediatric Patients: Implications for the Selection of Dosage Regimens

BACKGROUND: Intravenous colistin is widely used to treat infections in pediatric patients. Unfortunately, there is a paucity of pharmacological information to guide the selection of dosage regimens. The daily dose recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) is the same body weight-based dose traditionally used in adults. The aim was to increase our understanding of the patient factors that influence the plasma concentration of colistin, and assess the likely appropriateness of the FDA and EMA dosage recommendations. METHODS: There were 5 patients, with a median age of 1.75 (range 0.1-6.25) years, a median weight of 10.7 (2.9-21.5) kg, and a median creatinine clearance of 179 (44-384) mL/min/1.73m2, who received intravenous infusions of colistimethate each 8 hours. The median daily dose was 0.21 (0.20-0.21) million international units/kg, equivalent to 6.8 (6.5-6.9) mg of colistin base activity per kg/day. Plasma concentrations of colistimethate and formed colistin were subjected to population pharmacokinetic modeling to explore the patient factors influencing the concentration of colistin. RESULTS: The median, average, steady-state plasma concentration of colistin (Css,avg) was 0.88 mg/L; individual values ranged widely (0.41-3.50 mg/L), even though all patients received the same body weight-based daily dose. Although the daily doses were ~33% above the upper limit of the FDA- and EMA-recommended dose range, only 2 patients achieved Css,avg ≥2mg/L; the remaining 3 patients had Css,avg <1mg/L. The pharmacokinetic covariate analysis revealed that clearances of colistimethate and colistin were related to creatinine clearance. CONCLUSIONS: The FDA and EMA dosage recommendations may be suboptimal for many pediatric patients. Renal functioning is an important determinant of dosing in these patients.