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Clin Infect Dis. 2019 Jan 26. doi: 10.1093/cid/ciz067. [Epub ahead of print]

Population pharmacokinetics of intravenous colistin in pediatric patients: Implications for selection of dosage regimens.

Author information

1
Department of Pediatrics, Sarawak General Hospital, Kuching, Sarawak, Malaysia.
2
Institute of Health and Community Medicine, Universiti Malaysia Sarawak, Kota Samarahan, Sarawak, Malaysia.
3
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
4
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia.
5
Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.

Abstract

Background:

Intravenous colistin is widely used to treat infections in pediatric patients. Unfortunately, there is a paucity of pharmacological information to guide 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 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:

Five patients with median age 1.75 (range 0.1-6.25) years, weight 10.7 (2.9-21.5) kg and creatinine clearance 179 (44-384) mL/min/1.73m 2 received 8-hourly intravenous infusions of colistimethate. Median daily dose was 0.21 (0.20-0.21) million IU/kg, equivalent to 6.8 (6.5-6.9) mg colistin base activity per kg/day. Plasma concentrations of colistimethate and formed colistin were subjected to population pharmacokinetic modeling to explore patient factors influencing the concentration of colistin.

Results:

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. Despite that the daily dose was ~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 with creatinine clearance.

Conclusions:

The FDA and EMA dosage recommendations may be suboptimal for many pediatric patients. Renal function is an important determinant of dosing in these patients.

PMID:
30722017
DOI:
10.1093/cid/ciz067

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