MAJOR ARTICLE 1962 • CID 2019:69 (1 December) • Ooi et al Clinical Infectious Diseases Population Pharmacokinetics of Intravenous Colistin in Pediatric Patients: Implications for the Selection of Dosage Regimens Mong How Ooi, 1,2 Sing Jiat Ngu, 1 Yek Kee Chor, 1 Jian Li, 3,4 Cornelia B. Landersdorfer, 5,a and Roger L. Nation 3,a 1 Department of Pediatrics, Sarawak General Hospital, Kuching, and 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, 4 Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, and 5 Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia 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. Te 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. Te aim was to increase our understanding of the patient factors that infuence the plasma concentration of colistin, and assess the likely appropriateness of the FDA and EMA dosage recommendations. Methods. Tere 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/1.73m 2 , who received intravenous infusions of colistimethate each 8 hours. Te 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 infuencing the concentration of colistin. Results. Te median, average, steady-state plasma concentration of colistin (C ss,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 C ss,avg ≥2mg/L; the remaining 3 patients had C ss,avg <1mg/L. Te pharmacokinetic covariate analysis revealed that clearances of colistimethate and colistin were re- lated to creatinine clearance. Conclusions. Te FDA and EMA dosage recommendations may be suboptimal for many pediatric patients. Renal functioning is an important determinant of dosing in these patients. Keywords. intravenous colistin; pediatric patients; population pharmacokinetics; infuence of renal impairment and augmented renal clearance; assessment of current dosage recommendations. With the global surge in infections caused by multidrug-resistant (MDR), gram-negative bacteria, there has been an increased need in pediatric patients for intravenous colistin, which is adminis- tered as its inactive prodrug, colistimethate (also known as colis- tin methanesulfonate [CMS]) [1–11]. The CMS dosage regimen currently recommended for pediatric patients by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is 75 000–150 000 international units (IU) per kg per day (~2.5–5 mg colistin base activity [CBA] per kg per day) [12, 13]. There appears to be no basis for this dose range, other than its correspondence to the body weight–based daily dose range traditionally used in adult patients [12]. Unfortunately, the substantially increased clinical neces- sity for CMS in pediatric patients has not been matched by increased knowledge on the disposition of CMS and the colis- tin formed from it in these patients: knowledge that is required to inform the selection of CMS dosage regimens. Tere have been only 3 brief reports on the plasma concentrations of CMS and colistin in pediatric patients older than 1 month [14–16]. Across these studies, data from a total of 11 patients, ranging in age from 1.5 months to 14 years, were reported. Unfortunately, in the largest of these studies (7 patients) [15], the data are not useful, because the plasma colistin concentrations reported were substantially overestimated due to the post-collection conversion of CMS or partially sulfomethylated derivatives to colistin [17, 18]. A total of 14 plasma samples were collected Received 28 August 2018; editorial decision 16 January 2019; accepted 20 January 2019; published online January 26, 2019. a C. B. L. and R. L. N. contributed equally to this manuscript. Correspondence: R. L. Nation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia (roger.nation@monash.edu). Clinical Infectious Diseases ® 2019;69(11):1962–8 © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. DOI: 10.1093/cid/ciz067 Downloaded from https://academic.oup.com/cid/article/69/11/1962/5301788 by guest on 06 June 2022