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Predictive Performance of a Gentamicin Population Pharmacokinetic Model in Neonates Receiving Full-Body Hypothermia

Sampson, Mario R. PharmD*,†; Frymoyer, Adam MD; Rattray, Benjamin DO§; Cotten, C. Michael MD§; Smith, P. Brian MD, MHS, MPH*,§; Capparelli, Edmund PharmD; Bonifacio, Sonia L. MD; Cohen-Wolkowiez, Michael MD, PhD*,§

doi: 10.1097/FTD.0000000000000056
Original Article

Background: Population pharmacokinetic (popPK) models derived from small pharmacokinetics (PK) studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated.

Methods: A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (University of California–San Francisco) data set. The predictive performance of this model was evaluated in an external retrospective data set from the University of California–San Francisco (validation A) and another from Duke University (validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions.

Results: Forty-one neonates (n = 18 validation A; n = 23 validation B) with median (range) gestational age of 40 weeks (33–42) and birth weight of 3.3 kg (1.9–4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36 hours after dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (validation A; median average fold error = 1.1 and numerical prediction distribution error P > 0.05) but underpredicted concentrations from the outside institution (validation B; median average fold error = 0.6 and numerical prediction distribution error P < 0.05).

Conclusions: The model demonstrated adequate predictive performance for an external data set in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.

Supplemental Digital Content is Available in the Text.

*Duke Clinical Research Institute, Durham;

Department of Pharmacotherapy and Experiment Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC;

Department of Pediatrics, Stanford University, Palo Alto, CA;

§Department of Pediatrics, Duke University Medical Center, Durham, NC;

Schools of Medicine and Pharmacy, University of California San Diego, La Jolla; and

Department of Pediatrics, University of California, San Francisco.

Correspondence: Michael Cohen-Wolkowiez, MD, PhD, Duke Clinical Research Institute, P.O. Box 3499, Durham, NC 27710 (e-mail: michael.cohenwolkowiez@duke.edu).

Supported by the US government: 1T32GM86330 (M.R.S.); T32GM07546 (A.F.); 1K23NS082500-01A1 (S.L.B.); DHHS-1R18AE000028-01, HHSN267200700051C, HHSN275201000003I, and UL1TR001117 (P.B.S.); R01 HL105702 (C.M.C.); U54 HD071600-01 (E.C.); and 1K23HD064814, UL1TR001117, 1U01FD004858-01, and HHSO100201300009C (M.C.W.). The following authors also receive non-government support: GlaxoSmithKline (C.M.C.); Trius, Cerexa, Pharmaceuticals, Abbott, and Theravance (E.C.); Thrasher Research Fund (M.C.W.); www.dcri.duke.edu/research/coi.jsp (P.B.S., M.C.W.).

The authors declare no conflict of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.drug-monitoring.com).

Received October 25, 2013

Accepted January 21, 2014

© 2014 by Lippincott Williams & Wilkins