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Optimal study design for pioglitazone in septic pediatric patients

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Abstract

The objective was to demonstrate the methodology and process of optimal sparse sampling pharmacokinetics (PK). This utilized a single daily dose of pioglitazone for pediatric patients with severe sepsis and septic shock based upon adult and minimal adolescent data. Pioglitazone pharmacokinetics were modeled using non-compartment analysis WinNonlin Pro (version 5.1) and population kinetics using NONMEM (version 7.1) with first order conditional estimation method (FOCE) with interaction. The initial model was generated from single- and multiple-dose pioglitazone PK data (15 mg, 30 mg, and 45 mg) in 36 adolescents with diabetes. PK models were simulated and overlaid upon original data to provide a comparison best described by a single compartment, first order model. The optimal design was based on the simulated oral administration of pioglitazone to three groups of pediatric patients, age 3.8 (2–6 years), weight 14.4 (7–28 kg); age 9.6 (6.1–11.9 years), weight 36.5 (28.1–48 kg) and age 15.5 (12–17 years,) weight 61.6 (48.1–80 kg). PFIM (version 3.2) was used to evaluate sample study size. Datasets were compiled using simulation for each dose (15, 30 and 45 mg) for the potential age/weight groups. A target dose of 15 mg daily in the youngest and middle groups was considered appropriate with area under the curve exposure levels (AUC) comparable to studies in adolescents. The final optimal design suggested time points of 0.5, 2, 6 and 21 h for 24 h dosing. This methodology provides a robust method of utilizing adult and limited adolescent data to simulate allometrically scaled, pediatric data sets that allow the optimal design of a pediatric trial. The pharmacokinetics of pioglitazone were described adequately and simulated data estimates were comparable to literature values. The optimal design provided clinically attainable sample times and windows.

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Acknowledgments

The authors would like to acknowledge financial support from the following NIH grant 5T32AR007594-15 (CMTS), 1K24HD050387-04 (AV) and K08GM093135-01 (JK). The authors would like to thank and acknowledge the authors from the publication by Christensen et al. [12] for sharing their data.

Conflict of interest

The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Catherine M. T. Sherwin, Michael G. Spigarelli & Alexander A. Vinks

  2. Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Lili Ding

  3. Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Jennifer Kaplan

  4. Clinical Trials Office, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Michael G. Spigarelli

  5. Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    Jennifer Kaplan, Michael G. Spigarelli & Alexander A. Vinks

  6. Division of Clinical Pharmacology and Clinical Trials Office, Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, 2S010, Salt Lake City, UT, 84108, USA

    Catherine M. T. Sherwin

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  1. Catherine M. T. Sherwin
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  2. Lili Ding
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Correspondence to Catherine M. T. Sherwin.

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Sherwin, C.M.T., Ding, L., Kaplan, J. et al. Optimal study design for pioglitazone in septic pediatric patients. J Pharmacokinet Pharmacodyn 38, 433–447 (2011). https://doi.org/10.1007/s10928-011-9202-8

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  • DOI: https://doi.org/10.1007/s10928-011-9202-8

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