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Escitalopram and Sertraline Population Pharmacokinetic Analysis in Pediatric Patients

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Abstract

Background and Objective

Escitalopram and sertraline are commonly prescribed for anxiety and depressive disorders in children and adolescents. The pharmacokinetics (PK) of these medications have been evaluated in adults and demonstrate extensive variability, but studies in pediatric patients are limited. Therefore, we performed a population PK analysis for escitalopram and sertraline in children and adolescents to characterize the effects of demographic, clinical, and pharmacogenetic factors on drug exposure.

Methods

A PK dataset was generated by extracting data from the electronic health record and opportunistic sampling of escitalopram- and sertraline-treated psychiatrically hospitalized pediatric patients aged 5–18 years. A population PK analysis of escitalopram and sertraline was performed using NONMEM. Concentration-time profiles were simulated using MwPharm++ to evaluate how covariates included in the final models influence medication exposure and compared to adult therapeutic reference ranges.

Results

The final escitalopram cohort consisted of 315 samples from 288 patients, and the sertraline cohort consisted of 265 samples from 255 patients. A one-compartment model with a proportional residual error model best described the data for both medications. For escitalopram, CYP2C19 phenotype and concomitant CYP2C19 inhibitors affected apparent clearance (CL/F), and normalizing CL/F and apparent volume of distribution (V/F) to body surface area (BSA) improved estimations. The final escitalopram model estimated CL/F and V/F at 14.2 L/h/1.73 m2 and 428 L/1.73 m2, respectively. For sertraline, CYP2C19 phenotype and concomitant CYP2C19 inhibitors influenced CL/F, and empirical allometric scaling of patient body weight on CL/F and V/F was significant. The final sertraline model estimated CL/F and V/F at 124 L/h/70 kg and 4320 L/70 kg, respectively. Normalized trough concentrations (Ctrough) for CYP2C19 poor metabolizers taking escitalopram were 3.98-fold higher compared to normal metabolizers (151.1 ng/mL vs 38.0 ng/mL, p < 0.0001), and normalized Ctrough for CYP2C19 poor metabolizers taking sertraline were 3.23-fold higher compared to normal, rapid, and ultrarapid metabolizers combined (121.7 ng/mL vs 37.68 ng/mL, p < 0.0001). Escitalopram- and sertraline-treated poor metabolizers may benefit from a dose reduction of 50–75% and 25–50%, respectively, to normalize exposure to other phenotypes.

Conclusion

To our knowledge, this is the largest population PK analysis of escitalopram and sertraline in pediatric patients. Significant PK variability for both medications was observed and was largely explained by CYP2C19 phenotype. Slower CYP2C19 metabolizers taking escitalopram or sertraline may benefit from dose reductions given increased exposure.

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Acknowledgments

We thank Josh Courter for helping set up the Vigilanz Alert System, the CCHMC Clinical Laboratories for sample collection, and Ashley Sarbell, Jada Bouyer, and Kynnedi Williams for data collection. We acknowledge the Center for Clinical & Translational Science and Training (CCTST) at the University of Cincinnati supports REDCap and is funded by the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program, grant UL1TR001425. The CTSA program is led by the NIH's National Center for Advancing Translational Sciences (NCATS).

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Authors and Affiliations

  1. Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Ethan A. Poweleit

  2. Department of Biomedical Informatics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    Ethan A. Poweleit

  3. Division of Research in Patient Services, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH, 45229, USA

    Ethan A. Poweleit & Laura B. Ramsey

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

    Ethan A. Poweleit, Zachary L. Taylor, Tomoyuki Mizuno & Laura B. Ramsey

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

    Tomoyuki Mizuno, Samuel E. Vaughn & Laura B. Ramsey

  6. Division of Child and Adolescent Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Samuel E. Vaughn & Jeffrey R. Strawn

  7. Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, IN, USA

    Zeruesenay Desta & Jeffrey R. Strawn

  8. Department of Psychiatry and Behavioral Neuroscience, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    Jeffrey R. Strawn

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  1. Ethan A. Poweleit
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Correspondence to Laura B. Ramsey.

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Disclosures/Conflicts of Interest

LBR has received research support from BTG International. JRS has received research support from Abbvie, the National Institutes of Health, PCORI, the Yung Family Foundation, and receives material support from Myriad. He receives royalties from UpToDate and Cambridge and has consulted with Cerevel, Otsuka, and Intracellular Therapeutics. All other authors declared no competing interests for this work.

Funding Information

Funding from the Center for Pediatric Genomics at Cincinnati Children’s Hospital Medical Center supported this project. EAP is supported by the National Institute of Mental Health of the National Institutes of Health under award number F31MH132265. ZLT was supported by the National Institute of Child Health and Development T32 Cincinnati Pediatric Clinical Pharmacology Training Program (T32HD069054). ZD is supported by R35GM145383 from NIGMS. JRS, EAP, and LBR are supported by NICHD (R01HD099775).

Data Availability

Data for this study may be available upon reasonable request from the corresponding author.

Ethics Approval

This study was approved by the Institutional Review Board at Cincinnati Children’s Hospital Medical Center and was determined to be exempt in accordance with applicable regulations and institutional policy.

Consent to Participate

A waiver of informed consent was granted by the IRB at Cincinnati Children’s Hospital Medical Center.

Consent for Publication

Not applicable.

Code Availability

The code generated for the analysis may be available upon reasonable request from the corresponding author.

Author Contributions

All authors contributed to the study conception and design. Data collection was performed by EAP, SEV, and ZD. Data analysis was performed by EAP, ZLT, and TM. The first draft of the manuscript was written by EAP and all authors edited and approved the final manuscript.

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Poweleit, E.A., Taylor, Z.L., Mizuno, T. et al. Escitalopram and Sertraline Population Pharmacokinetic Analysis in Pediatric Patients. Clin Pharmacokinet 62, 1621–1637 (2023). https://doi.org/10.1007/s40262-023-01294-8

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