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Population pharmacokinetics of lisinopril in hypertensive children and adolescents with normal to mildly reduced kidney function
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  • Eva Degraeuwe,
  • Louis Sandra,
  • Paulien De Bruyne,
  • Siegrid De Baere,
  • Siska Croubels,
  • Jan Van Bocxlaer,
  • Ann Raes,
  • Johan Vande Walle,
  • Elke GASTHUYS,
  • An Vermeulen
Eva Degraeuwe
Ghent University

Corresponding Author:eva.degraeuwe@ugent.be

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Louis Sandra
Janssen Pharmaceutica NV
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Paulien De Bruyne
Ghent University
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Siegrid De Baere
Ghent University
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Siska Croubels
Ghent University
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Jan Van Bocxlaer
Ghent University
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Ann Raes
Ghent University
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Johan Vande Walle
Ghent University
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Elke GASTHUYS
Ghent University
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An Vermeulen
Ghent University
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Abstract

Background: Lisinopril, an angiotensin-converting enzyme inhibitor (ACEi), is a frequently prescribed antihypertensive drug in the pediatric population, while being used off-label under the age of 6 years in the US and for all pediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive pediatric patients corresponding with the day-to-day clinical population. Methods: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05mg.kg-1 to 0.2 mg.kg-1. Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2kg (median 53.2kg). All data were analyzed using Monolix version 2020R1 (Lixoft®, France) and R version 3.6.2. Results: A one-compartment model with 1st order absorption and 1st order elimination optimally describes the data. Parameter estimates of ka (0.077h-1 [9.6%], typical value [relative standard error]), V/F (32.9L 70.g-1 [37%]) and CL/F (23.1L h-1 .70kg-1[8.5%]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a power law parameterization centered around 105 mL.min.1.73m2. The effects of body weight were implemented using fixed allometric exponents centered around an adult weight of 70kg. Conclusion: Lisinopril dose and regimen adjustments for pediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.
16 Jun 2023Submitted to British Journal of Clinical Pharmacology
16 Jun 2023Submission Checks Completed
16 Jun 2023Assigned to Editor
16 Jun 2023Review(s) Completed, Editorial Evaluation Pending
06 Jul 2023Reviewer(s) Assigned
08 Aug 2023Editorial Decision: Revise Major
06 Oct 20231st Revision Received
06 Oct 2023Submission Checks Completed
06 Oct 2023Assigned to Editor
06 Oct 2023Review(s) Completed, Editorial Evaluation Pending