ESPN 53rd Annual Meeting

ESPN 2021


 
A Bayesian population approach to determine lisinopril exposure in hypertensive paediatric patients with mild to moderate renal impairment
LOUIS SANDRA 2 EVA DEGRAEUWE 1 ELKE GASTHUYS 2 PAULIEN DE BRUYNE 1 An Vermeulen 2 ANN RAES 1 JOHAN VANDE WALLE 1

1- DEPARTMENT OF INTERNAL MEDICINE AND PAEDIATRICS (GE35), GHENT UNIVERSITY
2- LABORATORY OF MEDICAL BIOCHEMISTRY AND CLINICAL ANALYSIS, FACULTY OF PHARMACEUTICAL SCIENCES, GHENT UNIVERSITY
 
Abstract:

Objective:Lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, is the most frequently prescribed antihypertensive therapeutic in the paediatric population, despite being used off-label (1). The SAFEPEDDRUG project studied lisinopril exposure and blood pressure effects in a dose-escalation pilot study, envisioning safe and dose-optimized usage of lisinopril in children with primary or secondary hypertension including patients with mild renal impairment, corresponding to the vast majority of the day-to-day clinical paediatric population (2). Methods:The SAFEPEDDRUG lisinopril pilot study included 13 children with primary/secondary hypertension who received oral lisinopril once daily, doses ranging from 0.05 mg kg-1 to 0.2 mg kg-1. A total of 46 peak and trough plasma samples were collected. Patients were aged between 1.9 and 17.9 years (median: 13.5 years) and had a total body weight between 9.62 and 97.2 kg (median: 53.2 kg). eGFR was measured between 55.5 and 180 mL/min/1.73m2 (median: 99.9 ml/min/1.73m2). 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 analyzed data. Significant covariate effects include total bodyweight on elimination clearance and distribution volume and eGFR on elimination clearance. The effects of total bodyweight are parametrized in terms of fixed allometric exponents (0.75 for clearance, 1 for volume), centered around a total body weight of 70 kg (3). The effects of eGFR on the elimination clearance are optimally described by a power law parametrization centered around 105 mL/min/1.73m2. Estimated population elimination clearance equals 23.12 L/h/70kg and distribution volume equals 32.91 L/70kg and are in line with results published by Thompson et al (4). Conclusion: Lisinopril dose and regimen adjustments for paediatric patients should include eGFR on top of weight adjustments. Extending the model to characterize pharmacodynamic effect is required to identify the optimal dose and dosing regime.