Population pharmacokinetics of Rimeporide: a sodium-hydrogen exchanger (NHE-1) inhibitor for patients with Duchenne Muscular Dystrophy (DMD)
Christian Laveille (1), Nicolas Simon (2), Hanane Gheit (3), Florence Porte-Thomé (3)
(1) Calvagone, Lyon, France, (2) Marseille Université, service de pharmacologie clinique, Hôpital Ste Marguerite, Marseille, France, (3) EspeRare Foundation, Geneva, Switzerland
Objectives: To build a population model for Rimeporide based on healthy adult data in order to simulate Rimeporide concentrations in young boys suffering from DMD (6 to 14 years old). To check the adequacy of the model developed in adults with the concentrations obtained in patients in an ongoing phase Ib clinical trial.
Methods: Rimeporide plasma concentrations, after intravenous and oral administrations in adult healthy volunteers, were obtained from 6 clinical studies. After IV administration, the dose range was 25 to 350 mg while for oral administration the range was 25 to 600 mg after single dose and 50 to 200 mg tid after multiple doses. Plasma concentrations were modelled with non-linear mixed-effects approaches using NONMEM V7.3.0. Available covariates were Age, ALT, AST, Bilirubin, BMI, Body Weight, Creatinine clearance, Dose, Food, Lean Body Weight and Serum creatinine. A pilot phase Ib, open-label, ascending oral doses, trial is currently ongoing in young boys suffering from DMD. There are 4 dose levels, with 5 boys dosed by cohort: patients with body weight ≤ 30kg receive 50, 100, 150 or 200mg tid and patients with body weight > 30 kg received 75, 150, 200 or 300 mg tid.
Results: The final population model to describe Rimeporide PK in adults (156 HV for 3302 observations) was a three-compartment disposition model with a complex absorption process described by a transit compartment model and first-order elimination. The residual error model was an additive model for the log transformed data. Body weight and renal function were found to affect Rimeporide PK parameters. Pred-corr VPC were performed in order to confirm the predictive performance of the adult model. Preliminary results on the first cohorts of the paediatric trial, confirm that the exposure after body weight correction is similar to what was observed in healthy adult volunteers.
Conclusion: The PK model built on adult data from healthy volunteers described the Rimeporide data well and was successfully used to analyse the preliminary data obtained in an ongoing paediatric study. After the completion of the phase Ib study in children, the Rimeporide PK model will be refined and potential relationships between muscle damage biomarkers and PK will be investigated.
