Philippe Pierrillas (1), Delphine Labolle (2), Florence Porte-Thomé (2), Christian Laveille (1)
(1) Calvagone, France (2) EspeRare Foundation, Switzerland
Objectives:
Duchenne Muscular Dystrophy (DMD) is a rare genetic disorder characterized by the progressive loss and degeneration of skeletal and cardiac muscles affecting boys [1]. Mutations in the dystrophin gene lead to disease by preventing the expression of dystrophin, a structural component in muscle tissue. The lack of the dystrophin protein leads to membrane instability and uncontrolled intracellular homeostasis including calcium which accumulation contributes to the disease [2].
NHE-1 (sodium-hydrogen exchanger type 1) is a key membrane transporter regulating intracellular Na+ concentration and pH by catalysing the electroneutral counter transport of Na+ and H+ through the plasma membrane [3]. The NHE-1 isoform is ubiquitous and is present on muscle fibers. When activated, it leads to a significant increase in intracellular Na+ triggering an intracellular Ca2+ overload through the Na/Ca exchanger. Therefore, inhibiting NHE-1 transporters can regulate intracellular Na+ and Ca2+.
Rimeporide is a potent and selective NHE-1 inhibitor which has been shown to be cardioprotective and to improve skeletal muscle phenotype in animal models of DMD. A previously reported pharmacokinetic model [4] was built based on healthy adult data in order to simulate Rimeporide concentrations in young boys suffering from DMD.
The aim of this work was to refine the existing Rimeporide PK model after pooling the data coming from these adult healthy volunteers studies and from a clinical study in paediatric DMD patients.
Methods:
Rimeporide plasma concentrations after intravenous and oral administrations obtained from 6 clinical studies in adult healthy volunteers and from one phase Ib study in children with DMD were pooled for the analysis. In total, plasma samples from 176 individuals (156 adults and 20 children from 6 to 11 years) after administrations of Rimeporide at different dose levels and dosing regimen were available for the analysis.
Available covariates were: age, ALT, AST, bilirubin, BMI, body weight, glomerular filtration rate, dose, food, lean body weight, serum creatinine and cystatin C (DMD disease impacting serum creatinine values, Cystatin C was used instead for computation of the glomerular filtration rate).
The modelling exercise was performed using the FOCE-I method implemented in NONMEM 7.3 and model development was guided by residual- and simulation-based diagnostics.
Results:
The refined population PK model to describe Rimeporide concentrations was a three-compartment disposition model with an absorption phase described by multiple transit compartments and a first-order elimination process.
A stepwise covariate modelling analysis revealed that the absorption rate was lower in fed condition (~50% lower) and clearance decreased when GFR was low ()a reduction of 20% was found in indivudla with the lowest GFR compared to a typical individual), confirming the elimination pathway of Rimeporide.
Incorporation of serum creatinine levels on distribution process was found to be better than bodyweight in order to explain both adults and DMD children, indicating that Rimeporide might be distributed in muscle tissues (body composition being altered in DMD disease with a loss of muscle mass). A reduction of 25% was found on the individual volume of distribution in the child with the lowest value of serum creatinine compared to a typical individual with a serum creatinine level of 115 µmol/L.
Model evaluation by goodness-of-fit and pred-corrected Visual Predictive Check were satisfactory.
Conclusion:
The presented PK model built from both adult healthy volunteers and young boys suffering from DMD studies described satisfactorily the Rimeporide data. The Rimeporide PK model will be expanded to investigate potential relationships between Rimeporide concentrations and muscle damage biomarkers as they will be available.
References:
[1] Mendell JR et al. Evidence-based path to newborn screening for Duchenne disease dystrophy. Ann Neurol, 2012 Mar;. 71 (3): p. 304-313.
[2] Iwata Y and Wakabayashi S. Abnormal ion homeostasis and cell damage in muscular dystrophy. Muscular Dystrophy, 2012.
[3] Orlowski J and Grinstein S. The sodium-hydrogen exchanger: from molecule to its role in disease. 2004. Kluwer Academlic Publishers.
[4] Laveille C. et al. Population pharmacokinetics of Rimeporide: a sodium-hydrogen exchanger (NHE-1) inhibitor for patients with Duchenne Muscular Dystrophy (DMD). PAGE 26 (2017) Abstr 7177 [www.page-meeting.org/?abstract=7177]
Reference: PAGE 27 (2018) Abstr 8476 [www.page-meeting.org/?abstract=8476]
Poster: Drug/Disease Modelling - Paediatrics