M. Faisal, W. Cawello, S. Laer
Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University, Duesseldorf, Germany.
Objectives: Since many years, children with chronic heart failure are lacking approved drug and child appropriate dosage formulation in Europe and in the USA [1]. A European drug and dosage form development program for off-patent drug enalapril using an oro-dispersible mini-tablet (ODMT) aims at to evaluate the pharmacokinetics (PK) of administered inactive pro-drug enalapril and its active metabolite enalaprilat by developing a combined population PK model. As a first step, enalapril was administered as 10 mg ODMTs versus a marketed 10 mg Renitec® formulation to 24 healthy adults during a phase I clinical trial [2]. The detailed model informed PK analysis was used to evaluate the impact of dosage formulation on the PK of enalapril and enalaprilat by evaluating the difference in PK of the administered drug and metabolite in serum and urine.
Methods: A simultaneous semi-mechanistic population PK model was developed to predict full profile serum and urine concentrations of enalapril and enalaprilat using NONMEM software version 7.4.0. First-order conditional estimation with interaction was used to estimate parameters including mean transit time (MTT), rate constants of absorption and elimination, the volume of distribution (VD), bioavailability, inter-compartmental distribution and rate constant of metabolite formation. Relationship of model parameters with biometric covariates was evaluated. Model performance was evaluated using the goodness of fit plots. Visual predictive check, bootstrap confidence interval, and sampling importance-resampling procedures were used for model validation. Parameter estimates of enalapril and enalaprilat of both formulations were correlated using paired t-test with p
Results: One and two-compartment model adequately predicted serum enalapril and enalaprilat concentrations, respectively. Delay phase of enalarpil absorption and enalaprilat formation was predicted using transit compartments. Normalized body weight was identified as covariate related to VD of enalapril. Only a significant difference (p=0.03) in MTT of enalapril absorption by 5 minutes from ODMT was found compared to reference tablets. No other difference in the PK of enalapril and enalaprilat was observed in serum and urine.
Conclusions: The Inactive prodrug Enalapril administered using child-appropriate ODMTs appeared 5 minutes earlier in serum compared to the reference formulation. However, no difference in the formation and disposition of active metabolite enalaprilat was observed in serum and urine. The use of enalapril ODMTs is expected to have similar pharmacodynamics response as compared to conventional formulations.
References:
[1] Faisal M, Cawello W, Laer S. Model-dependent pharmacokinetic analysis of enalapril administered to healthy adult volunteers using orodispersible minitablets for use in pediatrics. 2019;481–90.
[2] ClinicalTrials.gov [Internet]. Ethicare GmbH: National Library of Medicine (US). 562 30/9/2014. Identifier NCT02252692, Relative availability study with enalapril in 563 healthy volunteers; 2014 Sep 30.
Reference: PAGE 28 (2019) Abstr 8955 [www.page-meeting.org/?abstract=8955]
Poster: Drug/Disease Modelling - Paediatrics