Development of a joint dissolution and pharmacokinetic model of propafenone and its hydroxylated metabolite
Sara Carolina Henriques (1), Marival Bermejo (2), Luís Almeida (3), Nuno Elvas Silva (1)
(1) Research Institute for Medicine and Pharmaceutical Science (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal; (2) Department Engineering Pharmacy Section, Miguel Hernandez University, 03550 San Juan de Alicante, Alicante, Spain; (3) BlueClinical, Porto, Portugal.
Introduction: Propafenone (PRO) is a class 1C antiarrhythmic agent, indicated to prolong the time to recurrence of symptomatic atrial fibrillation in patients with episodic atrial fibrillation who do not have structural heart disease. PRO undergoes extensive and saturable first-pass metabolism, resulting in a dose and dosage form dependent absolute bioavailability (3.4% and 10.6% for a 150 mg and 300 mg immediate release (IR) tablets, and 21.4% for a 300 mg solution). The relative bioavailability of the sustained release (SR) dosage form is lower than the IR formulation, as the more gradual release of PRO from the SR preparation results in an increase of overall first-pass metabolism.
Two genetically determined patterns of PRO metabolism are found in the population. The drug is rapidly and extensively metabolized with an elimination half-life (t1/2) from 2 to 10 h in over 90% of patients (extensive metabolizers). These patients metabolize PRO into two active metabolites: 5-hydroxypropafenone (5-OHP) which is formed by CYP2D6 and N-depropylpropafenone, which is formed by both CYP3A4 and CYP1A2. In less than 10% of patients (defined as poor metabolizers), metabolism of PRO is slower because the 5-OHP metabolite is not formed or is minimally formed, resulting in higher PRO plasma concentrations and prolonged elimination t1/2 (from 10 to 32 h) [1-4]. Poor metabolisers are identified through the diminished ability to metabolize debrisoquine.
Objectives: The aim of the present study was to investigate PRO and 5-OHP pharmacokinetics (PK) following oral administration of SR PRO, through the development of a joint PK model able to characterize the dissolution, absorption and disposition kinetic processes.
Methods: A joint PK model was developed from plasma concentration-time data for PRO and 5-OHP obtained for 65 healthy subjects (27 males [41.5%] and 38 females [58.5%]; with 60 subjects being extensive metabolizers [92.3%] and 5 poor metabolizers [7.7%]) included in two bioequivalence studies conducted under fed conditions (high fat high calorie) with 425 mg PRO SR capsules. The model included in vitro dissolution data to correlate with in vivo PRO dissolution for a better prediction of the absorption kinetics of the drug. Additionally, a parent-metabolite PK model was also included using nonlinear mixed-effects modelling implemented in Phoenix NLME version 8.3. Different structural models of increasing complexity were investigated. Prediction errors of the PK metrics (Cmax and AUC), as well as goodness of fit plots and normalized prediction distribution error method were used for model validation.
Results: In vitro fraction dissolved of the parent drug was modelled using a Weibull kinetic function. The in vitro dissolution parameters were then scaled to mimic the in vivo absorption delays. Additionally, a first-pass effect was considered into the model, i.e., pre-systemic transformation of PRO into its 5-OHP metabolite, with the inclusion of a fraction FP ~ 5% of the PRO dose leading to the parent and a fraction 1-FP leading to the metabolite, prior reaching the main systemic circulation (central compartment). The disposition of PRO was characterized by a two-compartmental model, with linear elimination from the central compartment (CLP), and non-linear conversion to the metabolite ((VMax*CP)/(KM+CP)), from the central compartment. The disposition of 5-OHP was also characterized by a two-compartmental model, with linear elimination from the central compartment (CLM).
Conclusions: The average predictability of the model was less than 2% for PRO and 5-OHP AUC, and was moderately high for Cmax (19% for PRO and 17% for 5-OHP). Nevertheless, the developed joint model adequately described plasma concentration-time profiles for PRO and 5-OHP in healthy subjects.
References:
[1] U.S. Food and Drug Administration (FDA). RYTHMOL SR (propafenone hydrochloride extended-release capsules), for oral use. Revised Version: February 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021416s015lbl.pdf.
[2] U.S. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review. Application No.: NDA 21-416, Rythmol. Jan 2003. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-416_Rythmol%20SR_BioPharmr.pdf
[3] Hii JT, Duff HJ, Burgess ED. Clinical pharmacokinetics of propafenone. Clin Pharmacokinet. 1991 Jul;21(1):1-10. doi: 10.2165/00003088-199121010-00001. PMID: 1914339.
[4] Hollmann M, Brode E, Hotz D, Kaumeier S, Kehrhahn OH. Investigations on the pharmacokinetics of propafenone in man. Arzneimittelforschung. 1983;33(5):763-70. PMID: 6683556.
