Mar Ribera Armengol (1), Michael J. Chappell (1)
(1) School of Engineering, University of Warwick, Coventry, CV4 7AL, United Kingdom (corresponding author e-mail: mar.ribera-i-armengol@warwick.ac.uk)
Background: Overactive bladder (OAB) is a condition that refers to the appearance of unwanted and uncontrolled contractions in the bladder during its filling stage and is common in Spinal Cord Injury (SCI) patients [1]. Anticholinergics have traditionally been the most widely used drugs for treatment of the symptoms of OAB, however, due to the typical appearance of adverse effects such as dry mouth or constipation, a novel drug has been developed with the aim of eliminating these unwanted effects. This new drug is called Mirabegron and it is the first selective β3-adrenoceptor agonist drug for treatment of the OAB syndrome [2]. An understanding of the duration of its effects relating to the contractility levels of the bladder is required in order to accurately determine appropriate individualised dosing levels
Aim: The overall objective of this study is to develop a mathematical model that characterises the kinetics of orally administered Mirabegron in the detrusor of the bladder.
Methods: Previously published data from different studies [3], [4], [5], [6], [7], [8] and [9] for patients receiving a 50mg oral dose of controlled release Mirabegron tablets have been evaluated. Plasma concentration vs. time profiles of Mirabegron have been considered as the only measured observation from the cited studies. A 5-compartment, 7-parameter, linear mixed effects model of the reaction pathway of the oral administration of Mirabegron in the bladder has been developed and fitted to all available data. Mirabegron plasma concentrations have been used to establish the PK model parameterisation in a population context. Monolix [10] has been applied to fit the model to all available data.
Results: A structural identifiability analysis has been performed on the model using a Mathematica application developed by a research team at the Fraunhofer-Chalmers Centre in Gothenburg, Sweden [11]. The result of the identifiability analysis, where the model observation is given by the concentration of Mirabegron in plasma, is that the model is at least locally identifiable, supporting confidence in the subsequent practical identifiability analysis/parameter estimation performed. The Mirabegron PK model accurately reproduces the known plasma concentration profiles of Mirabegron. The population estimates of the absorption rates which form an absorption input chain (ka1, ka2, ka3), Mirabegron flow from plasma to detrusor rate (k45), Mirabegron flow from detrusor back into plasma rate (k54), elimination rate (kel) and volume of plasma compartment (Vi) are 0.75 h-1 (20% IIV), 2.26 h-1 (126% IIV), 0.88 h-1 (40% IIV), 0.25 h-1 (16% IIV), 0.067 h-1 (63% IIV), 0.095 h-1 (40% IIV) and 3.5 L (123% IIV), respectively. The maximum RSE (%) value of the fixed effects is 33.8 for ka2, while the maximum RSE (%) values of the standard deviations (SD) of the random effects (RE) are 56.9 and 121 for the parameters kel and k45, respectively. High inter-subject variability has been observed in the plasma concentration vs. time data which explains the high RSE (%) values of the SD of the RE for kel and k45. Model evaluation has been performed using goodness-of-fit plots and by comparing the predicted and the observed area under the curve (AUC) values for Mirabegron. The average of the relative error between the overall observed and predicted AUC values is of 0.096.
Conclusion: Overall, a linear mixed effects model that characterises Mirabegron plasma concentrations has been developed that yields responses that are in good agreement with time course data available in the literature. This model will be used in combination with other PK and fluid dynamic models for the design of a smart catheter to support SCI patients who habitually suffer with overactive bladder problems. Future work will consider the pharmacodynamic effects of Mirabegron in order to predict when the contractility of the bladder is going to restart after the oral intake of Mirabegron. [10]
[1] P. Angelico, C. Velasco, L. Guarneri, G. Sironi, A. Leonardi, and R. Testa, “Urodynamic effects of oxybutynin and tolterodine in conscious and anesthetized rats under different cystometrographic conditions,” BMC Pharmacol., vol. 5, p. 14, Oct. 2005, doi: 10.1186/1471-2210-5-14. [2] T. Hatanaka et al., “In vitro and in vivo pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in rats.,” Naunyn. Schmiedebergs. Arch. Pharmacol., vol. 386, no. 3, pp. 247–253, Mar. 2013, doi: 10.1007/s00210-012-0821-4.[3] S. Rittig et al., “The pharmacokinetics, safety, and tolerability of mirabegron in children and adolescents with neurogenic detrusor overactivity or idiopathic overactive bladder and development of a population pharmacokinetic model–based pediatric dose estimation,” J. Pediatr. Urol., vol. 16, no. 1, pp. 31.e1-31.e10, 2020, doi: https://doi.org/10.1016/j.jpurol.2019.10.009. [4] H. Iitsuka et al., “Pharmacokinetics of mirabegron, a β3-adrenoceptor agonist for treatment of overactive bladder, in healthy Japanese male subjects: results from single- and multiple-dose studies.,” Clin. Drug Investig., vol. 34, no. 1, pp. 27–35, Jan. 2014, doi: 10.1007/s40261-013-0146-1. [5] W. Krauwinkel et al., “Pharmacokinetic properties of mirabegron, a β3-adrenoceptor agonist: results from two phase I, randomized, multiple-dose studies in healthy young and elderly men and women.,” Clin. Ther., vol. 34, no. 10, pp. 2144–2160, Oct. 2012, doi: 10.1016/j.clinthera.2012.09.010.[6] H. Iitsuka, M. van Gelderen, M. Katashima, S. Takusagawa, and T. Sawamoto, “Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects.,” Clin. Ther., vol. 37, no. 5, pp. 1031–1044, May 2015, doi: 10.1016/j.clinthera.2015.02.021.[7] J. Lee et al., “Effects of food intake on the pharmacokinetic properties of mirabegron oral controlled-absorption system: a single-dose, randomized, crossover study in healthy adults.,” Clin. Ther., vol. 35, no. 3, pp. 333–341, Mar. 2013, doi: 10.1016/j.clinthera.2013.02.014. [8] C. Eltink et al., “Single dose pharmacokinetics and absolute bioavailability of mirabegron, a??3-adrenoceptor agonist for treatment of overactive bladder,” Int. J. Clin. Pharmacol. Ther., vol. 50, pp. 838–850, Sep. 2012, doi: 10.5414/CP201782.[9] M. Malik et al., “Proarrhythmic safety of repeat doses of mirabegron in healthy subjects: a randomized, double-blind, placebo-, and active-controlled thorough QT study.,” Clin. Pharmacol. Ther., vol. 92, no. 6, pp. 696–706, Dec. 2012, doi: 10.1038/clpt.2012.181. [10] Antony, “Monolix version 2020R1.” Lixoft SAS, France, 2020.[11] J. Karlsson, M. Anguelova, and M. Jirstrand, “An Efficient Method for Structural Identifiability Analysis of Large Dynamic Systems,” IFAC Proc. Vol., vol. 45, no. 16, pp. 941–946, 2012, doi: https://doi.org/10.3182/20120711-3-BE-2027.00381.
Reference: PAGE 30 (2022) Abstr 10012 [www.page-meeting.org/?abstract=10012]
Poster: Drug/Disease Modelling - Other Topics