(W-115) Leveraging PBPK modeling to advance spironolactone complex disposition knowledge

Natalia De Moraes, NA – Assistant professor, Pharmaceutics, Center for Pharmacometrics & Systems Pharmacology; Valvanera Vozmediano, NA – Assistant professor, pharmaceutics, Center for Pharmacometrics & Systems Pharmacology

Objectives: Spironolactone (SP) is a potassium-sparing diuretic medication that has been in the market for more than 60 years. SP has complex pharmacokinetics (PK) which includes poor solubility, complex metabolism, and multiple active metabolites. Limited research has comprehensively addressed SP clinical PK, efficacy and safety, resulting in persisting knowledge gaps. Additionally, SP has been used off-label in pediatrics since its approval. Several challenges are thus faced to inform SP use in pediatrics derived from this lack of substantial information on the PK in adults and pediatrics. We developed PBPK models for SP and its active metabolites canrenone (CAN) and 7α thio-methyl spironolactone (TMS) in adults to advance the knowledge on SP PK, serving as a foundation to predict PK and optimize dosing strategies for preterm neonates.

Methods: A comprehensive literature review was conducted to gather physicochemical properties, ADME processes and clinical PK for SP, CAN and TMS, guiding the input parameters for the drug-dependent PBPK model in SimCYP® V23. First, an adult PBPK model for SP was established and subsequently evaluated with oral PK from Overdiek et al [1]. An assumption was made that SP is entirely converted to CAN and TMS by CES1 enzymes, with the CES1–mediated metabolism fitted to the parent-metabolite model using PK data[1]. The PBPK models were rigorously graphically and numerically verified with published PK studies in adults. PBPK models integrating ontogeny for CES1[2] will be employed to anticipate PK in the pediatric population.

Results: PBPK models for SP, CAN and TMS were developed and adequately described the observed PK data in healthy adults[1]. Graphical comparisons demonstrated consistency between simulated and observed plasma PK profiles for all three compounds. The ratios of the predicted versus observed Cmax and AUC0–∞ for SP were within the acceptable range of 0.5–2 with exception for Cmax for Vlase et al[3] which was 2.25. This discrepancy could be explained by variable formulations bioavailability and/or food effect. The predicted/observed ratios for Cmax and AUC0–∞ for CAN and TMS were all within the acceptable range of 0.50–2 suggesting the utility of the developed models and validity of the assumption of CES1 enzymes as the main contributor to SP metabolism.

Conclusions: The PBPK models developed for SP, CAN and TMS successfully predicted the in vivo PK in adults. The adult PBPK model serves as a pivotal step toward extrapolating to pediatrics, enabling a priori predictions of PK in children and preterm neonates. By virtually assessing dosing scenarios, particularly in populations where clinical studies pose challenges, these models offer valuable insights to inform dosing decisions and optimize therapeutic outcomes.

Citations:
[1] Overdiek H et al. The Metabolism and Biopharmaceutics of Spironolactone in Man. J Clin Pharmacol Ther 5, 469-474 (1987).
[2] Boberg M et al. Age-dependent absolute abundance of hepatic carboxylesterases (CES1 and CES2) by LC-MS/MS proteomics: Application to PBPK modeling of oseltamivir in vivo pharmacokinetics in infants. Drug Metab. Dispos 45, 216–223 (2017).
[3] Vlase L et al. Determination of spironolactone and canrenone in human plasma by high-performance liquid chromatography with mass spectrometry detection. Croat Chem Acta 84, 361–366 (2011).