Population pharmacokinetic modeling of esaxerenone: a novel nonsteroidal mineralocorticoid receptor blocker
Masato Fukae (1), Kris Jamsen (2), Takako Shimizu (1), Ophelia Yin (3), Helen Kastrissios (2), Kazutaka Yoshihara (1)
(1) Daiichi Sankyo Co., Ltd. Tokyo, Japan, (2) Certara, L.P., NJ, USA (3) Daiichi Sankyo Inc., NJ, USA
Objectives: Esaxerenone is a novel nonsteroidal mineralocorticoid receptor blocker that was approved as an antihypertensive agent in Japan in 2019. In the present study, a population pharmacokinetic (PopPK) modeling was performed to 1) characterize typical PK of esaxerenone, 2) identify influential covariates, and 3) aid dose-adjustment recommendations.
Methods: Analysis included a total of 8263 esaxerenone plasma concentrations collected from 1623 Japanese subjects across 15 studies (7 Phase I studies, including one intravenous administration arm, 5 Phase II studies and 3 Phase III studies). Esaxerenone doses administered were ranged from 0.625 up to 200 mg. Development of the base model was guided by data exploration, biological/pharmacological plausibility, objective function value, precision of parameter estimates, and goodness-of-fit (GOF) plots. Since drug-drug interaction (DDI) studies reported that itraconazole and rifampicin affected the exposure to esaxerenone, and a single ascending dose study suggested lower absolute bioavailability (F) at high doses (equal to or more than 50 mg), these effects were incorporated into the base model. Afterwards a full covariate modeling was performed. The following covariates were tested on both clearance (CL) and central volume of distribution (Vc): hypertension, diabetic nephropathy, sex, age and body weight at baseline. Additional covariates were tested on CL, including alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), gamma-glutamyl transferase (GGT), estimated glomerular filtration rate based on serum creatinine (eGFR), smoking status, concomitant use of strong inhibitors/inducers of CYP3A taken systemically in the Phase II/III studies, and moderate renal impairment. The performance of the final model was evaluated by the standard GOF procedures and a prediction-corrected visual predictive check. Based on the final model, simulations were performed to visualize the influence of identified covariates on the exposure at steady state to esaxerenone. The analysis was performed in NONMEM 7.2 via PsN 4.6.0, where first order conditional estimation with a log-transform both sides approach was employed. Post-processing and model evaluations were performed in R version 3.3.1.
Results: Observed plasma esaxerenone concentrations were described adequately by a three-compartment model with sequential zero- and first-order absorption and first-order elimination. The parameter estimates (inter-individual variability, expressed as % coefficient of variation) of F, CL and Vc were 0.853 (not estimated), 3.28 L/h (18.2%) and 43.4 L (16.9%), respectively. The final PopPK model included the following covariates: concomitant use of itraconazole or rifampicin and high doses on F; age, body weight, smoking status, AST, eGFR and concomitant use of itraconazole or rifampicin on CL; and age and body weight on Vc. None of the other covariates tested (hypertension, diabetic nephropathy, sex, ALP, ALT, TBIL, GGT, moderate renal impairment, strong inhibitor and inducer of CYP3A in Phase II/III studies) had substantial effects on esaxerenone exposure. Simulation from the final model showed 63.8% increase and 68.4% decrease in average concentration at steady-state (CavSS) by itraconazole and rifampicin use, respectively. Compared to patients with typical body weight (68 kg), patients with extremely light (40 kg) and heavy (120 kg) body weight showed a 35.7% increase and a 28.3% decrease, respectively, in CavSS. The effects of the other covariates were within the traditional bioequivalence range of 80% to 125%, suggesting that they are unlikely to be clinically meaningful.
Conclusions: The present analysis revealed the small variability in esaxerenone PK, detected influential covariates and quantified the effects of these covariates. These results indicated that no dose adjustment is necessary on the basis of these covariates from a viewpoint of PK.