Population PK and Semimechanistic PK/PD Modeling and Simulation of Relugolix Effects on Testosterone Suppression in Men with Prostate Cancer

Abstract

Relugolix, the first orally active, nonpeptide gonadotropin-releasing hormone receptor antagonist, is approved in the United States and the European Union for the treatment of adult patients with advanced prostate cancer. The recommended dosing regimen is a 360-mg loading dose followed by a 120-mg daily dose. Relugolix and testosterone concentration data and clinical information from two phase I studies, two phase II studies, and the phase III safety and efficacy study (HERO) were used to develop a population pharmacokinetic (PopPK) model and a semimechanistic population pharmacokinetic/pharmacodynamic (PopPK/PD) model that characterized relugolix exposure and its relationship to testosterone concentrations. Age, body weight, and Black/African American race had at most minimal effects on relugolix exposure or testosterone concentrations with no clinical relevance. Simulations using the PopPK/PD model confirmed the recommended dosing regimen of relugolix, with the median simulated testosterone concentrations predicted to achieve castration levels (< 50 ng/dL) and profound castration levels (< 20 ng/dL) by day 2 and day 9, respectively, and demonstrated that 97.3% and 85.5% of the patients remained at castration levels (< 50 ng/dL) upon temporary interruption of treatment for 7 days and 14 days, respectively. Collectively, simulations based on the PopPK and PopPK/PD models were consistent with actual data from clinical studies, reflecting the high predictiveness of the models and supporting the reliability of model-based simulations. These models can be used to provide guidance regarding dosing recommendations under various circumstances (e.g., temporary interruption of treatment, if needed) for relugolix.Prostate cancer is the second most common cancer in men and the fifth leading cause of cancer death in men, with over 1.2 million cases diagnosed and 358,000 deaths reported annually worldwide. 1 Prostate cancer is defined as advanced when it has metastasized beyond the prostate 2 ; the term "advanced" is also used for the disease with prostate-specific antigen biochemical relapse following

Adherence to Hormonal Therapies in Prostate Cancer

“…Simulation studies showed that treatment interruptions of up to 7 days did not significantly impact testosterone suppression with relugolix (Table 2). 34 Interestingly, following a 7-day treatment interruption, simulated testosterone concentrations predicted that the percentage of patients on relugolix who remained at castration levels was still higher (97.3%) than the observed population treated with leuprolide (88.8%) during the HERO study (Table 1). After a temporary interruption of 7 days or longer, a loading dose of 360 mg of relugolix is recommended.…”

“…35 The simulated testosterone concentrations are predicted to return to steady state approximately 13 days after the resumption of the 120-mg daily dose. 34…”

“…35 The simulated testosterone concentrations are predicted to return to steady state approximately 13 days after the resumption of the 120-mg daily dose. 34 Oral therapy provides flexibility in managing adverse events and drug interactions. Real-world data on adherence to relugolix will be available in early 2024.…”

“…https://ascpt.onlinelibrary.wiley.com/doi/10.1002/ cpt.2743. Adapted under license CC BY 4.0 (https://creativecommons.org/ licenses/by-nc/4.0/) 34.…”

Is Higher Docetaxel Clearance in Prostate Cancer Patients Explained by Higher CYP3A? An In Vivo Phenotyping Study with Midazolam

“…Patients with prostate cancer had to have a castration level of testosterone (1.73 nmol/L or less). 22 Adequate hematologic, hepatic, and renal function were required for participation. Patients using concomitant CYP3Amodulating drugs, herbs, or food 14 days before the start of the study or within 5 half-lives of the drug and patients who smoked during or within 7 days before the start of the study were excluded.…”