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.

中文翻译：

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Relugolix 对前列腺癌男性睾酮抑制作用的群体 PK 和半机械 PK/PD 建模和模拟

Relugolix 是第一个具有口服活性的非肽类促性腺激素释放激素受体拮抗剂，已在美国和欧盟获准用于治疗成年晚期前列腺癌患者。推荐的给药方案是 360 毫克负荷剂量，然后是 120 毫克每日剂量。来自两项 I 期研究、两项 II 期研究和 III 期安全性和有效性研究 (HERO) 的 Relugolix 和睾酮浓度数据和临床信息被用于开发群体药代动力学 (PopPK) 模型和半机械群体药代动力学/药效学 (PopPK) /PD) 模型表征了 relugolix 暴露及其与睾酮浓度的关系。年龄、体重、黑人/非裔美国人种族对 relugolix 暴露或睾酮浓度的影响至多很小，与临床无关。使用 PopPK/PD 模型进行的模拟证实了 relugolix 的推荐给药方案，预计到第 2 天和第 9 天达到去势水平 (< 50 ng/dL) 和深度去势水平 (< 20 ng/dL) 的中位模拟睾酮浓度，并证明在暂时中断治疗 7 天和 14 天后，97.3% 和 85.5% 的患者分别保持去势水平（< 50 ng/dL）。总的来说，基于 PopPK 和 PopPK/PD 模型的模拟与临床研究的实际数据一致，反映了模型的高预测性并支持基于模型的模拟的可靠性。