State University of New York at Buffalo, Buffalo, NY, USA.
College of Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA.
Br J Clin Pharmacol. 2019 Feb;85(2):366-376. doi: 10.1111/bcp.13802. Epub 2018 Nov 22.
Treatment of prolactinomas with ergoline dopamine agonists can be complicated by intolerance and resistance. This study investigated the pharmacokinetics and pharmacodynamics of the nonergot dopamine agonist ropinirole, to assess its therapeutic potential as a novel therapy for prolactinomas.
Five female subjects with prolactinomas participated in this dose-response study. Subjects received up to three doses of ropinirole (0.5, 1.0 and 2.0 mg), each on separate occasions. Frequent blood samples for prolactin and ropinirole were collected for 24 h following drug administration. Data were analysed using noncompartmental and compartmental pharmacokinetic-pharmacodynamic (PKPD) techniques.
Seven 24-h curves revealed increased systemic drug exposure with increasing ropinirole doses. Ropinirole concentrations peaked at 4.4 ± 2.7 h and exhibited a half-life of 5.8 ± 1.7 h. A dose-dependent prolactin nadir occurred 4.4 ± 1.2 h after drug intake and prolactin concentrations transiently normalized in two of five subjects. PKPD modelling revealed that single-dose PK of ropinirole is dose-independent and can be described with a one-compartment model with linear absorption and elimination. An indirect response model successfully captures the inhibitory effect of ropinirole on prolactin secretion and incorporates time-dependent receptor desensitization for three of five subjects whose prolactin concentrations nadired before ropinirole reached C .
This data-rich study has informed our understanding of the clinical pharmacokinetics and pharmacodynamics of ropinirole, which are successfully captured by the proposed semi-mechanistic PKPD model. This model can be used to further investigate the PKPD of ropinirole and may facilitate the identification of optimal dose regimens for the treatment of prolactinomas and the establishment of a new therapeutic option for patients impacted by this rare disease.
使用麦角类多巴胺激动剂治疗催乳素瘤可能会出现不耐受和抵抗。本研究旨在研究非麦角类多巴胺激动剂罗匹尼罗的药代动力学和药效动力学，评估其作为治疗催乳素瘤的新疗法的治疗潜力。
5 名催乳素瘤女性患者参与了这项剂量反应研究。患者分别接受了罗匹尼罗（0.5、1.0 和 2.0mg）的 3 个剂量，每个剂量分别在不同的时间点给药。给药后 24 小时内频繁采集血液样本，以检测催乳素和罗匹尼罗的浓度。数据使用非房室和房室药效动力学（PKPD）分析方法进行分析。
7 个 24 小时的曲线显示，随着罗匹尼罗剂量的增加，系统药物暴露量增加。罗匹尼罗浓度在 4.4±2.7 小时达到峰值，半衰期为 5.8±1.7 小时。药物摄入后 4.4±1.2 小时出现催乳素的最低值，5 名患者中的 2 名患者的催乳素浓度短暂恢复正常。PKPD 模型表明，罗匹尼罗的单次剂量 PK 与剂量无关，可用线性吸收和消除的单室模型来描述。间接反应模型成功地捕捉了罗匹尼罗对催乳素分泌的抑制作用，并将受体脱敏的时间依赖性纳入了其中 3 名催乳素浓度在罗匹尼罗达到 C 之前达到最低值的患者的模型中。
这项数据丰富的研究使我们深入了解了罗匹尼罗的临床药代动力学和药效动力学，所提出的半机理 PKPD 模型成功地捕捉到了这些特征。该模型可用于进一步研究罗匹尼罗的 PKPD，并可能有助于确定治疗催乳素瘤的最佳剂量方案，为受这种罕见疾病影响的患者提供新的治疗选择。
