Lim Chay Ngee, Salem Ahmed Hamed
Clinical Pharmacology and Pharmacometrics, AbbVie, 1 North Waukegan Road, Dept. R4PK, Bldg AP13A-3, North Chicago, IL, 60064-6145, USA.
Clin Pharmacokinet. 2015 Sep;54(9):963-73. doi: 10.1007/s40262-015-0251-9.
Leuprolide is a gonadotropin-releasing hormone (GnRH) agonist, which inhibits gonadotropin secretion by down-regulating pituitary GnRH receptor when administered continuously at therapeutic doses. The objectives of this analysis were to develop a population model that can describe the pharmacokinetics of the 6-month depot formulation of leuprolide acetate in patients with prostate cancer and to characterize the relationship of leuprolide plasma concentrations and serum testosterone concentrations.
The pharmacokinetic and pharmacodynamic analyses were performed using a non-linear mixed-effect modeling approach. Observations were pooled from studies on healthy male volunteers and prostate cancer patients, who were administered a single 1 mg intravenous dose of immediate-release leuprolide acetate and two intramuscular doses of 45 mg of the depot formulation, respectively. The covariates that were screened for the pharmacokinetic model included body weight, creatinine clearance, liver function markers (total bilirubin, blood urea nitrogen, AST, alanine aminotransferase), age, and body mass index.
A two-compartment model with parallel first- and zero-order absorption processes and a delayed first-order process well-characterized the multi-phasic absorption profile of leuprolide acetate depot formulation. Typical population values of the absorption rate constant of the immediate and delayed processes were estimated to be 0.357 and 0.017 day(-1), respectively, with a mean transit time of 9.5 days. No covariates were significant in this analysis. A semi-mechanistic model, which accounts for down-regulation of the GnRH receptor via an inhibitory maximum effect (E max) model and the stimulatory effect of activated receptors on testosterone levels, adequately described serum testosterone profiles following dosing. The equilibrium dissociation constant of leuprolide and the typical leuprolide plasma concentration required to achieve a castration testosterone level of ≤0.5 ng/mL were 0.3 and 0.03 ng/mL, respectively.
Population pharmacokinetics and pharmacodynamics of the leuprolide depot formulation were characterized using an integrated semi-mechanistic model. The developed model adequately describes the leuprolide-testosterone relationship and can potentially be used to facilitate design of clinical studies for new formulations, to aid in the selection of candidate formulations, and for the optimization of doses and dosing schemes.
亮丙瑞林是一种促性腺激素释放激素（GnRH）激动剂，当以治疗剂量持续给药时，它通过下调垂体GnRH受体来抑制促性腺激素分泌。本分析的目的是建立一个群体模型，该模型能够描述醋酸亮丙瑞林6个月长效剂型在前列腺癌患者体内的药代动力学，并表征亮丙瑞林血药浓度与血清睾酮浓度之间的关系。
采用非线性混合效应建模方法进行药代动力学和药效学分析。观察数据来自对健康男性志愿者和前列腺癌患者的研究，他们分别接受了1 mg醋酸亮丙瑞林速释剂的单次静脉注射剂量以及45 mg长效剂型的两次肌肉注射剂量。药代动力学模型筛选的协变量包括体重、肌酐清除率、肝功能指标（总胆红素、血尿素氮、谷草转氨酶、谷丙转氨酶）、年龄和体重指数。
具有平行一级和零级吸收过程以及延迟一级过程的二室模型很好地描述了醋酸亮丙瑞林长效剂型多相吸收曲线。即时和延迟过程吸收速率常数的典型群体值分别估计为0.357和0.017天⁻¹，平均转运时间为9.5天。在此分析中，没有协变量具有显著性。一个半机制模型，通过抑制性最大效应（E max）模型解释GnRH受体的下调以及活化受体对睾酮水平的刺激作用，充分描述了给药后的血清睾酮曲线。亮丙瑞林的平衡解离常数以及达到去势睾酮水平≤0.5 ng/mL所需的典型亮丙瑞林血药浓度分别为0.3和0.03 ng/mL。
使用综合半机制模型表征了亮丙瑞林长效剂型群体药代动力学和药效学。所建立的模型充分描述了亮丙瑞林 - 睾酮关系，并且有可能用于促进新剂型临床研究的设计、辅助候选剂型的选择以及剂量和给药方案的优化。
