A Population Pharmacokinetic Analysis of PF-5190457, a Novel Ghrelin Receptor Inverse Agonist in Healthy Volunteers and in Heavy Alcohol Drinkers.
A Population Pharmacokinetic Analysis of PF-5190457, a Novel Ghrelin Receptor Inverse Agonist in Healthy Volunteers and in Heavy Alcohol Drinkers.
复制标题
DOI：
10.1007/s40262-020-00942-7
复制
发表时间：
2021-04
影响因子：
4.5
通讯作者：
Akhlaghi F
中科院分区：
文献类型：
--
作者：
Cobbina E;Lee MR;Leggio L;Akhlaghi F
生长激素释放肽受体（GHS-R1 a）是酒精使用障碍（AUD）的潜在靶点。PF-5190457是第一个进入临床开发阶段的GHS-R1 a反向激动剂，具有治疗AUD的潜力。我们在非重度饮酒者（ALC=0）和重度饮酒者（ALC=1）中提供了PF-5190457的群体药代动力学（popPK）模型;并确定了可能影响其PK的相关因素。合并非重度饮酒者（n=35）和重度饮酒者（n=12）的血浆浓度-时间数据，用于popPK模型开发。评估了各种协变量的影响，包括饮酒状况（ALC）。还使用自举法和视觉预测检查评估了模型的准确性、精密度和稳健性。二室模型最佳描述了PF-5190457的PK。表观分布容积（V2/F）= 44.5 L，表观清除率（CL/F）= 72.0 L/hr，表观外周分布容积（V3/F）= 271 L，表观分布清除率（Q/F）= 28.7 L/hr，一级吸收速率常数（ka）= 0.27 hr−1，具有准确度和精密度。重度饮酒者的V2/F高3.8倍（169 L），与相同剂量下重度饮酒者的Cmax低于非重度饮酒者相关;剂量> 50 mg时重度饮酒者嗜睡的发生率相应降低。这项工作提供了一个准确、精密和稳健的二室模型，该模型描述了PF-5190457的PK，并表明PF-5190457药代动力学与嗜睡可能存在联系。ClinicalTrials.gov标识号NCT 01247896和NCT 02039349
The ghrelin receptor (GHS-R1a) is a potential target for alcohol use disorders (AUD). PF-5190457 is the first inverse agonist of GHS-R1a to progress to clinical development with potential to treat AUD. We present a population pharmacokinetic (popPK) model for PF-5190457 in non-heavy (ALC=0) and heavy alcohol drinkers (ALC=1); and to identify relevant factors that can influence its PK. Plasma concentration-time data from non-heavy (n=35) and heavy drinkers (n=12) were pooled for the popPK model development. The influence of various covariates, including alcohol consumption status (ALC) were evaluated. The accuracy, precision and robustness of the model were also evaluated using bootstrapping and visual predictive checks. A two-compartment model best described the PK of PF-5190457. The apparent volume of distribution (V2/F) = 44.5 L, apparent clearance (CL/F) = 72.0 L/hr, apparent peripheral volume of distribution (V3/F) = 271 L, apparent distributional clearance (Q/F) = 28.7 L/hr, and first order absorption rate constant (ka) = 0.27 hr−1, were accurate and precise. The V2/F was 3.8-fold higher (169 L) in heavy drinkers, and correlated with a lower Cmax in heavy drinkers compared to non-heavy drinkers at the same dose; and a corresponding reduced incidence of somnolence in heavy drinkers at doses > 50 mg. This work provides an accurate, precise, and robust two compartment model that describes the PK of PF-5190457 and suggests a possible link of PF-5190457 pharmacokinetics with somnolence. ClinicalTrials.gov identifier numbers NCT01247896 and NCT02039349
登录
查看更多内容
DOI：
10.1007/164_2017_79
发表时间：
2018-01-01
期刊：
NEUROPHARMACOLOGY OF ALCOHOL
影响因子：
--
作者：
Litten, Raye Z.;Falk, Daniel E.;Leggio, Lorenzo
通讯作者：
Leggio, Lorenzo
影响因子：
4.2
作者：
Bhattacharya, Samit K.;Andrews, Kim;Zhang, Yingxin
通讯作者：
Zhang, Yingxin
影响因子：
168.9
作者：
Johnson, BA;Ait-Daoud, N;Ma, JZ
通讯作者：
Ma, JZ
DOI：
10.1073/pnas.0800708105
发表时间：
2008-04-29
影响因子：
11.1
作者：
Gutierrez, Jesus A.;Solenberg, Patricia J.;Hale, John E.
通讯作者：
Hale, John E.
DOI：
10.1111/j.1530-0277.2010.01273.x
发表时间：
2010-11-01
影响因子：
3.2
作者：
Garbutt, James C.;Kampov-Polevoy, Alexei B.;Flannery, Barbara A.
通讯作者：
Flannery, Barbara A.