Investigating CNS distribution of PF-05212377, a P-glycoprotein substrate, by translation of 5-HT6 receptor occupancy from non-human primates to humans

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Aarti Sawant-Basak, Laigao Chen, Peter Lockwood, Tracey Boyden, Angela C. Doran, Jessica Mancuso, Kenneth Zasadny, Timothy McCarthy, Evan D. Morris, Richard E. Carson, Irina Esterlis, Yiyun Huang, Nabeel Nabulsi, Beata Planeta, Terence Fullerton
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Abstract

PF-05212377 (SAM760) is a potent and selective 5-HT6 antagonist, previously under development for the treatment of Alzheimer’s disease. In vitro, PF-05212377 was determined to be a P-gp/non-BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF-05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (Cbu/Cpu) of 0.05 in rat and 0.64 in non-human primates (NHP). Based on pre-clinical evidence, brain penetration and target engagement of PF-05212377 was confirmed in NHP using positron emission tomography (PET) measured 5-HT6 receptor occupancy (%RO). The NHP Cpu EC50 of PF-05212377 was 0.31 nM (consistent with the in vitro human 5HT6 Ki: 0.32 nM). P-gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non-human primates and human; brain penetration of PF-05212377 in humans was postulated to be similar to that in non-human primates. In humans, PF-05212377 demonstrated dose and concentration dependent increases in 5-HT6 RO; maximal 5-HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC50 of 0.37 nM (which was similar to the in vitro human 5HT6 binding Ki 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF-05212377, a P-gp/non-BCRP substrate.

Clinical trial number: NCT01258751.

Abstract Image

通过将5-HT6受体占据从非人灵长类动物转化为人类来研究P-糖蛋白底物PF-05212377的中枢神经系统分布
PF-05212377(SAM760)是一种强效和选择性5-HT6拮抗剂,以前正在开发用于治疗阿尔茨海默病。在体外,PF-05212377被确定为P-gp/非BCRP人转运蛋白底物。在PF-05212377的体内脑渗透中观察到物种差异,大鼠脑内未结合浓度/血浆中未结合浓度之比(Cbu/Cpu)为0.05,非人灵长类动物(NHP)为0.64。基于临床前的证据,使用正电子发射断层扫描(PET)测量的5-HT6受体占有率(%RO),在NHP中证实了PF-05212377的脑穿透和靶点参与。PF-05212377的NHP-Cpu EC50为0.31nM(与体外人5HT6 Ki:0.32nM一致)。据报道,P-gp在大鼠血脑屏障中以更高的丰度表达,在非人灵长类动物和人的血脑屏障上以相似的丰度表达;PF-05212377在人类中的脑渗透被认为与在非人类灵长类动物中的相似。在人类中,PF-05212377显示5-HT6 RO的剂量和浓度依赖性增加;人体在剂量≥15 mg时测得最大5-HT6 RO为~80%,估计未结合血浆EC50为0.37 nM(与体外人体5HT6结合Ki 0.32 nM相似)。总之,来自NHP和人体PET RO评估的累积证据证实,NHP比大鼠更适合预测PF-05212377的人脑渗透,P-gp/非BCRP底物。临床试验编号:NCT01258751。
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来源期刊
CiteScore
3.60
自引率
0.00%
发文量
35
审稿时长
6-12 weeks
期刊介绍: Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes: - animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites, - in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man - studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition, - simulation and modeling in drug discovery and development - theoretical treatises - includes themed issues and reviews and exclude manuscripts on - bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation - analytical methods
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