Investigating CNS distribution of PF‐05212377, a P‐glycoprotein substrate, by translation of 5‐HT ₆ receptor occupancy from non‐human primates to humans

Abstract PF‐05212377 (SAM760) is a potent and selective 5‐HT 6 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 (C bu /C pu ) 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‐HT 6 receptor occupancy (%RO). The NHP C pu EC 50 of PF‐05212377 was 0.31 nM (consistent with the in vitro human 5HT6 K i : 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‐HT 6 RO; maximal 5‐HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC 50 of 0.37 nM (which was similar to the in vitro human 5HT6 binding K i 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.