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P2‐010: Pharmacocokinetic and Pharmacodynamic Study (54861911ALZ1006) with a Bace Inhibitor, JNJ‐54861911, in Healthy Elderly Japanese Subjects
Author(s) -
Shimizu Hiroko,
Tritsmans Luc,
Santoh Tomoko,
Shiraishi Ayako,
Takahashi Masayoshi,
Tominaga Yushin,
Streffer Johannes
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1214
Subject(s) - tolerability , pharmacodynamics , pharmacokinetics , placebo , medicine , dosing , cohort , pharmacology , plasma concentration , cerebrospinal fluid , gastroenterology , adverse effect , pathology , alternative medicine
for pharmacokinetic and Abeta (x-40, x-42 and total) biomarker analysis. Results: No clinical abnormalities were identified and no significant changes on safety ECG, telemetry, vital signs, or labs were observed up to 360 mg single dose. Doses were escalated up to the pre-defined exposure limit and maximum tolerated dose has not been established. Following single doses under fasted condition, PF-06648671 was absorbed rapidly with median tmax of 1 to 1.5 hours. The mean terminal t1/2 was 13.9 to 23.1 hours. The Cmax and AUCinf increased by approximately 88and 140-fold over the dose range of 2 to 360 mg. With high-fat meal, a delayed median tmax of 4 hours was observed. AUCinf slightly increased by 23% while Cmaxdecreased by 24% compared to the fasted state. Significant, dose-dependent reductions in plasma Abeta42, 40 and total were observed. The placebo-adjusted maximal change from baseline was -56.9% and -68.8% for plasma Abeta42 and 40, respectively, after a single dose of 360 mg. As expected, the reduction in Abeta total was substantially less than in Abeta40 and 42. Conclusions: PF-06648671 was generally safe and well tolerated in healthy subjects after single oral doses up to 360 mg. Robust and dose-dependent reductions in plasma Ab40 and Ab42 were observed following single dose administrations. A multiple ascending dose study in healthy adult and elderly is ongoing with CSF Ab effect evaluated at steady state.