Prediction of H3 receptor occupancy diurnal fluctuations using population modeling and simulation with focus on guiding dose selection in a Phase IIa study.
OBJECTIVE
4-[(1S,2S)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl]benzamide (“AZ1”) is a histamine 3 (H3) autoreceptor in vivo antagonist. Sleep disturbance is a well-known class-effect for H3 antagonists and associated with high H3 receptor occupancy (RO) at night. The objective of the present work was to investigate if it was possible to obtain large diurnal fluctuations in RO for AZ1 and to suggest suitable doses for a Phase IIa study.


METHODS
Four Phase I studies were pooled and used to build a population pharmacokinetic model in NONMEM. Based on simulations of the PK model and the reported Ki-value for H3 RO from a human PET-study, RO vs. time profiles were simulated.


RESULTS
The model well described the AZ1 pharmacokinetics. Simulations predicting plasma concentration and RO vs. time profiles for several doses were explored and doses with a wide range of fluctuation in RO over the dosing interval could be identified.


CONCLUSIONS
By using population modeling and simulations of PK data and the Ki-value from a human PET study, predictions of RO vs. time for unstudied doses of AZ1 was made. Using this methodology it was possible to suggest doses with expected large diurnal fluctuations in RO.
Emma
E
Boström
Yi-Fang
YF
Cheng
Niclas
N
Brynne
Märta
M
Segerdahl
D000293:Adolescent; D000328:Adult; D001549:Benzamides / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006633:Histamine Antagonists / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D055815:Young Adult
D001549:Benzamides; D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; C037689:benzamide