Translational pharmacokinetic-pharmacodynamic modelling; application to cardiovascular safety data for PF-00821385, a novel HIV agent.
OBJECTIVE
To assess the translation of pharmacokinetic-pharmacodynamic (PK-PD) relationships for heart rate effects of PF-00821385 in dog and man.


METHODS
Cardiovascular telemetric parameters and concentration data were available for animals receiving active doses (0.5-120 mg kg(-1), n= 4) or vehicle. PF-00821385 was administered to 24 volunteers and pharmacokinetic and vital signs data were collected. PK-PD models were fitted using nonlinear mixed effects.


RESULTS
Compartmental models with linear absorption and clearance were used to describe pharmacokinetic disposition in animal and man. Diurnal variation in heart and pulse rate was best described with a single cosine function in both dog and man. Canine and human heart rate change were described by a linear model with free drug slope 1.76 bpm microM(-1)[95% confidence interval (CI) 1.17, 2.35] in the dog and 0.76 bpm microM(-1) (95% CI 0.54, 1.14) in man.


CONCLUSIONS
The preclinical translational of concentration-response has been described and the potential for further interspecies extrapolation and optimization of clinical trial design is addressed.
Langdon
Grant
G
Clinical Pharmacology, Pfizer Inc., Sandwich, UK. grant.langdon@pfizer.com <grant.langdon@pfizer.com>
Davis
John D
JD
McFadyen
Lynn M
LM
Dewhurst
Mark
M
Brunton
Neil S
NS
Rawal
Jaiessh K
JK
Van der Graaf
Piet H
PH
Benson
Neil
N
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015331:Cohort Studies; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015658:HIV Infections / Q000188:drug therapy; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D055815:Young Adult
C551123:5-((1S)-2-((2R)-4-benzoyl-2-methyl-piperazin-1-yl)-1-methyl-2-oxo-ethoxy)-4-methoxy-pyridine-2-carboxylic acid methylamide; D019380:Anti-HIV Agents; D010879:Piperazines; D011725:Pyridines
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