Document Detail

Translational pharmacokinetic-pharmacodynamic modelling; application to cardiovascular safety data for PF-00821385, a novel HIV agent.
MedLine Citation:
PMID:  20406218     Owner:  NLM     Status:  MEDLINE    
AIM: 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.
Grant Langdon; John D Davis; Lynn M McFadyen; Mark Dewhurst; Neil S Brunton; Jaiessh K Rawal; Piet H Van der Graaf; Neil Benson
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial    
Journal Detail:
Title:  British journal of clinical pharmacology     Volume:  69     ISSN:  1365-2125     ISO Abbreviation:  Br J Clin Pharmacol     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-21     Completed Date:  2010-08-02     Revised Date:  2011-07-27    
Medline Journal Info:
Nlm Unique ID:  7503323     Medline TA:  Br J Clin Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  336-45     Citation Subset:  IM    
Clinical Pharmacology, Pfizer Inc., Sandwich, UK. <>
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MeSH Terms
Administration, Oral
Anti-HIV Agents / administration & dosage,  pharmacokinetics*,  pharmacology*
Cohort Studies
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
HIV Infections / drug therapy
Heart Rate / drug effects*
Linear Models
Metabolic Clearance Rate
Middle Aged
Piperazines / pharmacology*
Pyridines / pharmacology*
Young Adult
Reg. No./Substance:
0/5-((1S)-2-((2R)-4-benzoyl-2-methyl-piperazin-1-yl)-1-methyl-2-oxo-ethoxy)-4-methoxy-pyridine-2-carboxylic acid methylamide; 0/Anti-HIV Agents; 0/Piperazines; 0/Pyridines

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