title: Translational pharmacokinetic-pharmacodynamic modelling; application to cardiovascular safety data for PF-00821385, a novel HIV agent.
abstract: 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.
authors.affiliation: Clinical Pharmacology, Pfizer Inc., Sandwich, UK. grant.langdon@pfizer.com <grant.langdon@pfizer.com>
authors.forename: Grant
authors.initials: G
authors.lastname: Langdon
authors.forename: John D
authors.initials: JD
authors.lastname: Davis
authors.forename: Lynn M
authors.initials: LM
authors.lastname: McFadyen
authors.forename: Mark
authors.initials: M
authors.lastname: Dewhurst
authors.forename: Neil S
authors.initials: NS
authors.lastname: Brunton
authors.forename: Jaiessh K
authors.initials: JK
authors.lastname: Rawal
authors.forename: Piet H
authors.initials: PH
authors.lastname: Van der Graaf
authors.forename: Neil
authors.initials: N
authors.lastname: Benson
mesh_terms: 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
chemical_list: 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
references.citation: J Infect Dis. 2000 Aug;182(2):607-10
references.pmid: 10915097
references.citation: Clin Pharmacol Ther. 2005 Jun;77(6):572-82
references.pmid: 15961988
references.citation: CNS Drug Rev. 2003 Summer;9(2):187-98
references.pmid: 12847558
references.citation: Am J Vet Res. 2001 Jan;62(1):37-42
references.pmid: 11197557
references.citation: Lab Anim. 2002 Jan;36(1):1-19
references.pmid: 11833526
references.citation: Clin Pharmacol Ther. 2005 Nov;78(5):508-19
references.pmid: 16321617
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H59-68
references.pmid: 18456734
references.citation: Br J Clin Pharmacol. 2000 Sep;50(3):227-35
references.pmid: 10971307
references.citation: Cardiovasc Res. 2001 Mar;49(4):741-50
references.pmid: 11230973
references.citation: Comput Methods Programs Biomed. 2004 Aug;75(2):85-94
references.pmid: 15212851
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11013-8
references.pmid: 12930892
references.citation: Comput Methods Programs Biomed. 2005 Sep;79(3):241-57
references.pmid: 16023764
references.citation: Am J Ther. 1995 Aug;2(8):541-545
references.pmid: 11854824
references.citation: J Toxicol Sci. 2005 Aug;30(3):229-37
references.pmid: 16141656
references.citation: Trends Pharmacol Sci. 2008 Apr;29(4):186-91
references.pmid: 18353445
references.citation: Am J Ther. 1995 Aug;2(8):532-536
references.pmid: 11854822
references.citation: Clin Pharmacol Ther. 2007 Jul;82(1):21-32
references.pmid: 17522597
references.citation: Comput Methods Programs Biomed. 1999 Jan;58(1):51-64
references.pmid: 10195646
references.citation: Annu Rev Immunol. 2001;19:253-74
references.pmid: 11244037
references.citation: Fundam Clin Pharmacol. 2002 Apr;16(2):125-40
references.pmid: 12031065
references.citation: Drug Discov Today. 2007 Dec;12(23-24):1018-24
references.pmid: 18061880
references.citation: Lab Anim. 2006 Apr;40(2):123-36
references.pmid: 16600072
references.citation: Am J Ther. 1995 Aug;2(8):537-540
references.pmid: 11854823
references.citation: J Pharmacol Exp Ther. 1997 Mar;280(3):1176-83
references.pmid: 9067301
references.citation: Clin Pharmacol Ther. 2008 Jun;83(6):909-12
references.pmid: 18388873