title: Translational PK/PD modeling for cardiovascular safety assessment of drug candidates: Methods and examples in drug development.
abstract: BACKGROUND
  Cardiovascular toxicity is a significant cause of candidate failure in drug development. Pharmacokinetic/pharmacodynamic (PK/PD) modeling may reduce attrition by improving the understanding of the relationship between drug exposure and changes in cardiovascular endpoints. Diverse examples are discussed that elucidate how modeling can facilitate the interpretation of cardiovascular safety data in animals and enable quantitative translation of preclinical findings to man.
  
  
  METHODS
  Twelve compounds under development in diverse therapeutic areas were tested in cardiovascular safety studies in the telemetered beagle dog and cynomolgus monkey. Drug-induced changes observed in different cardiovascular endpoints (QRS complex and QTc interval of the ECG, heart rate, blood pressure, and myocardial contractility) were described by means of PK/PD modeling. A range of direct and indirect effect models were employed to characterize the plasma concentration-cardiovascular effect relationship for each compound.
  
  
  RESULTS
  For every drug candidate the proposed PK/PD models appropriately described the cardiovascular effects observed in dog and monkey. Two of the compounds subsequently reached clinical development and cardiovascular data were generated in first-in-human clinical trials. For one drug candidate, a threshold model was used to describe QTc prolongation in the monkey and man. Blood pressure changes induced by the second compound were linked to plasma exposure in dog and human via an indirect response model. In both cases it was found that translational modeling accurately predicted the human response observed during clinical development.
  
  
  CONCLUSIONS
  In this article, a range of PK/PD models are discussed that successfully described cardiovascular safety findings in the preclinical setting. Where clinical data were available, it was found that translational modeling enabled the accurate prediction of outcomes in man and facilitated the description of the therapeutic index. PK/PD modeling is thus demonstrated as a powerful tool to aid in the quantitative cardiovascular safety assessment of drug candidates and the optimization of early clinical study protocols.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland. Electronic address: antonello.caruso@roche.com.
authors.forename: Antonello
authors.initials: A
authors.lastname: Caruso
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Frances
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Meille
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Greiter-Wilke
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hillebrecht
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lavé
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004285:Dogs; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000188:drug therapy; D008252:Macaca fascicularis; D008297:Male; D008962:Models, Theoretical; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism*; D017751:Safety Management / Q000379:methods; D013686:Telemetry / Q000379:methods; D057170:Translational Research, Biomedical / Q000379:methods
chemical_list: D004364:Pharmaceutical Preparations
keywords: Cardiovascular safety pharmacology; Nonlinear mixed effects modeling; PK/PD modeling; Telemetry studies; Translation to human