Towards a drug concentration effect relationship for QT prolongation and torsades de pointes.
Preclinical strategies to evaluate torsades de pointes (TdP) have progressed significantly over recent years with reliable and robust in vitro and in vivo methodologies available to assess QT prolongation. Increased emphasis is now being placed on collecting adequate pharmacokinetic data in preclinical studies in order to carry out pharmacokinetic/pharmacodynamic analysis. Free plasma concentrations are being utilized for inter-species comparisons and for relating in vivo and in vitro results, and this approach appears to be optimal. Data obtained in these assays are predictive of the potential of a compound to prolong QT and, by inference, cause TdP. Concentration/effect relationships are apparent such that compounds with positive results in preclinical assays may prove safe, provided that the maximum concentrations expected in the patient population are significantly lower than those required to prolong QT.
Webster
Rob
R
Pfizer Global Research and Development, Department of Drug Metabolism, Ramsgate Road, Sandwich, Kent, CT13 9NG, UK. rob_webster@sandwich.pfizer.com
Leishman
Derek
D
Walker
Don
D
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004358:Drug Therapy; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D014116:Toxicology / Q000379:methods*