An integrative pharmacokinetic-cardiovascular physiology modelling approach based on in vivo dog studies including five reference compounds

Bai, 1993, Pharmacokinetics of the enantiomers of verapamil in the dog, Chirality, 5, 436, 10.1002/chir.530050608 Bartow, 1998, Formoterol: An update of its pharmacological properties and therapeutic efficacy in the Management of Asthma, Drugs, 55, 303, 10.2165/00003495-199855020-00016 Bazett, 1920, An analysis of the time-relations of electrocardiograms, Heart, 7, 353 Bell, 2016, The pharmacokinetics of pimobendan enantiomers after oral and intravenous administration of racemate pimobendan formulations in healthy dogs, Journal of Veterinary Pharmacology and Therapeutics, 39, 54, 10.1111/jvp.12235 Bennett, 1984, Changes in vascular capacity in awake dogs in response to carotid sinus occlusion and administration of catecholamines, Circulation Research, 55, 440, 10.1161/01.RES.55.4.440 Bhatt, 2019, Preclinical to clinical translation of hemodynamic effects in cardiovascular safety pharmacology studies, Toxicological Sciences: An Official Journal of the Society of Toxicology, 169, 272, 10.1093/toxsci/kfz035 Borghardt, 2016, Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach, British Journal of Clinical Pharmacology, 81, 538, 10.1111/bcp.12780 Brand, 2008, Higher lung deposition with Respimat® soft mistTM inhaler than HFA-MDI in COPD patients with poor technique, International Journal of Chronic Obstructive Pulmonary Disease, 3, 763 Champeroux, 2009, Calculation of QT shift in non clinical safety pharmacology studies, Journal of Pharmacological and Toxicological Methods, 59, 73, 10.1016/j.vascn.2008.11.001 Chen, 2005, Pharmacokinetics interaction of captopril and low-dosage aspirin in dog, Journal of Chinese Pharmaceutical Sciences, 40, 696 Cook, 2014, Lessons learned from the fate of AstraZeneca’s drug pipeline: A five-dimensional framework, Nature Reviews. Drug Discovery, 13, 419, 10.1038/nrd4309 Cooke, 1998, Calcium Channel blockers in veterinary medicine, Journal of Veterinary Internal Medicine, 12, 123, 10.1111/j.1939-1676.1998.tb02107.x Damlen, 1999, Gibbs sampling for Bayesian non-conjugate and hierarchical models by using auxiliary variables, Journal of the Royal Statistical Society: Series B (Statistical Methodology), 61, 331, 10.1111/1467-9868.00179 Duchin, 1988, Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases, Clinical Pharmacokinetics, 14, 241, 10.2165/00003088-198814040-00002 Fasanmade, 1995, An improved pharmacodynamic model for formation of methemoglobin by antimalarial drugs, Drug Metabolism and Disposition: The Biological Fate of Chemicals, 23, 573 Food and Drug Administration, HHS, 2005, International conference on harmonisation; guidance on E14 clinical evaluation of QT/QTc interval prolongation and Proarrhythmic potential for non-antiarrhythmic drugs; availability. Notice, Federal Register, 70, 61134 Friberg, 2006, Pharmacokinetic–pharmacodynamic modelling of QT interval prolongation following citalopram overdoses, British Journal of Clinical Pharmacology, 61, 177, 10.1111/j.1365-2125.2005.02546.x Fridericia, 1920, Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken, Acta Medica Scandinavica, 53, 469, 10.1111/j.0954-6820.1920.tb18266.x Gordon, 2008, Chapter 17—Drugs used in the management of heart disease and cardiac arrhythmias Hendrickx, 2018, Translational model to predict pulmonary pharmacokinetics and efficacy in man for inhaled bronchodilators. CPT: Pharmacometrics & Systems, Pharmacology, 7, 147 Herring, 2018 Hodges, 1983, Bazett’s QT correction reviewed: Evidence that a linear QT correction for heart rate is better, Journal of the American College of Cardiology, 1, 694 Holzgrefe, 2007, Novel probabilistic method for precisely correcting the QT interval for heart rate in telemetered dogs and cynomolgus monkeys, Journal of Pharmacological and Toxicological Methods, 55, 159, 10.1016/j.vascn.2006.05.007 Holzgrefe, 2014, Preclinical QT safety assessment: Cross-species comparisons and human translation from an industry consortium, Journal of Pharmacological and Toxicological Methods, 69, 61, 10.1016/j.vascn.2013.05.004 Howell, 1958, Evaluation of variability in the cardiac output of dogs, American Journal of Physiology-Legacy Content, 196, 193, 10.1152/ajplegacy.1958.196.1.193 Keefe, 1981, Verapamil protein binding in patients and in normal subjects, Clinical Pharmacology and Therapeutics, 29, 21, 10.1038/clpt.1981.4 Kitzen, 1988, Pimobendan, Cardiovascular Drug Reviews, 6, 265, 10.1111/j.1527-3466.1988.tb00380.x Klumpp, 2006, Optimizing the experimental environment for dog telemetry studies, Journal of Pharmacological and Toxicological Methods, 54, 141, 10.1016/j.vascn.2006.03.010 Laverty, 2011, How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?, British Journal of Pharmacology, 163, 675, 10.1111/j.1476-5381.2011.01255.x Lawson, 1991, Captopril-induced reversal of nitroglycerin tolerance: Role of sulfhydryl group vs. ACE-inhibitory activity, Journal of Cardiovascular Pharmacology, 17, 411, 10.1097/00005344-199103000-00009 Manzo, 2009, Comparative study of heart rate variability between healthy human subjects and healthy dogs, rabbits and calves, Laboratory Animals, 43, 41, 10.1258/la.2007.007085 Markert, 2004, A novel propellant-free inhalation drug delivery system for cardiovascular drug safety evaluation in conscious dogs, Journal of Pharmacological and Toxicological Methods, 50, 109, 10.1016/j.vascn.2004.03.006 McDermott, 2002, Importance of species selection in Arrythmogenic models of Q-T interval prolongation, Antimicrobial Agents and Chemotherapy, 46, 938, 10.1128/AAC.46.3.938-939.2002 Münzel, 2019, Heart rate, mortality, and the relation with clinical and subclinical cardiovascular diseases: Results from the Gutenberg health study, Clinical Research in Cardiology, 108, 1313, 10.1007/s00392-019-01466-2 Ohte, 1997, The Cardiac Effects of Pimobendan (But Not Amrinone) Are Preserved at Rest and During Exercise in Conscious Dogs with Pacing-Induced Heart Failure, Journal of Pharmacology and Experimental Therapeutics, 282, 23 Parkinson, 2013, Translational pharmacokinetic-pharmacodynamic modeling of QTc effects in dog and human, Journal of Pharmacological and Toxicological Methods, 68, 357, 10.1016/j.vascn.2013.03.007 Piotrovsky, 2005, Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation, The AAPS Journal, 7, E609, 10.1208/aapsj070363 Rees, 1996, Which cardiac potassium channel subtype is the preferable target for suppression of ventricular arrhythmias?, Pharmacology & Therapeutics, 69, 199, 10.1016/0163-7258(95)02063-2 Rohatgi Sagie, 1992, An improved method for adjusting the QT interval for heart rate (the Framingham heart study), The American Journal of Cardiology, 70, 797, 10.1016/0002-9149(92)90562-D Sasaki, 1982, Disposition and metabolism of formoterol fumarate, a new bronchodilator, in rats and dogs, Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 12, 803, 10.3109/00498258209038952 Singhvi, 1981, Pharmacokinetics of captopril in dogs and monkeys, Journal of Pharmaceutical Sciences, 70, 1108, 10.1002/jps.2600701005 Smith, 1992, Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man, Xenobiotica, 22, 709, 10.3109/00498259209053133 Snelder, 2014, Drug effects on the CVS in conscious rats: Separating cardiac output into heart rate and stroke volume using PKPD modelling, British Journal of Pharmacology, 171, 5076, 10.1111/bph.12824 Snelder, 2013, PKPD modelling of the interrelationship between mean arterial BP, cardiac output and total peripheral resistance in conscious rats, British Journal of Pharmacology, 169, 1510, 10.1111/bph.12190 Stowe, 1986, Review of Calcium-Channel Blockers, The Nurse Practitioner, 11, 10.1097/00006205-198604000-00006 Trudeau, 1995, HERG, a human inward rectifier in the voltage-gated Potassium Channel family, Science, 269, 92, 10.1126/science.7604285 Van de Water, 1989, An improved method to correct the QT interval of the electrocardiogram for changes in heart rate, Journal of Pharmacological Methods, 22, 207, 10.1016/0160-5402(89)90015-6 Venkatasubramanian, 2020, Semi-mechanistic modelling platform to assess cardiac contractility and haemodynamics in preclinical cardiovascular safety profiling of new molecular entities, British Journal of Pharmacology, 177, 3568, 10.1111/bph.15079 Wallman, 2021, Dog-PKCV, GitHub Wallman, 2021 Wallman, 2021, An integrative approach for improved assessment of cardiovascular safety data, The Journal of Pharmacology and Experimental Therapeutics., 10.1124/jpet.120.000348 Yata, 2016, Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs, Journal of Veterinary Pharmacology and Therapeutics, 39, 45, 10.1111/jvp.12243