Raja Venkatasubramanian (1), Teresa A. Collins (2), Lawrence J. Lesko (1), Jay T. Mettetal (3), Mirjam N. Trame (1)
(1) Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA; (2) Drug Safety and Metabolism, AstraZeneca, Cambridge, UK; (3) Drug Safety and Metabolism, AstraZeneca, Waltham, Massachusetts, USA
Objectives: Cardiovascular safety is one of the most frequent causes of safety related attrition both pre-clinically and clinically. Much progress has been made in the area of preclinical to clinical translation of QT interval prolongation and Torsades de Pointes (TdP), however, less progress has been made in areas related to contractility and hemodynamic changes from inotropic agents. Our objective was to develop a mechanism based platform to assess drug induced changes in contractility along with hemodynamic end-points routinely measured in dog telemetry studies.
Methods: Data from contractility (dPdTmax), heart rate (HR), preload (left ventricular end-diastolic pressure; LVEDP) and blood pressure (MAP) were available from dog telemetry studies for atenolol (n=27), albuterol (n=5), L-NG-Nitroarginine methyl ester (L-NAME; n=4), and milrinone (n=4). PPP&D modeling approaches were utilized for the development of PK/PD correlations using FOCEI method in NONMEM 7.3. The model developed by Snelder et al. [1,2] was used as a starting point and was adapted to include dPdTmax and LVEDP as covariate on dPdTmax to correct for preload effect. Diurnal rhythms were tested on dPdTmax, HR, and MAP. Separate drug effects for all drugs included in this analysis were evaluated using linear and (sigmoid) Emax relations on dPdTmax, HR and/or TPR. Nonparametric bootstrap (n=1000) was performed to assess model robustness.
Results: A Population PK model was developed for atenolol and milrinone using available PK data from dog studies and literature data [3,4], while for albuterol and LNAME PK, earlier developed models [5,6] in dogs were used. Diurnal variations for dPdTmax and MAP were captured using a single 24h cosine rhythm, while two (24&6h) cosine rhythms were required for HR. Drug effects of atenolol, albuterol, LNAME and milrinone were included on either dPdTmax, HR and/or TPR capturing the drug effects adequately well for all studies. Incorporation of LVEDP on dPdTmax, using a time-varying linear covariate model was found to be significant and resulted in ~11% correction of dPdTmax for every 10 mmHg LVEDP. Bootstrap analysis obtained adequate model robustness with comparable mean values of parameter estimates to the final model.
Conclusions: The developed mechanism based platform can be used to simultaneously capture drug induced changes in dPdTmax along with other hemodynamic end-points, HR and MAP, for multiple drugs in order to assess the hemodynamic safety profiles.
References:
[1] N. Snelder et al., “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, no. 22 (2014)
[2] N. Snelder et al., “PKPD Modelling of the Interrelationship between Mean Arterial BP, Cardiac Output and Total Peripheral Resistance in Conscious Rats,” British Journal of Pharmacology 169, no. 7 (2013)
[3] James McAinsh and Brian F. Holmes, “Pharmacokinetic Studies with Atenolol in the Dog,” Biopharmaceutics & Drug Disposition 4, no. 3 (1983)
[4] J. Edelson et al., “High-Performance Liquid Chromatographic Analysis of Milrinone in Plasma and Urine. Intravenous Pharmacokinetics in the Dog,” Journal of Chromatography 276, no. 2 (1983)
[5] Eleanor Howgate, “Cross-Species Scaling of Cardiovascular Safety Pharmacology Using PKPD Modelling and Simulation,” Thesis, Univ. of Manchester, (2013)
[6] B. Auclair et al., “A Population Analysis of Nebulized (R)-Albuterol in Dogs Using a Novel Mixed Gut-Lung Absorption PK-PD Model,” Pharmaceutical Research 17, no. 10 (2000)
Reference: PAGE 25 (2016) Abstr 5953 [www.page-meeting.org/?abstract=5953]
Poster: Drug/Disease modeling - Safety