S.Polak(1,2), D.Tomaszewska(1), N.Patel(2), M.Jamei(2), A.Rostami-Hodjegan(2,3)
(1) Unit of Pharmacoepidemiology and Pharmacoeconomics, Faculty of Pharmacy, Jagiellonian University Medical College, Poland; (2) Simcyp, a Certara Company, Sheffield, UK; (3) Centre for Applied Pharmacokinetics Research, School of Pharmacy and Pharmaceutical Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
Objectives: Chronopharmacology may play an important role for drugs with narrow therapeutic window particularly for patients predisposed to safety issues due to the genetic factors. Clinical studies are not common to test the diurnal variation in PK and/or PD effects. The objective of this study was to establish and validate methodology allowing for simulation of QT change for an orally taken drug with use of mechanistic methods accounting for population variability.
Methods: The PK simulations for quinidine and its 3-hydroxy metabolite were carried out using Simcyp platform (V12) and its compound library files in virtual healthy Caucasians. It was assumed that the morning/night differences in PK are predominantly caused by the differences in absorption and bioavailability as the known chronological variations in gastric emptying time (h) and small intestinal transit time (h) can influence these parameters. Gastric emptying half-life in fasted state was set to 0.4 and 2 h and corresponding intestinal transit times were 3.5 and 7 h (1,2) for 10am and 10pm respectively. Virtual patients mimicked the clinical study reported by Rao (3) (8 males, 18-26 yo). PD endpoint was ΔQTcF derived from the pseudoECG simulated by the ToxComp system based on the in vitro currents inhibition and the predicted free plasma concentrations separately for all individuals (4). Circadian changes to baseline and drug effects on QT were accounted for by applying the diurnal changes to heart rate and K+, Na+, Ca2+ ions in plasma.
Results: Observed study reported prolongation of Tmax (1.29 fold), no change in Cmax (0.97 fold) and 1.13 fold increase in AUC with the pm administration. Simulated diurnal changes in Cmax (0.98 fold) and AUC (1.13 fold) were consistent with observations. Simulated prolongation of Tmax (1.61 fold) appeared to be more than observed magnitude. Predicted ΔQTcF values were concentration dependent and followed circadian rhythm. Maximum population ΔQTcF for 10pm and 10am scenarios were 38 (3am) and 43 (1pm) ms respectively.
Conclusions: Results demonstrate the potentials of the mechanistic in vitro in vivo extrapolation (IVIVE) for incorporating the knowledge of chronological variations in physiological system parameters leading to PK or PD variations. The simulations may assist with determining the PD variability occurring diurnally using the in vitro data on drugs and are suitable for designing studies which might be affected by the chronobiology of PK and/or PD.
References:
[1] Goo RH, Moore JG, Greenberg E, Alazraki NP. Circadian variation in gastric emptying of meals in humans. Gastroenterology 93:515–518, 1987.
[2] Gorard DA, Libby GW, Farthing MJG. Ambulatory small intestinal motility in 'diarrhoea' predominant irritable bowel syndrome. Gut 35:203-210, 1994.
[3] Rao BR, Rambhau D. Diurnal oscillations in the Serum and Salivary Levels of Quinidine. Arzneimittel-Forschung/Drug Research 45:681-683, 1995.
[4] Polak S, Wisniowska B, Fijorek K, Glinka A, Polak M, Mendyk A. ToxComp ‐ in vitro–in vivo extrapolation system for the drugs proarrhythmic potency assessment. Computing in Cardiology 39:789-793, 2012.
Reference: PAGE 22 (2013) Abstr 2667 [www.page-meeting.org/?abstract=2667]
Poster: Safety (e.g. QT prolongation)