H Mishra, M Jamei, A Rostami-Hodjegan, S Polak
Simcyp Ltd
Objectives: To investigate the application of modelling and simulation in predicting the extent of the increased proarrhythmic potency of domperidone (DOMP) in the presence of a CYP3A inhibitor, ketoconazole (KETO). Early studies of high-dose DOMP showed QTc prolongation and arrythymias as a side-effect [1].
Methods: Physiologically-Based Pharmacokinetic and Pharmacodynamic (PBPK/PD) models within Simcyp® (v11.1) were used to predict population PK/PD behaviour in healthy volunteers. A library compound file for DOMP was developed within Simcyp using published sources [2, 3]. Subsequently, the observed clinical data [4] were fitted by obtaining optimal values for the intestinal permeability, intrinsic clearance and renal clearance (Parameter Estimation module within Simcyp). DOMP and KETO interaction was simulated replicating the clinical study design of Boyce et al. 2012 [5]. ToxComp platform (v1.3) was used to simulate the drug induced QTc interval change (Fridericia correction). In vitro IKr ionic current inhibition data for both drugs were taken from the literature [6, 7], IKs current inhibition was predicted with the QSAR model [8].
Results: The simulation results at the steady state (day 7) following DOMP alone and DOMP+KETO [5], together with the corresponding observed values are summarised in Table 1.
Table 1: Observed vs. Simcyp simulated PK parameters for single DOMP and DOMP+KETO combination.
|
Dose |
Cmax |
SD |
Tmax |
SD/Range |
AUC |
SD |
AUC |
SD |
|
Obs DOMP |
23.5 |
7.4 |
9.0 |
0.5 to 14 |
249 |
65 |
|
|
|
Sim DOMP |
23.3 |
2.6 |
12.7 |
0.04 |
260 |
38 |
|
|
|
Obs DOMP+KETO |
67.9 |
21.1 |
5.0 |
0.5 to 14.1 |
878 |
268 |
3.53 |
|
|
Sim DOMP+KETO |
56.7 |
4.4 |
12.8 |
0.03 |
738 |
71 |
2.88 |
0.44 |
Predicted concentration values were further utilized to predict QTc [ms] for males (M) and females (F) following DOMP alone and DOMP+KETO combination. The average QTcF[obs] / QTcF[sim] ratios at various time points were close to unity: DOMP-M = 1.11, DOMP-F = 0.97, DOMP+KETO-M = 1.09, DOMP+KETO-F = 0.95.
Conclusion: The combination of mechanistic PBPK and Tox modelling and simulation tools (Simcyp+ToxComp) was able to recover PK and toxicological effect of the single drug and its combination with pharmacokinetically and pharmacodynamically interacting drug (ketoconazole). ToxComp tends to underpredict QTc for males and overpredict QTc for females what can come from the heart rate variability. In general model-based drug development proved to be a valuable cardiac safety assessment tool.
References:
[1] Bruera, E., et al., Q-T interval prolongation and ventricular fibrillation with i.v. domperidone. Cancer Treat Rep, 1986. 70(4): p. 545-6.
[2] Chang, S.Y., et al., Mechanism-based inhibition of human cytochrome P4503A4 by domperidone. Xenobiotica, 2010. 40(2): p. 138-45.
[3] Ward, B.A., et al., Characterization of human cytochrome P450 enzymes catalyzing domperidone N-dealkylation and hydroxylation in vitro. Br J Clin Pharmacol, 2004. 58(3): p. 277-87.
[4] Huang, Y.C., et al., Pharmacokinetics and dose proportionality of domperidone in healthy volunteers. J Clin Pharmacol, 1986. 26(8): p. 628-32.
[5] Boyce, M.J., K.J. Baisley, and S.J. Warrington, Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study. Br J Clin Pharmacol, 2012. 73(3): p. 411-21.
[6] Claassen, S. and B.J. Zunkler, Comparison of the effects of metoclopramide and domperidone on HERG channels. Pharmacology, 2005. 74(1): p. 31-6.
[7] Ridley, J.M., et al., Inhibition of the HERG K+ channel by the antifungal drug ketoconazole depends on channel gating and involves the S6 residue F656. FEBS Lett, 2006. 580(8): p. 1999-2005.
[8] Polak S., et al., Slow delayed rectifying potassium current (IKs) – analysis of the in vitro inhibition data and predictive model development, J Appl Toxicol, 2012 [Epub].
Reference: PAGE 21 () Abstr 2460 [www.page-meeting.org/?abstract=2460]
Poster: Safety (e.g. QT prolongation)