Gianluca Nucci and Roberto Gomeni
GlaxoSmithKline - Clinical Pharmacokinetics/Modelling and Simulation
Background & Objective: Enterohepatic recycling (ER) is associated with multiple peaks in concentration-time profile. Therefore a model analysis is always needed to assess the pharmacokinetics (PK), and in particular T1/2 and AUCinf of ER drugs. Recently Funaki [1] and Ezzet et al [2] used a population analysis approach for describing the PK of ER drugs. However in these works the timing and number of times the gallbladder emptied were either arbitrarily fixed or limited to one. To overcome these limitations Wajima et. al [3] proposed a new model exploiting periodic transfer rates that accounted for multiple peaks in the plasma profile. Therefore the goal of this study was to apply and optimize the periodic transfer function approach in a population PK study and to assess the impact of different modulating functions.
Methods: 25 subjects dosed with 0.3 – 6 mg single oral administration of an antidepressant drug contributed to the 321 data samples analyzed. The last sample times ranged from 3 – 191 h post dose. These data, exhibiting ER profiles, were described with a three compartment model (central, peripheral and a bile) with first order absorption and lag time. The bile compartment controls the ER since its transfer rate to plasma is modulated by a periodic function. We tested different periodic functions and several modulating frequencies (either fixed or estimated) and compared them in terms of log likelihood and goodness of fit.
Results: The best model, based on the modulating function ABS(sin(2*pi* (t+phi)/w)), provided adequate fit to the pooled data. A large intra-patient variability was observed for the estimated amount returning from the bile to the central compartment while the feeding frequency and the delay (from dosing time) for starting the ER process were fairly constant.
Conclusion: The model developed in this study is suitable for the analysis of population PK of ER drugs. It accounts for multiple peaks, can be applied to multiple dosing without increasing the number of parameters or fixing the feeding time estimation and enables to estimate the optimal recycling frequency.
References:
1- Funaki T. J Pharm Pharmacol 51, 1999.
2– Ezzet F. et al. Clin. Ther. 23,2001
3– Wajima et al. JPP 54, 2002
Reference: PAGE 12 () Abstr 365 [www.page-meeting.org/?abstract=365]
Poster: poster