Whole-Body Physiologically-based Pharmacokinetic (WB-PBPK) Population Modelling to Simulate the Influence of Weight and Age on the Pharmacokinetics (PK) of a combined Oral Contraceptive Containing Drospirenone (DRSP) and Ethinylestradiol (EE)
C. Becker(1), K. Coboeken(1), L. Kuepfer(1), J. Lippert(1), R. Nubbemeyer(2), H. Blode(2)
(1) Bayer Technology Services GmbH, Competence Centre Systems Biology, D-51368 Leverkusen, Germany; (2) Bayer Schering Pharma AG, D-13342 Berlin, Germany
Objectives: Obesity has reached epidemic proportions. WHOs latest projections indicate that in 2005 approximately 1.6 billion adults were overweight.(1) The body fat fraction is an important determinant of the PK and can become the dominant factor for highly lipophilic compounds such as steroids. This study aimed to use a WB-PBPK model to investigate the influence of age and weight on the PK to be expected after administration of a fixed dose combination of EE and DRSP in a combined oral contraceptive (COC).
Methods: WB-PBPK models were built for DRSP and EE using the software PK-Sim®.(2,3) The simulated plasma concentration-time profiles were validated using observed data from 48 women.(4-6) In a second step, the PK-Pop module of PK-Sim® was used to build virtual populations of normal weight, overweight, obese and highly obese females aged 14-45 yrs using the body mass index (BMI) to discriminate between weight groups. Steady state (SS) PK parameters (AUC, Cmax, Ctrough, t1/2) and concentration time profiles of DRSP and EE were compared between the different virtual populations.
Results: The WB-PBPK model matched the experimentally measured concentration-time profiles and derived PK parameters in the validation population(4-6) comprising women with slight underweight to slight overweight very well. Age-related differences of PK parameters were not observed for DRSP and EE in women >14 yrs. Plasma AUC and Ctrough were simulated to be similar for both compounds at SS across the different BMI groups. In silico tissue distribution suggest a substantial distribution of both hormones in fat resulting in a decrease in the EE Cmax to Ctrough ratio and a decrease of Cmax and Ctrough of DRSP in the obese compared to the normal weight population. Nevertheless, a prospective post-marketing surveillance study found DRSP/EE containing COCs to be equally effective in obese and non-obese populations.(7)
Conclusions: The WB-PBPK population modelling approach provided an excellent description of the experimental data. Our analysis complements the classic population PK approach since we could mechanistically study the influence of co-factors like age or BMI. The possibility to predict tissue concentrations enables model-based PK/PD predictions for populations of interest not covered by available clinical data.
 World Health Organization (WHO) Obesity and Overweight pages http://www.who.int/topics/obesity/en/
 Willmann, S., Lippert, J., Sevestre, M., Solodenko, J., Fois, F., Schmitt, W. 2003 Biosilico. PK-Sim: A physiologically based pharmacokinetic ‘whole-body’ model. 1(4):121–124
 PK-Sim® 4.0, Software Package for physiology-based pharmacokinetic (PBPK) Modelling. Bayer Technology Services, 2008
 Bayer Schering Pharma Clinical Study Report 8235
 Bayer Schering Pharma Research Report A734
 Bayer Schering Pharma Clinical Study Report A03328
 Dinger, J., Heinemann, L.A.J., Westhoff, C., Cronin, M., Schellschmidt, I. ACOG 2007 (Poster) Contraceptive efficacy of oral contraceptives in real world clinical practice: The impact of age, weight, BMI, dose, and duration of use.