TO ELUCIDATE THE EFFECTS OF RITONAVIR ON INTRATUMOURAL METABOLISM AND ANTI TUMOUR EFFECT OF DOCETAXEL IN A MOUSE MODEL FOR HEREDITARY BREAST CANCER

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1 DEVELOPMENT OF A TUMOURGROWTH INHIBITIONMODEL TO ELUCIDATE THE EFFECTS OF RITONAVIR ON INTRATUMOURAL METABOLISM AND ANTI TUMOUR EFFECT OF ETAXEL IN A MOUSE MODEL FOR HEREDITARY BREAST CANCER Huixin Yu, Jeroen J.M.A. Hendrikx, Alfred H. Schinkel, Sven Rottenberg, Jan H.M. Schellens, Jos H. Beijnen, Alwin D.R. Huitema

2 Docetaxel () An anticancer agent for several types of cancer, such as lung, breast, gastric and prostate cancer It acts by the inhibition of cell mitosis Oral ingestion of docetaxel increases convenience for patients comparing to intravenous administration One major limitation for oral docetaxel is its low bioavailability due to its affinity for P-glycoprotein (Pgp) and Cytochrome P450 (CYP) 3A Huixin Yu 2 Hersonissos, 4 th June 2015

3 Docetaxel () An anticancer agent for several types of cancer, such as lung, breast, gastric and prostate cancer It acts by the inhibition of cell mitosis Oral ingestion of docetaxel increases convenience for patients comparing to intravenous administration One major limitation for oral docetaxel is its low bioavailability due to its affinity for P-glycoprotein (Pgp) and Cytochrome P450 (CYP) 3A Ritonavir () An HIV protease inhibitor and also a strong CYP3A4 inhibitor It has been suggested to have an anti-cancer effect Gaedicke S et al. Cancer Res. 2002,62(23):6901 8; Kariya R et al.cancer Lett. 2014,342:52 9; Srirangam A et al. Clin cancer Res. 2006,12(6): Huixin Yu 3 Hersonissos, 4 th June 2015

4 Co administration of docetaxel and ritonavir PK: In both mice and humans, co-administration results in an enhanced docetaxel plasma concentration by CYP3A4 inhibition docetaxel pharmacology.com Huixin Yu 4 Hersonissos, 4 th June 2015

5 Co administration of docetaxel and ritonavir PK: In both mice and humans, co-administration results in an enhanced docetaxel plasma concentration by CYP3A4 inhibition docetaxel Ritonavir pharmacology.com Huixin Yu 5 Hersonissos, 4 th June 2015

6 Co administration of docetaxel and ritonavir PK: In both mice and humans, co-administration results in an enhanced docetaxel plasma concentration by CYP3A4 inhibition docetaxel Ritonavir pharmacology.com PK: Will ritonavir i inhibit docetaxel intratumoural t metabolism? PD: Will co-administration enhance anticancer effect? Huixin Yu 6 Hersonissos, 4 th June 2015

7 Preclinical experiment study design + Host: Cyp3a knock-out Tumour: inherent Cyp3a expression Arm1: Control (n=15) Arm2: (p.o.) (n=15) Arm3: (i.v.) (n=20) Arm4: + (n=20) Days Huixin Yu 7 Hersonissos, 4 th June 2015

8 Preclinical experiment PK data Huixin Yu 8 Hersonissos, 4 th June 2015

9 Preclinical experiment PD data Huixin Yu 9 Hersonissos, 4 th June 2015

10 Preclinical experiment PD data Days to reach 1500 mm 3 Arm Median Mean ± SD Control ± ± ± ± 8.6 Huixin Yu 10 Hersonissos, 4 th June 2015

11 Objectives To develop a PK- PD model based on docetaxel concentration and tumour sizes from preclinical study To further evaluate and quantify the effects of ritonavir on systemic and intratumoral concentration and anti-tumour effects of docetaxel when co-administered i d Huixin Yu 11 Hersonissos, 4 th June 2015

12 PK model ritonavir dose KA central CL Vc KaT tumour KeT Koolen SLW, et al. J Clin Pharmacol. 2012,52(3): Huixin Yu 12 Hersonissos, 4 th June 2015

13 PK model ritonavir dose KA central CL Vc KaT tumour KeT Koolen SLW, et al. J Clin Pharmacol. 2012,52(3): Huixin Yu 13 Hersonissos, 4 th June 2015

14 PK model docetaxel dose periph. Qi central CL Vp Vc KaT tumour KeT Koolen SLW, et al. J Clin Pharmacol. 2012,52(3): Huixin Yu 14 Hersonissos, 4 th June 2015

15 PK model docetaxel dose periph. Qi central CL Vp Vc KaT tumour KeT Koolen SLW, et al. J Clin Pharmacol. 2012;52(3): Huixin Yu 15 Hersonissos, 4 th June 2015

16 PK model co administration of docetaxel and ritonavir dose dose Periph. Qi central CL E KA central CL Vp Vc Vc 1-C,tumour /(IC50 + C,tumour ) KaT KaT tumour KeT tumour KeT Tran TH, et al. Drug Metab Dispos. 2002,30(12): Huixin Yu 16 Hersonissos, 4 th June 2015

17 PK model co administration of docetaxel and ritonavir dose dose E KA Periph. Qi central CL central CL Vp Vc 1-C,tumour /(IC50 + C,tumour ) Vc KaT KaT tumour KeT tumour KeT Tran TH, et al. Drug Metab Dispos. 2002,30(12): Huixin Yu 17 Hersonissos, 4 th June 2015

18 PK model conclusions In Cyp3a knock-out host, ritonavir slightly decreased docetaxel systemic clearance by 8% when co-administered In tumour with inherent Cyp3a expression, ritonavir inhibited docetaxel metabolism resulting in docetaxel tumour AUC 2.5-fold higher when co-treated with ritonavir Huixin Yu 18 Hersonissos, 4 th June 2015

19 PK PD model Exponential tumour growth model Kg 0 Nonperturbed cells Huixin Yu 19 Hersonissos, 4 th June 2015

20 PK PD model docetaxel treated tumour growth inhibition (TGI) model Docetaxel tumour PK C,tumour /(EC50 + C,tumour ) KKe KK anti- tumour effect Nonperturbed cells Kg=Kg 0 e λ t (λ= week -1 ) Kg 0 Kg Huixin Yu 20 Hersonissos, 4 th June 2015

21 PK PD model docetaxel treated tumour growth inhibition (TGI) model Huixin Yu 21 Hersonissos, 4 th June 2015

22 PK PD model ritonavir co treated TGI model Docetaxel tumour PK Ritonavir tumour PK C,tumour /(EC50 + C,tumour ) KKe KK anti- tumour effect Nonperturbed cells Kg 0 Kg Huixin Yu 22 Hersonissos, 4 th June 2015

23 Hypothesis test TGI model with docetaxel treated TGI and PK parameters Docetaxel tumour PK Ritonavir i tumour PK C,tumour /(EC50 + C,tumour ) KKe antitumour effect Kg 0 Kg KK Nonperturbed cells Huixin Yu 23 Hersonissos, 4 th June 2015

24 Hypothesis test TGI model with docetaxel treated TGI and PK parameters - Slight underestimation of anti-tumour effect in early phase of treatment - Underestimation of the time to tumour re-growth Huixin Yu 24 Hersonissos, 4 th June 2015

25 Hypothesis test estimation of ritonavir anti tumour effect Docetaxel tumour PK Ritonavir tumour PK C,tumour /(EC50 + C,tumour ) C,tumour KKe anti- tumour effect anti- tumour effect KK KK KKe Nonperturbed cells Kg 0 Kg Huixin Yu 25 Hersonissos, 4 th June 2015

26 Hypothesis test estimation of ritonavir anti tumour effect - Bias in the model prediction of tumour volume in the co-administration disappeared - Objective function value dropped d 59 points comparing to the model estimation without ritonavir anti-tumour effect Huixin Yu 26 Hersonissos, 4 th June 2015

27 Final PK PD model E dose KA Ritonavir PK Peripheral Qi central CL central CL Vp Vc 1-C,tumour /(IC50 + C,tumour ) Vc KaT KaT Docetaxel PK tumour KeT tumour KeT C,tumour /(EC50 + C,tumour ) C,tumour KKe anti- tumour effect KK KK antitumour effect KKe TGI Kg 0 or Kg Non- perturbe d cells

28 Final PK PD model visual predictive check Huixin Yu 28 Hersonissos, 4 th June 2015

29 Conclusions A PK-PD PD model has been successfully developed describing the complex interaction between docetaxel and ritonavir when co-administered in a mouse model for hereditary breast cancer We showed that the enhanced tumour growth inhibition observed in the co-administration of docetaxel with ritonavir is mainly caused by boosting the tumour concentration of docetaxel and to a minor extent by a direct tumour growth inhibitory effect of ritonavir Huixin Yu 29 Hersonissos, 4 th June 2015

30 Acknowledgement thenetherlands Cancer Institute Dept. Pharmacy & Pharmacology Jeroen J.M.A. Hendrikx Alwin DR D.R. Huitema Jos H. Beijnen Jan H.M. Schellens Alfred H. Schinkel Sven Rottenberg Coen van Hasselt PAGE committee & PAGE student sponsorship Huixin Yu 30 Hersonissos, 4 th June 2015