Physiologically based pharmacokinetic model to predict drug-drug interaction in patients receiving antiretroviral and antineoplastic therapies

Transcrição

1 Physiologically based pharmacokinetic model to predict drug-drug interaction in patients receiving antiretroviral and antineoplastic therapies José Moltó MD, PhD Fundació Lluita contra la Sida Hospital Universitari Germans Trias i Pujol Badalona, Spain 16 th HIVHEPPK. Alexandria, VA 26 th May 2015

2 Background Incidence of non-aids defining malignancies is increasing. Administration of chemotherapy is challenging due to drug-drug interactions with cart. Specific data on DDI remain scant Erlotinib (ERL) and gefitinib (GEF) are two EGFR inhibitors used to treat patients with non-small cell lung cancer. ERL is dosed at 150 mg qd (MTD) GEF is dosed at 250 mg qd (1/3 MTD) ERL and GEF are metabolized by CYP3A4

3 Objective To evaluate DDIs between ERL or GEF and antiretroviral drugs including ritonavir (RTV), efavirenz (EFV) or etravirine (ETR) using a PBPK model, and to hypothesize potential dose adjustments to overcome these DDIs.

4 PBPK modelling DRUG PROPERTIES PATIENTS CHARACTERISTICS TRIAL DESIGN Venous blood Lung Heart Adipose Brain Muscle Skin Liver logp pka fu B/P Gut Arterial blood New formulations PK special populations Drug-drug interactions

5 Methods 1.- Validation of PBPK models for each drug ERL, GEF, RTV, EFV, ETR, MVC and MDZ given separately 2.- Validation of DDI models with CYP3A4 probe drugs Midazolam +/- RTV Maraviroc +/- EFV / ETR 3.- Simulate concentrations of ERL/GEF +/- ARVs 4.- Predict dose adjustments to overcome DDIs

6 Methods - Simbiology (in MATLAB, version 2013b) - Virtual cohort of 50 healthy volunteers - Drugs dosing (14 days) - ERL 150 mg qd - RTV 100 mg qd - MDZ 2 mg (sd) - GEF 250 mg qd - EFV 600 mg qd - MVC 300 mg bid - ETR 200 mg bid - Model validation Simulated data vs. reference values - Evaluation of DDI

7 Methods. In vitro parameters ERL GEF RTV ETR EFV MVC MDZ pka logp fu B/P Clint (ml/min/pmol) Induction data Inibition CYP3A4 CYP3A CYP3A CYP2D CYP1A CYP1A CYP 3A CYP2D CYP3A CYP 2D CYP3A4 Indmax 13.4 Ind µM CYP2C CYP3A CYP3A4 Indmax 2.5 CYP2B6 5 CYP2A CYP3A CYP3A CYP3A4 Indmax 5.7 Ind µm CYP2B6 Indmax 6.5 Ind µm Ki 0.04 µm Ki 20 µm Kinact 0.3 min -1 CYP3A4 1.7 (ISEF 0.2) CYP3A4 2

8 Model validation for each drug separately 100 EFV ERL 10 Simulated AUC 0-t (mg.h/l) MDZ RTV ETR GEF MVC Simulated C max (mg/l) 1 RTV GEF ETR ERL MVC EFV Observed AUC 0-t (mg.h/l) 1 10 Observed C max (mg/l) Hidalgo et al. J Clin Oncology 2001; Adjei et al. Clin Canc Res 2007; Efavirenz product information; Schöller-Gyüre et al. Clin Pharmacokinet Kirby et al. Drug Metab Disp Kakuda et al. Antimicrob Agents Chemother 2011

9 Model validation for CYP3A4 probe DDIs MDZ+RTV Simulated AUC ratio 10 1 MVC+ETR MVC+EFV 1 10 Observed AUC ratio Simulated C max ratio 1 MVC+ETR MVC+EFV Observed C max ratio Kirby et al. Drug Metab Disp 2011 Abel et al. Br J Clin Pharmacol 2008 Kakuda et al. AAC 2011

10 Erlotinib/Gefitinib & RTV 13 ERL 150 mg qd ERL 150 mg ERL ERL mg qd qd + RTV RTV qd mg qd 1.5 GEF 250 mg qd GEF 250 mg qd + RTV 100 mg qd 10 ERL (mg/l) 8 5 GEF (mg/l) ERL 150mg qd + RTV 100mg qd (vs ERL 150mg qd) GEF 250mg qd + RTV 100mg qd (vs GEF 250mg qd) AUC ( ) AUC ( ) Cmax 3.79 ( ) C max 3.12 ( )

11 Dose adjustment for ERL/GEF + RTV 13 ERL 150 mg qd ERL 150 mg ERL 150 mg qd + RTV 100 mg qd ERL 150 qd + RTV 100 qd ERL 25 mg qd + RTV 100 mg qd ERL 25 qd RTV 100 qd 1.5 GEF 250 mg qd GEF 250 mg qd + RTV 100 mg qd GEF 125 mg qd + RTV 100 mg qd 10 ERL (mg/l) 8 5 GEF (mg/l) ERL 25mg qd + RTV 100mg qd (vs ERL 150mg qd) 0.0 GEF 125mg qd + RTV 100mg qd (vs GEF 250mg qd) AUC ( ) AUC ( ) C max 0.61 (6 0.66) C max 1.61 ( )

12 Erlotinib & EFV/ETR 3 ERL 150 mg qd ERL 150 mg qd + EFV 600 mg qd 3 ERL 150 mg qd ERL 150 mg qd + ETR 200 mg bid ERL (mg/l) 2 ERL (mg/l) ERL 150mg qd + EFV 600mg qd (vs ERL 150mg qd) ERL 150mg qd + ETR 200mg bid (vs ERL 150mg qd) AUC ( )) AUC (5 0.66) C max 0.89 ( ) C max 0.69 ( )

13 Dose adjustment for ERL + EFV/ETR 3 ERL 150 mg qd ERL 150 mg qd + EFV 600 mg qd ERL 200 mg qd + EFV 600 mg qd 3 ERL 150 mg qd ERL 150 mg qd + ETR 200 mg bid ERL 200 mg qd + ETR 200 mg bid ERL (mg/l) 2 ERL (mg/l) ERL 200mg qd + EFV 600mg qd (vs ERL 150mg qd) ERL 200mg qd + ETR 200mg bid (vs ERL 150mg qd) AUC ( ) AUC ( ) C max 1.14 ( ) C max 0.99 ( )

14 Gefitinib & EFV/ETR GEF 250 mg qd GEF 250 mg qd + EFV 600 mg qd GEF 250 mg qd GEF 250 mg qd + ETR 200 mg bid GEF (mg/l) GEF (mg/l) GEF 250mg qd + EFV 600mg qd (vs GEF 250mg qd) GEF 250mg qd + ETR 200mg bid (vs GEF 250mg qd) AUC ( ) AUC (8 0.71) C max 0.71 ( ) C max 0.70 ( )

15 Dose adjustment for GEF + EFV/ETR GEF 250 mg qd GEF 250 mg qd + EFV 600 mg qd GEF 375 mg qd + EFV 600 mg qd GEF 250 mg qd GEF 250 mg qd + ETR 200 mg bid GEF 375 mg qd + ETR 200 mg bid GEF (mg/l) GEF (mg/l) GEF 375mg qd + EFV 600mg qd (vs GEF 250mg qd) GEF 375mg qd + ETR 200mg bid (vs GEF 250mg qd) AUC ( ) AUC ( ) C max 1.07 ( ) C max 1.15 ( )

16 Conclusions The developed PBPK model predicted the in vivo pharmacokinetics of ERL or GEF, and their interactions with RTV, EFV or ETR. Potential simulated dose adjustments in that scenario Alone + RTV 100 mg qd + EFV 600 mg qd +ETR 200 mg bid ERL 150 mg qd 25 mg qd 200 mg qd GEF 250 mg qd 125 mg qd 375 mg qd The simulated dose-adjustments may represent valuable strategies to optimise antineoplastic therapy in HIV patients receiving cart. The PBPK approach may be a useful tool for both prediction of DDI and selection of doses to explore in prospective clinical trials.

17 Acknowledgments University of Liverpool (UK) Marco Siccardi Rajith Rajoli Andrew Owen Saye Khoo David Back HUGTIP, Badalona (Spain) Beatriz Cirauqui Teresa Moran Cristina Miranda IIB St Pau, Barcelona (Spain) Marta Valle