What the regulator must know

Transcription

1 What the regulator must know David R. Katerere Associate Professor Tshwane University of Technology

2 Outline Introduction Meet the Transporters P-gp BSEP Regulatory applications and implications Conclusion

3 Engineering the Great Escape

4 In vitro to in-life Metabolic Stability CYP IVIVE? Transporter PK

5 Transporters Barrier to Absorption Determinant of Tissue Distribution Modulators of Metabolism Modulators in Elimination Passive Transporter Solute Carrier (SLC) transporters Active Transport ABC transporters - P-gp; MRP - BCRP Glucose transporters - GLUT1-5 SLC transporters OATPs; OCT & OATs Silverman, 2005 (AAPS Workshop)

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7 P- gp

8 Permeability- glycoprotein (P- gp) ATP- binding cassette (ABC) superfamily Ubiquitous in distribution GIT biliary ductules proximal tubules of the kidneys BBB Encoded by the multidrug resistance gene (MDR1/ABCB1) expression and function shows large interindividual differences Environmental Genetic factors

9 P-gp substrates Steroid compounds: Progesterone Hydrocortisone Cortisol Corticosterone Dexamethasone Anticancer agents: Doxorubicin Daunorubicin Vinca alkaloids Actinomycin D Epotoside Immunosuppressive agents: Cyclosporin FK 506 Methotrexate Protease inhibitors: Indinavir Nelfinavir Ritonavir Antibiotics: Erythromycin Rifampicin CVS: Digoxin Quinidine Statins (Lovastatin, simvastatin) Calcium channel blockers: Nifedipine & analogues, verapamil* Opioids: Methadone Loperamide Fentanyl Bauer B, Hartz AM, Fricker G, Miller D. Modulation of p-glycoprotein Transport Function at the Blood-Brain Barrier. Experimental Biology and Medicine Feb. 2005;230:118-27

10 P-gp Inhibitors

11 P-gp: implications for the regulator? - Pharmacodynamic - Drug resistance (MDR) Pharmacokinetic - Efflux --> PK? Treatment of cancers in HIV -? direct inhibition? CVD and infection - digoxin, rifampicin -? competitive binding

12 BSEP

13 Bile Salt Excretion Pump (BSEP) sp-gp ATP- binding cassette (ABC) superfamily Limited in distribution biliary ductules Encoded by gene ABCB11 Disruption maybe genetic or drug induced Potential for disruption difficult to pick up in preclinical drug development

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15 BSEP function Substrates - pravastatin, vinblastine - Bile acid (taurocholic acid) Inhibitors - erythromycin estolate - nefazodone

16 N.B: BSEP assay is not predictive of liver injury related to other mechanisms, so Paracetamol, zonisamide, CCl 4, are in negative range (IC 50 > 135μM) Morgan R E et al. Toxicol. Sci. 2010;118:

17 Application of the science to regulation METRONIDAZOLE CLARITHROMYCIN AMOXYCILLIN CIPROFLOXACIN Ref: SOLVO

18 What are the implications for the clinician? Understand the often confusing nomenclature for drug transporters (e.g. P-gp - MDR1 - ABCB1) Understand the basic mechanisms Beware of the increasing regulatory guidance in preclinical drug development and clinical use labelling Access good quality information

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20 What are the implications for the regulator? Understand assay choice & validity Hepatotoxicity is hard to predict (BSEP) Implications of clinical DDI Dose adjustment Labelling changes (Black Box) Withdrawal

21 Implications for regulators In 1997 FDA instituted preclinical studies to test for DDI of CYP enzymes In 2006 Various reported interactions may be due to the inhibition of induction of transport proteins P-gp is the most well understood and may be appropriate to evaluate..? BSEP?OATs, OCTs

22 What to look for? Over-expression induction Inhibition Competitive binding (Digoxin, Indinavir)

23 Twist in the tail Competing Complementary Synergistic? HERBAL PRODUCTS Ritonavir Saquinavir Ketoconazole Cyclosporine A

24 Conclusion Transporters are cell membrane proteins involved in movement of endobiotics, nutrients and xenobiotics Drug efficacy and toxicity may arise from Drug Transporter interactions Compounds are created, drugs are invented Regulators must understand the science of transporters to become effective gatekeepers

25 Acknowledgements NRF Emory University, Atlanta, GA Scynexis Inc, RTP, NC Tshwane University of Technology MCC Andy Gray

26 THANK YOU