12/9/2015. Drug Interactions. Sarah Robertson, Pharm.D. Director, Department of Clinical Pharmacology Vertex Pharmaceuticals Inc.

Transcription

1 Drug Interactions Sarah Robertson, Pharm.D. Director, Department of Clinical Pharmacology Vertex Pharmaceuticals Inc. Boston, MA, USA December 10,

2 Overview Epidemiology and Categories of Drug Interactions Mechanisms Affecting Drug Absorption Alteration in Drug Distribution Drug Interactions by Alteration in Drug Metabolism Modulation of Transport Proteins Alteration in Renal Elimination Enzyme/Transporter Interplay and Complex Drug Interactions Clinical Interpretation of Drug Interactions Drug Interaction Information in Product Labeling Resources 2 2

3 Abbreviations AUC BCRP CAR Cmax CNS CYP450 DDI GI IC50 NDA NSCLC OAT OCT OATP P-gp PPI PXR TB UGT Vd Area under the concentration vs. time curve Breast Cancer Resistance Protein Constitutive Androstane Receptor Maximum Observed Concentration Central Nervous System Cytochrome P450 Drug-drug interactions Gastrointestinal Half-maximal inhibition concentration New Drug Application Non-Small Cell Lung Cancer Organic anion transporter Organic cation transporter Organic anion transporting polypeptide P-glycoprotein Proton-pump inhibitor Pregnane X receptor Tuberculosis UDP glucuronosyltransferase Volume of distribution 3 3

4 Epidemiology of Drug Interactions True incidence not easily quantifiable Review of Medicaid records for 8860 patients from found 16.6% had 1 clinically significant DDI 1 risk among elderly, patients with comorbidities or polypharmacy An FDA review of NDAs approved in 2013: 2 All compounds were metabolized by at least one CYP450 enzyme (77% by CYP3A) 77% showed possible inhibition or induction of 1 metabolizing enzyme in vitro; 85% showed a possible interaction with 1 transport protein in vitro Overall, 45% had a metabolism-based DDI that resulted in a change in exposure of clinical significance 4 1 Nelson SD et al, J Pharm Pract. Aug 2014 Epub; 2 Yu J et al, Drug Metab Dispos. Sept 2014 Epub 4

5 Types of Drug Interactions Pharmacodynamic Related to drug s effect on target (either safety or efficacy) One drug modulates that of another (additive, synergistic, or antagonistic) Most frequently identified in recent review by Nelson et al (mainly among drugs used to treat psychiatric/seizure/sleep disorders and pain) Pharmacokinetic Impact how a drug is absorbed, distributed, metabolized, or excreted (i.e. impact the concentration of drug at the site of activity or at a site of toxicity) Most commonly the result of inhibition or induction of CYP450 enzymes 5 5

6 Pharmacodynamic Interactions Additive combinations Pharmacologic effect = sum of the 2 drugs Beneficial: ibuprofen + acetaminophen Harmful: neutropenia with zidovudine + ganciclovir Synergistic combinations Pharmacologic effect > sum of the 2 drugs Beneficial: aminoglycosides + penicillin Harmful: barbiturates + alcohol Antagonistic combinations Pharmacologic effect < either drug alone Beneficial: naloxone for opiate overdose Harmful: zidovudine + stavudine in treatment of HIV 6 6

7 Pharmacokinetic Interactions Absorption: Gastrointestinal (GI) motility, ph, chelate formation, GI transport proteins Distribution: Transport proteins, plasma protein binding Metabolism: Phase I (CYP450 enzymes) +/- transport proteins, Phase II (conjugation) Elimination: Renal excretion (glomerular filtration; tubular secretion), biliary secretion 7 7

8 Altered Absorption: ph Affects Many drugs are dependent on ph for optimal solubility Increasing ph in the gut with H2-antagonists (e.g. ranitidine) or PPIs (e.g. omeprazole) can or drug absorption Examples: Atazanavir and omeprazole: Atazanavir AUC by 94% Raltegravir and omeprazole: Raltegravir AUC 3-fold Erlotinib and omeprazole: Erlotinib AUC ~50% Retrospective review of patient records found concurrent treatment with acid suppressors and erlotinib was sig. associated with shorter overall survival after accounting for other factors (12.9 vs months) Chu MP et al, Clin Lung Cancer. Aug2014 Epub. 8

9 Altered Absorption: GI Motility Decreased GI motility (e.g. methadone) or increased motility (e.g. metoclopramide) can affect bioavailability motility by methadone didanosine (ddi) degradation in the gut ( bioavailability) motility by metoclopramide posaconazole bioavailability ddi alone ddi + methadone 9 Rainey PM, et al. J Acquir Immune Defic Syndr. 2000;24: Krishna G, et al. Antimicrob Agents Chemother. 2009;53:

10 Altered Absorption: Chelation Irreversible binding of drug in the GI tract Usually can be avoided by separation of administration E.g. Tetracyclines, quinolone antibiotics with ferrous sulfate (Fe +2 ), antacids (Al +3, Mg +2 ), dairy products (Ca +2 ) Trovafloxacin Alone / Maalox 2 hrs after Trovafloxacin / Trovafloxacin + omeprazole Maalox 30 min before Trovafloxacin 10 10

11 Mechanism of Drug Transporters Passive diffusion Uptake protein (i.e. OATP) Extracellular Space: Cell Membrane: Intracellular space: Efflux protein (i.e. P-glycoprotein) 11 11

12 Altered Absorption: Transport Proteins in Intestinal Lumen Drug blood levels Efflux of drug back into the gut 12 Figure from: Hillgren KM et al. Clin Pharmacol Ther. 2013;94:

13 Altered Absorption: Transport Proteins in Intestinal Lumen Uptake and efflux transporters in the gut can be inhibited or induced by drugs, which may or bioavailability of drugs that rely on the transporters (i.e. substrates) Reliance on uptake/efflux transporters for absorption depends largely on compound permeability The lower the permeability of a compound, the more its absorption is affected by membrane transporters. Of the many gut transporters, only 2 are generally associated with clinical DDIs: P-glycoprotein (P-gp, MDR1, ABCB1) Breast Cancer Resistance Protein (BCRP, ABCG2) 13 13

14 Altered Absorption: Transport Proteins in Intestinal Lumen E.g. DDI between quinidine (P-gp inhibitor) and digoxin (sensitive substrate) is well documented. In a perfusion catheter study, quinidine caused a 2.5-fold increase in the amount of digoxin absorbed 1 Digoxin DDI studies are often conducted as part of development for new drugs found to be potential P-gp inhibitors in vitro Clinical P-gp inhibitors include: cyclosporine, erythromycin, verapamil, itraconazole, and others 14 1 Igel S, et al. Clin Pharmacokinet. 2007;46:

15 Altered Distribution: Protein Binding Theoretical mechanism of DDI for restrictively cleared drugs (i.e. small fraction of drug is extracted during passage through eliminating organ) Only unbound drug in plasma is cleared. Thus, fu leads to an increase in total drug CL (and in plasma concentrations) However, unbound plasma concentrations typically return to pre-displacement values after a transient increase Only likely to be clinically significant for drugs with high protein binding, small V d, and narrow therapeutic index (e.g. warfarin) the overall clinical importance of plasma protein binding displacement interactions continues to be overstated Sansom LN & Evans AM. Drug Safety 1995;12: Rolan PE. Br J Clin Pharmacol 1994;37:

16 Altered Distribution: Protein Binding Warfarin pharmacodynamic effect Total drug conc. decreases Free drug conc. returns to predisplacement level Displacing drug added 16 Atkinson AJ, Huang S-M, Lertora JJL, Markey SP (Editors), Principles of Clinical Pharmacology, Edition 3,

17 Altered Distribution: Transport Proteins Transport proteins play a role in the distribution of drugs to organ systems protected by blood-organ barriers, such as the brain, placenta, and kidneys Induction or inhibition can result in altered distribution of the substrate Drug - substrate Inhibitor / inducer Interaction Effect Loperamide Quinidine P-gp inhibition Digoxin Paroxetine P-gp inhibition Desipramine Ritonavir OCT1 inhibition Penicillin Probenecid OAT inhibition Increased CNS penetration of loperamide Increased CNS penetration of digoxin Decreased hepatic uptake with poorer access to CYP3A4 Prolonged penicillin half-life by reduced renal clearance 17 Girardin F, Dialogues Clin Neurosci. 2006;8:

18 Metabolism Overview Phase 1: CYP450 enzymes, present in gut and liver Primary source of adverse drug interactions Proportion of drugs metabolized by CYP450 enzymes: 1 CYP3A4/5 CYP2D6 CYP1A/2 CYP2C19 CYP2C8/9 CYP2E1 CYP2B6 Phase 2: Conjugation enzymes; most prevalent in liver UGTs, Methyltransferase, sulfotransferases, N-acetyltransferase, etc. Modulation of Phase 2 enzymes is rarely associated with clinically significant DDIs 18 1 Kashuba and Bertino. In Drug Interactions in Infectious Diseases. Humana Press

19 Altered Metabolism: Inhibition of CYP450 enzymes May occur in the liver and/or GI tract Results in substrate potential for toxicity Usually by competitive binding to enzyme site Onset and offset of effect generally occurs quickly (depends on the time to steady-state of the inhibitor) Time to maximum interaction effect dependent on time required for substrate drug to reach new steady-state 19 19

20 Substrate Concentration (μg/ml) 12/9/2015 CYP450 Inhibition 40 Steady-state concentration of substrate prior to addition of CYP inhibitor New Steady-state achieved after addition of inhibitor CYP Inhibitor Days 20 20

21 Altered Metabolism: Inhibition of CYP45 enzymes Effect of inhibition on substrate exposure is greater if the substrate relies on the inhibited enzyme as its sole route of metabolism (e.g. Midazolam and CYP3A4); drugs with >1 route of metabolism are less sensitive to inhibition of 1 route (e.g. voriconazole: CYP2C9, 2C19, 3A4) Mechanism-based enzyme inactivation Formation of reactive metabolites which bind covalently to enzyme or form a metabolic inhibitory complex (MIC) Results in irreversible or quasi-irreversible inactivation of CYP More profound and prolonged inhibitory effect Examples include macrolides, grapefruit juice Duration of inhibition depends on time to restore active enzyme 21 21

22 Example: CYP3A Inhibition by Ritonavir Triazolam: 100% metabolized by CYP3A Zolpidem: 60% by CYP3A; 40% by other CYPs 20-fold AUC 28% AUC 22 Greenblatt et al. J Acquir Immune Defic Syndr. 2000;24:

23 Altered Metabolism: Induction Involves increased DNA transcription via nuclear receptor activation (e.g. PXR, CAR) synthesis of new CYP enzymes Slower onset and offset relative to inhibition; depends on halflife of inducer, time to make new CYP proteins, and rate of degradation of CYP proteins Results in substrate potential for reduced activity, or formation of toxic metabolites Removal of inducer without a dose adjustment of substrate may lead to toxic concentrations of substrate Unlike inhibition, induction can be significant even when the particular CYP enzyme being induced is a minor pathway for the substrate 23 23

24 Substrate Concentration (μg/ml) 12/9/2015 CYP450 Induction 40 Steady state concentrations of Substrate prior to addition of CYP inducer 30 New Steady state achieved with inducer Days CYP Inducer

25 Example: CYP450 Induction by Rifampin Investigational anti-tb drug, PA-824 is metabolized partially by CYP3A (20%) DDI study with rifampin (strong CYP3A inducer) PA-824 AUC 66%, Cmin 85% Half-life (t1/2) shortened from 19 to 8 hours 25 Dooley KE et al. Antimicrob Agents Chemother. 2014;58:

26 Classification of Common CYP450 Inhibitors/Inducers Inhibitors Inducers Strong Moderate Weak Strong Moderate Weak CYP3A CYP2D6 CYP1A2 CYP2C19 Clarithromycin Itraconazole Posaconazole Ritonavir Telithromycin Voriconazole Bupropion Fluoxetine Paroxetine Ciprofloxacin Fluvoxamine Fluconazole Fluvoxamine Ticlopidine Aprepitant Diltiazem Erythromycin Fluconazole Grapefruit juice Verapamil Duloxetine Terbinafine Mexiletine Zileuton Esomeprazole Fluoxetine Omeprazole Voriconazole Alprazolam Atorvastatin Cimetidine Cyclosporine Fluoxetine Isoniazid Celecoxib Diltiazem Sertraline Acyclovir Allopurinol Famotidine Verapamil Carbamazepine Cimetidine Ethinyl Estradiol Etravirine CYP2C8 Gemfibrozil None Fluvoxamine Trimethoprim CYP2C9 None Amiodarone Fluconazole Cotrimoxazole Fluvastatin Avasimibe Carbamazepine Phenobarbital Phenytoin Rifampin St. John s wort Bosentan Efavirenz Etravirine Modafinil Nafcillin None None None None Montelukast Phenytoin Cigarette smoking Aprepitant Armodafinil Pioglitazone Prednisone Moricizine Omeprazole Phenobarbital None Rifampin Artemisinin None Rifampin None None Carbamazepine Rifampin Aprepitant Bosentan 26 26

27 Altered Hepatic or Biliary Elimination: Transport Proteins Inhibition of uptake transporters (e.g. OATP1B1) decreased hepatic update less hepatic metabolism, higher systemic exposure Inhibition of efflux transporters (e.g. BCRP) decreased biliary excretion higher systemic exposure (or increased hepatic metabolism, if drug is metabolized) 27 Figure from: Hillgren KM et al. Clin Pharmacol Ther. 2013;94:

28 Example: OATP2 Inhibition by Gemfibrozil Rosuvastatin AUC 88% 28 Schneck DW et al. Clin Pharmacol Ther. 2004;75:

29 Transporter/CYP interplay Example: Atorvastatin Substrate for CYP3A, P-gp, OATP1B1, OATP2B1 Interacting Drug Effect on Atorvastatin AUC Cyclosporine - P-gp inhibitor - OATP1B1 inhibitor - Weak CYP3A inhibitor Clarithromycin - P-gp inhibitor - Strong CYP3A inhibitor Diltiazem - P-gp inhibitor - Moderate CYP3A inhibitor Gemfibrozil - OATP1B1 inhibitor 8.7-fold 4.4-fold 51% 35% 29 29

30 Altered Elimination: Renal 30 30

31 Altered Elimination: Renal Inhibition of uptake transporters (e.g. OAT1, OAT3) decreased renal elimination increased systemic exposure Inhibition of efflux transporters (e.g. P-gp) decreased secretion into urine increased systemic exposure E.g. Cimetidine (OCT inhibitor): metformin and pramipexole exposure E.g. Probenecid (OAT1/3 inhibitor): cidofovir, furosemide, acyclovir exposure 31 Figure from: Hillgren KM et al. Clin Pharmacol Ther. 2013;94:

32 Complex Drug Interactions Concurrent inhibition and induction of one enzyme (e.g. ritonavir and CYP3A) unpredictable and time-dependent effect on substrates Concurrent inhibition or induction of an enzyme and transporter potentially additive effect on substrate Combination of 2 inhibitors of different enzymatic pathways used by 1 substrate (e.g. CYP3A and CYP2C9) greater increase in substrate exposure than either drug alone (effect may be synergistic, not additive) Inhibition of the alternative enzyme pathway in a population of poor metabolizers (PMs) of the primary enzymatic pathway greater effect on substrate Enzyme/transporter inhibitors in patients with altered renal or hepatic elimination due kidney or liver disease 32 32

33 Predicting Clinical DDIs In early drug development, clinically relevant DDIs are predicted with in vitro experiments (e.g. recombinant CYP enzymes, liver microsomes, hepatocytes, liver slices, etc.) Elucidate method of elimination Describes study drug potential as a victim If metabolized, which enzyme is responsible? If renally eliminated, is active transport involved? If excreted in bile, are efflux transporters involved? Determine if study drug causes inhibition or induction of enzymes or transporters? Describes study drug potential as a perpetrator 33 33

34 Predicting Clinical DDIs, cont. If inhibition/induction of enzymes or transporters is observed in vitro, the probability of an in vivo effect is determined: Concentration at which inhibition or induction is observed in vitro (e.g. IC50) is compared to in vivo concentrations (e.g. Cmax or [I]) If inhibition/induction is possible (e.g. [I]/IC50 > 0.1), clinical DDI studies must be considered, or mechanistic modeling may be performed to evaluate potential for DDI in vivo 34 34

35 Assessing Clinical DDIs: Phase 1 studies Initially probe DDI studies are performed: For a substrate, assess effect of a strong inhibitor (e.g. Itraconazole for CYP3A) and strong inducer (e.g. Rifampin for CYP3A) on the study drug For a potential perpetrator, assess effect on a sensitive substrate (e.g. single dose oral midazolam for CYP3A; digoxin for P-gp; rosuvastatin for OATP1B1) Depending on results of these initial studies, addt l DDI studies should be considered: Likely coadministered drugs Moderate inhibitors or inducers Drugs with mixed enzyme/transporter effects Proton-pump inhibitor DDI for ph-dependent solubility drugs Etc

36 Evaluating Risk in the Clinical Setting Consider the therapeutic index of the victim drug E.g. 50% increase in atorvastatin not likely clinically significant; 50% increase in tacrolimus may be clinically significant Are other potential perpetrators involved? What is the likely time course of the interaction? Consider both the addition and withdrawal of potential perpetrators and the implications to the substrate Is the DDI a class effect? Or are there other options? E.g. rosuvastatin vs. simvastatin different susceptibility to DDIs and different therapeutic indices Are there other confounders that may magnify the DDI? (e.g. organ impairment, older age) 36 36

37 DDI Information in U.S. Product Labeling 1. Indications and Usage 2. Dosage and Administration 3. Dosage Forms and Strengths 4. Contraindications 5. Warnings and Precautions 6. Adverse Reactions 7. Drug Interactions 8. Use in Specific Populations 9. Drug Use and Dependence 10. Overdosage 11. Description 12.Clinical Pharmacology 13. Nonclinical Toxicology 14. Clinical Studies 37 37

38 Section 7: Drug Interactions Describes Clinical Interpretation of DDI Study Results or In Vitro Findings Example: Kalydeco (ivacaftor) Potential for other drugs to affect ivacaftor 7.1 Inhibitors of CYP3A Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold. Based on simulations of these results, a reduction of the KALYDECO dose to 150 mg twice a week is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin. Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dose to 150 mg once daily is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin. Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, food containing grapefruit or Seville oranges should be avoided during treatment with KALYDECO [see Clinical Pharmacology (12.3)]. 7.2 Inducers of CYP3A Co-administration with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John s Wort is not recommended [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. 38 Kalydeco (ivacaftor) USPI, June Vertex Pharmaceuticals Inc., Boston, MA. 38

39 Section 12: Clinical Pharmacology Provides DDI Study Results in Table or Forest Plot Figure 2: Impact of Other Drugs on KALYDECO Note: The data obtained for KALYDECO without co-administration of inducers or inhibitors are used as reference. The vertical lines are at 0.8, 1.0 and 1.25, respectively. 39 Kalydeco (ivacaftor) USPI, June Vertex Pharmaceuticals Inc., Boston, MA. 39

40 Resources and Tools Site Martindale 1 Micromedex 1 UCSF 2 Indiana University 3 Natural Products Database 4 Lexi-Comp Lexi-Interact 1 University of Washington Drug Interaction Database 5 Web Address Includes all drugs; paid subscription required 2 Focus on HIV meds; free 3 Exhaustive tables of CYP substrates, inhibitors, and inducers; free 4 Focuses on natural products; paid subscription required 5 Comprehensive and thoroughly referenced database of in vitro and in vivo data related to DDIs, including transporter-mediated DDIs; database serves as a reference for FDA guidance and decision trees 40 40

41 Questions 41 41