1. Drug Interactions Cara L. Alfaro, Pharm.D. Clinical Reviewer Division of Neuropharmacological Drug Products Food and Drug Administration This presentation was prepared by Dr. Alfaro in her private capacity. No official support or endorsement by the FDA is intended or should be inferred.

2. Incidence of Drug-Drug Interactions  True incidence difficult to determine  Data for drug-related hospital admissions do not separate out drug interactions, focus on ADRs  Lack of availability of comprehensive and easy to access databases  Difficulty in assessing OTC and herbal drug therapy use  Difficulty in determining contribution of drug interaction in morbidity of medically complicated patients

3. Drug Interactions  Pharmacodynamic  Related to the drug’s effects in the body  Receptor site occupancy  Pharmacokinetic  Related to the body’s effects on the drug  Absorption, distribution, metabolism, elimination,

4. Pharmacodynamic Interactions

5. Pharmacodynamic Drug Interactions  Additive, synergistic, or antagonistic effects from co-administration of two or more drugs  Synergistic actions of antibiotics  Overlapping toxicities - ethanol & benzodiazepines  Antagonistic effects - anticholinergic medications (oxybutinin or amitriptyline w/ acetylcholinesterase inhibitors)

6. Pharmacokinetic Drug Interactions  Alteration in absorption  Protein binding effects  Alteration in elimination  Changes in drug metabolism

7. Pharmacokinetic Absorption Interactions

8. Alterations in Absorption  Administration with food  For many drugs, decrease rate of absorption but not extent  Indinavir - rapidly absorbed in fasted state, AUC and Cmax decreased by ~80% with high calorie/fat/protein meal  Saquinavir - administration with high fat meal increases AUC by ~570% for this low F drug (4%)  Patient issues??

9. Alterations in Absorption  Chelation  Irreversible binding of drugs in the GI tract  Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe +2 ), antacids (Al +3, Ca +2, Mg +2 ), dairy products (Ca +2 )  Usually separating administration of chelating drugs by 2+ hours decreases interaction effect  Dose tetracycline 1 hour before or 2 hours after dairy products

10. Thyroxine and Ferrous Sulfate  TSH on stable thyroxine dose before and after 12 weeks co-ingestion with 300 mg FeSO4  TSH 1.6 ± 0.4 before  TSH 5.4 ± 2.8 after  9/14 had clinical symptoms of hypothyroidism  Thyroxine + FeSO4 invitro - complexation  Mgmt?? Campbell NRC et al. Ann Intern Med 1992;/117:1010-1013 Variability of interaction

11. Alterations in Absorption  Alteration in GI motility  Increased motility - cisapride (R.I.P.), metoclopramide  Decreased motility - narcotics  Altering GI tract pH  Increase in GI pH (antacids, omeprazole, cimetidine) may decrease absorption of drugs which require acidic pH for optimal absorption such as ketoconazole and itraconazole

12. Ketoconazole Interactions pH-dependent absorption Piscitelli S et al. Antimicrob Agents Chemother 1991;35:1765-1771

13. Pharmacokinetic Protein Binding Displacement Interactions

14. “…the overall clinical importance of plasma protein binding displacement interactions continues to be overstated…” “Despite the theoretical and experimental data to the contrary, the concept that plasma protein binding displacement is a common cause of clinically significant interactions may still be widely taught in some medical schools, often appears in textbooks and is accepted by many in the medical community and by drug regulators.” Protein Binding Interactions Sansom LN & Evans AM. Drug Safety 1995;12:227-233. Rolan PE. Br J Clin Pharmacol 1994;37:125-128.

15. Protein Binding Interactions  Competition between drugs for protein or tissue binding sites  Increase in free (unbound) concentration may lead to enhanced pharmacological effect  Many interactions previously thought to be PB interactions, were found to be primarily metabolism interactions  Warfarin - sulfamethoxazole (partially metabolism interaction)  PB interactions are not usually clinically significant

16.  Restrictively cleared drugs  Small fraction of drug extracted during single passage through the eliminating organ  CL is directly proportional to f u  Increase in f u leads to proportional increase in CL and decrease in Css  No change in Cl u, Css u will return to predisplacement value after transient increase  phenytoin and valproic acid; decrease in phenytoin Css and C u unchanged Protein Binding Interactions

17. Principles of Clinical Pharmacology, pg 64

18.  Nonrestrictively cleared drugs  Eliminating organ removing most of the drug being presented to it, including the fraction bound to plasma proteins  Increase in fu will not lead to a proportional increase in CL Protein Binding Interactions

19.  Drugs for which pure plasma protein binding displacement interactions will lead to sustained changes in Css u  Extensively bound to plasma proteins  Nonrestrictively cleared  Administered by non-oral route  alfentanil, buprenorphine, lidocaine, verapamil  Very few orally administered drugs exhibiting properties of extensive plasma protein binding, high hepatic first-pass extraction and narrow therapeutic index

20. Pharmacokinetic Metabolism Interactions

21. Drug Metabolism Interactions  Drug metabolism inhibited or enhanced by coadministration of other drugs  CYP 450 system has been the most extensively studied  CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and others  Phase 2 metabolic interactions (glucuronidation, etc.) occur, research in this area is increasing

22. CYP 450 Substrates  Metabolism by a single isozyme (predominantly)  Few examples of clinically used drugs  Desipramine/CYP2D6  Examples of drugs used primarily in research on drug interaction potential  Debrisoquin, sparteine, dextromethorphan, mephenytoin  Metabolism by multiple isozymes  Most drugs metabolized by more than one isozyme  Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19  If co-administered with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme

23. Proportion of Drugs Metabolized by CYP450 Isozymes CYP3A436% CYP2E1 CYP2B6 CYP2A6 CYP1A2 CYP2D619% CYP2C9 CYP2C19

24. CYP 450 Inhibitors  Drugs can inhibit a specific CYP even though they are not metabolized by that isozyme  Quinidine - most potent CYP2D6 inhibitor but metabolized primarily by CYP3A4  Drugs which are metabolized by a specific CYP may not potently inhibit that CYP  Venlafaxine is metabolized by CYP3A4 but is not a potent inhibitor of CYP3A4  Determining whether a drug is a substrate or an inhibitor (or inducer) of a specific CYP are different questions

25. Examples of CYP 450 Substrates, Inhibitors, & Inducers Substrates*InhibitorsInducers CYP3A4AlprazolamLovastatinQuetiapineClarithromycinRitonavirKetoconazoleRifampinCarbamazepine CYP2D6RisperidoneDesipramineDonepezilQuinidineFluoxetineParoxetine None identified CYP1A2ClozapineTheophyllineCaffeineFluvoxamineCimetidineSmokingOmeprazole Cruciferous veg *Primary metabolic pathway

26. CYP 450 Inducers  The “usual suspects”  Rifampin  Rifabutin  Carbamazepine  Phenobarbital  Phenytoin

27. CYP 450 Enzyme Induction  Gradual onset and offset  Onset - accumulation of inducing agent and increase in enzyme production  Offset - elimination of inducing agent and decay of enzymes  Results in reduction of plasma concentration of substrate drugs

28. CYP 450 Inhibitors  The “usual suspects”  Cimetidine  Erythromycin  Ketoconazole  Ritonavir  Fluoxetine, paroxetine (CYP2D6)  Nefazodone (CYP3A4)

29. CYP 450 Enzyme Inhibition  Usually by competitive binding to enzyme site  Onset and offset dependent on the half-life and time to steady-state of the inhibitor  Fluoxetine & CYP2D6  Time to maximum interaction effect dependent on time required for substrate drug to reach new steady-state

30. Fluoxetine, Sertraline & Desipramine Interaction Preskorn SH et al. J Clin Psychopharmacol 1994;14:90-98 3 week SSRI washout

31. Review of NDAs # NMEs increased 2-fold # DDI studies increased 4.6 fold Marroum PJ et al. Clin Pharmacol Ther 2000;68:280-5

32. Drug Interaction Studies by Medical Division 1992-1997 Antivirals15% Cardio-renal17% Endocrine13% Neuropharmacol24% Anti-infectives13% < 10% PulmonaryAnalgesicsGIOncologyReproductive

33. NDAs - Drug Interactions  Most common single agent drug interactions  Cimetidine  Digoxin  Antacids  Warfarin  Propranolol  Theophylline  Approaches to drug interaction studies > 1995 focused on mechanism based interactions  Effects of drugs on specific CYP isozymes  Predicting drug interactions

34. Investigating Drug Interaction Potential of NMEs  cDNA expressed isozymes  Drug probes (in vivo) - drugs with fairly specific metabolic pathways  Dextromethorphan, debrisoquin - CYP2D6  Midazolam - CYP3A4  Caffeine - CYP1A2  Bupropion - CYP2B6  Tolbutamide - CYP2C9 DextromethorphandextrorphanCYP2D6

35. Drug Labeling “An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes. In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of dextromethorphan…”

36. Drug Withdrawals Drug Interactions & QT Prolongation Terfenadine(Seldane®)Fexofenadine(Allegra®) Cisapride(Propulsid®) Astemizole(Hismanal®) + Norcisapride? Norastemizole? Risk Benefit Analysis Labeling changes - impact??

37. Terfenadine & Ketoconazole Interaction  Terf Cp at usual doses = undetectable  QT prolongation correlated to terf Cp (R 2 = 0.6, p = 0.001) ~45 ng/ml = 70 to 110 ms increase in QTc BaselineTerf Terf + Keto

38. Drug Interaction Liability Risk vs. Benefit Analysis (Competitive Marketplace Decision too) Mibefradil(Posicor®) Terfenadine Astemizole Ritonavir(Norvir®) Fluoxetine(Prozac®) TherapeuticArea Antihistamines Liability DDI - QT prolongation Antihypertensive (Calcium Channel Blocker) CYP3A4 Inhibition - DDIs Competitive in class? HIV Protease Inhibitor CYP3A4, CYP2D6 Inhibition - DDIs Antidepressant CYP2D6 Inhibition - DDIs Attempted R-fluoxetine DDI - QT prolongation CYP3A4 CYP3A4 Inhibition - DDIs Competitive in class?

39. Pharmaceutical Industry Competitive in Market

41. CYP1A2 Inhibition Fluvoxamine & Clozapine Drug Interaction Wetzel H et al. J Clin Psychopharmacol 1998;18:2-9 x 14 days *p<0.0001 vs. baseline §p<0.05 vs. baseline * § N = 16, clozapine dose 202 ± 36 mg/day

42. CYP2D6 Inhibition Correlation to Paroxetine Cp Alfaro CL et al. J Clin Pharmacol 2000;40:58-66 EM PM Outlier, 2D6*2 gene duplication

43. Herb - Drug Interactions

44.  Since not regulated by FDA, safety & efficacy not required  Little information available regarding drug interactions  Extrapolation of data to available products difficult  Independent lab tests many products (http://www.consumerlabs.com/) http://www.consumerlabs.com/  6/13 SAMe preparations did not pass testing  no detectable SAMe noted in one product  8/17 valerian preparations did not pass testing  4 - no detectable levels of valerenic acid  4 - 1/2 the amount claimed on the label Herb-Drug Interactions Limitations

45. St. John’s wort: CYP3A4 Induction Effects IndinavirIndinavir + SJW Piscitelli SC et al. Lancet 2000;355:547-8  8 normal volunteers  Indinavir AUC determined before and after 14 days SJW 300 mg TID  Indinavir AUC decreased by 57 ± 19% in presence of SJW

46. Garlic - Saquinavir Interaction  N = 10 healthy subjects  Saquinavir 1200 mg TID x 3d - AUC  Garlic caplets BID x ~3 weeks  Repeat saquinavir AUC  Discontinue garlic x 10 days  Repeat saquinavir AUC Saq Saq + Garlic Piscitelli S et al. Clin Infect Dis 2002;34:234-238

47. Grapefruit Juice Interactions  Flavinoids in grapefruit juice can inhibit gastrointestinal CYP3A4 and first pass metabolism  Can increase concentrations of various CYP3A4 substrates - esp. those with low F  Saquinavir AUC increases 50 - 200%  Benzodiazepines  Calcium channel blockers  Wide variability - amount of GF juice, timing of intake and drug dosing, interpatient variability in CYP3A4 gut activity

48. Grapefruit Juice & Felodipine Lundahl J et al. Eur J Clin Pharmacol 1995;49:61-67 Control 0101244 *** * *Sign. Diff from Control

49. Beneficial Drug Interactions  Saquinavir & ritonavir  Saquinavir poorly absorbed, TID dosing, high pill burden  Combination with ritonavir results in 20-fold increase in Css  Allows for BID dosing and decreased dose from 1800 mg TID to 400 mg BID  Cyclosporin and ketoconazole  Clozapine and fluvoxamine??

50. Recognizing Drug Interactions  High index of suspicion  Patient’s demonstrating exaggerated toxicity or drug effects  Patient could also be poor metabolizer of dependent isozyme  Genotyping may aid in future, but would not pick up “phenocopy” effects  Patient’s demonstrating treatment failure or loss of drug effect  Induction vs. absorption interactions

51. Evaluation of Drug Interactions  What is the time-course of the interaction  Immediately or over a period of time  Clozapine and rifampin  Is it a drug class effect  Cimetidine vs. ranitidine; ketoconazole vs. fluconazole  Is the interaction clinically significant  Therapeutic index of drugs, toxicity?, loss of efficacy?  How should the interaction be managed?

52. Drug Interaction Resources Correction to Dr. Flockhart’s website: http://medicine.iupui.edu/flockhart