1. Drug Interactions Clinical Pharmacology Spring Course 2006 M. E. Blair Holbein, Ph.D. Clinical Pharmacologist Presbyterian Hospital

2. Why study drug interactions?

3. Ref: Institute of Medicine, National Academy Press, 2000, Lazarou J et al. JAMA 1998;279(15):1200–1205, Gurwitz JH et al. Am J Med 2000;109(2):87–94. Johnson JA et al. Arch Intern Med 1995;155(18):1949–1956, Leape LL et al. N Engl J Med 1991;324(6):377–384, Classen DC et al. JAMA 1997;277(4):301–306 Clinical Significance of Drug Interactions  Over 2 MILLION serious ADRs and 100,000 deaths yearly  ADRs 4th leading cause of death ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents and automobile deaths  Greater than total costs of cardiovascular or diabetic care  ADRs cause 1 out of 5 injuries or deaths per year to hospitalized patients  Mean length of stay, cost and mortality for ADR patients are DOUBLE that for control patients  Account for 6.5% hospital admissions  Nursing home patients ADR rate—50,000 yearly  Ambulatory patients ADR rate—unknown  Many clinical implications  Libby Zion case  Clinical Trials, OPI  International Intrigue?

4. erer

5. Preventable drug interactions  1/3 of adverse drug events and  1/2 cost.

6. Wright JM. 2000. Drug Interactions. In: Carruthers SG, Hoffman BB, et al., ed. Melmon and Morrelli’s Clinical Pharmacology: Basic Principles in Therapeutics, 4th ed. New York:McGraw-Hill. DefinitionDefinition  A drug interaction is defined as a measurable modification (in magnitude or duration) of the action of one drug by prior or concomitant administration of another substance (including prescription and nonprescription drugs, food, or alcohol)  May be harmful: toxicity, reduced efficacy  May be beneficial: synergistic combinations, pharmacokinetic boosting, increased convenience, reduced toxicity, cost reduction.

7. Characterizing Drug Interactions Mechanism  Pharmacodynamic  Receptor inhibition  Additive effects  Pharmacokinetic  Altered absorption, distribution, metabolism, or elimination Interacting agents  Drug - Disease  Drug-drug  Prescription  Non-prescription  Illicit, recreational  Food, supplements, herbal products Clinical Significance  Major  Substantial morbidity and mortality  Therapy altering  Manageable  Little or no change in therapy  Optimize therapy  Intentional  Additive or synergistic effects  Enhanced pharmacokinetics

8. Mechanisms of Interactions Pharmacodynamic Receptor Non-receptor Pharmacokinetic Absorption Distribution Metabolism Excretion

9. Mechanisms of Interactions Pharmacodynamic Receptor Non-receptor

10. Pharmacodynamic: Pharmacological  Interaction at the drug receptor  Activity is function of intrinsic activity and affinity for receptor  Agonist and antagonists  Effect also function of concentration at receptor  Effect can be additive  Several agents that act via the same receptor  Example, several agents with anticholinergic activity or side effects can result in serious anticholinergic toxicity especially in elderly patients.

11. Pharmacodynamic: Physiological  Agents that can act in concert or in opposition via different cellular mechanisms.  Both theophylline and  -receptor agonists can cause bronchiolar muscle relaxation  Sensitization of myocardium to arrhythmogenic action of catecholamines by general anesthetics.  Combinations of antihypertensive (can be intentional)

12. Pharmacodynamic: Altered physiology  Altered cellular environment  Aging effects  Blunted sympathetic nervous system; blunted responses  Agents that change the state of the host  Ex. Hypokalemia caused by diuretics increases toxicity of digoxin.

13. Pharmacodynamic: Neutralization  Neutralization systemically in the host (as opposed to prior to absorption)  Protamine used to neutralize heparin  Purified antidigoxin Fab fragments used to treat digoxin toxicity

14. Mechanisms of Interactions Pharmacodynamic Receptor Non-receptor Pharmacokinetic Absorption Distribution Metabolism Excretion

15. Mechanisms of Interactions Pharmacokinetic Absorption Distribution Metabolism Excretion

16. Mechanisms of Interactions Pharmacokinetic Absorption Distribution Metabolism Excretion

17. Pharmacokinetic: Absorption  Alters rate that drug enters the system with altered level or time to peak  Mechanisms:  Physical interaction, chelation, binding. e.g. tetracyclines and cations  Altered GI function: changes in pH (ketoconazole), motility, mucosal function, metabolism, absorption sites, perfusion

18. Absorption: in the gut Sucralfate, some milk products, antacids, and oral iron preparations Omeprazole, lansoprazole, H2-antagonists Didanosine (given as a buffered tablet) Cholestyramine Block absorption of quinolones, tetracycline, and azithromycin Reduce absorption of ketoconazole, delavirdine Reduces ketoconazole absorption Binds raloxifene,thyroid hormone, and digoxin

19. Interactions: Presystemic Elimination  Gut transit and metabolism  Intestinal wall CYP3A4 metabolizes a number of drugs  Inhibition/induction results in altered bioavailability  Ex: grapefruit juice inhibits intestinal CYP3A4  Results in increased bioavailability of calcium channel blockers (dihydropyridine), cyclosporin, saquinavir (HIV-1 protease inhibitors), carbamazepine, lovastatin, terazosin, triazolam and midazolam.  High intrinsic hepatic clearance dependent upon hepatic blood flow  Inhibition results in increased bioavailabilty.  Propranolol, metoprolol, labetalol, verapamil, hydralazine, felodipine, clhlorpromazine, imipramine, amitriptyline, morphine

20. Wilkinson, G. R. N Engl J Med 2005;352:2211-2221 First-Pass Metabolism after Oral Administration of a Drug, as Exemplified by Felodipine and Its Interaction with Grapefruit Juice

21. Wilkinson, G. R. N Engl J Med 2005;352:2211-2221 Some Common Drugs with Low Oral Bioavailability and Susceptibility to First-Pass Drug Interactions

22. Wilkinson, G. R. N Engl J Med 2005;352:2211-2221 Consequences of the Inhibition of First-Pass Metabolism, as Exemplified by the Interaction between Felodipine and Grapefruit Juice

23. Induction of P-glycoprotein and Intestinal CYP450  Intestinal epithelium with CYP450  Sufficient amout to result in presystemic clearance of some drugs  Highly variable  Enterocytes have transporter proteins  Organic anion-transporting polypeptide (OATP)  Organic cation transporters (OCTs)  P-glycoprotein (P-gp)  Product of human multidrug resistance gene (mdr1)  Contributesto resistance to a variety of chenotherapeutic agents  Decreases the intracellular accumulation of anticancer drugs  Efflux transporter in Gi epithelium, liver, kidney, edothelial cells of blood-brain barrier  Complements CYP450 interactions

24. Intestinal Transporter - P-glycoprotein

25. Intestinal Monoamine Oxidase  Intestinal MAO inhibited by nonselective irreversible agents and inhibit metabolism of dietary tyramine resulting in increased release of norepi from sympathetic postganglionic neurons  Less problematic for selective MAO B inhibitor selegiline and reversible agent moclobemide

26. Mechanisms of Interactions Pharmacokinetic Absorption Distribution Metabolism Excretion

27. Pharmacokinetic: Distribution  Protein-binding displacement  Relative to :  Concentration - a high concentration of one drug relative to another will shift the binding equilibrium  Relative binding affinity - only relatively highly bound drugs will be effected  Volume of distribution - small Vd allows for greater proportional effect  Therapeutic index - mostly drugs with a narrow TI are clinically significant  Alterations in protein-binding capacity  hypoalbuminemia (acidic drugs)   1-acid glycoprotein (basic drugs)  acute phase reactants

28. Pharmacokinetic: Distribution  Protein-binding displacement  Effect is rapid and transient and usually compensated by increased elimination  May result in transient pharmacologic effect  Overall result is unpredictable  New steady-state attained

29. Pharmacokinetic: Distribution  Cellular distribution interactions  Cellular transport systems  “Promiscuous” and affect several agents requiring active transport  Best studied example is P-glycoprotein (PGP) an organic anion transporter system.  Cyclosporin A, quinidine, verapamil, itraconazole and clarithromycin inhibit PGP  Some correlation with CYP3A4 affinities  May be significant for some anticancer drugs

30. Mechanisms of Interactions Pharmacokinetic Absorption Distribution Metabolism Excretion

31. Drug Metabolism  Phase I  Oxidation  Cytochrome P450 monooxygenase system  Flavin-containing monooxygenase system  Alcohol dehydrogenase and aldehyde dehyddrogenase  Monoamine oxidase (Co-oxidation by peroxidases)  Reduction  NADPH-cytochrome P450 reductase  Reduced (ferrous) cytochrome P450  Hydroloysis  Esterases amd amidases  Epoxide hydrolase  Phase II  Glutathione S-transferases  UDP-Glucoron(os)yltranasferases  N-Acetyltransferases  Amino acid N-acyl transferases  Sulfotransferases

32. Interactions in the Phases of Drug Metabolism  Drug interactions due to metabolic effects nearly always due to interaction at Phase I enzymes, rather than Phase II  CYP450 system responsible for the majority of oxidative reactions and subsequent interactions  Significant polymorphism in many.  CYP2C9, CYP2C19, and CYP2D6—can be even be genetically absent!  Drugs may be metabolized by a single isoenzyme  Desipramine/CYP2D6; indinavir/CYP3A4; midazolam/CYP3A; caffeine/CYP1A2; omeprazole/CYP2C19  Drugs may be metabolized by multiple isoenzymes  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.  Drugs may be metabolized by a combination of enzymatic systems.

33. Pharmacokinetic: Elimination - Metabolism  Interactions can result from increased as well as decreased metabolism  Clinical relevance is dependent upon timing of interaction, therapeutic index of affected drug, duration of therapy, metabolic fate of affected drug, metabolic capacity of host.  Host factors include age, genetic makeup (acetylation, CYP2D6), nutritional state, disease state, hormonal milieu, environmental and exogenous chemical exposure.  P450 isoenzymes are variously affected.  Isoenzymes characterized  Substrates  Inhibiting agents  Inducing agents  No consistent correlation of substrate versus inhibitor or inducer  Good reference: http://medicine.iupui.edu/flockhart/ (alias: www.drug- interactions.com)http://medicine.iupui.edu/flockhart/

34. Pharmacokinetic: Elimination - Metabolism Characteristics of interactions with DECREASED metabolism  Inhibition of metabolizing enzymes  Timeframe is rapid  Duration and extent of effect is dependent upon concentration of agents and enzyme affinities.  Maximum effect seen in 4-5 half-lifes  Mostly in hepatic microsomal enzymes (mixed-function oxidases of cytochrome P450 system)  Other systems affected; less well characterized  Conjugation, acetylation, etc.  P450 isoenzymes are variously affected.  Most important with drugs with narrow TI, brittle hosts, agents with few alternate metabolic pathways  Ex: theophylline, antihypertensive agents, hypoglycemic agents, chemotherapeutic agents, some hormonal agents, HAART agents

35. Pharmacokinetic: Elimination - Metabolism Characteristics of interactions due to INCREASED metabolism  Induction of metabolizing enzymes  Timeframe is slow  “Recovery” to basal state is also slow  Mostly in hepatic microsomal enzymes but also in other tissues  Clinical relevance is dependent upon timing of interaction, therapeutic index of affected drug, duration of therapy.  Most frequently encountered inducing agents:  Phenobarbital, phenytoin, carbamazepine  Rifampin > rifabutin  Cigarettes and charred or smoked foods  Prolonged and substantial ethyl alcohol ingestion  Isoniazid

36. Wilkinson, G. R. N Engl J Med 2005;352:2211-2221 Mechanism of Induction of CYP3A4-Mediated Metabolism of Drug Substrates (Panel A) The Resulting Reduced Plasma Drug Concentration (Panel B)  Common Drug Substrates and Clinically Important Inhibitors of CYP2D6

37. BiotransformationsBiotransformations  Phase I  Oxidation  Cytochrome P450 monooxygenase system  Flavin-containing monooxygenase system  Alcohol dehydrogenase and aldehyde dehddrogenase  Monoamine oxidase (Co-oxidation by peroxidases)  Reduction  NADPH-cytochrome P450 reductase  Reduced (ferrous) cytochrome P450  Hydroloysis  Esterases amd amidases  Epoxide hydrolase  Phase II  Glutathione S-transferases  Mercapturic acid biosynthesis  UDP-Glucoron(os)yltranasferases  N-Acetyltransferases  Amino acid N-acyl transferases  Sulfotransferases

38. Proportion of Drugs Metabolized by CYP450 Enzymes

39. Cytochrome P450 3A4,5,7  Largest number of drugs metabolized  Present in the largest amount in the liver.  Present in GI tract  Not polymorphic  Inherent activity varies widely, e.g. 1,000 fold  Activity has been shown to predominate in the gut.  Responsible for metabolism of:  Most calcium channel blockers  Most benzodiazepines  Most HIV protease inhibitors  Most HMG-CoA-reductase inhibitors  Cyclosporine  Most non-sedating antihistamines  Cisapride

40. Cytochrome P450 3A4,5,7 -continued  Substrates:  macrolide antibiotics – clarithromycin, erythromycin; benzodiazeines- diazepam, midazolam; cyclosporine, tacrolimus,; HIV Protease Inhibitors – indinavir, ritonavir; chlorpheniramine; Calcium Channel Blockers – nifedipine, amlodipine; HMG Co A Reductase Inhibitors – atorvastatin, lovastatin; haloperidol, buspirone; sildenafil, tamoxifen, trazodone, vincristine  Inhibited by:  HIV Protease Inhibitors, cimetidine, clarithromycin, fluoxetine, fluvoxamine, grapefruit juice, itraconazole, ketoconazole, verapamil  Induced by:  carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wort, troglitazone

41. Cytochrome P450 2D6  Second largest number of substrates.  Polymorphic distribution  Majority of the population is characterized as an extensive or even ultra-extensive metabolizer.  Approximately 7% of the U.S. Caucasian population and 1-2% of African or Asian inheritance have a genetic defect in CYP2D6 that results in a poor metabolizer phenotype.  Substrates include: many  -blockers – metoprolol, timolol, amitriptylline, imipramine, paroxetine, haloperidol, risperidone, thioridazine, codeine, dextromethorphan, ondansetron, tamoxifen, tramadol  Inhibited by: amiodarone, chlorpheniramine, cimetidine, fluoxetine, ritonavir

42. Pharmacog enetics of Nortriptylin e Weinshilboum, R. N Engl J Med 2003;348:529-537 Pharmacogenetics of Nortriptyline Variability of CYP2D6 Expression

43. Pharmacogenetics of CYP2D6 Weinshilboum, R. N Engl J Med 2003;348:529-537 Pharmacogenetics of CYP2D6

44. Cytochrome P450 2C9  Note: Absent in 1% of Caucasian and African- Americans.  Substrates include: many NSAIDs – ibuprofen, tolbutamide, glipizide, irbesartan, losartan, celecoxib, fluvastatin, phenytoin, sulfamethoxazole, tamoxifen, tolbutamide, warfarin  Inhibited by: fluconazole, isoniazid, ticlopidine  Induced by: rifampin

45. Cytochrome P450 1A2  Substrates include: caffeine, theophylline, imipramine, clozapine  Inhibited by: many fluoroquinolone antibiotics, fluvoxamine, cimetidine  Induced by: smoking tobacco

47. Cytochrome P450 2C19  Note: Absent in 20-30% of Asians, 3-5% of Caucasians  Substrates include: omeprazole, diazepam, phenytoin, phenobarbitone, amitriptylline, clomipramine, cyclophosphamide, progesterone  Inhibited by: fluoxetine, fluvoxamine, ketoconazole, lansoprazole, omeprazole, ticlopidine

48. Cytochrome P450 2B6  Substrates include: bupropion, cyclophosphamide, efavirenz, methadone  Inhibited by: thiotepa  Induced by: phenobarbital, rifampin

49. Cytochrome P450 2E1  Substrates include: acetaminophen

50. Cytochrome P450 2C8  Substrates; paclitaxel, torsemide, amodiaquine, cerivastatin, repaglinide  Inhibited by: trimethoprim, quercetin, glitazones, gemfibrozil, montelukast  Induced by: rifampin

51. The “Usual Suspects” - Inhibitors  Amiodarone  Ketoconazole  Cimetidine  Ciprofloxacin (1A2)  Diltiazem  Erythromycin (3A4)  Ethanol (acute)  Fluconazole (3A4)  Fluoxetine (2C9, 2C19, 2D6)  Fluvoxamine (1A2, 2C19, 3A4)  Grapefruit (3A4)  Isoniazid (2E1)  Itraconazole (3A4)  Ketaconazole (3A4)  Metronidazole  Miconazole (3A4)  Nefazodone (3A4)  Oral contraceptives  Paroxetine (2D6)  Phenylbutazone  Quinidine (2D6)  Sulfinpyrazone  Valproate  Verapamil

52. The “Usual Suspects” - Inducers  Barbiturates (2B)  Carbamazepine (2C19, 3A4/5/7)  Charcoal-broiled food (1A2)  Dexamethasone  Ethanol (chronic) (2E1)  Griseofulvin  Isoniazid (2E1)  Primidone (2B)  Rifabutin (3A4)  Rifampin (2B6, 2CB, 2C19, 2C9, 2D6, 3A4/5/7)  Tobacco smoke (1A2)

53. Probe Substrates and Inhibitors for P450s

54. SubstratesInhibitors P450 PreferredAcceptablePreferredAcceptable CYP1A2 Ethoxyresorufin, phenacetinCaffeine (low turnover), theophylline (low turnover), acetanilide (mostly applied in hepatocytes), methoxyresorufin Furafyllinea-Naphthoflavone (but coan also activate and inhibit CYP3A4) CYP2A6 CoumarinMethoxypsoralenCoumarin (but high turnover), Sertraline (but also inhibits CYP2D6) CYP2B6 S-Mephytoin (4-hydroxy metabolite) Ephenytoin (N-desmethyl metabolite)Bupropion (metabolite standards?) CYP2C8 Glitazones (?) CYP2C9 CYP2C19 S-Mephytoin (4-hydroxy metabolite), omeprazole Ticlopidine (but also inhibits CYP2D6), nootkatone (also inhibits CYP2A6) CYP2D2 Bufuralol dextromethorphanMetoprolol, debrisoquine, codeineQuinidine CYP2E1 Chlorzoxazone4-Nitrophenol, lauric acidClomethiazole4-Methyl pyrazole CYP3A Midazolam, testosterone (test at least 2) Nifedipine, felodipine, cyclosporin A, terfenadine, erythromycin, simvastatin Ketoconazole (not specific, also inhibits CYP2C8) Cyclosporin A Adapted from Bjornsson TD, Callaghan JT, Einolf HJ, etal. Drug Met Disp 2003; 31:815-832; See also Tucker GT, Houston JB and Hyang SM. Pharm Res 2001; 18: 1071-1080.

55. Drug Metabolism  Phase I  Oxidation  Cytochrome P450 monooxygenase system  Flavin-containing monooxygenase system  Alcohol dehydrogenase and aldehyde dehddrogenase  Monoamine oxidase (Co-oxidation by peroxidases)  Reduction  NADPH-cytochrome P450 reductase  Reduced (ferrous) cytochrome P450  Hydroloysis  Esterases amd amidases  Epoxide hydrolase  Phase II  Glutathione S-transferases  UDP-Glucoron(os)yltranasferases  N-Acetyltransferases  Amino acid N-acyl transferases  Sulfotransferases

56. Monoamine Oxidase  Many interactions  112 listed for Selegiline!  May be very significant  Used less frequently due to safer agents

57. Relative Contribution to Drug Metabolism - Phase I Evans & Relling Science 1999

58. Weinshilboum, R. N Engl J Med 2003;348:529-537 Pharmacogenetics of Phase I Drug Metabolism

59. Relative Contribution to Drug Metabolism - Phase II Evans & Relling Science 1999

60. Pharmacogen etics of Phase II Drug Metabolism Weinshilboum, R. N Engl J Med 2003;348:529-537 Pharmacogenetics of Phase II Drug Metabolism

61. Pharma cogene tics of Acetyla tion Weinshilboum, R. N Engl J Med 2003;348:529-537 Pharmacogenetics of Acetylation

62. Drug Interactions: Phase II  Rarely rate-limiting step in either elimination or detoxification  Phase I reactions increase polarity and excretion due to increased water solubility

63. Assessing the Clinical Relevance of CYP450 Drug Interactions 1. Therapeutic Index and toxic potential of the substrate 2. Alternate pathways of metabolism 3. Role of active metabolites 4. Consequences of metabolic inhibition of metabolites 5. Are multiple P450s inhibited by inhibitor 6. Polymorphism of isoenzyme and patient’s metabolizer status 7. Inhibitory potential of metabolites 8. Is inhibition helpful or harmful

64. Mechanisms of Interactions Pharmacokinetic Absorption Distribution Metabolism Excretion

65. Pharmacokinetic: Excretion  Filtration  Renally cleared drugs affected notably digoxin and aminoglycoside antibiotics  Metabolic products of parent drug  Highly dependent upon GFR of host, elderly of great concern  Active secretion  Two non-specific active transport systems (pars recta)  Organic acids  Organic bases  Also digoxin in distal tubule  Reabsorption  Distal tubule and collecting duct  Dependent on flow, pH  Useful for enhancing excretion of selected agents with inhibition  Probenecid, drug ingestions

66. Interactions Due to Altered Renal Excretion  Drugs excreted by glomerular filtration unlikely to have significant interactions  Drugs that are actively secreted into the tubular lumen can be inhibited by other drugs  Sometimes useful:  Probenecid decreases Cl of penicillin  Sometimes toxic  Methotrexate secretion inhibited by aspirin  Lithium carbonate excretion affected by total body Na balance  Altered sodium balance: thiazide and loop diuretics, some NSAIDs

67. Characterizing Drug Interactions Mechanism  Pharmacodynamic  Receptor inhibition  Additive effects  Pharmacokinetic  Altered absorption, distribution, metabolism, or elimination Interacting agents  Drug - Disease  Drug-drug  Prescription  Non-prescription  Illicit, recreational  Food, supplements, herbal products Clinical Significance  Major  Substantial morbidity and mortality  Therapy altering  Manageable  Little or no change in therapy  Optimize therapy  Intentional  Additive or synergistic effects  Enhanced pharmacokinetics

68. Drug-Disease Interactions  Liver disease  Renal disease  Cardiac disease (hepatic blood flow)  Acute myocardial infarction?  Acute viral infection?  Hypothyroidism or hyperthyroidism?  SIRS ?

69. Drug-Food Interactions  Tetracycline and milk products  Warfarin and vitamin K-containing foods  Grapefruit juice  Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics.

70. Dresser GK et al Clin Pharmacol Ther 2000;68(1):28–34 Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics

71. Drug-Herbal Interactions  St. John’s wort with indinavir  St. John’s wort with cyclosporin  St. John’s wort with digoxin?  Many others

72. After St. John’s wort

73. Prediction of Drug Interactions, In vitro  In Vitro Screening  Non-mammalian in vivo systems have very limited clinical utility  In vitro systems to screen for CYP450-mediated drug interactions include microsomes, hepatocytes, liver slices, purified P450 systems, and recombinant human P450 enzymes.  Most useful for screening inhibitory effects.  Less useful for drugs with multiple metabolic pathways.  Least useful for studying induction.  Unknown appropriate concentration of inhibitor in vitro that would correlate with in vivo exposure.  Utility in guiding subsequent clinical trials

74. In Vivo Drug-Drug Interaction Studies  Pharmacokinetic interactions must be evaluated relative to clinical relevance.  Studies should be used for OPI  Study design dictated by clinical objective (ex. cross-over versus parallel)  Chronic versus acute dosing  Sequence  Relevant concentrations  Steady-state versus acute short interval  Endpoints (pharmacokinetic vs. pharmacodynamic)  Sample size, statistical considerations  Demonstration of “Lack of effect” vs. “Magnitude of effect”

75. In Vivo Drug-Drug Interaction Studies, cont’d.  Study populations  Population pharmacokinetic approach  In vitro characterization of likely targets  Subgroups  Safety concerns  Clinical trials  Concurrent pharmacokinetic studies  Case Reports

76. Prediction of Drug Interactions, Resources  Clinical Trials  CDER Guidance for Industry [http://0- www.fda.gov.lilac.une.edu/cder/guidance/clin3.pdf] CDER Guidance for Industry  The Conduct of In Vitro and In Vivo Drug-Drug Interaction Studies: A Pharmaceutical Research and Manufacturers of America (PhRMA) Perspective. TD Bjornsson, and Others. Drug Met Disp 2003; 31: 815- 832.Drug Met Disp 2003; 31: 815- 832  Case Reports: MedWatch @ FDA

77. General Approach to Managing Drug Interactions  Each contact with the patient includes a review of all medications - prescribed and OTC.  Information on medications prescribed by any and all health-care providers is reviewed  Specifically query for problematic food and nutriceutical products  Keep a high “Index of Suspicion” for all toxic events and therapeutic failures  When possible, use agents which are the least problematic  Sometimes, timing of doses may minimize interactions, especially with food  Proactively instruct patients about avoiding interactions  Usually, management of interactions requires minimal alterations in therapeutic plan

78. ConclusionsConclusions  Drug-drug interactions are part of drug therapy  May be beneficial or hazardous  Polypharmacy (therapy with many agents) is often unavoidable  Estimated that for 5 or more agents the probability of interaction approaches 100%  Managing drug interactions is often more important than avoiding  Be most cautious with narrow TI agents  Make use of resources  Some interactions are absolutely contraindicated  Drug interactions are significant cause of adverse drug events and cost billions in additional health care costs.  At-risk patients are most affected, e.g. the elderly, the very young, the critically ill.

79. Summary: Drug Interactions  Pharmacokinetic drug interactions are defined as those that alter drug absorption, distribution, metabolism, or excretion.  Pharmacodynamic drug interactions result in an alteration of the biochemical or physiological effects of a drug. Interactions of this type are more difficult to characterize than pharmacokinetic interactions.

80. Summary: Drug Interactions  Drug interactions that alter the rate of absorption are usually of lesser concern that those that affect the extent.  Overall outcomes of interactions of agonists and antagonists at the drug receptor are dependent on the varying affinities and activities of the different agents involved.

81. Summary: Drug Interactions Summary: Drug Interactions  Alteration of metabolism of drugs in the liver, gut and other sites is an important but not singular source of significant drug interactions.  In general, those drugs that are susceptible to the effects of induction of metabolism are also subject to inhibition.  Drug interactions involving induction of metabolism develop more slowly than those involving inhibition.

82. Summary: Drug Interactions  A full profile of the interaction potential of any given drug generally takes an extended amount of time in the marketplace to be characterized. Many, but not all, important drug interactions are described in the official labeling.

83. Summary Drug Metabolism  Polymorphism of CYP gene(s) can result in a “poor metabolizer” phenotype, but occurs in less than 20% of the U.S. general population.  Prototypic inhibiting agents include:  Ciprofloxacin, Erythromycin, Fluconazole, Fluoxetine, Grapefruit juice, Itraconazole  Prototypic inducing agents include:  Carbamazepine (2C19, 3A4/5/7)  Rifampin (2B6, 2CB, 2C19, 2C9, 2D6, 3A4/5/7)

84. Questions?Questions?  Blair Holbein, Ph.D.  Presbyterian Hospital of Dallas  Email: bholbein@hcin.netbholbein@hcin.net  Website: http://phdres.caregate.nethttp://phdres.caregate.net  Annotated bibliography  Slides