INTERPATIENT VARIABILITY OF DRUG DISPOSITION & DOSAGE ADJUSTMENT Readings (Applied Biopharm & PK 5th Ed.): Chp 12. Pharmacogenetics p 355-68. Chp 21. Renal & Hepatic Disease p 673-714 Chp 20. Peds/Geriatrics/Obesity p 634-42. Several articles will be posted on-line.

Objectives Identify variation in response Understand underlying genetic, environmental and pathophysiological factors responsible for patient differences in drug response. Evaluate clinical significance Individualize drug therapy based on specific patient factors (using knowledge, logic and available equations). “Personalized Medicine”

One Size (or Dose) Fits All 20th Century Medicine: One Size (or Dose) Fits All Currently use “trial and error” method of prescribing

IS IT EFFECTIVE? Drugs Non-responders TNFa inhibitors >40% Medicine’s Dirty Little Secret- only 50% of patients respond to major drug groups. Drugs Non-responders TNFa inhibitors >40% Tricyclic antidepressants 20-50 % SSRI antidepressants 10-25 % Beta-blockers 15-35 % ACE inhibitors 10-30 % 5-HT1 blockers (migraine) 20-45 % HMG CoA red. inhibitors 10-30 % Interferons 60-90 % Anti-neoplastics 50-70 %

IS IT SAFE? Adverse drug reactions (ADRs) represent the 4th leading cause of hospitalization and is responsible for 100,000 deaths/yr in the U.S. U.S. Health Management Organization (HMO) data suggest that the healthcare cost of treating drug ADRs exceeds the cost of providing the medications themselves 2 million hospitalizations/yr in US Cost estimates range between 30-150 billion/ yr in US.

Interpatient variability of drug response Inter-patient variability in response to drug therapy is the rule, not the exception for almost all medications. Research in the past 5- 15 years has identified many sources of inter-patient variability- which can be used for drug and dosage selection. New knowledge, particularly in the area of pharmacogenetics, is progressing at a rapid pace.

Variation in drug response Why? Environment & Physiology Genetics Absorption Distribution Metabolism Excretion Target Interaction Drug Response Drug

Warfarin From Brian Gage; http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4194S1_Slide-Index.htm Other relevant slides: http://www.fda.gov/ohrms/dockets/ac/05/slides/5 http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4194S1_02_02-Huang.ppt

Factors which impact warfarin dose requirements Environmental Age Gender Drugs Body wt Race Diet Others UNKNOWN CYP2C9 VKORC1 Genetic <Caldwell M., CPSC Advisory Committee Meeting, November 14, 2005> http://www.fda.gov/ohrms/dockets/ac/05/slides/8>

ENVIRONMENTAL & PHYSIOLOGICAL FACTORS - Exposure to drugs / toxins/ pollutants - Diet - Disease - Age - Weight - Gender/ hormones - Exercise - Others? Lets look at several important examples of environmental factors which impact the absorption / distribution / elimination of drugs. Multiple factors can play a role.

A. Absorption Influenced by: Permeability Motility Active Transporters Metabolic Enzymes 1. May be altered in diseases of GIT Colitis- diarrhea, flu  motility;  absorption Inflammation (Crohn’s, IBD) scar tissue:  absorption Cystic fibrosis Mucus & electrolyte changes, Malabsorption Malnourishment  F of Vitamin & minerals Achlorhydria  pH -Dose dumping of Enteric coated

uptake transporters :  oatp 2. May be altered by diet. Grapefruit juice  CYP3A4 & PGP in gut  (up to 3X) drug concentrations: cyclosporin A (CsA) , terfenadine, midazolam, felodipine, Ca++ channel blockers, talinolol uptake transporters :  oatp Altered bioavailability of substrates such as fexofenadine, digoxin, pravastatin, atorvastatin

Example Effect of Grapefruit juice (300 ml- taken with drug) on bioavailability of fexofenadine. GFJ decreases intestinal expression of OATP- an active transporter involved in the uptake (absorption) of fexofenadine. Bioavailability reduced by half.

3) May be altered by drugs or natural products Herbal products Induction of intestinal CYP3A and PGP by St John's Wort. Decreased oral availability of drug substrates. (CsA, indinavir, digoxin) Cyclosporin- has resulted in numerous cases of organ transplant rejection. Decreased effectiveness of oral contraceptives. -Potential for unplanned pregnancy

B. Distribution Changes in body composition 1) Disease-associated changes in plasma protein concentrations. albumin:  binding:  Vd - NSAIDs  α1-acid glycoprotein:  binding,  Vd -propafenone, propranolol 2) Obesity  distribution of fat soluble drugs 3) Pregnancy  fat,  water,  weight, placenta Age Changes in body composition 5) Altered blood-brain barrier Disease-induced changes in expression of drug transporters at BBB Altered permeability of membrane * Will cover in more detail in future lectures

C. Elimination 1) Environmental Toxins 2) Food 3) Drugs 4) Disease There are numerous examples where hepatic and renal elimination is affected by environmental or physiological changes. 1) Environmental Toxins 2) Food 3) Drugs 4) Disease 5) Age 6) Pregnancy

Environmental Pollutants: Polycyclic Hydrocarbons induce P450s Smoking Charcoal Broiling Pollutants Increased drug clearance: theophylline, phenacetin Food: High protein diet:  creatinine Alcohol:  P450 Red Wine:  Cyclosporin A levels

Some known CYP P450 Inducers: DRUGS http://medicine.iupui.edu/ flockhart/table.htm A. Induction of Metabolism Some known CYP P450 Inducers: CYP 1A2 cigarette smoke, omeprazole, phenobarbitone CYP2D6 dexamethasone, rifampin CYP2E1 Ethanol, isoniazid CYP3A Barbiturates, carbamazepine, ethosuximide, glucocorticoids, phenobarbital, phenytoin, rifampicin, …..

Some known CYP P450 Inhibitors: DRUGS B. Inhibition of Metabolism Some known CYP P450 Inhibitors: CYP 1A2 - cimetidine, fluoroquinolones CYP2D6 - fluoxetine, quinidine, paroxetine CYP2E1 - cimetidine, disulfiram CYP3A - eg. HIV protease inhibitors, antimicrobials (clarithromycin, erthryomycin, ketoconazole) - many more

C. Inhibition of Hepato-Biliary Secretion DRUGS C. Inhibition of Hepato-Biliary Secretion P-glycoprotein (efflux transporter) Quinidine/ quinine + digoxin: -  CLbile digoxin (50-60%) Oatp (influx transporter) Gemfibrozil + statins: - 2X ↑ AUC pravastatin (ed hepatic uptake) - 4 X ↑ AUC cerivastatin Cyclosporin A + statins: - 4X ↑ AUC cerivastatin - 7 X ↑ AUC rosuvastatin (ed hepatic uptake)

D. Inhibition of Renal Secretion DRUGS D. Inhibition of Renal Secretion P-glycoprotein (efflux transporter) Quinidine + digoxin: -  CLr digoxin (50-60%) Ritonavir + digoxin: - CLr digoxin Oatp (influx transporter) Probenecid + Cephalosporins: - CLr - 1.8X CLr with 2.4 X ↑ AUC cephradine OCT (organic cation transporter) Cimetidine : - CLr procainamide from 347 to 196 ml/min (↑AUC procainamide) - CLr metformin from 527 to 378 ml/min

Diseases Drug metabolism and secretion is decreased in a variety of diseases which are associated with an inflammatory response. infection, arthritis, Crohn’s disease, renal disease, cancer etc.. Altered drug PK and drug response is seen both clinically and in experimental animal disease models.

Cancer Inflammatory response induced by tumor growth has been shown to decrease activity of drug metabolizing enzymes in Cancer patients. (14C- Erythromycin Breath test) in Cancer Patients CYP 3A Enzyme Activity Levels of Inflammation Marker (C-reactive Protein)

Arthritis CYP P450 Activity  Protein binding

Increased Fetal Accumulation Increased Maternal Accumulation Bacterial Infection - Altered disposition of P-Glycoprotein Substrate (99Tc-Sestamibi) in Pregnant Rats Increased Fetal Accumulation * Increased Maternal Accumulation -Infection Brain Liver Kidney Intestine Placenta Altered Maternal and Fetal Disposition- due to decreased expression and activity of P-glycoprotein

Advanced kidney disease can impact the Renal Disease Advanced kidney disease can impact the metabolism, intestinal and/or hepatobiliary elimination of non-renally cleared drugs 1)  Pgp and CYP3A in intestine: ↑ oral bioavailability of Pgp/CYP3A substrates. - erythromycin, propranolol, tacrolimus 2)  CYP3A & CYP2C11 in Liver:  hepatic metabolism of substrates. 3)  Hepatic expression of Oatp uptake transporter:  hepatobiliary CL?

Ex. Repaglinide in Renal Disease - non-renally cleared oral hypoglycemic (<8% Clr) - Excreted via bile: - extensively metabolized (glucuronidation, CYP3A, CYP2C8) - active transport via Oatp1B1 and ABCB1 Mild/mod disease Severe disease Increased AUC due to decreased hepatobiliary clearance: OATP & CYP3A