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”

2020thth Century Medicine: Century Medicine: 2020thth Century Medicine: Century Medicine:

• Currently use “trial and error” method of prescribing

One Size One Size (or Dose)(or Dose)Fits AllFits All

IS IT EFFECTIVE?

TNFTNF inhibitors inhibitors >40% >40%

Tricyclic antidepressants 20-Tricyclic antidepressants 20-50 %50 %

SSRI antidepressants 10-25 SSRI antidepressants 10-25 %%

Beta-blockers Beta-blockers 15-35 15-35 %%

ACE inhibitors ACE inhibitors 10-30 10-30 %%

5-HT5-HT11 blockers (migraine) 20- blockers (migraine) 20-45 %45 %

HMG CoA red. inhibitors 10-HMG CoA red. inhibitors 10-30 %30 %

Interferons Interferons 60-90 60-90 %%

Anti-neoplastics Anti-neoplastics 50-70 50-70 %%

Drugs Non-responders

Medicine’s Dirty Little Secret- only 50% of patients respond to major drug groups.

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?

AbsorptionAbsorptionDistributionDistributionMetabolismMetabolismExcretionExcretion

Target InteractionTarget Interaction

GeneticsGeneticsGeneticsGenetics

Drug Drug Drug Drug DrugDrug

ResponseResponseDrugDrug

ResponseResponse

EnvironmentEnvironment & & PhysiologyPhysiology

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

CYP2C9CYP2C9

CYP1A1CYP1A1CYP1A2CYP1A2CYP3A4CYP3A4

Oxidized Vitamin KOxidized Vitamin K Reduced Vitamin KReduced Vitamin K

OO22

HypofunctionalHypofunctionalF. II, VII, IX, XF. II, VII, IX, X

Protein C, S, ZProtein C, S, Z

Functional Functional F. II, VII, IX, XF. II, VII, IX, X

Proteins C, S, ZProteins C, S, Z

γ--glutamyl glutamyl carboxylasecarboxylase

Vitamin K Vitamin K ReductaseReductase

COCO22

WarfarinWarfarin

Calumenin

Warfarin

VKORC1VKORC1

CYP2C9CYP2C9

Age

Gender

Drugs

Body wt

Race

Diet

Others

UNKNOWN

<Caldwell M., CPSC Advisory Committee Meeting, November 14, 2005><Caldwell M., CPSC Advisory Committee Meeting, November 14, 2005> http://www.fda.gov/ohrms/dockets/ac/05/slides/8>http://www.fda.gov/ohrms/dockets/ac/05/slides/8>

Factors which impact warfarin dose requirements

Environmental

Genetic

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 fibrosisMucus & electrolyte changes,

Malabsorption

• Malnourishment F of Vitamin & minerals

• Achlorhydria

pH -Dose dumping of Enteric coated

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

ExampleEffect of Grapefruit juice (300 ml- taken

with drug) on bioavailability of fexofenadine.

0

100

200

300

400

0 2 4 6 8

Hours

Fexo

fena

dine [

C]

ng/m

l Water

GFJ

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

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

4) Age Changes in body composition

5) Altered blood-brain barrierDisease-induced changes in expression of drug transporters at BBB

Altered permeability of membrane

* Will cover in more detail in future lectures

C. Elimination

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:

CYP 1A2

cigarette smoke, omeprazole,

phenobarbitone

CYP2D6

dexamethasone, rifampin

CYP2E1

Ethanol, isoniazid

CYP3A

Barbiturates, carbamazepine, ethosuximide,

glucocorticoids, phenobarbital, phenytoin, rifampicin, …..

A. Induction of Metabolism

DRUGS

http://medicine.iupui.edu/ flockhart/table.htm

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

B. Inhibition of Metabolism

DRUGS

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)

C. Inhibition of Hepato-Biliary Secretion

DRUGS

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

D. Inhibition of Renal Secretion

DRUGS

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.

CYP 3A EnzymeActivity

Levels of Inflammation Marker (C-reactive Protein)

(14C- Erythromycin Breath test) in Cancer Patients

PropranololArthritic vs Control Rats

10000-

1000-

100-

TIME

Arthritic

Control

Conc

CYP P450 Activity Protein binding

Arthritis

0

200

400

600

800

1000

1200

1400

1600

1800

Tc-MIBI %Control

Effect of LPS on 99mTc-sestamibi Disposition (4h) in Pregnant Rats

Brain Liver Kidney Intestine Placenta

-Infection

Altered Maternal and Fetal Disposition- due to decreased expression and activity of P-glycoprotein

Bacterial Infection

- Altered disposition of P-Glycoprotein Substrate

(99Tc-Sestamibi) in Pregnant Rats

*

Accumulation of 99 Tc-sestamibi in Fetus

0

100

200

300

400

500

Fet

al: P

lace

nta

Ratio

(%

Cont

rol)

Control

LPS

Increased Fetal Accumulation

Increased Maternal Accumulation

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

Increased AUC due to decreased hepatobiliary clearance: OATP & CYP3A

Mild/mod disease

Severe disease