INTERPATIENT VARIABILITY OF DRUG DISPOSITION & DOSAGE ADJUSTMENT Readings (Applied Biopharm & PK 5...
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![Page 1: INTERPATIENT VARIABILITY OF DRUG DISPOSITION & DOSAGE ADJUSTMENT Readings (Applied Biopharm & PK 5 th Ed.): Chp 12. Pharmacogenetics p 355-68. Chp 21.](https://reader036.fdocuments.in/reader036/viewer/2022081513/56649e245503460f94b135f3/html5/thumbnails/1.jpg)
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.
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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”
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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
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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.
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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.
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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.
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Variation in drug response
Why?
AbsorptionAbsorptionDistributionDistributionMetabolismMetabolismExcretionExcretion
Target InteractionTarget Interaction
GeneticsGeneticsGeneticsGenetics
Drug Drug Drug Drug DrugDrug
ResponseResponseDrugDrug
ResponseResponse
EnvironmentEnvironment & & PhysiologyPhysiology
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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
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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
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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.
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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PropranololArthritic vs Control Rats
10000-
1000-
100-
TIME
Arthritic
Control
Conc
CYP P450 Activity Protein binding
Arthritis
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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
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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?
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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