Transcript No Slide Title

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”
20th Century Medicine:
One Size
(or Dose)
Fits All
• Currently use “trial and error”
method of prescribing
IS IT EFFECTIVE?
Medicine’s Dirty Little Secretonly 50% of patients respond to major drug groups.
Drugs
Non-responders
TNFa inhibitors
Tricyclic antidepressants
SSRI antidepressants
Beta-blockers
ACE inhibitors
5-HT1 blockers (migraine)
HMG CoA red. inhibitors
Interferons
Anti-neoplastics
>40%
20-50 %
10-25 %
15-35 %
10-30 %
20-45 %
10-30 %
60-90 %
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.
2 million hospitalizations/yr in US
• U.S. Health Management Organization
(HMO) data suggest that the healthcare
cost of treating drug ADRs exceeds the
cost of providing the medications
themselves
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
Drug
Absorption
Distribution
Metabolism
Excretion
Target Interaction
Drug
Response
Warfarin
Sw
ar
fa
rin
rin
rfa
wa
S-
CYP1A1
CYP1A2
CYP3A4
Rwa
rf a
rin
Warfarin
in
r
a
rf
a
w
RVitamin K
Reductase
Oxidized Vitamin K
CYP2C9
Reduced Vitamin K
CO2
O2
Calumenin
Hypofunctional
F. II, VII, IX, X
Protein C, S, Z
γ-glutamyl
carboxylase
Functional
F. II, VII, IX, X
Proteins C, S, Z
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
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
Fexofenadine [C]
ng/ml
Example
Effect of Grapefruit juice (300 ml- taken
with drug) on bioavailability of
fexofenadine.
400
300
Water
200
GFJ
100
0
0
2
4
6
8
Hours
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 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
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
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, …..
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
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)
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
Propranolol
Arthritic vs Control Rats
10000-
Arthritic
Conc
1000-
100-
Control
TIME
 CYP P450 Activity
 Protein binding
Bacterial Infection
- Altered disposition of P-Glycoprotein Substrate
(99Tc-Sestamibi) in Pregnant Rats
Fetal: Placenta Ratio (%
Control)
Increased
Fetal
Accumulation
Accumulation
of 99 Tc-sestamibi
in Fetus
500
Control
400
LPS
300
200
100
*0
Increased Maternal Accumulation
Effect of LPS on 99mTc-sestamibi Disposition (4h) in Pregnant
Rats
1800
1600
-Infection
1400
Tc-MIBI 1200
1000
%Control 800
600
400
200
0
Brain
Liver
Kidney
Intestine
Placenta
Altered Maternal and Fetal Disposition- due to
decreased expression and activity of P-glycoprotein
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