pharmacokinetics and pharmacodynamics applications in pharmacotherapy

Dalia A. HamdyBPSc, MSc, PhD, RP(ACP), MRSC

4th March 2016dr.daliahamdy@gmail.com

Pharmacokinetics and Pharmacodynamics Applications

in Pharmacotherapy

Part I

Learning Objectives1. Identify and provide examples using basic

pharmacokinetic concepts commonly used in clinical practice, including

elimination rate constant, volume of distribution, clearance, bioavailability.

Dr. Dalia A. Hamdy (FS15AY)2

Learning Objectives2. Describe specific pharmacokinetic characteristics of

a. commonly used therapeutic agents: aminoglycosides vancomycin phenytoin digoxin

b. pharmacokinetic alterations in patients with renal and hepatic disease.

3. Define important issues as they pertain to drug concentration sampling and interpretation.

Session Outline (Part I) Introduction to Clinical Pharmacokinetics and

individualization of therapy

Basic PK refresher

Introduction to Transporters and metabolic enzymes

Drug Interactions involving transporters/enzymes

Pharmacogenetics and personalized medicine

References Smith CL. Updates in Therapeutics®: The Pharmacotherapy

Preparatory Review and Recertification Course. 2015 Edition. The American College of Clinical Pharmacy. Pharmacokinetics/Pharmacodynamics Chapter.

Shargel L, Wu-Pong S, Andrew B.C.U. Applied Biopharmaceutics and Pharmacokinetics. 5 th Edition. McGraw-Hil ; 2005

Gibson G and Skett P. Introduction to Drug Metabolism. 3rd Edition. Nelson Thrones ; 2001.

Russel F.G.M. Transporters: Importance in Drug Absorption, Distribution, and Removal. Enzyme- and Transporter-Based Drug-Drug Interactions. Elservier; 2010.

References Mccarthy, J and Nussbaum, RL.

Genomic and Precision Medicine online course. University of California San Fransisco. Through Coursera online courses.

Shahin, MHA et al. Pharmacogenet Genomics. 2011 March ; 21(3): 130–135.

Ekladious, SM et al. Mol Diagn Ther. 2013 Dec;17(6):381-90.

Pharmacokinetics & Pharmacodynamics

Revision

I. Basic PK refresher

Revision

One compartment PK model:

-Denoted by a closed box

-Assumes the body is composed of a single homogenous compartment

-The drugs distributes equally and uniformly to all the body

Revision

Two compartment PK model:

-Denoted by two closed boxes

-Assumes the body is composed of a two compartments

- Central ( highly perfused)

- Peripheral (poorly perfused)

-The drug is usually eliminated from the central compartment

Revision

Route of

administration

Elimination rate

constant

Cp Zero order

Amount of drug eliminated per unit time is constant

First order

Amount of drug eliminated per unit time is proportional to the drug remaining

Revision

Route of

administration

Elimination rate

constant

The rate of change of Cp at any time is calculated by

Input-output

Revision

Route of

administration

Elimination rate

constant

Routes of administration1. IV Bolus The entire dose

enters the body immediately and 100% bioavailable F=1

2. Continuous IV infusionThe dose is infused slowly with constant rate and 100% bioavailable F=1

3. Oral absorption The dose is

administered orally in form of granules, tablets, liquids or capsules, F is usually less than 1

Revision

Route of

administration

Elimination rate

constant

Routes of administration1. IV Bolus

0 5 10 15 20 25 30 35 40 45 500.1

f(x) = 4.6448833152949 exp( − 0.0466272811835 x )R² = 0.99348768952414

C0 = highest concentration

Revision

Route of

administration

Elimination rate

constant

Routes of administration2. Continuous IV

infusion

C0 = 0

Time (h)

CssRate of drug input= Rate of drug output (infusion rate) (elimination rate)

Revision

Route of

administration

Elimination rate

constant

Routes of administration2. Continuous IV

infusion

C0 = 0

Time (h)

Revision

Route of

administration

Elimination rate

constant

Routes of administration3. Oral absorption

Cmax is when Ka=K

C0 = 0C

IV Bolus IV infusion Oral absorption

Cp= C0X e-kt

Revision

Cp= C0X e-kt X (1- e-kt)

Revision

Vd·KKa·F ·Dose

Vd (Ka-K)

Χ (e-Kt -e-Kat)

K -slope (method of residuals)

-slope (method of residuals)-slope post infusion cessation

-slope (method of residuals)

Revision

Vd·KKa·F ·Dose

Vd (Ka-K)

Χ (e-Kt -e-Kat)

-slope (method of residuals)BE Ware of Flip-Flop phenomenon

CL =(Dose.F)/AUC

F=1 F=1 F≤1 (oral clearance)

Revision

Vd·KKa·F ·Dose

Vd (Ka-K)

Χ (e-Kt -e-Kat)

-slope (method of residuals)BE Ware of Flip-Flop phenomenon

CL =(Dose.F)/AUC

F=1 F=1 F≤1 (oral clearance)

Vd= CL/K Note Vc= Dose/C0

-If calculated from oral data then it is oral Vd

Revision

Vd·KKa·F ·Dose

Vd (Ka-K)

Χ (e-Kt -e-Kat)

Bioavailability

The rate and extent to which the active ingredients is absorbed and available at systemic circulation

F = AUC test X Dose referenceAUC reference Dose test

If test=IV Absolute BioavailabilityIf test=other route Relative

Bioavailability

RevisionAUC (Trapezoidal Rule)

What is the Difference Between IV Bolus and Oral?

RevisionCss Time to reach Css

What is the importance of a loading dose ?

LD = Css desired Χ Vd =

Revision What are the differences between one and

two compartments in infusion??

Hepatic Metabolism

Hepatic ClearanceCLT= CLr + CL nr

=CLr + CLH + CL other

Dr. Dalia A. Hamdy (FS15AY) 29

First Pass Metabolism

Hepatic clearance

First PassPortal vein

Hepatic ClearanceHepatic artery

Relation between first pass, extraction ratio and

bioavailability?!

First Pass Effect1. Blood that perfuses through GI tissues passes through the liver by means of the hepatic portal vein.

a. 50% rectal blood supply bypasses the liver (middle and inferior hemorrhoidal veins).

b. Drugs absorbed in the buccal cavity bypass the liver.

What about other routes of administration?Intraperitoneal, nasal, iv, …etc?

First Pass Effect2. Examples of drugs with significant first-pass effect

Enterohepatic Recirculation-Drugs have biliary (hepatic) elimination and good oral absorption

excreted through the bile into the duodenum,metabolized by the normal flora in the GI

tract, reabsorbed into the portal circulation.

-Drug is concentrated in the gallbladder and expelled on sight, smell, or ingestion of food. (lifecycle of bile)

Enterohepatic Recirculation

Practices

II. Introduction to Transporters and

metabolic enzymes

Drug transporters- Drugs enter to cells through diffusion and active

transport.

- Active transport is through transporters (Membrane transport proteins)

- Active transport can be divided into - Primary: does not require ATP- Secondary: uses energy

Drug transporters- Play a critical role in absorption, distribution, and

excretion of drugs.

- There are two main classes of transporters - Solute carriers (SLC)

- ATP binding cassette (ABC)

Drug transportersSolute Carriers (SLC) Transporters:

Can be further divided into:-- Organic anion transporting peptide (OATp)

- SLCO family of genes - Organic anion transporter (OAT)

- acidic drug transport - Part of SLC22A family of genes

- Organic cation transporter (OCT) - Basic drug transport - Part of SLC22A family of genes

Drug transportersATP binding cassette (ABC):

The subfamilies mostly involved in drug transport are ABCB, ABCC, ABCG examples:

ABCB1 : P-glycoproteins (P-gp)/ Multidrug resistance protein (MDR)

ABCC2: Multidrug resistance associated protein (MRP2)

ABCG2: Breast cancer resistance protein (BCRP)

Drug transporters- Mechanistically they are divided into

- Influx/Uptake transport proteinsImport drugs into the cells and do not usually require energy

- Efflux transportersExport drug out of the cell. Usually against concentration gradient therefore they need energy

Role of transporters in Absorption EnterocytesPEPT1: peptide transporter SLC15A family of genes -Role of P-gp in oral absorption?- Digoxin- Tacrolimus

Role of PEPT1:acyclovir oral bioavailability was enhanced by a factor of 2–3 via its valine ester (valacyclovir), which is a PEPT1 substrate

Role of transporters in Distribution and elimination

Hepatocyte

Role of BCRP in bile excretion? - topotecan Role of bile salt export pump, BSEP/ABCB11?- Mostly removal of bile

acid to bile- Vinblastine, taxol,

pravastatin

Role of transporters in Distribution and elimination

Human renal proximal tubular cell

-Methotrexate and NSAID interaction!

P-Glycoprotein functions as an efflux pump

Results in opioids tolerance : chronic use of opioids induces P-glycoprotein

decrease the opioid effect

P-glycoprotein is also found in tumor cells, resulting in the efflux of chemotherapeutic agents from the cell and, ultimately, multidrug resistance.

Where is P-Gp Located?

Xenobiotics undergo biotransformation before being eliminated from our body.

Drug Metabolism, mainly in liver, is usually divided into 2 Phases:

Phase 1: Functionalization reactions (introduction of a functional group)

Phase 2: Conjugative reactions(Conjugation with endogenous compounds)

Metabolism

Phase 1 metabolism

By introducing or unmasking more polar a functional gp

more readily excretable in

urine or bileDr. Dalia A. Hamdy (FS15AY) 56

Metabolism

Chemical reactionsGlucuronidation/glycosidationSulfationMethylationAcetylationAmino acid conjugationFatty acid conjugation

Phase 2 metabolism- Conjugation reactions are mostly located in

the cytosol except for glucuronidation which occurs in endoplasmic reticulum

1. UDP-Glucuronosyl transferase2. Glutathione S-transferase3. Sulfotransferase4. Amino acid transferase5. N-acetyl transferase6. N-, O-, S- methyl transferase

Drug Metabolism

Cytochrome P450-Dependant Mixed Function Oxidation Reactions:Mixed function oxidases are membrane proteins compose of

- CYP P450- NADPH dependent CYP P450- Phospholipids

Drug Metabolism

Cytochrome P450-Dependant Mixed Function Oxidation Reactions:

Drug Metabolism

CYP P450:- Terminal oxidase component of an

electron transfer system present in ER

RH ROH- It is a haem-containing enzyme

(haemoprotein called protoporphyrin IX)

Drug Metabolism

CYP P450:

- Nomenclature is derived from the fact that the cytochrome exhibits a spectral absorbance maximum at 450 nm when reduced Fe(II) heme binds to CO.

- Is a family of enzymes rather than a single enzyme

Drug Metabolism

Cytochrome P450-Dependant Mixed Function Oxidation Reactions:CYP P450 Nomenclature :

- Family: CYP + Arabic numerical (share > 40% homology of amino acid sequence ex: CYP1 , CYP2, CYP3..etc)

- Subfamily: Additional letter (share > 55% homology of amino acid sequence ex: CYP1A , CYP2D, CYP3A..etc)

- Isoenzyme : Additional Arabic number ex: CYP3A4

Drug Metabolism

CYP P450 Inhibition is substrate-independent.

Some substrates are metabolized by more than one CYP (e.g., tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs]).

Enantiomers may be metabolized by a different CYP (e.g., R- vs. S-warfarin).

Differences in inhibition may exist within the same class of agents (e.g., fluoroquinolones, azole antifungals, macrolides, calcium channel blockers, histamine-2 blockers).

CYP P450 Substrates can also be inhibitors (e.g., erythromycin,

verapamil, diltiazem)

Most inducers and some inhibitors can affect more than one isozyme (e.g., cimetidine, ritonavir, fluoxetine, erythromycin).

Inhibitors may affect different isozymes at different doses fluconazole inhibits CYP2C9 at doses of 100 mg/day or greater inhibits CYP3A4 at doses of 400 mg/day or greater

Cytochrome P450-Dependant Mixed Function Oxidation Reactions:CYP P450 Nomenclature :

- Italics indicates genes (CYP3A4)

- Regular fonts indicate enzymes (CYP3A4)

- Small letters indicate mouse enzymes (cyp1a1)

http://study.hiberniacollege.net/novartis/2014/novartis_clpap/session3/task0/novartis_clpap_s3_t0_s3/presentation.html

Drug Metabolism

III. Drug Interactions involving

transporters/enzymes

CYP3A4 and P-glycoprotein

Most CYP3A4 substrates are also P-glycoprotein substrates

Many CYP3A4 inhibitors/inducers also inhibit/induce P-glycoprotein, affecting bioavailability.

Examples of P-glycoprotein absorption drug interactions a. Dabigatran is affected by rifampin, St. John’s wort, quinidine, ketoconazole, verapamil, amiodarone, and dronedarone.b. Digoxin is affected by St. John’s wort, quinidine, verapamil, amiodarone, and dronedarone or dabigatran.

CYP3A4 and P-glycoprotein

c. Human immunodeficiency virus protease inhibitors are affected by rifampin and St. John’s wort.

Examples of P-Gp drug interactions at elimination level: quinidine/digoxin, cyclosporine/digoxin, and propafenone/digoxin

IV. Pharmacogenetics and personalized

medicine

Pharmacogenetics

The study of how genes affect a person’s response to drugs

Pharmacology

(Science of Drugs)

Genomics(Study of genes

and their functions)

Pharmacogenomics

What is a Gene?

DNA (deoxyribonucleic acid), the cell’s hereditary material.

DNA is a polymer of nucleotides (sugar, phosphate and one of four nitrogenous bases (A,T,G,C)

DNA Sequence

What is a Gene? Human genome consists of

about 3.2 billion base pair (bp)

Every person has two copies of each gene, one inherited from each parent (6.4 billion bp)

DNA molecule is packaged into thread-like structures called chromosomes.

23 pairs of Chromosomes Sex chromosome XX or XY 22 pairs autosomes

What is a Gene?

The exact function of most of the DNA in the human genome is unknown

Protein-coding genes ≈ 2%

Blueprint for the production of proteins (enzymes, structural elements, signaling molecules)

What is a Gene?The exact function of most of the DNA in the human genome is unknown

Protein-coding genes ≈ 2%

SNV and SNP Gene mutations

Inherited from a parent Acquired during a person’s lifetime

Mutations range in size from single base-pair mutation that occurs at

a specific site in the DNA sequence (SNV)

to a large segment of a chromosome (CNV)

SNP = SNV which occur in at least 1-2% of the population

Population in general is divided into poor, intermediate, extensive, and ultrarapid metabolizers;

Thus metabolism is considered polymorphic.

Why is Pharmacogenomics and SNP Knowledge

important?

Personalized Medicine “is the tailoring of medical treatment to the individual characteristics of each patient”

The Age of Personalized Medicine

“The science of individualized prevention and therapy”

National Institute of Health

optimize drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects

One Size fits all medicine

Personalized medicine

Alleles and Egyptian Population Warfarin a good candidate for personalized medicine?

-Anticoagulant with narrow therapeutic window.- Widely prescribed-High interpatient variability individual in the required dose due to different alleles of the following genes or enzymes

CYP2C9VKORC1CYP4F2APOECALU

Alleles and Egyptian Population Warfarin Dosing

VKORC1 (1173C>T) contributes to the 20.5% of warfarin dose variability.

the warfarin algorithm developed by Egyptian researchers were comparable with those of the IWPC and Gage algorithms with the advantage of using one SNP (VKORC1 1173C>T) only. (for doses>35 mg/week)

Alleles and Egyptian Population

FDA 120 FDA approved drugs with

Pharmacogenomic Biomarkers in Drug Labeling

includes specific actions to be taken based on the biomarker information

http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm

Drug Therapeutic Area

HUGO Symbol

Referenced Subgroup

Labeling Sections

WarfarinCardiology or Hematology

VKORC1 VKORC1 rs9923231 A allele carriers

Dosage and Administration, Clinical Pharmacology

Warfarin

Cardiology or Hematology

CYP2C9 CYP2C9 intermediate or poor metabolizers

Dosage and Administration, Drug Interactions, Clinical Pharmacology

End of Part I

Dalia A. HamdyBPSc, MSc, PhD, RP(ACP), MRSC

11th March 2016dr.daliahamdy@gmail.com

Pharmacokinetics and Pharmacodynamics Applications

in Pharmacotherapy

Part II

Session Outline (Part II) Pharmacogenetics and personalized medicine Non Linear PK Data Collection and analysis PK in renally impaired patients PK in hepatic impaired patients Pharmacodynamics

References Smith CL. Updates in Therapeutics®: The Pharmacotherapy

Preparatory Review and Recertification Course. 2015 Edition. The American College of Clinical Pharmacy. Pharmacokinetics/Pharmacodynamics Chapter.

Shargel L, Wu-Pong S, Andrew B.C.U. Applied Biopharmaceutics and Pharmacokinetics. 5 th Edition. McGraw-Hil ; 2005

Gibson G and Skett P. Introduction to Drug Metabolism. 3rd Edition. Nelson Thrones ; 2001.

Russel F.G.M. Transporters: Importance in Drug Absorption, Distribution, and Removal. Enzyme- and Transporter-Based Drug-Drug Interactions. Elservier; 2010.

References Mccarthy, J and Nussbaum, RL.

Genomic and Precision Medicine online course. University of California San Fransisco. Through Coursera online courses.

Shahin, MHA et al. Pharmacogenet Genomics. 2011 March ; 21(3): 130–135.

Ekladious, SM et al. Mol Diagn Ther. 2013 Dec;17(6):381-90.

V. Non Linear PK

In Linear PK PK parameters will not change between single

and multiple doses

Non Linear Pk ( dose-dependant PK) Increased doses or chronic medication cause PK

deviation from those after single low dose

Nonlinear PK

Reasons: Saturable absorption Saturable protein binding Saturable metabolism (capacity limited

metabolism) Saturable renal elimination Saturable biliary excretion

Nonlinear PK

Dr. Dalia A. Hamdy (FS15AY)

Saturable MetabolismProcess that requires energy and has a

maximal rate

Described byMichaelis-Menten kinetics:

LinearMichaelis-MentenProtein binding or autoinduc-tion

Dose (mg)

Css (mg/L)

maximum rate of metabolism

Dr. Dalia A. Hamdy (FS15AY)

Michaelis-Menten Kinetics

Michaelis constant (affinity)

MICHAELIS-MENTEN KINETICS

Rate of metabolism= Cp . VmaxCp + Km

At steady state:Rate of drug input= Rate of drug output

Similar to the PD Hill equation

Dosing rate = Cp . VmaxCp + Km

Dosing rate = mg/dayCp= mg/LVmax= mg/L/dayKm= mg/L

-dCp/dt = Cp . VmaxCp + Km

If Cp >>Km

Zero order kinetics

= Vmax

-dCp/dt = Cp . VmaxCp + Km

If Km>>Cp

First order kinetics

Units Vmax, K, Km

= Cp. Vmax Km

Increase 100% of dose = increase 80% of Css

Increase 17% of dose=Increase 81% of Css

Nonlinear Pk

0 1 2 3 4 5 6 7 80

Dose (mg)

VI. Data collection and analysis

Timing of Collection

1. Ensure completion of absorption and distribution phases (especially digoxin [8–12 hours] and vancomycin [30–60 minutes after 60-minute infusion]).

2. Ensure completion of redistribution after dialysis (especially aminoglycosides [3–4 hours after hemodialysis]).

Specimen Requirements1. Whole blood: Use anticoagulated tube. Examples: cyclosporine, amiodarone

2. Plasma: Use anticoagulated tube and centrifuge; clotting proteins and some blood cells are maintained.

3. Serum: Use red top tube, allow to clot, and centrifuge. Examples: most analyzed drugs including aminoglycosides, vancomycin, phenytoin, and digoxin

Assay Terminology1. Precision (reproducibility): Closeness of agreement among the results of repeated analyses performed on the same sample a. Standard deviation (SD): Average difference of the individual values from the mean

b. Coefficient of variation (CV): SD as a percentage of the mean (relative rather than absolute variation)

4. Sensitivity: Ability of an assay to quantitate low drug concentrations accurately; usually the lowest concentration an assay can differentiate from zero.

5. Specificity (cross-reactivity): Ability of an assay to differentiate the drug in question from like substances

Assay Methodology1. Immunoassays

a. Radioimmunoassay

i. Advantages: Extremely sensitive (picogram range)

ii. Disadvantages: -limited shelf life kits due to short half-life of labels, radioactive waste-cross-reactivity.• Used for digoxin and cyclosporine assay

Assay Methodologyb. Enzyme immunoassay; e.g., enzyme multiplied immunoassay technique (EMIT)

i. Advantages: Simple, automated, highly sensitive, inexpensive and stable reagents, widely available equipment, no radiation hazards

ii. Disadvantages:- enzyme activity may be affected by plasma

constituents, - less sensitive than radioimmunoassays

Assay Methodologyc. Fluorescence immunoassay: TDx (e.g., fluorescence polarization immunoassay (FPIA)): Most common therapeutic drug monitoring assayi. Advantages: Simple, automated, highly sensitive, inexpensive and stable reagents, inexpensive and widely available equipment, no radiation hazardsii. Disadvantages: Background interference attributable to endogenous serum fluorescence

Assay Methodology2. High-pressure liquid chromatography

3. Gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry

4. Flame photometry

5. Bioassay

Population Pharmacokinetics in TDM1. Population pharmacokinetics useful when:

a. Drug concentrations are obtained during complicated dosing regimens

b. Drug concentrations are obtained before steady state.

c. Only a few drug concentrations are feasibly obtained (limited sampling strategy).

What is population

Population Pharmacokinetics in TDM2. Bayesian pharmacokineticsa. Prior population information is combined with patient-specific data to predict the most probable individual parameters.

b. When patient-specific data are limited, there is greater influence from population parameters; when patient-specific data are extensive, there is less influence.

c. With a small amount of individual data, Bayesian forecasting generally yields more precise results.

Popular TDM Drugs

Cyclosporine and erythrocytes binding!

VI. PK in renally impaired patients

PK in renal disease: considerationsKidney:

The processes by which drug is excreted:

1. Glomerular Filtration

2. Active Secretion

3. Tubular reabsorption

1. Filtration GFR is used to describe kidney function. The National Kidney Foundation defines normal kidney function as

140 ± 30 mL/minute/1.73m2 for young healthy men126 ± 22 mL/minute/1.73m2 for young healthy women

PK in renal disease: considerations

1. FiltrationCL due to glomerular filtration CLgf

CLgf= fu X GFR

fu= unbound fraction

Estimation of Kidney Function Through Glomerular Filtration Rate (GFR)/Creatinine Clearance

1. Creatinine production and eliminationa. Creatine is produced in the liver.b. Creatinine is the product of creatine metabolism in skeletal muscle; formed at a constant rate for any one personc. Creatinine is filtered at the glomerulus, where it undergoes limited secretion.

Estimation of Kidney Function Through Glomerular Filtration Rate (GFR)/Creatinine Clearance

1. Creatinine production and elimination.d. CrCl is useful in approximating GFR because: i. At normal concentrations of creatinine, secretion is low.

ii. The creatinine assay picks up a noncreatinine chromogen in the blood but not in the urine.

PK in renal disease: considerations2. CrCl calculation to estimate GFR

• CrCl is calculated from a 24-hour urine collection and the following equation:

PK in renal disease: considerations 3. CrCl estimation to estimate GFR

a. Factors affecting SCr concentrationsi. Sexii. Ageiii. Weight/muscle massiv. Renal function. Caveats: CrCl estimations worsen as renal function worsens (usually an overestimation).

b. Jellife

PK in renal disease: considerations Factors Affecting CrCl estimates1. Patient characteristics2. Disease state and clinical conditions3. Diet4. Drugs and endogenous compounds

PK in renal disease: considerations Drug Dosing in renal diseases1. Loading dosea. In general, no alteration is necessary, but it should be given to hasten the achievement of therapeutic drug concentrations.

b. Alterations in loading dose must occur if the Vd is altered secondary to renal dysfunction. Example: digoxin

PK in renal disease: considerations Drug Dosing in renal diseases2. Maintenance dose: Alterations should be made in either the dose or the dosing interval.a. Changing the dosing interval i. Use when the goal is to achieve similar steady-state concentrations.ii. Less costlyiii. Ideal for limited-dosage forms (i.e., oral medications)b. Changing the dose i. Use when the goal is to maintain a steady therapeutic concentration. ii. More costly

PK in renal disease: considerations Drug Dosing in renal diseases2. Maintenance dose: Alterations should be made in either the dose or the dosing interval.a. Changing the dose and the dosing intervali. Often necessary for substantial dosage adjustment with limited-dosage formsii. Often necessary for narrow therapeutic index drugs with target concentrations(a) If a drug is given more than once daily, then adjust the interval.(b) If a drug is given once daily or less often, then adjust the dose.

VI. PK in hepatically impaired patients

Revision ClH= Q.E

E=Extraction ratio range from 0-1

If E>0.7 High extraction ratio ClH is affected by QIf E<0.3 Low extraction ratio ClH is affected by Clint

Clint = fu. Clint’i.e. unbound fraction of the drugEnzyme numbers and affinityP.S. Intermediate E (0.3-0.7) is affected by both (Q & Clint)

High Extraction Ratio Drugs Discuss

Low Extraction Ratio Drugs Discuss

PK in hepatic disease: considerations A. Dosage Adjustment in Hepatic Disease1. Clinical response is the most important factor in adjusting doses in hepatic disease.2. Low hepatic extraction ratio drugs (E<0.3)a. Adjustment of maintenance dose is necessary only when hepatic disease alters the intrinsic clearance (Clint)b. Alterations in protein binding alone do not require alteration of maintenance dose, even though total drug concentrations decline.

c. Loading doses may require reduction.

PK in hepatic disease: considerations3. High hepatic extraction ratio drugs (E > 0.7)a. Intravenous administration i. Usually necessary to decrease maintenance dose rate as hepatic blood flow changesii. Consider effect of hepatic disease on protein binding as it alters free concentrations.

b. Oral administration: Similar to low hepatic extraction ratio drugs; necessary to decrease maintenance dose rate when hepatic disease alters Clint

PK in hepatic disease: considerationsB. Rules for Dosing in Hepatic Disease

1. Hepatic elimination of high extraction ratio drugs is more consistently affected by liver disease than hepatic elimination of low extraction ratio drugs.

2. The clearance of drugs that are exclusively conjugated is not substantially altered in liver disease.(Phase II metabolism)

VI. Pharmacodynamics

Sigmoid Emax model

Emax: maximal effectEC50: plasma conc needed to get 50% Emax

Emax Model

concentration

Sigmoid Emax model

(Hill equation)Effect = Emax. Cn

n= shape factor

Emax Model

concentration

tEC50 + Cn

Sigmoid Emax model

(Hill equation)Effect = Emax. Cn

n= 1 simple Emax model

Emax Model

concentration

tEC50 + Cn

Observations regarding Emax model

1. Rate of decline in plasma concentrations is >>

That of effect

Emax Model

Why?Exponential

linear

2. It is possible to see effect with no detectable concentrations in plasma ? When?

Emax Model

3. In multicompartment drugs, where there is a long distribution phase and effect receptors are located in the peripheral compartment

……..in the effect

Emax Model

4. Concentrations should be measured postdistributive to be indicative of that at site of action (Css)

Emax Model

5. For some drugs there is no relation between concentration and effect . This may indicate that mechanism of the drug is really complicated.

Emax Model

6. Similar situation would be noticed when the entity responsible for action is the metabolite. There would be a lag and the response would differ according to route of administration e.x. oral or iv

Emax Model

7. Chirality : chiral drugs administered as racemates (equal proportions of two enantiomers) if there is a difference in activity then total concentration would not be indicative of the effect.

Emax Model

8. Single dose: it is hard to find relationship between concentration and effect as in aspirin, beta agonists.

Emax Model

It is time related discordance between effect and plasma concentration

A. Clockwise: -inhibitory metabolite-depletion of substrate required for positive response-non stereospecific assays

Hysteresis

It is time related discordance between effect and plasma concentration

B. Anticlockwise: -Lag time for distribution-Active metabolite

Hysteresis

End of Part II

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