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Pharmacokinetics and Pharmacodynamics Applications in Pharmacotherapy

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Text of Pharmacokinetics and Pharmacodynamics Applications in Pharmacotherapy

Dalia A. Hamdy BPSc, MSc, PhD, RP(ACP), MRSC

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

4th March [email protected]

Pharmacokinetics and Pharmacodynamics Applications in PharmacotherapyPart I

Learning ObjectivesIdentify 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 vancomycinphenytoin digoxinb. pharmacokinetic alterations in patients with renal and hepatic disease.

3. Define important issues as they pertain to drug concentration sampling and interpretation.Dr. Dalia A. Hamdy (FS15AY)3

Session Outline (Part I)Dr. Dalia A. Hamdy (FS15AY)4Introduction 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

ReferencesDr. Dalia A. Hamdy (FS15AY)5Smith 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.

ReferencesDr. Dalia A. Hamdy (FS15AY)6Mccarthy, 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): 130135.

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

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Pharmacokinetics & PharmacodynamicsDr. Dalia A. Hamdy (FS15AY)7

Revision8Dr. Dalia A. Hamdy (FS15AY)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 body9Dr. Dalia A. Hamdy (FS15AY)

Revision

Two compartment PK model:

Denoted by two closed boxes

Assumes the body is composed of a two compartmentsCentral ( highly perfused)Peripheral (poorly perfused)

The drug is usually eliminated from the central compartment

10Dr. Dalia A. Hamdy (FS15AY)

Revision

DoseRoute of

administrationElimination rate constantCpZero order

Amount of drug eliminated per unit time is constantFirst order

Amount of drug eliminated per unit time is proportional to the drug remaining11Dr. Dalia A. Hamdy (FS15AY)

Revision

DoseRoute of

administrationElimination rate constantCpThe rate of change of Cp at any time is calculated by

Input-output

12Dr. Dalia A. Hamdy (FS15AY)

Revision

DoseRoute of

administrationElimination rate constantCpRoutes of administrationIV Bolus The entire dose enters the body immediately and 100% bioavailable F=1

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

Oral absorption The dose is administered orally in form of granules, tablets, liquids or capsules, F is usually less than 113Dr. Dalia A. Hamdy (FS15AY)

Revision

DoseRoute of

administrationElimination rate constantCpRoutes of administrationIV Bolus

C0 = highest concentration

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Revision

DoseRoute of

administrationElimination rate constantCpRoutes of administrationContinuous IV infusion

C0 = 0

15Dr. Dalia A. Hamdy (FS15AY)

Revision

DoseRoute of

administrationElimination rate constantCpRoutes of administrationContinuous IV infusion

C0 = 0

16Dr. Dalia A. Hamdy (FS15AY)

Revision

DoseRoute of

administrationElimination rate constantCpRoutes of administrationOral absorption

Cmax is when Ka=K

C0 = 0

Cmaxtmax17Dr. Dalia A. Hamdy (FS15AY)

IV BolusIV infusionOral absorptionCp=

C0X e-kt

Revision18Dr. Dalia A. Hamdy (FS15AY)

IV BolusIV infusionOral absorptionCp=

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

RevisionKoVdKKaF DoseVd (Ka-K) (e-Kt -e-Kat)19Dr. Dalia A. Hamdy (FS15AY)

IV BolusIV infusionOral absorptionCp=

C0X e-kt X (1- e-kt)K-slope (method of residuals)-slope (method of residuals)-slope post infusion cessation-slope (method of residuals)

RevisionKoVdKKaF DoseVd (Ka-K) (e-Kt -e-Kat)20Dr. Dalia A. Hamdy (FS15AY)

IV BolusIV infusionOral absorptionCp=

C0X e-kt X (1- e-kt)K-slope (method of residuals)-slope (method of residuals)-slope post infusion cessation-slope (method of residuals)BE Ware of Flip-Flop phenomenonCL =(Dose.F)/AUCF=1F=1F1 (oral clearance)

RevisionKoVdKKaF DoseVd (Ka-K) (e-Kt -e-Kat)21Dr. Dalia A. Hamdy (FS15AY)

IV BolusIV infusionOral absorptionCp=

C0X e-kt X (1- e-kt)K-slope (method of residuals)-slope (method of residuals)-slope post infusion cessation-slope (method of residuals)BE Ware of Flip-Flop phenomenonCL =(Dose.F)/AUCF=1F=1F1 (oral clearance)Vd= CL/KNote Vc= Dose/C0-If calculated from oral data then it is oral Vd

RevisionKoVdKKaF DoseVd (Ka-K) (e-Kt -e-Kat)22Dr. Dalia A. Hamdy (FS15AY)

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Bioavailability

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

F = AUC test X Dose referenceAUC referenceDose test23Dr. Dalia A. Hamdy (FS15AY)If test=IV Absolute BioavailabilityIf test=other route Relative Bioavailability

Rate and extent of absorption, PK parameters involved, first pass brief introduction, then let us go deeper into the different factors within the critically ill patients. You can start referring to the relationship between F and Extraction ratio and refer them to the later elaboration23

RevisionAUC (Trapezoidal Rule)

What is the Difference Between IV Bolus and Oral?

24Dr. Dalia A. Hamdy (FS15AY)

Dr. Dalia A. Hamdy (FS15AY)25

RevisionCssTime to reach Css

What is the importance of a loading dose ?

LD = Css desired Vd =

Css =

KoK26Dr. Dalia A. Hamdy (FS15AY)KoCl

Dr. Dalia A. Hamdy (FS15AY)27

RevisionWhat are the differences between one and two compartments in infusion??28Dr. Dalia A. Hamdy (FS15AY)

Hepatic Metabolism

Hepatic ClearanceCLT= CLr + CL nr =CLr + CLH + CL other

Dr. Dalia A. Hamdy (FS15AY)29First Pass MetabolismHepatic clearance

First PassPortal veinHepatic ClearanceHepatic artery

Relation between first pass, extraction ratio and bioavailability?!

PharmD7-Clinical Pharmacokinetics I25/03/2016Dr. Dalia A. Hamdy29

First Pass EffectDr. Dalia A. Hamdy (FS15AY)301. 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 EffectDr. Dalia A. Hamdy (FS15AY)312. Examples of drugs with significant first-pass effect

Enterohepatic RecirculationDr. Dalia A. Hamdy (FS15AY)32-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 RecirculationDr. Dalia A. Hamdy (FS15AY)33

PracticesDr. Dalia A. Hamdy (FS15AY)34

=(25/50)*(100/200)=25%34

Dr. Dalia A. Hamdy (FS15AY)35

Ld=160 mgCalculate k, then co the vdFrom vd calculate the doseAnswer c

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Dr. Dalia A. Hamdy (FS15AY)36

hAlf life is almost 3 daysDose given at 24 make conc of (12.1+23.8)=35.9After 3 days one half life conc almost 18After 6 days 2 half lifes is ok Mg/l is the same as ug/mlAnswer c

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Dr. Dalia A. Hamdy (FS15AY)37

B37

Dr. Dalia A. Hamdy (FS15AY)38

CDraw the curves and show the difference

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Dr. Dalia A. Hamdy (FS15AY)39

B

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40Dr. Dalia A. Hamdy (FS15AY)II. Introduction to Transporters and metabolic enzymes

Drug transportersDr. Dalia A. Hamdy (FS15AY)41

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 ATPSecondary: uses energy

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Drug transportersDr. Dalia A. Hamdy (FS15AY)42

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)

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Drug transportersDr. Dalia A. Hamdy (FS15AY)43

Solute Carriers (SLC) Transporters:

Can be further divided into:- Organic ani

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