CHAPTER-I

CLINICAL PHARMACOKINETICS

BYProf. C.Ramasamy,

Head, Dept of Pharmacy PracticeSRM College of Pharmacy,

SRM University

This supplements the other course materialYou can view it on line or download it to your computer and view it without being connected to the internet.Work through the presentation at the start of the course and note any issue which are not clear. Read up on areas that you are not familiar with and revisit the presentation from time to time.Try the powerpoint based exercises

HOW TO USE THIS POWERPOINT PRESENTATION

Study of the time course of a drug’s movement through the body.

Understanding of what the body does to (or with) the drug.

Application of Therapeutic Drug Monitoring (TDM) and individualisation of drug therapy.

WHAT IS CLINICAL PHARMACOKINETICS ?

Review of ConceptsClearance, K, Half-Life, Volume of Distribution

Therapeutic drug Monitoring

Pharmacokinetic Drug Interactions

Cases

Discussion/Questions

OUTLINE

PK - What the body does to the drug?Absorption; distribution, metabolism, excretion (ADME)

PD - What the drug does to the body?Drug concentration at the site of action or in the plasma is related to a magnitude of effect

PHARMACOKINETICS (PK) & PHARMACODYNAMICS (PD)

Plasma SiteConcen- oftration Action

Effects

PK PD

PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD)

Dose

Fluoxetine increases plasma concentrations of amitriptyline. This is a pharmacokinetic drug interaction.

Fluoxetine inhibits the metabolism of amitriptyline and increases the plasma concentration of amitriptytline.

PHARMACOKINETICS VS PHARMACODYNAMICS…CONCEPT

If fluoxetine is given with tramadol serotonin syndrom can result. This is a pharmacodynamic drug interaction.

Fluoxetine and tramadol both increase availability of serotonin leading to the possibility of “serotonin overload” This happens without a change in the concentration of either drug.

PHARMACOKINETICS VS PHARMACODYNAMICS…CONCEPT

In the next few slides the basic concepts and paramaters will be described and explained.

In pharmacokinetics the body is represented as a single or multiple compartments in to which the drug is distributed.

Some of the parameters are therefore a little abstract as we know the body is much more complicated !

BASIC PARAMETERS

V

Volume 100 L

Clearance10 L/hr

Volume of Distribution, Clearance and Elimination Rate Constant

V

Volume 100 L (Vi)

Clearance10 L/hr

Volume of Distribution, Clearance and Elimination Rate Constant

V2Cardiac and

Skeletal Muscle

VVolume 100 L (Vi)

Clearance10 L/hr

V2Cardiac and

Skeletal Muscle

Volume of Distribution =

Dose_______Plasma Concentration

VVolume 100 L (Vi)

Clearance10 L/hr

V2Cardiac and

Skeletal Muscle

Clearance =Volume of blood cleared of drug per unit time

VVolume 100 L (Vi)

Clearance10 L/hr

V2Cardiac and

Skeletal Muscle

Clearance = 10 L/hrVolume of Distribution = 100 LWhat is the Elimination Rate Constant (k) ?

CL = kVk = 10 Lhr -1 = 0.1 hr -1

100 L

10 % of the “Volume” is cleared (of drug) per hour k = Fraction of drug in the body removed per hour

CL = kVIf V increases then k must decrease as CL is constant

VD is a theoretical Volume and determines the loading doseClearance is a constant and determines the maintenance doseCL = kVDCL and VD are independent variablesk is a dependent variable

IMPORTANT CONCEPTS

Apparent volume of distribution is the theoretical volume that would have to be available for drug to disperse in if the concentration everywhere in the body were the same as that in the plasma or serum, the place where drug concentration sampling generally occurs.

VOLUME OF DISTRIBUTION

An abstract concept

Gives information on HOW the drug is distributed in the body

Used to calculate a loading dose

VOLUME OF DISTRIBUTION

Loading Dose

Dose = Cp(Target) x VD

What Is the is the loading dose required fro drug A if;Target concentration is 10 mg/LVD is 0.75 L/kgPatients weight is 75 kg

Answer is on the next slide

QUESTION

Dose = Target Concentration x VDVD = 0.75 L/kg x 75 kg = 56.25 LTarget Conc. = 10 mg/LDose = 10 mg/L x 56.25 L

= 565 mgThis would probably be rounded to 560 or even 500 mg.

ANSWER: LOADING DOSE OF DRUG A

Ability of organs of elimination (e.g. kidney, liver to “clear” drug from the bloodstreamVolume of fluid which is completely cleared of drug per unit timeUnits are in L/hr or L/hr/kgPharmacokinetic term used in determination of maintenance doses

CLEARANCE

Maintenance Dose = CL x CpSSav

CpSSav is the target average steady state drug concentration

The units of CL are in L/hr or L/hr/kg

Maintenance dose will be in mg/hr so for total daily dose will need multiplying by 24

MAINTENANCE DOSECALCULATION

What maintenance dose is required for drug A if;Target average SS concentration is 10 mg/LCL of drug A is 0.015 L/kg/hrPatient weighs 75 kg

Answer on next slide.

QUESTION

Maintenance Dose = CL x CpSSav

CL = 0.015 L/hr/kg x 75 = 1.125 L/hr

Dose = 1.125 L/hr x 10 mg/L = 11.25 mg/hr

So will need 11.25 x 24 mg per day= 270 mg

ANSWER

Half-life is the time taken for the drug concentration to fall to half its original valueThe elimination rate constant (k) is the fraction of drug in the body which is removed per unit time.

HALF-LIFE AND K

Drug Concentration

Time

C1

Exponential decaydC/dt ∝ C

= -k.CC2

Log Concn.

Time

C0

C0/2 t1/2

t1/2

t1/2

Time to eliminate ~ 4 t1/2

Integrating:

Cp2 = Cp1.e-kt

Logarithmic transform:lnC2= lnC1 - kt

logC2 = logC1 - kt/2.303

Elimination Half-Life:t1/2 = ln2/k

t1/2 = 0.693/k

Steady-state occurs after a drug has been given for approximately five elimination half-lives. At steady-state the rate of drug administration equals the rate of elimination and plasma concentration -time curves found after each dose should be approximately superimposable.

STEADY-STATE

100

187.5194

175

150

7587.5 94 97

50

200

100…

…

Accumulation to Steady State100 mg given every half-life

C

t

Cpav

Four half lives to reach steady state

Rate in = Rate Out

Reached in 4 – 5 half-l ives (linear kinetics)

Important when interpreting drug concentrations in TDM or assessing clinical response

WHAT IS STEADY STATE (SS) ?WHY IS IT IMPORTANT ?

Some Principles

THERAPEUTIC DRUG MONITORING

Therapeutic index = toxic dose/effective dose

This is a measure of a drug’s safetyA large number = a wide margin of safetyA small number = a small margin of safety

THERAPEUTIC INDEX

An established relationship between concentration and response or toxicityA sensitive and specific assayAn assay that is relatively easy to perfA narrow therapeutic rangeA need to enhance response/preventtoxicity

DRUG CONCENTRATIONS MAY BEUSEFUL WHEN THERE IS:

Lack of therapeutic responseToxic effects evidentPotential for non-complianceVariability in relationship of dose andconcentrationTherapeutic/toxic actions not easilyquantified by clinical endpoints

WHY MEASURE DRUG CONCENTRATIONS?

Assuming patient is at steady-state

Assuming patient is actually taking the drug as prescribed

Assuming patient is receiving drug as prescribed

Not knowing when the drug concentration was measured inrelation to dose administration

Assuming the patient is static and that changes in condition don’t affect clearance

Not considering drug interactions

POTENTIAL FOR ERROR WHEN USING TDM