clinical pharmacokinetics€¦ · application of therapeutic drug monitoring ... individualisation...
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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
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