clinical pharmacokinetics
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‘Good surgeons and physicians’ Clinical trial
Clinical PKAndClinical trials
Dr.U.P.Rathnakar MD.DIH.PGDHMwww.pharmacologyfordummies.blogspot.com
Why physicians and surgeons should waste time on pharmacology?
• Dose predictions
• Dose? ←Narrow TI[Digoxin, Li]• Range →OK for Wide TI• Mfrs → Dose range• Doses →Mfrs. [Population PK]• PK →Dose• PD →Effect of drugs & ADE• Pharmacology →Therapeutics• Clinical knowledge → Diagnosis
Dose• Treatment• ↓• No effect or adverse effect• ↓• Why?• ↓• Plasma concn. Less or More• ↓• How much to increase or decrease? Is
loading dose required?• ↓• Clinical pharmacokinetics
Target concentration[Dose]
Quinidine 8 mg/L80% chance of beneficial effect
20% chance of adverse effect
•No attention was paid PK•Target concn.-based on PD-good & bad
IDEA!
Drug concn. Therapeutic decisions
Target concentration[Dose][Therapeutic triangle]
Dose
PK
[Plasma] Concentration Effect
PD
Target Concentrationintervention
Rational Therapeutics
VDCL
Emax
EC50
Appropriate dose Desired Th.effect
PK Parameters for Target concn.strategy
• Bioavailability- F• Elimination half life- t½• Clearance- CL• Volume of dist. aVD
10 Equations!• [1]- t½=0.7xV/CL• [2]- Cpss=Dose rate/CL• [3] Dosing rate=Target CpssxCL• [4] Dosing rate=Target CpssxCL/F• [5] Loading dose=targetCpxV/F• [6] Revised dose rate=Previous D.R x
Target Cpss/Measured Cpss• [7] CL=Rate of elimination/Plasma
concn.• [8] V=Amount of drug in the
body/Plasma concn.
• [9] F= AUC oral/AUC i.v
2 Equations!
=Rate of elimination
Plasma concn.
=Amount of drug in the body Plasma concn.
Bio-availability [Foral]• Fraction• i.v. = 100%• Propranolol→95% absorbed →Plasma concn-25%-
45% [0.25-0.45]• F [Fractional availability]= AUC oral
AUC i.v.
AUC oral
Concn Toxic concn.
Th.Concn.
AUC i.v.
Time
V.D• Factors affecting1.Lipidsolubility & Ionization-
Lignocaine and Heparin2.Plasma protein binding3.Tissue binding-Digoxin bound to
heart,liver4.Disease-CHF, Uremia5.Fat:Lean body mass
Drug in beaker Drug + Charcoal in beaker
Drug=10mgConcn=20mg/LaVD=10/20mg/L =0.5L =Vol.of beaker
Drug=10mgConcn=2mg/LaVD=10/2mg/L =5L =Much more thanVol.ofBeakerand charcoal
Apparent Volume of Distribution
0.5L
5L
0.5L
Apparent volume of distribution• aVD: “The volume that would accommodate all
the drug in the body, if the concn.throughout was the same as in plasma”
• Lipid insoluble: Small aVD-Eg.Gentamicin-.25L/kg
• Highly protein bound-Eg.Diclofenac-0.15L/kg.
• Highly tissue bound-Eg.Morphine-3.5L/kg
High vol. of distribution-poisoning-difficult to remove by dialysis
Distribution. Where do drugs go?
Volume of distribution
• Plasma: 4 liters.• Interstitial volume:
10 liters.• Intracelullar
volume: 28 liters
Relative size of various distribution volumes withina 70-kg individual
Plasma compartment
• Vd: around 5 L. • Very high molecular weight
drugs, or drugs that bind to plasma proteins excesively
• Example: Heparin 4L (3-5)
Extracellular fluid
Vd: between 4 and 14 L. Drugs that have a low
molecular weight but are hydrophilic.
Example:Atracuronium 11 L (8-15)
Vd equal or higher than total body water
• Diffusion to intracelullar fluid . Vd equal to total body water.– Ethanol 38 L (34-41)– Alfentanyl 56 L (35-77)
• Drug that binds strongly to tissues. Vd higher than total body water.– Fentanyl: 280 L– Propofol: 560 L– Digoxin:385 L
Plasma half life [t½][Elimination half life]
It is the time required for the . plasma conco f the drug to be reduced to half of its original value
Single dose 4-5 t½
100
50
150
75
175
87.5
187.5
93.5
193.5
96.5
196.5
98
198
99
199
100
Takes 4-5 halflives to reach steady state concn.
Steady state[Plataeu principle]
Multiple doses
194 mg
198.5197194
97
199
100
99.2598.5
100100100
Concn
Time
Loading Dose•Drugs with long t1/2•In emergency
Steady state plasma concn.
194
Models of drug distribution and elimination
Kinetics of Elimination1. Clearance THE CLEARANCE OF A DRUG IS THE
THEORETICAL VOLUME OF PLASMA FROM WHICH THE DRUG IS
COMPLETELY REMOVED IN UNIT TIME. Rate of elimination
CL= …………………………
.Plasma conc ( C)
First order[Constant Fraction]
10% of 200mg=20mg
10% of 180mg=18mg
10% of 160mg=16mg
Pharmacokinetics
10mg
10mg
10mg
Q. A Pt. is suffering from acute asthma.What is the rate of i.v. infusion and loadingdose of Theophylline to achieve a TARGET CONCN. OF 10MG./L in a patient Weighing 70kg.?Also calculate the maintenance dose by oral route for 8th hourly,12 hourly and oncea day administration.
Data: 1. CL=2.8L/h/70kg. 2. Foral = 0.96. 3. aVD= 35L
Calculation Loading dose:Loading dose:VD= Total amount of drug in the body
Plasma concn.= Loading dose = VD x Target concn. = 35L x 10mg/L =Loading dose= 350mg. Given as bolus i.v
Data: 1. CL=2.8L/h/70kg. 2. Foral = 0.96. 3. aVD= 35L4. Target concn.=10mg/L
[Loading dose][target concn]
Calculation: Dosing rate:
Dosing rate:CL = Rate of elimination
Plasma concn. = Rate of administration! [Dosing rate] =CLx Target concn
=Dosing rate = 2.8 L/h x 10mg/L == Dosing rate[i.v.infusion]= 28mg/h/70kg man.
Data: 1. CL=2.8L/h/70kg. 2. Foral = 0.96. 3. aVD= 35L4. Target concn=10mg/L
[Rate of administration!][Target concn.!]
CalculationDivided oral doses:=Dosing rate = 28mg/h = 720mg[Appx]/24h•But F= 0.96•So Oral Dosing rate = i.v dosing rate/ 0.96= 750mg.= Once a day dose = 750mg, = 8th hourly = 750/3 = 250mg tid= 12th hourly = 750mg/2 = 350 mg bid.
I.V
8 th hourly
Once a day
Dosage regimens• Target level strategy: Why?Effect not quantifiable[anti-epileptic, anti-
deppressants]Narrow safety margin[Theophylline,
Digoxin]• Loading and maintenance dose: Why?• Drugs with long t1/2-If the initial dose is large to achieve target
level- subsequent doses leads accumulation and toxicity
If small dose are tried takes very long for the effect
194 mg
198.5197194
97
199
100
99.2598.5
100100100
Concn
Time
Loading Dose•Drugs with long t1/2•In emergency
Steady state plasma concn.
Dose is large
Small dose
TDM• Monitoring of therapy by measuring
plasma concn.•Utilizes the principle that the clinical response of a drug is directly related to its concentration in blood
•Monitoring is carried out to support the management of patients receiving certain drugs
TDM Monitoring of therapy by measuring plasma concn
Useful
• Low safety margin- eg.digoxin, Theophylline
• Individual variations large-Li
• Renal failure-AG• Failure to
respond-AMA• Check Pt.
compliance
Not useful
• Response easy to measure-BP, blood sugar, GA
• Activated in body-levodopa
• Hit & run drugs-Reserpine
• Irreversible action- OP
Revised dosing rate• Cpss- Depends on V, CL, F• Each of these show individual variation• Cpss May vary between 1/3 to 3 times.
• Revised dosing = Previous D.R x Target CpssRate Measured Cpss
• 750mg/day x 10mg/L = 500mg/day15mg/L
Consider liver and renal functions
Thank You
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