‘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