Clinical Pharmacokinetics
This document was uploaded by user and they confirmed that they have the permission to share it. If you are author or own the copyright of this book, please report to us by using this DMCA report form. Report DMCA
Overview
Download & View Clinical Pharmacokinetics as PDF for free.
More details
- Words: 1,096
- Pages: 36
od surgeons and physicians’
Clinical trial Clinical PK And Clinical trials
Dr.U.P.Rathnakar
MD.DIH.PGDHM www.pharmacologyfordummies.blogspot.c
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/L
80% chance of beneficial eff
20% chance of adverse effe
o attention was paid PK arget concn.-based on PD-good & ba IDEA!
Drug concn. decisions
Therapeutic
Target concentration[Dose] [Therapeutic triangle] Appropriate dose Rational Therapeutics
Desired Th.effect
PD
PK VD CL
Dose
Target Concentration intervention
[Plasma] Concentration
Emax EC50
Effect
PK Parameters for Target concn.strategy
• BioavailabilityF • Elimination half lifet½ • ClearanceCL • Volume of dist.
10 Equations! • [1]-
t½=0.7xV/CL Cpss=Dose rate/CL Dosing rate=Target CpssxCL Dosing rate=Target
• [2]• [3] • [4] 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
2 Equations!
=Amount of drug in the body Plasma concn.
=Rate of elimination 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. Toxic concn.
Concn AUC i.v.
Th.Concn. AUC oral Time
V.D • Factors affecting • Lipidsolubility & Ionization-Lignocaine and Heparin • Plasma protein binding • Tissue binding-Digoxin bound to heart,liver • Disease-CHF, Uremia • Fat:Lean body mass
Apparent Volume of Distribution Drug in beaker
0.5L
Drug=10mg Concn=20mg/ L aVD=10/20m g/L =0.5L =Vol.of beaker
Drug + Charcoal in beaker Drug=10mg
0.5L 5L
Concn=2mg/L aVD=10/2mg/ L =5L =Much more thanVol.of Beaker and charcoal
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 Relative size of various distribution volumes • Plasma: 4 within liters. a 70-kg individual
• Interstitial volume: 10 liters. • Intracelullar volume: 28 liters
Plasma compartment • Vd: around 5 L. • Very high molecular weight drugs, or drugs that bind to plasma proteins excesively • Example: Heparin 4L (35)
Extracellular fluid Vd: between 4 and 14 L. Drugs that have a low molecular weight but are hydrophilic. Example: Atracuronium 11 L (815)
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 conc. of the drug to be reduced to half of its original value
Single dose
4-5 t½
Takes 4-5 halflives to reach steady state concn. 196.5 198 199 193.5
Steady state [Plataeu principle
187.5 175 150
93.5
96.5
98
99
87.5 100 75 50
100 Multiple
doses
194
Loading Dose •Drugs with long t1/2 •In emergency Concn 194
97 194 mg
100
197
199 198.5
98.5
99.25
100
100
Time
Steady state plasma concn
100
Models of drug distribution and elimination
Kinetics of Elimination
1. 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 loading dose 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 once a day administration. Data: 1. CL=2.8L/h/70kg. 2. Foral = 0.96. 3. aVD= 35L
Calculation Loading dose: Loading dose:
dose] VD= Total amount of drug[Loading in the body Plasma concn. [target 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= 35L 4. Target concn.=10mg/L
Calculation: Dosing rate: Dosing rate: [Rate of administration!] CL = Rate of elimination [Target concn.!] 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= 35L 4. Target
Calculation
d oral doses:
ng rate = 28mg/h = 720mg[Appx]/24h F= 0.96 ral Dosing rate = i.v dosing rate/ 0.96= 7 ce a day dose = 750mg, hourly = 750/3 = 250mg tid hourly = 750mg/2 = 350 mg bid. Once a day
8 th hourly I.V
Dosage regimens • Target level strategy: Why? Effect not quantifiable[anti-epileptic, antideppressants] 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
Loading Dose •Drugs with long t1/2 •In emergency
Dose is large Concn 194
197
199 198.5
Steady state plasma concn Small dose
97 194 mg
100
98.5
99.25
100
100
Time
100
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 margineg.digoxin, Theophylline • Individual variations large-Li • Renal failure-AG • Failure to respondAMA • Check Pt. compliance
Not useful
• Response easy to measure-BP, blood sugar, GA • Activated in bodylevodopa • Hit & run drugsReserpine • Irreversible actionOP
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 Cpss Rate Measured Cpss • 750mg/day x 10mg/L 15mg/L
= 500mg/day
Consider liver and renal functions
Thank You
Clinical trial Clinical PK And Clinical trials
Dr.U.P.Rathnakar
MD.DIH.PGDHM www.pharmacologyfordummies.blogspot.c
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/L
80% chance of beneficial eff
20% chance of adverse effe
o attention was paid PK arget concn.-based on PD-good & ba IDEA!
Drug concn. decisions
Therapeutic
Target concentration[Dose] [Therapeutic triangle] Appropriate dose Rational Therapeutics
Desired Th.effect
PD
PK VD CL
Dose
Target Concentration intervention
[Plasma] Concentration
Emax EC50
Effect
PK Parameters for Target concn.strategy
• BioavailabilityF • Elimination half lifet½ • ClearanceCL • Volume of dist.
10 Equations! • [1]-
t½=0.7xV/CL Cpss=Dose rate/CL Dosing rate=Target CpssxCL Dosing rate=Target
• [2]• [3] • [4] 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
2 Equations!
=Amount of drug in the body Plasma concn.
=Rate of elimination 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. Toxic concn.
Concn AUC i.v.
Th.Concn. AUC oral Time
V.D • Factors affecting • Lipidsolubility & Ionization-Lignocaine and Heparin • Plasma protein binding • Tissue binding-Digoxin bound to heart,liver • Disease-CHF, Uremia • Fat:Lean body mass
Apparent Volume of Distribution Drug in beaker
0.5L
Drug=10mg Concn=20mg/ L aVD=10/20m g/L =0.5L =Vol.of beaker
Drug + Charcoal in beaker Drug=10mg
0.5L 5L
Concn=2mg/L aVD=10/2mg/ L =5L =Much more thanVol.of Beaker and charcoal
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 Relative size of various distribution volumes • Plasma: 4 within liters. a 70-kg individual
• Interstitial volume: 10 liters. • Intracelullar volume: 28 liters
Plasma compartment • Vd: around 5 L. • Very high molecular weight drugs, or drugs that bind to plasma proteins excesively • Example: Heparin 4L (35)
Extracellular fluid Vd: between 4 and 14 L. Drugs that have a low molecular weight but are hydrophilic. Example: Atracuronium 11 L (815)
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 conc. of the drug to be reduced to half of its original value
Single dose
4-5 t½
Takes 4-5 halflives to reach steady state concn. 196.5 198 199 193.5
Steady state [Plataeu principle
187.5 175 150
93.5
96.5
98
99
87.5 100 75 50
100 Multiple
doses
194
Loading Dose •Drugs with long t1/2 •In emergency Concn 194
97 194 mg
100
197
199 198.5
98.5
99.25
100
100
Time
Steady state plasma concn
100
Models of drug distribution and elimination
Kinetics of Elimination
1. 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 loading dose 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 once a day administration. Data: 1. CL=2.8L/h/70kg. 2. Foral = 0.96. 3. aVD= 35L
Calculation Loading dose: Loading dose:
dose] VD= Total amount of drug[Loading in the body Plasma concn. [target 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= 35L 4. Target concn.=10mg/L
Calculation: Dosing rate: Dosing rate: [Rate of administration!] CL = Rate of elimination [Target concn.!] 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= 35L 4. Target
Calculation
d oral doses:
ng rate = 28mg/h = 720mg[Appx]/24h F= 0.96 ral Dosing rate = i.v dosing rate/ 0.96= 7 ce a day dose = 750mg, hourly = 750/3 = 250mg tid hourly = 750mg/2 = 350 mg bid. Once a day
8 th hourly I.V
Dosage regimens • Target level strategy: Why? Effect not quantifiable[anti-epileptic, antideppressants] 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
Loading Dose •Drugs with long t1/2 •In emergency
Dose is large Concn 194
197
199 198.5
Steady state plasma concn Small dose
97 194 mg
100
98.5
99.25
100
100
Time
100
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 margineg.digoxin, Theophylline • Individual variations large-Li • Renal failure-AG • Failure to respondAMA • Check Pt. compliance
Not useful
• Response easy to measure-BP, blood sugar, GA • Activated in bodylevodopa • Hit & run drugsReserpine • Irreversible actionOP
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 Cpss Rate Measured Cpss • 750mg/day x 10mg/L 15mg/L
= 500mg/day
Consider liver and renal functions
Thank You
Related Documents
Clinical Pharmacokinetics
May 2020 8
Pharmacokinetics
December 2019 19
Pharmacokinetics
May 2020 12
Pharmacology3(pharmacokinetics)
December 2019 18
