Understand how to calculate the pharmacokinetic properties of drugs and the inter-relationship

Understand how pharmacokinetic principles are applied to clinical situations

Supplemental Reading: The Pharmacological Basis of Therapeutics, 12th edition, Chapter 2, pages 17-39. Katzung & Trevor’s Pharmacology Examination & Board Review, 10th ed., Chapter 3

Important relationship between drug dosage, pharmacokinetic processes, and pharmacological response with respect to plasma drug concentration (Cp)

Bioavailability, volume of distribution, t1/2 life, and clearance are pharmacokinetic factors used to calculate dosing regimens

F can be expressed as a percentage, % Bioavailability = F x 100

Presence of food and other drugs can significantly change bioavailability

Area under the curve (AUC) analysis used to determine F

F = AUC (area under blood concentration curve) PO (any route)/AUC IV

Actual drug amount absorbed = Dose x F

Dose=Actual drug amount absorbed/F

New Dosage = Amount absorbed from old dosage / F of new dosage form

(100 mg/25%=100mg/0.25=400 mg)

anything given another path will have lower fraction

related:

clearance express in L/hr

half-life

New Dosage = Amount absorbed from old dosage / F of new dosage form

((200 mg X 0.6)/0.8=150 mg)

(Note: Cp0 is plasma conc. @ time 0, determined from drug elimination curve)

Vd = 1000 mg / 250 mg /L plasma , adm IV

Vd = 1000 mg / 10 mg /L plasma, adm IV

Vd = Loading dose (LD) / Ther. Cp

LD = Vd x Cp (IV administration); for PO adm must divide by F value

can determine half life

etc.

Bioavailability=50%; plasma concentration =150 g/L , Calculate the volume of distribution

Vd = D x F / Cp

= 100 mg x 0.5 / (150 ug/l)

= 50 mg / (0.150 mg/l)

= 333 liters

Vd = 7.3 L/kg x 70 kg =511L

LD = Vd x Cp / F (need F when not IV)

= 511L x (1.5 ug/L) / 0.62

=766.5 ug / 0.62

= 1236 ug or 1.24 mg (PO)

First Order – change in pharmacokinetic rate reaction proportional to dosage; drugs have a fixed T1/2, most drugs

Zero Order – change in pharmacokinetic rate reactions not proportional to dosage; drugs have no fixed T1/2 (eg, alcohol). These drugs in overdose accumulate faster to significantly raise Cp

T 1/2 is the time required to change the amount of drug in the body by one-half during elimination, not the duration of action

*T1/2 = 0.7 / k (0.7: natural log of 2; k= elim. rate constant)*

Determine k from elimination rate curve

*Drug conc in different tissues not equal, but at equilibrium and proportional to Cp*

Drug conc in different tissues varies proportionately as Cp changes

*Characteristic of drugs that are predominantly water soluble*

Central compartment – high blood flow, blood, brain, lungs, heart, liver, kidney

Peripheral compartment – low blood flow, tissues with inc % fat (skin, muscle, adipose); destination of lipid soluble drugs with large Vd

Drugs always enter exit central compartment.

one compartment shows 16… 2nd compartment shows 31

Rate at which drug is cleared from body, defined as volume of fluid (plasma) from which drug is removed in given time eg. mls / min or liters/hr

CL = Vd x ke or CL = Vd x 0.7 / t 1/2

Rearrange for T1/2 = Vd x 0.7 / CL

CL has inverse relationship with T1/2

Vd and T1/2 have a proportional relationship

Adjustment based on ratio of patients creatinine clearance vs normal creatinine clearance (100-120 ml/min)

*Corrected dose= normal dose x ratio (patients creatinine clearance / 100 ml/min)*

Dosage and dosage interval must remain constant when determining Cpss

Plateau or Cpss is a function of T 1/2

Calculation of maintenance dose or dosage interval for CPSS

*Maintenance dose x F/T=CPSS x CL (T:dosing interval)*

Maintenance dose=CPSS x CL x T / F

CPSS = Dose x F / (CL x T)

after 5 dosages

1 – 50

2 – 75

3- 87.5

4 – 93.75

5- 96.88

Vd = Amount drug in body (DxF) Cp0 (Note: Cp0 is plasma conc. @ time 0, determined from drug elimination curve)

LD = Vd x Ther.Cp / F (need F when not IV)

2. Steady-state:

Maintenance dose = CL x CPSS x T / F

CPSS = Dose x F / (CL x T)

3. Drug elimination:

T1/2 = 0.7 / k (k= elim. rate const)

T1/2 = Vd x 0.7 / CL

CL = Vd x 0.7 / t ½

4. Always keep unit consistent throughout the calculation.