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Pharmacokinetics workshop

Mohammed El-Sakkar
MSc (Pediatrics), MD, PhD (Pharmacology) Allergy & Immunology consultant Professor of Pharmacology University of Alexandria 2013

If a patient taking 0.25 mg tablet of digoxin daily, requires IV administration of the drug.
What would an equivalent dose be? When F for tablet is 0.62.

F for I.V. doses is 1 F for tablet is 0.62


Amount reach to systemic circulation intact = Dose (extravascular) X F Amount reach to circulation intact = 0.25 X 0.62 = 0.155 mg I.V. dose = 0.155 mg

What is the equivalent dosage of oral theophylline for a patient receiving IV aminophylline at a rate of 80 mg/hr? N.B theophylline is completely absorbed on oral administration and 80% of aminophylline weight is theophylline.
I.V. aminophylline dose per day= 80 x 24 = 1920 mg/day

Aminophylline 100
1920

Theophylline 80
?

Oral theophylline dose = 1920x 80 = 1536 mg/day 100

A normal volunteer will receive a new drug in a phase I clinical trial. The clearance and volume of distribution of the drug in this subject are 1.386 L/h and 80 L, respectively. The half life of the drug in this subject will be approximately
Cl = 1.386 L/h t = 0.693 X Vd Cl 0.693 X 80 L 1.386 L/h = 40 h Vd = 80 L

t =

Estimate the oral loading dose of digoxin for a 70 kg man, which would be necessary to attain a plasma level of 1.5 g/L (microgram/L)? Vd of digoxin is reduced to 420 L, F for tablet is 0.62
Vd X Desired initial plasma concentration (amount/vol) Bioavailability (F) 420 (L) X 1.5 g/L 0.62 = 1016 g

Loading dose=

What is the apparent clearance of lidocaine in a patient who is receiving an IV infusion of 2 mg/min and has a steady state plasma level of 3 mg/L? (Given is: Vd = 7.3 L/Kg and F = 0.7)
Desired Plasma drug concentration ss (Cpss) X Cl (vol/time)

Maintenance dosing rate = (amount/time) Clearance (Cl) =

Bioavailability (F)
=

Maintenance dosing rate x F


Cpss

120 mg/h
3 mg/L = 40 L/h

Clearance (Cl) =

120 mg/h x 1
3 mg/L

120 mg/h
3 mg/L

Alia is a 70 year-old 68 kg with CHF and chronic renal failure (Clcr 25ml/min). It is decided that a loading dose of digoxin is to be administered orally. What must you consider in calculating the estimated loading dose? The desired Cp is 1.5 microgram/L, Vd of digoxin is reduced to 4.7L/kg, F for tablet is 0.62

Loading dose=

Vd

X Desired initial plasma concentration (amount/vol)

Bioavailability (F)
4.7 L x 68 kg X 1.5 g/L 0.62 Corrected dose = = 773 g

Average dose X Patients creatinine clearance 100 mL/min 25 Corrected dose in RF = 773 gX = 193.25 g 100

Ahmad, a 10 kg child is admitted to the hospital for an acute attack of asthma. His theophylline level obtained on admission was reported to be 5 mcg/ml. What dose of aminophylline is needed to rapidly increase the plasma level to 15 mcg/ml (mg/L)? The Vd of theophylline is 0.45 L/kg.
Vd x (Cdesired Cinitial) Bioavailability (F) = 45 mg theophylline

Incremental loading dose = Loading dose =

(0.45x10) x (15 mg/L 5 mg/L) 1.0

Aminophylline dose = 45 x 100/80 = 54 mg

What will be an appropriate maintenance infusion rate of aminophylline to keep the plasma level at 15 mcg/ml? The clearance of theophylline in arithmetic adults is 4.73L/hr
Maintenance dosing rate = (amount/time) Cpss X Cl (vol/time) Bioavailability (F)

15 mg/L X 4.73L/hr

1 Aminophylline maintemance dose = 70.95 x 100/80 = 88.6 mg/h

= 70.95 mg/h theophylline

A 70 kg patient states she ingested approximately 30 tablets of phenobarbitone each contain 100mg. Vd listed is 0.75 L/kg. Peak blood concentration measured by the lab is 60 mg/L, F=1. How can you verify the history?
Loading dose = Vd x Target concentration Bioavailability (F) 0.75 x 70x 60 = 3150 mg = 1 She say 30x 100 =

= 3000 mg

The history is correct

A 70 kg patient states she ingested approximately 30 tablets of phenobarbitone each contain 100mg. Vd listed is 0.75 L/kg. Peak blood concentration measured by the lab is 60 mg/L, F=1. How can you verify the history?
Loading dose = Vd x Target concentration Bioavailability (F) 3000 x 1 = 0.75 x 70 = 57 mg/L

LD x F Target concentration = Vd

The history is correct

A 70 kg patient ingested an unknown number of lithium cap (300 mg = 8 mEq) and has a peak concentration of 5 mEq/L . The patient is now agitated. What is the number of capsules ingested? Its Vd is 0.7L/kg, F=1.
Loading dose = Vd x Target concentration Bioavailability (F)

(0.7 x 70) x 5 mEq/L = 245 mEq Number of capsules ingested =

245 mEq = 30 cap of 300 mg 8 mEq

Despite your careful adherence to basic pharmacokinetic principles, your patient on digoxin therapy has developed digitalis toxicity. The plasma digoxin level is 4 ng/mL. Renal function is normal, and the plasma t for digoxin in this patient is 1.6 days. How long should you withhold digoxin in order to reach a safer yet probably therapeutic level of 1 ng/mL?
% of maximum
100

75
50 25 0 0 2

Stop infusion Start infusion


4
6

10

Time (number of half-lives)

Since the blood level for a drug with first-order kinetics drops by 50% during each half-life, the level will be 2 ng/mL after 1.6 days and 1 ng/mL after 3.2 days.

A new drug was studied in 20 healthy volunteers to determine basic pharmacokinetic parameters. A dose of 100 mg was administered as an intravenous bolus to each volunteer and blood samples were analyzed at intervals as shown in the graph below. The average plasma concentrations at each time are shown by the solid circles at 10 and 30 minutes and at 1, 2, 3, 4, 6, and 8 hours after administration. Determine :
Elimination half life Vd

Clearance

The elimination phase of the graph of plasma concentration follows a straight line on the semi logarithmic graph, so we can conclude that the new drug follows first-order kinetics, the first requirement for determining the half-life.

The straight-line portion of the graph shows a decline of 50% from the 2hour point (4 mglL) to the 8-hour sample (2 mglL).
Half-life = 8 hs minus 2 hours = 6 hours. Loading dose X Bioavailability (F)

Vd =

Target concentration (Cp0) 100 mg x 1 5 mg/L = 20 L

t =

0.693 X Vd Cl

Cl = 0.693 X Vd t Cl = 0.693 X 20L = 2.3 L/h 6h