1. Lecture 2 Clearance, maintenance dose and AUC

2. Explain the term “clearance”
AIMS
To describe the meaning of clearance and its application to maintenance dosage regimen design
OBJECTIVES By the end of the session you should be able to
Explain the term “clearance”
Calculate a maintenance dose from a target average steady state concentration and an estimate of clearance
Calculate AUC from dose and clearance

3. Clearance = Flow x Extraction Ratio
Clearance concepts
Extraction Ratio efficiency of drug removal
Cin - Cout Cin liver, Cout
Cin kidney…
cleared
Blood Flow efficiency of drug delivery to the organ
Clearance = Flow x Extraction Ratio
(Lh-1) (Lh-1)
5 mgL-1
10 mgL-1
ER = (10 – 5) / 10 = 0.5

4. Clearance and maintenance dose
6 mg in per hour
Drug concentration (mgL-1)
6 mg out per hour
Maintenance dose: rate in = rate out
Infusion rate (mgh-1) = Target Css (mgL-1) x CL (Lh-1)

5. Infusion rate (mgh-1) = Css (mgL-1) x Cl (Lh-1)/s
Continuous infusion: concentration-time profile
Infusion rate (mgh-1) = Css (mgL-1) x Cl (Lh-1)/s
Css (steady state)

6. Constant rate continuous infusion
e.g. vancomycin, theophylline
Infusion rate (mgh-1) = Css (mgL-1) x Cl (Lh-1)/s
s.IR (mgh-1)
Css (mgL-1) = Cl (Lh-1)
Cl (Lh-1) =
Css (mgL-1)

7. Oral dose (mg) = Cssav (mgL-1) x CL (Lh-1) x 24 h/Fs
Oral administration
Oral dose (mg) = Cssav (mgL-1) x CL (Lh-1) x 24 h/Fs

8. Area Under the Curve
Response may be related to the overall exposure of a patient (or the organism) to a drug, e.g. anticancer chemotherapy, antibiotic
“Exposure” depends on the dose administered and the patient’s ability to clear the dose
Daily Dose (mg)
AUC24 = (mg.h.L-1)
Clearance (L.h-1)

9. AUC = Dose / CL = 400 mg /2.5 Lh-1 = 160 mg.hL-1
For example: Dose mg Clearance 2.5 Lh-1
Volume 20 L
AUC = Dose / CL
= 400 mg /2.5 Lh-1 = 160 mg.hL-1

10. If dose is reduced from 400 mg to 200 mg
AUC = 200 mg / 2.5 Lh-1 = 80 mg.h.L-1

11. If clearance falls from 2.5 Lh-1 to 1.25 Lh-1
AUC = 400 mg / 1.25 Lh-1 = 320 mg.hL-1

12. Summary Loading dose Maintenance dose AUC D mg C V mg/L L DR mg/h
Css Cl mg/L L/h
AUC
F.D mg
AUC Cl mg.h/L L/h