Lecture 2 Clearance, maintenance dose and AUC

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Presentation transcript:

Lecture 2 Clearance, maintenance dose and AUC

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

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

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)

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)

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)

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

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)

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

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

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

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