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Transcript
Pharmacokinetics lecture 10 Contents ... • Extravascular administration • Determination of bioavailability for extravascular doses Extravascular administration Any route other than i.v. • An absorption stage will be involved • Bioavailability may not be 100% Principally oral but also intramuscular, subcutaneous etc Aa Ka Ab K Body Gut Rate of change in body load = Input - Output = Ka.Aa - K.Ab Extravascular administration Almost pure elimination Changing Ka 3h-1 Reduced Ka (Slower release) causes peaks to be lower and shifted to the right. 0.4h-1 Determination of F for extravascular doses Assume the same dose of a drug is administered on two occasions to the same individual. Either different dosage forms or routes of administration are used on the two occasions. Determination of F AUC = F.D Cl rearranges to D = AUC Cl F Drug administered on two occasions ... D1 = AUC1 Cl1 F1 D2 = AUC2 Cl2 F2 Dose and clearance will be same on both occasions D1 = D2 so Cl1 Cl2 AUC1 = AUC2 and F1 F2 F1 = AUC1 F2 AUC2 Absolute bioavailability Absolute bioavailability can be calculated if one of the doses is an i.v. injection. Say the other dose is oral ... Foral = AUCoral Fiv AUCiv Fiv is always 1.0, so Foral = AUCoral AUCiv Absolute oral bioavailability Relative bioavailability If neither of the doses is an i.v. injection, we can only calculate a relative bioavailability. If we give the same dose orally and by i.m. injection ... Foral = AUCoral Fim AUCim This term is the bioavailability of the oral dose relative to the i.m. dose. i.v. Oral AUCoral = Absolute oral bioavailability AUCiv Capsule Tablet AUCtablet = Bioavailability of tablet AUCcapsule (Relative to capsule) Practical methods for determining AUC • For an i.v. dose can use AUC = F.D Cl • For extravascular doses there is no simple formula. Have to use graphical methods. Trapezoidal rule Verticals dropped from each point. Points joined by straight lines. Conc Divides the area into a series of 6 trapezoids. 1 2 3 4 5 Time Total area of the trapezoids gives a good approximation of the AUC up to the last blood 6 sample. Area of each trapezoid C2 C1 Mean height = C1 + C2 2 Width = t2 - t1 Area = C1 + C2 x (t2 - t1) 2 t1 t2 Area of the ‘tail’ Conc 1.5 1.0 True AUC0- should include the ‘tail’ area beyond the last actual measured concentration. Calculate as: Tail = Final measured conc K 0.5 0.0 0 Time (h) 6 12 An example - Determination of absolute oral bioavailability 10mg of a drug have been administered on two occasions to the same subject. One dose i.v., one oral. Plan 1 From i.v. data, get clearance and AUCiv 2 From oral data, get AUCoral up to last blood sample 3 Semi-log plot of oral data to get K and area of tail 4 Get total AUC oral 5 Get F as AUCoral / AUCiv 1: Determine clearance and AUCiv (Not dealt with in detail, as already covered in Lecture 6.) Assume Clearance found to be 50 L/h. AUC = F.D Cl AUC = 1.0 x 10mg 50 L/h = 0.2 mg.h.L-1 = 200 µg.h.L-1 2: Use trapezoidal rule to get oral AUC0-12h Data from oral administration Time (h) Conc (µg/L) 1 9.6 2 11.0 4 12.0 6 9.4 8 5.0 10 2.5 12 1.25 Trap AUC ----------------------------------------------------------------1 (0 + 9.6) / 2 x (1 - 0) = 4.8 µg.h.L-1 2 (9.6 + 11.0) / 2 x (2 - 1) = 10.3 3 (11.0 + 12.0) / 2 x (4 - 2) = 23.0 4 (12.0 + 9.4) / 2 x (6 - 4) = 21.4 5 (9.4 + 5.0) / 2 x (8 - 6) = 14.4 6 (5.0 + 2.5) / 2 x (10 - 8) = 7.5 7 (2.5 + 1.25) / 2 x (12 - 10) = 3.75 ----------------------------------- Total = 85.15 µg.h.L-1 3: Tail area Tail area can be calculated from: Tail = Final conc K • ‘Final conc’ is the last measured concentration. • To get K, need semi-log plot of data Not C0, but can be used to get t-half (85 µg/L) Conc (µg/L) 50 By the later times, absorption is virtually complete and we are seeing almost pure elimination. 42.5 µg/L 30 10 Identify the terminal linear portion, extrapolate back to zero time and get elimination half life. 5 3 t ½ = 1.9 h 1 0 2 4 6 8 Time (h) 10 12 Area of tail K = 0.693 t½ = 0.693 1.9h = 0.365h-1 Tail = Final conc K = 1.25 µg/L 0.365h-1 = 3.42 µg.h.L-1 4: Total AUCoral Total area = AUC0-12h + Tail = 85.15 + 3.42 µg.h.L-1 = 88.57 µg.h.L-1 5: Absolute oral bioavailability F = AUCoral AUCiv = 88.57 µg.h.L-1 200 µg.h.L-1 = 44.3% Terms with which you should be familiar ... • Absolute bioavailability • Relative bioavailability • Trapezoidal rule • ‘Tail’ area What you should be able to do Describe and explain the characteristic shape of the graph of concentration versus time following an extravascular dose. Describe and explain the changes in this graph if a slow-release dosage form is used. Describe the distinction between an absolute and a relative bioavailabilty. Continued ... What you should be able to do (continued) Calculate AUC0- from a series of timed blood samples following an extravascular dose. Calculate bioavailability from a a pair of AUCs