Lecture 6 MECHANISTIC PHARMACOKINETICS COMPARTMENTAL MODELS Adv PKPD

Lecture 6 MECHANISTIC PHARMACOKINETICS: COMPARTMENTAL MODELS Adv PK/PD 2006 Lecture 6 1

One Compartment Model =V 1, k 10 Adv PK/PD 2006 Lecture 6 2

Two compartment model Model =V 1, k 10, k 12, k 21 V 2 = V 1 k 12 / k 21 CL 1 = V 1 k 10 CL 2 = V 1 k 12 Adv PK/PD 2006 Lecture 6 3

Three compartment model Model =V 1, k 10, k 12, k 21, k 13, k 31 V 2 = V 1 k 12 / k 21 V 3 = V 1 k 13 / k 31 CL 1 = V 1 k 10 CL 2 = V 1 k 12 CL 3 = V 1 k 13 Adv PK/PD 2006 Lecture 6 4

Two Compartment Model A 2 Adv PK/PD 2006 A 1 Lecture 6 5

Two Compartment Model Adv PK/PD 2006 Lecture 6 6

Two Compartment Model Adv PK/PD 2006 Lecture 6 7

Three Compartment Model Adv PK/PD 2006 Lecture 6 8

Three Compartment Model Adv PK/PD 2006 Lecture 6 9

Population Pharmacokinetics Ø General rule for compartment models: Ø Estimate the volumes and clearances Ø These are NOT the underlying physical reality, by they come closer than other methods of parameterizing the model Ø Volumes and clearances are the most likely to be normally distributed Adv PK/PD 2006 Lecture 6 10

Volume of Distribution at Steady State By definition, at steady state: C 1=C 2 = Css Adv PK/PD 2006 Lecture 6 11

Volume of Distribution at Steady State However, the statement C 1 = C 2 = Css only holds when elimination is from the central compartment If elimination occurs from compartment 2, then Vss is dependent on k 20 and hence on clearance Adv PK/PD 2006 Lecture 6 12

Saturable Elimination Adv PK/PD 2006 Lecture 6 13

Saturable distribution Ø Saturable plasma and/or tissue protein binding eg ACE inhibitors. Ø Ø CLu = unbound tissue clearance Cu = unbound concentration n. Pt = total number of binding sites in tissue Ka = association constant of bound drug Adv PK/PD 2006 Lecture 6 14

Saturable distribution Adv PK/PD 2006 Lecture 6 15