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

One Compartment Model Model =V1, k10 Adv PK/PD 2006 Lecture 6

Two compartment model Model =V1, k10, k12, k21 V2 = V1 k12 / k21 CL1 = V1 k10 CL2 = V1 k12 Adv PK/PD 2006 Lecture 6

Three compartment model Model =V1, k10, k12, k21, k13, k31 V2 = V1 k12 / k21 V3 = V1 k13 / k31 CL1 = V1 k10 CL2 = V1 k12 CL3 = V1 k13 Adv PK/PD 2006 Lecture 6

Two Compartment Model A2 A1 Adv PK/PD 2006 Lecture 6

Two Compartment Model Adv PK/PD 2006 Lecture 6

Two Compartment Model Adv PK/PD 2006 Lecture 6

Three Compartment Model Adv PK/PD 2006 Lecture 6

Three Compartment Model Adv PK/PD 2006 Lecture 6

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

Volume of Distribution at Steady State By definition, at steady state: C1=C2 = Css Adv PK/PD 2006 Lecture 6

Volume of Distribution at Steady State However, the statement C1 = C2 = Css only holds when elimination is from the central compartment If elimination occurs from compartment 2, then Vss is dependent on k20 and hence on clearance Adv PK/PD 2006 Lecture 6

Saturable Elimination Adv PK/PD 2006 Lecture 6

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

Saturable distribution Adv PK/PD 2006 Lecture 6