1. Non-linear Pharmacokinetics Arthur G. Roberts

2. Linear Pharmacokinetics AUC dose K Cl dose [Drug] plasma time ln[Drug] plasma time Increasing Dose

3. Non-linear Pharmacokinetics A.K.A. Dose-dependent Pharmacokinetics Saturation – enzymes – carrier-mediated systems (e.g. transporters) – plasma binding proteins Pathological changes to Absorption, Distribution and Elimination

4. Non-linear Pharmacokinetics Metabolism Time-dependent pharmacokinetics Bioavailability Drug protein binding

6. Saturation or capacity-limited metabolism Not first order kinetics Elimination half-life is dose-dependent AUC not proportional to bioavailability Competition effects (drug requires same carrier system) Metabolite profile dose-dependent

7. Linear versus Non-linear Large dose small dose Expectation if the kinetics is linear What kinetics does A remind you of?

8. Which one exhibits non-linear pharmacokinetics

9. Michaelis-Menten Kinetics Units

10. Example Non-Linear V max = 0.5 mg/L*h K m = 0.1 mg/L How long for the [Drug] plasma to go from 20 to 12 mg/L?

11. Dose Decrease Time D 0 = starting dose D t = dose after time

12. Half Time

13. Saturation vs Not V max = 50 mg/(L*h) Km = 100 mg/L Half times for 25 mg, 50 mg, 200 mg, 400 mg

14. dose mg v (mg/hr) KmKm ~Linear ~Nonlinear

15. Time-dependent Pharmacokinetics a.k.a. Chronopharmacokinetics Cyclical (24 hours) Non-cyclical (>>24 hours) Auto-induction – carbamazepine induces enzymes that eliminate it Auto-inhibition – Biochemistry- Product inhibition Circadian Rhythms

16. Examples antimetabolite drug fluorouracil (FU) – least toxic in the morning. aminoglycoside – nephrotoxicity during the night

17. Bioavailability non-linear difficult to estimate. AUC increases disproportionally to the dose. – enzymes saturated – GI tract saturation limited

18. Drug-Protein Binding plasma bound not plasma bound prolongs half-life [Drug] plasma Decrease in slope

19. End of Non-linear Pharmacokinetics