Non-linear Pharmacokinetics Arthur G. Roberts

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

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

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

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

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

Which one exhibits non-linear pharmacokinetics

Michaelis-Menten Kinetics Units

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?

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

Half Time

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

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

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

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

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

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

End of Non-linear Pharmacokinetics