non-linear pharmacokinetics arthur g. roberts. linear pharmacokinetics auc dose k cl dose [drug]...
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Non-linear Pharmacokinetics
Arthur G. Roberts
Linear PharmacokineticsAU
C
doseK
dose
Cl
dose
[Dru
g]pl
asm
a
time
ln[D
rug]
plas
ma
time
Increasing Dose
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 KineticsUnits
Example Non-Linear
• Vmax = 0.5 mg/L*h
• Km = 0.1 mg/L
• How long for the [Drug]plasma to go from 20 to 12 mg/L?
Dose Decrease Time
D0 = starting doseDt = dose after time
Half Time
Saturation vs Not
• Vmax = 50 mg/(L*h)• Km = 100 mg/L• Half times for 25 mg, 50 mg, 200 mg, 400 mg
dose mg
v (m
g/hr
)
Km
~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
[Dru
g]pl
asm
a
Decrease in slope
End of Non-linear Pharmacokinetics