Ex. 2 L8: Nonlinear PK Flashcards
Nonlinear intro
The processes controlling the disposition involve processes that are mediated by specialized carriers or enzymes
When the capacity of these carriers or enzymes is reached; changes in dose may produce nonproportional changes
Absorption mechanisms
Saturable transport in gut wall
Intestinal metabolism
Drugs with low solubility in GI given in relatively high dose
Saturable gastric or GI decomposition
Example drugs: saturable transport in gut wall
Riboflavin, gebapentin, L-dopa, baclofen, ceftibuten
Example drugs: Intestinal metabolism
Salicylamide, propranolol
Example drugs: Drugs w/low solubility in GI given in relatively high dose
Chlorothiazide, griseofulvin, danazol
Example drugs: Saturable gastric or GI decomposition
Penicillin G, omeprazole, saquinavir
Distribution mechanisms
Saturable plasma protein binding
(Phenylbutazone, Lidocaine, salicylic acid, ceftriaxone, diazoxide, phenytoin, warfarin, disopyramide)
Cellular uptake
(methicillin (rabbit))
Tissue binding
(imipramine (rat))
CSF transport
(benzylpenicillins)
Saturable transport into or out of tissues
(Methotrexate)
Elimination Mechanisms:
(Renal Elimination)
Active Secretion
(Mezlocillin, para-aminohippuric acid)
Tubular reabsorption
(Riboflavin, ascorbic acid, cephapirin)
Change in urine pH
(Salicylic acid, dextroamphetamine)
((Metabolism))
Saturable Metabolism
(Phentoin, salicylic acid, theophyline)
Cofactor or enzyme limitation
(Acetaminophen, alcohol)
Enzyme induction
(carbamazepine)
Altered hepatic blood flow
(Propranolol, verapamil)
Metabolite inhibition
(Diazepam)
Examples of saturable processes
Dissolution
Metabolism
Facilitated Transport
Plasma Protein Binding
Linear Pharmacokinetics:
Drug concentrations are proportional to dose over time
Dose and time independent kinetics
-PK parameters of consistent
T1/2: ke: CL : Vd : F : CLr
Principles of superposition apply
Nonlinear Pharmacokinetics
Drug concentrations are disproportional to the dose or become so over time
Dose or time dependent kinetics
-PK parameters change:
T/12: ke: CL: Vd: F: CLr
Principles of superposition do not apply
Michaelis Menten: Linear vs Nonlinear
Linear:
Pk parameters (e.g. CL, V, T1/2) remain constant
Principle of superposition
Nonlinear System
Pk parameters differ with time or dose,
Saturable (capacity limited) process
Saturable elimination: Nonlinear Pharmacokinetics
Rate of elimination:
DCP/dt = Vmax * Cp
—————-
Km + Cp
CP - concentration of drug in plasma
Vmax - the max elimination rate
Km - the michaelis constant that reflects the capacity of the enzyme system
KM - is not an elimination constant
Km - is equal to the drug concentration or amount of drug in the body at 0.5 Vmax
KM and Vmax are dependent on the nature of the drug and the enzymatic process involved
When Cp is «km
Linear
First order
When Cp is»_space;km
Nonlinear
Zero order
Nonlinear PK: Phenytoin
Primarily used as an anticonvulsant / antiepileptic
Administered orall in single or divided doses of 200-400 mg/day
Narrow therapeutic index
CNS adverse effects that are concentration dependent
Elimination
-CYP2C9 substrate
-The metabolic capacity is limited
-Changes in the maintenance dose result in disproportionate changes in steady-state plasma concentrations
Other considerations
-Plasma protein binding is decreased in patients with renal failure, hypoalbuminemia, or due to drug interactions
Phenytoin levels
Conc: 10-20mg/L
F: 1
S: 0.92
Vd: 0.65L/kg
Clearance
Vmac: 7mg/kg/day
Km: 4mg/L
t1/2: Concentration dependent
fu: 0.1
Phenytoin loading dose calculation
S * F * Dose = Vd * Cssdesired
0.92 * 1 * Dose = 0.665L/kg * 70 kg * 20mg/L
Dose =989mg
Concentration dependent Clearance
For NONLINEAR:
(v) = Vmax * Cp
———————–
Km + Cp
Therefore,
Tau
=
KM + Cssavg
Maintenance calculation:
S.F. Is a 37 y/o 70kg man that will be started on phenytoin capsules for a seizure disorder. Calculate a maintenance dose
0.92* 1 * Dose/Tau
= 7* 70 * 10/(4+10)
Dose/Tau = 380mg per day
Maintenance dose adjustments: S.F. has partially been controlled with 300 mg/day of phenytoin capsules. His plasma phenytoin concentration has been measured twice over the past year and was 8 mg/L both times. Calculate a maintenance dose to achieve steady-state concentration of 15mg/L
Steps to adjusting phenytoin doses based on capacity-limited metabolism
1. Use the dose and measured concentrations to estimate Vmax while keeping Km the same
2. Using the new Vmax and Km along with the desired concentration, calculate a new dose
Phenytoin maintenance dose adjustments work
Step 1: Calculate vmax
0.921300mg/day = Vmax*8mg/L /4mg/L+8mg/L
Vmax = 414mg/day
Step 2: Calculate new dose
0.921Dose/1 day =
(414mg/day*15mg/L)/(4mg/L + 15mg/L)
Dose = 355mg/day
Nonlinear PK summary
Nonlinear pk generally occur when one or more enzyme or carrier mediated systems ae saturated
Ex:
1. active drug absorption: Saturable gut wall transport
2. Drug Disposition: Saturable protein binding of salicyclates
3: Drug metabolism: Saturable metabolism of phenytoin
4. Drug excretion: active secretion of penicillin G
Summary of Saturable Kinetics:
Elimination or absorption of drug does not follow simple first order kinetics
-The elimination or absorption kinetics are not linear and may be a combination of zero-order and first-order processes
2. The elimination/absorption half-lives change as doses are increased
-The half-life increases with increased dose due to saturation of an enzyme/transporter system important for drug elimination or absorption
3. The area under the curve (AUC) does not increase in a proportional manner to the administered dose of the drug
4. The saturation or capacity limited processes may be affected by other drugs (e.g. competition effects)
