Ex. 2 L8: Nonlinear PK

Question 1

Nonlinear intro

Answer 1

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

Question 2

Absorption mechanisms

Answer 2

Saturable transport in gut wall
Intestinal metabolism
Drugs with low solubility in GI given in relatively high dose
Saturable gastric or GI decomposition

Question 3

Example drugs: saturable transport in gut wall

Answer 3

Riboflavin, gebapentin, L-dopa, baclofen, ceftibuten

Question 4

Example drugs: Intestinal metabolism

Answer 4

Salicylamide, propranolol

Question 5

Example drugs: Drugs w/low solubility in GI given in relatively high dose

Answer 5

Chlorothiazide, griseofulvin, danazol

Question 6

Example drugs: Saturable gastric or GI decomposition

Answer 6

Penicillin G, omeprazole, saquinavir

Question 7

Distribution mechanisms

Answer 7

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)

Question 8

Elimination Mechanisms:

Answer 8

(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)

Question 9

Examples of saturable processes

Answer 9

Dissolution
Metabolism
Facilitated Transport
Plasma Protein Binding

Question 10

Linear Pharmacokinetics:

Answer 10

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

Question 11

Nonlinear Pharmacokinetics

Answer 11

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

Question 12

Michaelis Menten: Linear vs Nonlinear

Answer 12

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

Question 13

Saturable elimination: Nonlinear Pharmacokinetics

Answer 13

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

Question 14

When Cp is «km

Answer 14

Linear
First order

Question 15

When Cp is&raquo_space;km

Answer 15

Nonlinear
Zero order

Question 16

Nonlinear PK: Phenytoin

Answer 16

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

Question 17

Phenytoin levels

Answer 17

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

Question 18

Phenytoin loading dose calculation

Answer 18

S * F * Dose = Vd * Cssdesired

0.92 * 1 * Dose = 0.665L/kg * 70 kg * 20mg/L

Dose =989mg

Question 19

Concentration dependent Clearance

Answer 19

For NONLINEAR:
(v) = Vmax * Cp
———————–
Km + Cp

Therefore,

Tau

=

KM + Cssavg

Question 20

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

Answer 20

0.92* 1 * Dose/Tau
= 7* 70 * 10/(4+10)

Dose/Tau = 380mg per day

Question 21

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

Answer 21

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

Question 22

Phenytoin maintenance dose adjustments work

Answer 22

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

Question 23

Nonlinear PK summary

Answer 23

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

Question 24

Summary of Saturable Kinetics:

Answer 24

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)