BAHAN AJAR UNTUK TOPIK MINGGU KE-5

Topic 5 : Pharmacokinetic Linier and Non Linier

MATA KULIAH :

FARMAKOKINETIKA

Disusun oleh PJMK :

M.M. Farida Lanawati Darsono, S.Si.,M.Sc

Semester Genap
Tahun Akademik : 2021-2022

Universitas Katolik Widya Mandala Surabaya

Fakultas Farmasi

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 Topic 5 : Pharmacokinetic Linier and Non Linier
Objectives:
To understand the schemes and differential equations associated with nonlinear pharmacokinetic
models
• To understand the effect of parallel pathways
• To estimate the parameters Km and Vm
• To design appropriate dosage regimen for drugs with nonlinear elimination

introduction

what is meant by non-linear pharmacokinetics?

 when the dose of a drug is increased,
 we expect that the concentration at steady state will increase proportionately,
 i.e. if the dose rate is increased or decreased say two-fold, the plasma drug concentration will
also increase or decrease two-fold.
 However, for some drugs, the plasma drug concentration changes either more or less than
would be expected from a change in dose rate.
 This is known as non-linear pharmacokinetic behaviour and can cause problems when
adjusting doses.

what causes non-linear pharmacokinetic behaviour?

it was shown that the steady state blood concentration (Css) is a function of both the dose and the
clearance of the drug.

Differentiation between Linear and Nonlinear Kinetics.

 For these drugs (drugs with nonlinear kinetics or dose-dependent kinetics), the kinetic
parameters, such as clearance, volume of distribution, and half life, may vary depending on
the administered dose.
 The pharmacokinetic parameters of most drugs are not expected to change when different
doses are administered or when the drug is given through different routes of administration
or as single or multiple doses.
 The kinetics (e.g. clearance and volume of distribution) of these drugs are said to be linear
or dose-independent, and this is a characteristic of first-order kinetics.
 The term linear simply means that if the dose is increased, the plasma concentration or area
under the plasma concentration-time curve (AUQ will be increased proportionally
 However, for some drugs, this may not be valid.
 For example, when the dose of phenytoin is increased by 50 percent in a patient from 300
mg/day to 450 mg/day, the average steady state concentration may increase by as much as
ten fold.
 This dramatic increase in the concentration is due to the nonlinear pharmacokinetics of
phenytoin.
 This is because one or more of the kinetic processes of the drug (absorption, distribution,
and/or elimination) may be via a process other than simple first-order kinetics. For these
drugs, the relationship between the AUC or CSS and dose is not linear
 Additionally, different doses of these drugs may not result in parallel plasma
concentration-time courses expected for drugs with linear pharmacokinetics.

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 For example, for drugs with nonlinear metabolism, the initial decline in the plasma
concentrations may be slower at higher doses, compared with that after the administration
of the lower doses
 This means that the rate of elimination is not directly proportional to the plasma
concentration for these drugs.

Sources of Nonlinearity.
 As mentioned above, nonlinearity may be at different kinetic levels of absorption,
distribution, and/or elimination.
 For distribution, plasma protein binding of disopyramide is saturable at therapeutic
concentrations, resulting in an increase in the volume of distribution with an increase in
dose of the drug
 As for nonlinearity in renal excretion, it has been shown that the antibacterial agent
dicloxacillin has saturable active secretion in the kidneys, resulting in a decrease in renal
clearance with an increase in dose
 For metabolism, both phenytoin and ethanol have saturable metabolism which means an
increase in the dose would result in a decrease in hepatic clearance and a more than
proportionate increase in the drug AUC.
 Here, nonlinearity in the metabolism, which is one of the most common sources of
nonlinearity, will be discussed.

Capacity-limited metabolism is also called saturable metabolism

 Michaelis-Menten kinetics, or mixed-order kinetics.
 The process of enzymatic metabolism of drugs may be explained by the relationship
depicted
 First, the drug interacts with the enzyme to produce a drug-enzyme intermediate.
 Then, the intermediate complex is further processed to produce a metabolite and release
the enzyme.
 The released enzyme is recycled back to react with more drug molecules
 According to the principles of Michaelis-Menten kinetics, the rate of drug metabolism (v)
changes as a function of drug concentration as demonstrated.
 Based on this relationship, at very low drug concentrations, the concentration of available
enzymes is much larger than the number of drug molecules.
 Therefore, when the concentration of the drug is increased, the rate of metabolism is
increased almost proportionally (linearly).
 However, after certain points, as the concentration increases the rate of metabolism
increases less than proportional.
 The other extreme occurs when the concentration of the drug is very high relative to the
concentration of available enzyme molecules.
 Under this condition, all of the enzymes are saturated with the drug molecules, and when
the concentration is increased further, there will be no change in the rate of metabolism of
the drug
 In other words, the maximum rate of metabolism (V^sub max^) has been achieved

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Proses non-linier pada tahap ADME
 Absorpsi:
* transpor dalam dinding usus --- jenuh (riboflavin)
* tidak larut (griseofulvin)
* saturasi :fist past effect” (salisilamid, propanolol)
* perubahan motilitas --- perubahan efek farmakologi (metoklopramida)
* kejenuhan peruraian di lambung (penicilin)
 Distribusi :
* saturasi ikatan OP (salisilat)
* kejenuhan transpor (metotreksat)
 Metabolisme / non renal:
* saturasi enzaim/keterbatasan ko-faktor (fenitoin,
asam salisilat)
* induksi enzim (karbamazepin)
* hepatotoksik (parasetamol)
* perubahan aliran darah hepatik (propanolol)
* penghambat metabolit (diazepam)
 Ekskresi / renal:
* sekresi aktif (penisilin G)
* reabsorpsi aktif ( asam askorbat)
* perubahan pH urin, kejenuhan ikatan OP (asam salisilat)
* efek nefrotoksik (aminoglikosida)
* efek diuretik (teofilin)

Karakteristik atau fenomena kinetika non-linier

 Eliminasi obat ~ non linier ~ tidak mengikuti order satu
 T ½ eliminasi > bila dosis ditingkatkan
 AUC tidak sebanding dg dosis
 Eliminasi fipengaruhi obat yg lain yg memerlukan enzim/carrier yg sama
 Komposisi metabolit dipengaruhi oleh dosis
Kesulitan FNL : memprakirakan konsentrasi obat atas dasar dosis yg kecil

Obat-obat yg mengalami proses metabolisme terbatas/penjenuhan

 Salisilat -----konjugasi glisin
 Salisilamid ---konjugasi sulfat
 Asam p-aminobenzoat ----asetilasi
 Fenitoin ---eliminasi
Contoh proses yg dapat jenuh :
• Biotransformasi
• Sekresi tubular aktif ginjal

Studi FNL
 Tujuan : untuk menentukan suatu obat mengikuti kinetika non linier
 Cara :
(*) obat iberikan pada berbagai tingkat dosis
(*) dibuat suatu kurva konsentrasi pbat dalam plasma vs waktu untuk tiap dosis
(*) slop sejajar atau tidak

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 Review of Linear Pharmacokinetics

i.v.
i.v.
bolus
bolus
100

Log C
M
Log C

10 normalized
M
by dose
1 mg
1 M
10 mg 100
1 mg mg
1h
time
1h time
 Drug plasma concentrations are proportional to the dose
Drug plasma concentration-time profiles are superimposable when normalized
to the dose..

Review of Linear Pharmacokinetics

p. o. p. o.
Log C
Log C

2.5 M normalized
0.5 M by dose
25 mg 0.1
M
0.1 M 1
5 mg
1 mg mg
tmax time
tmax time
 Drug plasma concentrations are proportional to the dose.
 tmax remains unchanged.
Drug plasma concentration-time profiles are superimposable when normalized to
the dose.

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 Nonlinear Pharmacokinetics

i.v. bolus i.v.

800 M bolus
100 mg
Log C

Log C
normalized
20 M
by dose 8 M
10 mg
2 M
1 M
1
1 mg M 100
1 mg 10 mg mg
1h 1h
time time
 Drug plasma concentrations are not proportional to the dose.
 Drug plasma concentration-time profiles are not superimposable when
normalized to the dose.
1

Nonlinear Pharmacokinetics

p. o. p. o.
10 M
Log C

M normalized
Log C

1 M

1 M by dose
0.5
M
100 mg 1 mg
0.1 M

10 mg 10 mg
100
1 mg mg
time time
 Drug plasma concentrations are not proportional to the dose.
 tmax may or may not change.
Drug plasma concentrations are not superimposable when normalized to
the dose.

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Common Sources for Nonlinear Pharmacokinetics

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Linear vs. Nonlinear Pharmacokinetics

Linear Nonlinear
(dose-independent) (dose-dependent)

 ADME all obey first-order  at least one of the ADME

kinetics. processes is saturable.

 PK parameters (CL, V, F, Ka,  ≥1 PK parameters are dose-

and t1/2) are constant. dependent.

 AUC is directly proportional to  AUC is disproportional to the

the dose. dose.

 Concentration vs. time profile  Concentration vs. time profile is

is superimposable for all doses. not superimposable for different
doses.

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 e. g. - limited dissolution/solubility in the GI tract

normalized
to the dose - Griseofulvin is poorly
water-soluble (10
mg/L).
- Less proportion of the
drug is being dissolved
and absorbed with the
higher dose.
- F decreases as the
dose increases.
- tmax remains the same.

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e. g. - Saturable transport across the intestinal epithelium

375 mg - Amoxicillin is actively transported by

peptide transporter in the small
750 mg
intestine.
- The active transport becomes
saturated as the dose increases.
- F decreases as the dose increases.
1500 mg - tmax remains the same.
3000 mg

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 e. g. - Saturable first-pass metabolism

- Nicardipine is metabolized by CYP3A4 in the intestinal epithelium and

hepatocytes.
- First-pass metabolism is saturated as the dose increases.
- F increases as the dose increases.

e. g. - Saturable first-pass metabolism

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18
 - saturable plasma protein binding
- AUC and Cp of
trandolaprilat do not
increase proportionally with
D; Cp does not
accumulate with multiple
doses.
- As the dose increases,
binding to ACE
(angiotensin-converting
enzyme) in plasma is
saturated.
- Trandolaprilat is elminated
by glomerular filtration
CLR= fu GFR
2 g/day - As fu increases with higher
Cp, CLR increases.

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When concentration is about lower than 7

e. g. - capacity-limited renal excretion mg/L, it could be linear. Since clearance is
linear. But once it gets above 7, the
clearance rises, which makes it non-linear.
CLinulin
= GFR
p.o. 30-80 mg
When Cp above
10 mg/L starts
to saturate renal
reabs of Vit C.

i.v. 1.5-6 g

- Vitamin C is reabsorbed from urine by active transporter.

- Tubular reabsorption becomes saturated as Cp increases, i.e. as Cp increases,
CLreabsorption (= Ratereabsorption /Cp) decreases.
- ClR (=fu GFR –CLreabsorption) approaches GFR (fu=1) as Cp increases.
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 Capacity-Limited Metabolism (CLH ,F)

 Enzymatic reactions are saturable.

Vmax [ S ]
v
K m  [S ]

 Saturated hepatic metabolism decreases CLH.

 Saturated first-pass metabolism increases F.

e. g. - capacity-limited metabolism 23

- Phenytoin is eliminated by
hepatic metabolism only.
- As the dosing rate
increases, Cp increases
disproportionally.
- As the dosing rate
increases, hepatic
metabolism is saturated and
CL decreases.
- As the dosing rate
increases, it takes longer
time to reach steady state.

FD
 CL Css
 24

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 e. g. - capacity-limited metabolism
- Phenytoin is eliminated by
hepatic metabolism only.
- As the dosing rate
increases, Cp increases
disproportionally.
- As the dosing rate
increases, hepatic
metabolism is saturated and
CL decreases.
- As the dosing rate
increases, it takes longer
time to reach steady state.

FD
 CL Css
 24

Maintenance Dose Selection for Phenytoin

- Phenytoin is eliminated
by hepatic metabolism
(CYP2C9) only.
-Variability in Vmax and Km
values in patients causes
a wide range in the
effective doses needed to
achieve therapeutic
levels.

therapeutic range= 10-20 g/ml

= 10-20 mg/L
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 Maintenance Dose Selection for Phenytoin

A patient has been taking phenytoin (PHE) 150 mg b.i.d for 4

months. His plasma levels of PHE averaged 5 mg/L on this
dose. Adjustment in dose to 250 mg b.i.d eventually led to a
new plateau level of 20 mg/L. Assuming true steady state,
strict patient compliance and that the measured plasma
concentrations represent average levels over the dosing
interval.

a) use a graphical method to estimate the patient's operative

Vmax/F and Km values;

b) estimate a daily dose which should provide a steady-state

plasma level of 12 mg/L.
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 https://www.slideserve.com/leon/nonlinear-pharmacokinetics by Dr. Chalet Tan

 https://www.google.com/imgres?imgurl=https%3A%2F%2Fimage2.slideserve.com%2F4
246595%2Fslide6-l.jpg&imgrefurl


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