Non-linear

Pharmacokinetics
(Dose-dependent kinetics)
YUPPE RAJ
lour posslble ouLcomes followlng drug
admlnlsLraLlon
W Lfflcacy wlLhouL LoxlclLy
W Lfflcacy wlLh LoxlclLy
W 1oxlclLy wlLhouL efflcacy
W nelLher LoxlclLy nor efflcacy
1he Lerm llnear slmply means LhaL lf Lhe dose ls
lncreased Lhe plasma concenLraLlon or area under Lhe
plasma concenLraLlonLlme curve (AuC) wlll be
lncreased proporLlonally lf noL lL ls nonllnear
1hls could be poLenLlally dangerous because Lhe drug
remalns aL hlgh levels ln Lhe body for longer perlod of
Llme
lL was clear LhaL Lhe sLeady sLaLe blood concenLraLlon
(Css) ls a funcLlon of boLh Lhe dose and Lhe clearance
of Lhe drug"
Capac|tyL|m|ted Metabo||sm
W CapaclLyllmlLed meLabollsm ls also called
saLurable meLabollsm MlchaellsMenLen
klneLlcs or mlxedorder klneLlcs
W 1he process of enzymaLlc meLabollsm of drugs
may be explalned by Lhe relaLlonshlp deplcLed
ln flgure below
0eneroI reIofionship befween reocfion rofe ond subsfrofe
concenfrofion for ony en;yme cofoIysed reocfion
Rate
Substrate concentration
Graph becomes flatter as the
enzyme becomes saturated
with substrate.
Rate of
eliminat'n
Rate of
eliminat'n
Blood drug conc Blood drug conc
Lineur kinetics
{most drugs}
Non-Iineur
kinetics
{e,g, phenytoin}
Rate of
elim
=
Rate of
admin
Rate of
elim
=
Rate of
admin
Blood
drug
conc
Blood drug conc
Blood
drug
conc
Rate of admin Rate of admin
Blood drug conc
Linear Non-linear
t steudy stute ,,,
igh T.I.
%oxic
Safe and
effective
range
neffective
Low T.I.
Changes in
this range
cause no
problems
%oxic
Safe and
effective
range
neffective
Changes in
this range
cause serious
problems
Iiminofion of drugs wifh o Iow
fheropeufic index
Aminoglycosides
Lithium
Methotrexate
Digoxin
Procainamide
Lidocaine
Phenobarbital
Phenytoin
Quinidine
%heophylline
RenaI
Hepatic
Almost exclusively renal
Mainly renal (Some hepatic)
Approx equal renal/hepatic
Mainly hepatic
Accordlng Lo MM klneLlcs Lhe raLe of drug meLabollsm (v)
changes as a funcLlon of drug concenLraLlon as demonsLraLed
ln llgure
8ased on Lhls relaLlonshlp aL very low drug concenLraLlons
Lhe concenLraLlon of avallable enzymes ls much larger Lhan
Lhe number of drug molecules
W 1herefore when Lhe concenLraLlon of Lhe drug ls lncreased Lhe
raLe of meLabollsm ls lncreased almosL proporLlonally (llnearly)
W Powever afLer cerLaln polnLs as Lhe concenLraLlon lncreases Lhe
raLe of meLabollsm lncreases less Lhan proporLlonal
W 1he oLher exLreme occurs when Lhe concenLraLlon of Lhe drug ls
very hlgh relaLlve Lo Lhe concenLraLlon of avallable enzyme
molecules
W under Lhls condlLlon all of Lhe enzymes are saLuraLed wlLh Lhe
drug molecules and when Lhe concenLraLlon ls lncreased furLher
Lhere wlll be no change ln Lhe raLe of meLabollsm of Lhe drug
W ln oLher words Lhe maxlmum raLe of meLabollsm (vmox) bos beeo
ocbleveJ
ources of Non||near|ty
nonllnearlLy may be aL dlfferenL klneLlc levels of absorpLlon
dlsLrlbuLlon and/or ellmlnaLlon"
W lor example Lhe exLenL of absorpLlon of amoxlclllln decreases
wlLh an lncrease ln dose
W ln Lhe case of saLurable absorpLlon or reabsorpLlon
(meLhoLrexaLe clsplaLln) hlgher doses may resulL ln a
decreased proporLlonal AuC
W lor dlsLrlbuLlon plasma proLeln blndlng of dlsopyramlde ls
saLurable aL LherapeuLlc concenLraLlons resulLlng ln an lncrease
ln Lhe volume of dlsLrlbuLlon wlLh an lncrease ln dose of Lhe
drug
W lor meLabollsm boLh phenyLoln and eLhanol have
saLurable meLabollsm whlch means an lncrease ln
Lhe dose would resulL ln a decrease ln hepaLlc
clearance and a more Lhan proporLlonaLe lncrease
ln Lhe drug AuC
W As for nonllnearlLy ln renal excreLlon lL has been
shown LhaL Lhe anLlbacLerlal agenL dlcloxaclllln has
saLurable acLlve secreLlon ln Lhe kldneys resulLlng
ln a decrease ln renal clearance wlLh an lncrease ln
dose
nonllnear rocesses
- Lower concenLraLlon flrsL order
- Plgher concenLraLlon zero order
- ConcenLraLlon or dose dependenL klneLlcs
- Lnzyme reacLlon assoclaLed wlLh meLabollsm may be saLurable
- Lnzyme reacLlon may have a maxlmum raLe llmlLed by subsLraLe
- 8aslc enzyme klneLlcs have appllcaLlon Lo pharmacoklneLlcs
MlchaellsMenLen klneLlcs
W where vmax ls Lhe maxlmum raLe of meLabollsm
Wkm ls Mlchaells consLanL Lhe concenLraLlon of drug aL whlch Lhe raLe
ls Z maxlmum
WC ls Lhe drug concenLraLlon
W 1he maxlmum raLe of meLabollsm %vmox) ls
JepeoJeot oo tbe amounL (or concenLraLlon)
of enzymes avallable for meLabollsm of Lhe
drug
W whlle , ls tbe cooceottotloo wblcb ptoJoces
half of vmox ooJ ls lovetsely teloteJ to tbe
offlolty of tbe Jtoq Lo Lhe enzyme (Lhe hlgher
Lhe afflnlLy Lhe lower ls ,)
W lfferenLlal LquaLlon
W Slngle ellmlnaLlon paLhway
W dCp/dL vm-Cp/km + Cp
Lxamples of drugs followlng nLk
W vonoxerine uino/opri/ Poroxetine
Nophtho/ Met/oci//in Methy/prednisone
2',3'-dideoxycytidine, cefodroxi/
LquaLlon aL Low ConcenLraLlons
- km Cp
- km + Cp km
- 1herefore
dCp/dL vm-Cp/ km k-Cp
- pseudo flrsL order ellmlnaLlon
W LquaLlon aL Plgh ConcenLraLlon
W - Cp km
W - km + Cp Cp
W - 1herefore
W dCp/dL vm-Cp /Cp vm
W - zero order ellmlnaLlon
W Plgh ose ConcenLraLlon
W - Slope consLanL on llnear graph zero order
W - Slope approaches vm
W Low ose ConcenLraLlon
W - Slope consLanL on semllog graph flrsL order
W - Slope approaches vm/km
Lxample henyLoln
- Average km 4 mg/L (1 13 mg/L)
- Average vm 300 mg/day (100 1000 mg/day)
- 1herapeuLlc wlndow 10 20 mg/L (LoLal Cp)
- Cverdose posslble lf dose ad[usLmenL ls noL approprlaLe
- Palfllfe aL low doses 12 hr maybe greaLer Lhan 24 hr aL hlgher
doses
- lrom 23 Lo 23 mg/L ln 24 hours (cf 23 123 6
mg/L when L1/2 ls 12 hr)
EIIect oI MM Kinetics on t1/2
W L
1/2
larger as concenLraLlon lncreases le
slower ellmlnaLlon
W dC/ dL kel-C vm-C /km+ C
W slnce kel 0693/ L
1/2
W 0693/L
1/2
vm/km+ C
W L
1/2
0693- (km+ C) /vm
LffecL of MM klneLlcs on Cp
arallel aLhways
Llnear and nonllnear LllmlnaLlon
- AL low dose kem and vm/km ls larger Lhus L30 ls
smaller
- AL hlgher doses effecLlve (pseudo flrsL order) raLe
consLanL for MM process ls small Lhus L30 ls larger
doslng
W llrsL ose
W - use populaLlon (average) values for phenyLoln
W - vm 7 mg/kg/day and km 3 mg/L
W - Alm for Cp 13 mg/L ln 80 kg paLlenL
W - LquaLlon ose 8aLe vm-Cp/ km + Cp
W 7 x 80 x13/(3 +13)
W 420 mg/day
W 8 8ecommends 300 mg/day probably beLLer
Lo sLarL low
eLermlne Second ose 8eglmen
ive an initial dosage regimen and measure Cp
For example iI aIter 420 mg/day, Cp is 20 mg/L
Assume Km 5 mg/L and calculate Vm
Change ln ose
cefodroxi/
1 llnd m
2 llnd Lhe maxlmum clearancevmox fot tbls potleot
3 WhaL would be Lhe dose needed Lo achelve a sLeadysLaLe concenLraLlon of 10 q/ml ?
4 ?ou recommend changlng Lhe paLlenLs dosage reglmen Lo 300 mg/day
WhaL would be your paLlenLs sLeady sLaLe plasma concenLraLlon?