tdm in individualizacija odmerjanja zdravil iztok grabnar · formulations given pm vs. am....
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TDM in individualizacija TDM in individualizacija odmerjanja zdravilodmerjanja zdravil
Iztok GrabnarIztok Grabnar
Terapevtski ciljiTerapevtski cilji
Izbor zdravila in Izbor zdravila in rerežžima odmerjanjaima odmerjanja
Spremljanje terapevtskih in toksičnih učinkov
FK FD
NaNaččrtovanje terapije z zdravilirtovanje terapije z zdravili
Spremljanje terapije z zdraviliSpremljanje terapije z zdravili1. Klinični učinki
Indikacija
↑
odmerek
↓
odmerek
Znaki toksičnosti
FFuurroosemidsemid
Srčno popuščanje
↑
Edemi
Motnje elektrolitov
HipotenzijaDehidracija
KKarbidopaarbidopa/DOPA/DOPA
Parkinsonizem
Slaba kontrola
Diskinezije
Zmedenostsimptomov
Depresija
TiopentTiopentalal
Anestezija
Nezadostna
Pregloboka Zastojanestezija
anestezija
dihanja
Indikacija
↓odmerek ↑odmerek Znakitoksičnosti
VVarfarinarfarin
TE zapleti
visok
INR
nizek
INR
krvavitve
TTiiroroksksinin
Hipotiroidizem
nizek
TSH
visok
TSH
hipertiroidizem
StatinStatin
Zvišan holesterol
↑AST/CK
visok
hol.
miopatija
Spremljanje terapije z zdraviliSpremljanje terapije z zdravili2. Merjenje
terapevtskih
učinkov in vitro
Spremljanje terapije z zdraviliSpremljanje terapije z zdravili3. Merjenje koncentracije učinkovine
•Kvantitativni odnos med koncentracijo učinkovine in terpevtskimi in toksičnimi učinki•Plazemska koncentracija slabo korelira z odmerkom•Visoko tveganje za terapevtski neuspeh
(izostanek terapevtskih učinkov ali toksičnost)*
* Terapevtski neuspeh:
(1) Nizek terapevtski indeks
(2) Visoka variabilnost v farmakokinetiki
-
nasitljiva eliminacija-
genetski dejavniki
(slabi metabolizatorji)- sočasna obolenja- sočasna terapija z drugimi zdravili (interakcije)
Komplianca!
The uses of monitoring are
• to assess adherence to therapy
• to individualize therapy
• to diagnose toxicity
• to guide withdrawal of therapy
•
to determine whether a patient is already taking a drug before starting therapy (eg
theophylline in an unconscious patient with asthma)
•
in research (eg
to monitor for drug interactions in post-marketing surveillance using population pharmacokinetics).
TherapeuticTherapeuticRangeRange
Repeated Drug Dosing to Maintain SS LevelsRepeated Drug Dosing to Maintain SS LevelsWithin a Therapeutic RangeWithin a Therapeutic Range
•Lower limit set by the drug level giving perhaps 50% of the maximum therapeutic effect.
•The upper limit is defined by toxicity NOT therapeutic effect and is the level causing toxicity in <5-
10% patients.
TDM: AminoglycosidesTDM: Aminoglycosides
• Monitoring is mandatory in ALL patientsAG accumulate in the renal cortex to levels 100-fold > plasma
>95% of AG are cleared by glomerular filtration
•Toxicity manifests as:
•NEPHROTOXICITY (Proximal tubule)
•OTOTOXICITY (Hair cells)
Targets for IV GENTAMICINTargets for IV GENTAMICINConventional dosingConventional dosingpeak 30-60 min post-dose = 5-10 mg/L )
BUT toxicity can emerge below these levelsTrough before next dose < 2 mg/L ) if loop diuretics co-administered
Extended interval dosingExtended interval dosingpeak 30-60 min post-dose = 20-30 mg/L )Trough before next dose < 1
mg/L ) If impaired renal function either REDUCE DOSE or INCREASE DOSE INTERVAL(in anephric patients creatinine clearance = 0 : adjustment, knr/kr
= 1/20 so …dose reduced to 0.25mg/kg/d or interval increased to 160h)
cochlear (hearing deficits)-
neomycin/amikacin
vestibular (disturbed balance)-
streptomycin/gentamicin
TDM: Anticonvulsants (PHENYTOIN)TDM: Anticonvulsants (PHENYTOIN)•Therapeutic range -
40-80μmol/L (NB total drug)Hypoalbuminaemia and urea both ↑ the free fraction
•Toxicity -
manifests as nystagmus, ataxia and confusion(dose-dependent in that order)
Extensive but saturable hydroxylation in the liver I.e. switches from zero to 1st
order elimination within the TR -
‘apparent’
t1/2
may rise from 10-15h to >150h *
* dose increments within the TR should be no more than 25-50mg
Mild P450 inducer and will increase clearance of:warfarin, dexamethasone, cyA
and pethidine.
Alteration in ClearanceAlteration in Clearance increased decreased
rifampicin
erythromycinanticonvulsants
ciprofloxacinsmoking (>10cigs/d)
verapamilpropranolol
TDM: TheophyllineTDM: Theophylline
• Therapeutic range - 5-20μg/ml (28-110μmol/L)
• Toxicity -
manifest as tachyarrythmias, vomiting & convulsions.
•
PK problems -
Bioavailability varies widely between preparations
and lower in MR formulations given PM vs. AM. Non-linear CL: 90% eliminated by the liver & 10% unchanged in the urine (reversed ratio in neonates) I.e.No adjustment for renal failure required but
↓
dose in presence of impaired hepatocellular
function.
Whenever possible establish drug level before administering IV andif in doubt do not give bolus loading dose.
TDM: LithiumTDM: LithiumTherapeutic range 0.6-1.2 mmol/L NB at plateau (pre-dose) & avoid Li-heparin tubes!
Toxicity -
signs as a guide
-
TR:
fine tremor especially at dosing peak-
moderate intox
(1.5-3):
coarse tremor, ataxia & diarrhoea-
severe intoxication (>3): confusion & fits
PK problems Complete absorption -
SR formulations to reduce peak levels.>95% excreted by the kidney -
initial t1/2 12hbut terminal t1/2 much longer ⇒
70-80% reabsorbed in PCT with no distalreabsorption
(unlike Na) ∴PCT retention (hence toxicity risk ) is ↑
by:• reduced exchangeable Na from any cause• loop or thiazide diuretics• NSAIDs or ACEIs.
Special problems Pregnancy -
Dose requirements increase due to ↑
renal clearance.
Li is also teratogenic and excreted in breast milkSevere intoxication -
usually requires dialysis but because of slow clearance from some compartments rebound rises in Li levels
may necessitate repeated HD.
TDM: DigoxinTDM: Digoxin•
Therapeutic range 1-2ng/L (taken >6h post-dosing; 1ng/L=1.3nmol/L) for inotropic effect not AF.
•
Toxicity -
may be nonspecific eg
nausea, vomiting, abdo
pain & confusion but remember bradycardia with increasing of heart block especially with AV junctional escape rhythms and visual disturbance (xanthochromia).
•
PK problems -
10% population have enteric bacterium (E. lentum) that can metabolize digoxin. Large volume of distribution (≈ 5L/kg lean BW) and predomin
excreted unchanged in the urine with CL∝ GFR.
• Large number of interactions -
Mechanism Mechanism Condition/Drug(s)Condition/Drug(s)
PK ↑ Vd and CL Thyrotoxicosis/T4↓ Vd and/or CL Verapamil, amiodarone, propafenone↑ absorption Erythromycin, omeprazole↓ absorption Exchange resins, kaolin↓ GFR Any cause of renal impairment/Cyclosporine
PD increase block Hypokalaemia/Kaluretic diureticsof the Na pump
Enzyme Induction/inhibition by Anticonvulsants:Enzyme Induction/inhibition by Anticonvulsants:
Phenytoin, Phenytoin, phenobarbphenobarb, CBZ, CBZLamotrigineLamotrigineValproateValproateFelbamateFelbamate
EthosuximideEthosuximideGabapentinGabapentinTiagabineTiagabineVigabatrineVigabatrine
⇑⇑**
CYP/UGTCYP/UGT↑↑
UGT (weak)UGT (weak)↑↑
UGT/epoxidases/CYP2CUGT/epoxidases/CYP2C⇑⇑
3A43A4
↓↓
2C192C19
No EffectNo Effect
* * ↓↓=inhibition; =inhibition; ↑↑/ / ⇑⇑
=induction=induction
(+/++)
PopulaPopulacijska farmakokinetikacijska farmakokinetika
••
Kaj je populacijska farmakokinetiKaj je populacijska farmakokinetiččna / na / farmakodinamifarmakodinamiččna analizana analiza
••
Metode populacijske analize, identifikacija Metode populacijske analize, identifikacija parametrov modelaparametrov modela
••
PrednostiPrednosti//slabosti slabosti ••
Cilji populacijske analize/vloga pri razvoju zdravil Cilji populacijske analize/vloga pri razvoju zdravil in pri nain pri naččrtovanju individualne farmakoterapijertovanju individualne farmakoterapije
••
Primera: Primera: ••
Terapevtsko spremljanje koncentracije uTerapevtsko spremljanje koncentracije uččinkovineinkovine
••
Simulacija kliniSimulacija kliniččnega preizkunega preizkuššanjaanja
Populacijska farmakokinetika/farmakodinamikaPopulacijska farmakokinetika/farmakodinamika
••
je opis povezave med fiziologijo je opis povezave med fiziologijo /patofiziologijo in farmakokinetiko /patofiziologijo in farmakokinetiko /farmakodinamiko/farmakodinamiko
••
Interindividualna variabilnost Interindividualna variabilnost
••
Preostala Preostala ––
intraindividualna variabilnostintraindividualna variabilnost
SheinerSheiner
LBLB. D. Drugrug
MetabMetab
Rev. 1984; 15(1Rev. 1984; 15(1--2): 1532): 153--7171..
Kaj je ?Kaj je ?
Enoprostorni farmakokinetiEnoprostorni farmakokinetiččni modelni model Dolgotrajna intravenska infuzijaDolgotrajna intravenska infuzija
CpssCpss
= = kk00
/ / ClCl
±±
εε
εε
--
napaka meritvenapaka meritve, , intraindividualna intraindividualna variabilnostvariabilnost
Kon
cent
raci
ja
Čas
( )⎥⎥⎦
⎤
⎢⎢⎣
⎡−=
− tVCl
deClktCp 10
εε
ε ≈ N(0,σ)
Identifikacija parametrov modelaIdentifikacija parametrov modela
••
MatematiMatematiččni modelni model
••
MeritveMeritve
z(tz(tjj
) = y(t) = y(tjj
) + e(t) + e(tjj
) ) j = 1,...,mj = 1,...,m e(t) e(t) ~~
N(0, g(y(t), N(0, g(y(t), ββ))
ββ
––
vektor parametrov vektor parametrov modela variancemodela variance
••
ParametriParametri
αα
––
konstanta ali konstanta ali αα
~~
N(N(μμ, , ΩΩ); ); αα
~~
LN(LN(μμ, , ΩΩ))
( ) ( ) ( )( )
( ) ( ) ( )( )t,tr,,txhty
t,tr,,txfdt
tdx
α
α
=
= x(0)=cα
–
vektor parametrov
Vsota najmanjVsota najmanjšših kvadratovih kvadratov
Gauss
...the most probable value of unknown quantities will be that in which the sum of squares of the differences between the actually observed and computed values multiplied by numbers that measure the degree of precision is a minimum...
( ) ( )( )2
1∑=
−→m
jjjjWLS t,ytzwminˆ αα
Johann Carl Friedrich Gauss (1777Johann Carl Friedrich Gauss (1777--1855)1855)
Identifikacija
Model Meritve
α
NajveNajveččje verjetje (Maximum likelihood)je verjetje (Maximum likelihood)
Model napake
e(t) e(t) ~~
N(0, g(y(t), N(0, g(y(t), ββ))σj
= σinter
+ σslope
z(tj)
Ronald Aylmer Fisher (1890Ronald Aylmer Fisher (1890--1962)1962)
Hkratna identifikacija Hkratna identifikacija αα
in in ββ Kriterij je najveKriterij je največčje verjetjeje verjetje
( ) ( ) ( )[ ] ( )z|lmaxz|lz|lz|lmaxˆ mML ααααα =→ K21
Identifikacija
Model Meritve
p(α|z)
BayesBayes
Model napake
Parametri so nakljuParametri so naključčne ne spremenljivkespremenljivkeαα
~~
N(N(μμ, , ΩΩ), LN(), LN(μμ, , ΩΩ))
Predhodno vedenje p(α)
Thomas Bayes (1702Thomas Bayes (1702--1761)1761)
Samo en parameter:Samo en parameter:αα
~~
N(N(μμ, , ΩΩ))
( ) ( )( )( )( )
( )2
2
1
2
ασμα
βα
α −+
−→ ∑
=
m
j j
jjMAP ,tyg
t,ytzminˆ
Cl = Cl = metabolmetabolččnini
ooččistekistek
+ renal+ renalnini
ooččistekistek
Cl = Cl = ΘΘ
11
+ + ΘΘ
22
••
CCr CCr ±±
ηη
Oči
stek
uči
nkov
ine
Očistek
kreatinina
Kon
cent
raci
ja
Čas
ClCl
= = metabolmetabolččnini
ooččistekistek
+ renal+ renalnini
ooččistekistek
Cl = Cl = ΘΘ
11
+ + ΘΘ
22
••
CCr CCr ±±
ηη
Oči
stek
uči
nkov
ine
Očistek kreatinina
η ≈ N(0,ω)
Graphical illustration of the statistical model used in NONMEM for the special case of a one compartment model with first order absorption. (Vozeh et al. Eur J Clin Pharmacol 1982;23:445-451)
4321 ΘΘΘΘ=Θ
333213
322223
312111
ωωωωωωωωω
=Ω
332313
322212
312111
σσσσσσσσσ
=Σ
Mean, expected value, or some other point estimate:
Variability among subjects around that mean:
Residual
(unexplained) variability and/or model misspecification:
Responses on data input requirements from a questionnaire survey
of producers of software for population pharmacokinetic-pharmacodynamic analysis
Program Nature of input, Constraints Dosing histories specified in a flexible manner
How is covariate information specified?
BUGS ASCII, S-Plus data set
User has to supply code Variable in data set
MIXNLIN SAS data set User has to supply code Classified as inter-
and intra-individual
None, but must conform to covariates SAS conventions
NLINMIX SAS data set User has to supply code Variables in the SAS data set
NLME ASCII, spreadsheets and data bases
User has to supply code Variables in the data set
NLMIX ASCII, user responsible for writing input routine
User has to supply code As for input
NONMEM ASCII Yes (specified by the routine PREDPP)
Variables in the data set None (some dimensions areinitially set but these may bechanged by the user)
NPEM ASCII via USC*PACK program
Yes Either linked to a pharmacokinetic
99 days of time, 99 doses,
or numerical value. Interpolation99 values of dependent
between covariate values is possiblevariables (maximum of 6)
NPML
ASCII User has to supply code Variables in the data set
PPHARM Dedicated data base ASCII
Yes Variables in data base or in ASCII file
CiljiCilji
1. 1. Oceniti parametre populacijeOceniti parametre populacije(CL, V) (CL, V) ––
parametri stalnih uparametri stalnih uččinkov inkov
(f(fixedixed
eeffectsffects
parameters)parameters)
2. 2. Oceniti variabilnostOceniti variabilnost
––
nakljunaključčni uni uččinkiinki(random e(random effectsffects))
••
IntersubjeIntersubjekkttnana
variabilnostvariabilnost••
Preostala variabilnost Preostala variabilnost ((IntrasubjeIntrasubjekkttnana
variabilnostvariabilnost, , napaka meritevnapaka meritev, ,
napakanapaka
modelamodela))
3. 3. IdentiIdentifikacijafikacija
dejavnikov s katerimi lahko dejavnikov s katerimi lahko povepovežžemo intersubjektno variabilnostemo intersubjektno variabilnost
••
DemograDemografskifski::
Starost, telesna teStarost, telesna težža, povra, površšina, spol, rasaina, spol, rasa••
GenetGenetskiski::
CYP2D6, CYP2C19CYP2D6, CYP2C19
••
OkoljeOkolje::
kajenjekajenje, , prehranaprehrana••
FiziologijaFiziologija/Pat/Patofiziologijaofiziologija::
LedviLedviččna funkcijana funkcija
((OOččistek kreatininaistek kreatinina)),,
Jetrna funkcija (ALT, AST)Jetrna funkcija (ALT, AST), , Bolezenska stanjaBolezenska stanja••
SoSoččasna terapijaasna terapija
••
DrugiDrugi::
Vpliv hrane, Cirkadialni ritemVpliv hrane, Cirkadialni ritem, F, Farmacevtska oblikaarmacevtska oblika
PrednostiPrednosti
••
Redko vzorRedko vzorččenjeenje
(2(2--3 3 izmerjene izmerjene koncentracijekoncentracije//subjsubjekekt)t)
••
FazeFaze
II/III II/III klinikliniččnih raziskavnih raziskav••
SubpSubpopulaopulacijecije
((PediatriPediatrijaja, , GeriatrijaGeriatrija))
••
Veliko pacientovVeliko pacientov••
Manj omejitev glede kriterijev za vkljuManj omejitev glede kriterijev za vključčitev/izkljuitev/izključčitevitev
••
NeuravnoteNeuravnotežžen naen naččrt raziskavert raziskave••
RazliRazliččno no ššt. t. meritev koncentracijemeritev koncentracije//subjsubjekekt)t)
••
Ciljna reprezentativna populacijaCiljna reprezentativna populacija
SlabostiSlabosti
••
Kontrola kakovosti vhodnih podatkovKontrola kakovosti vhodnih podatkov••
OdmerkiOdmerki
inin
ččasi odvzema vzorcev, asi odvzema vzorcev,
rokovanje z vzorcirokovanje z vzorci••
Zapletena metodologijaZapletena metodologija••
NaNaččrtovanje optimalne izvedbe raziskavertovanje optimalne izvedbe raziskave
••
Nejasno razmerjeNejasno razmerje
Cost/BenefitCost/Benefit
NaNaččrtovanje individualnih rertovanje individualnih režžimov imov odmerjanjaodmerjanja
Èas (h)
0 100 200 300 400 500
Kon
cent
raci
ja v
anko
mic
ina
(um
ol/l)
0
10
20
30
40
50
Seru
msk
i kre
atin
in (m
mol
/l)
80
90
100
110
120
130
140
150
CR
P
0
50
100
150
200
250
300
Črni
krožci
so izmerjene
koncentracije
vankomicina, rdeča
krivulja
je z modelom
napovedana
koncentracija
vankomicina, modra
črta
ponazarja
potek
serumskega
kreatinina, zelena
pa CRP, črtkano
je prikazano
priporočeno
območje
minimalnih
koncentracij
(3-6 μmol/l).