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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

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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.

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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’ t1/2may 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) verapamil

propranolol

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 milk

Severe intoxication - usually requires dialysis but because of slow clearance from some compartments rebound rises in Li levels may necessitate repeated HD.

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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 predominexcreted 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 (+/++)

POPULAPOPULACIJSKACIJSKAFARMAKOKINETIKAFARMAKOKINETIKA

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

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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 modelDolgotrajna 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

•• MeritveMeritvez(tz(tjj) = y(t) = y(tjj) + e(t) + e(tjj) ) j = 1,...,mj = 1,...,me(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

Identifikacija

Model Meritve

α

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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)

wj ~ 1/σ2

σj = σinter + σslope z(tj)

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 ββKriterij je najveKriterij je največčje verjetjeje verjetje

( ) ( ) ( )[ ] ( )z|lmaxz|lz|lz|lmaxˆ mML ααααα =→ K21

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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)

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9

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

10

Kon

cent

raci

ja

Čas

Cl = Cl = metabolmetabolččnini ooččistekistek + renal+ renalnini ooččistekistek

Cl = Cl = ΘΘ11 + + ΘΘ22•• CCr CCr ±± ηη

Oči

stek

uči

nkov

ine

Očistek kreatinina

Kon

cent

raci

ja

Čas

ClCl = = metabolmetabolččnini ooččistekistek + renal+ renalnini ooččistekistek

Cl = Cl = ΘΘ11 + + ΘΘ22•• 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)

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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-individualNone, 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 pharmacokinetic99 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

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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

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i kre

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Črni krožci so izmerjene koncentracije vankomicina, rdeča krivulja je z modelom napovedanakoncentracija vankomicina, modra črta ponazarja potek serumskega kreatinina, zelena pa CRP, črtkano je prikazano priporočeno območje minimalnih koncentracij (3-6 μmol/l).

"How do you want it - the crystal mumbo-jumbo or statistical probability?"

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t (h)

0 20 40 60 80 100 120

Cp

(mg/

l)

0

10

20

30

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r (m

l/min

)

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(%)

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Terapevtsko spremljanje koncentracije Terapevtsko spremljanje koncentracije gentamicinagentamicina