TDM in individualizacija odmerjanja zdravil

Transcription

1 Načrtovanje terapije z zdravili TDM in individualizacija odmerjanja zdravil Iztok Grabnar FK Terapevtski cilji Izbor zdravila in režima odmerjanja FD Spremljanje terapevtskih in toksičnih učinkov Spremljanje terapije z zdravili 1. Klinični učinki Indikacija odmerek odmerek Znaki toksičnosti Furosemid Srčno popuščanje Edemi Motnje elektrolitov Hipotenzija Dehidracija Karbidopa/DOPA Parkinsonizem Slaba kontrola Diskinezije Zmedenost simptomov Depresija Tiopental Anestezija Nezadostna Pregloboka Zastoj anestezija anestezija dihanja 1

2 Spremljanje terapije z zdravili 2. Merjenje terapevtskih učinkov in vitro Spremljanje terapije z zdravili 3. Merjenje koncentracije učinkovine Indikacija odmerek odmerek Znaki toksičnosti 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)* Varfarin TE zapleti visok INR nizek INR krvavitve Tiroksin Hipotiroidizem nizek TSH visok TSH hipertiroidizem Statin Zvišan holesterol AST/CK visok hol. miopatija * 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 Repeated Drug Dosing to Maintain SS Levels Within a Therapeutic Range to assess adherence to therapy to individualize therapy to diagnose toxicity Therapeutic Range 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). 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. 2

3 TDM: Aminoglycosides Monitoring is mandatory in ALL patients AG 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) cochlear (hearing deficits) - neomycin/amikacin vestibular (disturbed balance) - streptomycin/gentamicin Targets for IV GENTAMICIN Conventional dosing peak min post-dose = 5-10 mg/l ) BUT toxicity can emerge below these levels Trough before next dose < 2 mg/l ) if loop diuretics co-administered Extended interval dosing peak min post-dose = 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) TDM: Anticonvulsants (PHENYTOIN) Therapeutic range μmol/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 1 st order elimination within the TR - apparent t 1/2 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. TDM: Theophylline Therapeutic range -5-20μg/ml (28-110μmol/L) Toxicity - manifest as tachyarrythmias, vomiting & convulsions. TDM: Lithium Therapeutic range 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 - 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 and if in doubt do not give bolus loading dose. PK problems Complete absorption - SR formulations to reduce peak levels. >95% excreted by the kidney - initial t 1/2 12h but terminal t 1/2 much longer 70-80% reabsorbed in PCT with no distal reabsorption (unlike Na) PCT retention (hence toxicity risk ) is by: reduced exchangeable Na from any cause loop or thiazide diuretics NSAIDs or ACEIs. Alteration in Clearance increased decreased rifampicin erythromycin anticonvulsants ciprofloxacin smoking (>10cigs/d) verapamil propranolol 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. 3

4 TDM: Digoxin Therapeutic range 1-2ng/L (taken >6h post-dosing; 1ng/L=1.3nmol/L) for inotropic effect not AF. Enzyme Induction/inhibition by Anticonvulsants: 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 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 diuretics of the Na pump Phenytoin, phenobarb,, CBZ Lamotrigine Valproate Felbamate Ethosuximide Gabapentin Tiagabine Vigabatrine * CYP/UGT UGT (weak) UGT/epoxidases/CYP2C 3A4 2C19 No Effect * =inhibition; / =induction (+/++) Populacijska farmakokinetika POPULACIJSKA FARMAKOKINETIKA Kaj je populacijska farmakokinetična na / farmakodinamična analiza Metode populacijske analize, identifikacija parametrov modela Prednosti/slabosti slabosti Cilji populacijske analize/vloga pri razvoju zdravil in pri načrtovanju individualne farmakoterapije Primera: Terapevtsko spremljanje koncentracije učinkovineu Simulacija kliničnega nega preizkušanja 4

5 Kaj je? Populacijska farmakokinetika/farmakodinamika je opis povezave med fiziologijo /patofiziologijo in farmakokinetiko /farmakodinamiko Interindividualna variabilnost Preostala intraindividualna variabilnost Sheiner LB.. DrugD Metab Rev. 1984; 15(1-2): Enoprostorni farmakokinetični ni model Dolgotrajna intravenska infuzija k 0 Cp() t 1 e Cl Cl t = Vd Cpss = k 0 / Cl ± ε ε - napaka meritve, intraindividualna variabilnost Koncentracija ε N(0,) ε Čas Identifikacija parametrov modela Matematični model dx() t = f ( x() t, α,r() t,t) x(0)=c dt y() t = h( x() t, α,r() t,t) α vektor parametrov Meritve z(t j ) = y(t j ) + e(t j ) j = 1,...,m e(t) ~ N(0, g(y(t), β) β vektor parametrov modela variance Parametri α konstanta ali α ~ N(μ, Ω); α ~ LN(μ, Ω) Model Identifikacija α Meritve 5

6 Vsota najmanjših 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... ˆ α WLS min m j= 1 w j ( ( ) ( )) 2 z t y α, t j j wj ~ 1/ 2 j = inter + slope z(t j ) Johann Carl Friedrich Gauss ( ) 1855) Največje je verjetje (Maximum likelihood) Model Model napake Meritve Hkratna identifikacija α in β Kriterij je največje je verjetje [ l( α z ) l( α z ) Kl( α z )] max l( α z) ˆ α max = ML 1 2 m e(t) ~ N(0, g(y(t), β) j = inter + slope z(tj) Identifikacija α Ronald Aylmer Fisher ( ) 1962) 6

7 Bayes Model Model napake Predhodno vedenje p(α) Meritve Identifikacija Parametri so naključne ne spremenljivke α ~ N(μ, Ω), LN(μ, Ω) p(α z) Thomas Bayes ( ) 1761) 7

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9 Samo en parameter: α ~ N(μ, Ω) ˆ α MAP min m ( z( t j ) y( α,t j )) j= 1 g( y( t ), β ) j 2 + ( α μ) 2 α 2 9

10 Cl = metabolčni očistek + renalni ni očistek Koncentracija Čas Koncentracija Cl = Θ 1 + Θ 2 CCr ± η Očistek učinkovine Čas Očistek kreatinina Cl = metabolčni očistek + renalni ni očistek Cl = Θ 1 + Θ 2 CCr ± η 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: ) η N(0,) Očistek učinkovine Očistek kreatinina 10

11 Mean, expected value, or some other point estimate: Variability among subjects around that mean: Residual (unexplained) variability and/or model misspecification: Θ = Θ Ω = Σ = 1 Θ2 Θ3 Θ 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 User has to supply code As for input routine NONMEM ASCII Yes (specified by the routine Variables in PREDPP) the data set None (some dimensions are initially set but these may be changed by the user) NPEM ASCII via USC*PACK program Yes Either linked to a pharmacokinetic 99 days of time, 99 doses, or numerical value. Interpolation 99 values of dependent between covariate values is possible variables (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 Cilji 1. Oceniti parametre populacije (CL, V) parametri stalnih učinkov u (fixed effects parameters) 2. Oceniti variabilnost naključni ni učinkiu (random effectse ffects) Intersubjektna na variabilnost Preostala variabilnost (Intrasubjektnana variabilnost, napaka meritev, napaka modela) 3. Identifikacija dejavnikov s katerimi lahko povežemo emo intersubjektno variabilnost Demografski fski: Starost, telesna teža, površina, spol, rasa Genetski ski: CYP2D6, CYP2C19 Okolje: kajenje, prehrana Fiziologija/Pat /Patofiziologija: Ledvična funkcija (Očistek kreatinina), Jetrna funkcija (ALT, AST), Bolezenska stanja Sočasna terapija Drugi: Vpliv hrane, Cirkadialni ritem,, Farmacevtska F oblika 11

12 Prednosti Redko vzorčenje (2-3 izmerjene koncentracije/subj subjekt) Faze II/III kliničnih nih raziskav Subpopula opulacije (Pediatrija, Geriatrija) Veliko pacientov Manj omejitev glede kriterijev za vključitev/izklju itev/izključitev Neuravnotežen en načrt raziskave Različno št. meritev koncentracije/subj subjekt) Ciljna reprezentativna populacija Slabosti Kontrola kakovosti vhodnih podatkov Odmerki in časi odvzema vzorcev, rokovanje z vzorci Zapletena metodologija Načrtovanje optimalne izvedbe raziskave Nejasno razmerje Cost/Benefit Načrtovanje individualnih režimov odmerjanja Koncentracija vankomicina (umol/l) Serumski kreatinin (mmol/l) CRP Èas (h) 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). "How do you want it - the crystal mumbo-jumbo or statistical probability?" 12

13 Terapevtsko spremljanje koncentracije gentamicina Cp (mg/l) ClCr (ml/min) Hct (%) t (h)