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Managing Seizure Disorders with the Help of Measured Drug Concentrations Dave Berry The Medical Toxicology Unit Guys & St Thomas’ Hospital Trust Avonley Road London SE14 5ER [email protected] Tel: 0207-771-5360 Mechnikov Medical Academy, St Petersburg 7th October 2008 1 What is Epilepsy? • • • • A propensity to have recurring seizures. There are many different types of seizures. Patients may have more than one seizure type. There are many different aetiologies. 2 Incidence and Prevalence • Second most common neurological disease (approx 1 in 200 of the worldwide population). • Occurs in 2.5 million Americans • 181,000 Americans are newly diagnosed annually • Highest incidence in age group <1 to 4 yrs. • Of all new cases 77% occurs before age 20 yrs. • Incidence increases again in the elderly 3 Mainstay of Treatment • Pharmaceutical (AEDs). • Treatment goal is prevention of seizures without medication toxicity. • 70% of patients managed effectively with a low dose of a single drug. • 30% are more refractory • Surgery • Vagus nerve stimulator 4 Drug Monitoring It is known that the usual dose of most drugs may have little effect in some people, cause severe toxicity in others and be fully satisfactory in the remainder. Drug monitoring is just one of the techniques which has been evolved to try to overcome inter-individual variation on response to drugs 5 What Is Therapeutic Drug Management (TDM)? Therapeutic Drug Monitoring = The practice of determining the concentration of a drug or several drugs (and metabolites) in plasma or serum in order to guide the adjustments in drug dosage which arise because of interindividual pharmacokinetic variation. Therapeutic Drug Management (TDM) = consideration of drug levels alongside clinical observations and using all the information together to manage patients more efficiently and effectively. (INDIVIDUALISATION OF TREATMENT) 6 Therapeutic Drug Management (TDM) in Epilepsy • Treatment of epilepsy is one of the areas where TDM has made the most significant contributions • Several reasons related to the nature of the disorder make TDM particularly useful to guide the individual treatment of patients with epilepsy 7 Guidelines for TDM of AEDs (Antiepileptic Drugs) • Most patients are improved when their serum level of AED is in a particular range • Drug effects correlates better with serum levels than drug dose • The road is long from the box of pills to the patient’s brain. Many factors influence serum levels of AEDs 8 Action of Drug on the Body vs Body on the Drug 9 Factors Affecting Pharmacokinetics • GENETICS – Enzymes/isoenzymes (CYP450) and the isoforms of UGT. • ENVIRONMENTAL – Diet, Interactions. • AGE • DISEASE– Liver, Cardiac, Renal, Thyroid SEVERAL OF THESE FACTORS CAN PRODUCE ABNORMAL BINDING OF A DRUG TO PROTEIN AND CONSEQUENT UNUSUAL FREE DRUG LEVELS AND DRUG EFFECTS 10 Monitoring AEDs – When? • • • • • • • • • • If there has been a treatment failure If a plasma Concentration/Effect Relationship is established Non-compliance is suspected Desired therapeutic effect not achieved Symptoms of toxicity observed Large inter-individual variation in drug disposition/or metabolism Drug disposition is altered as a consequence of secondary disease or an altered physiological state If drug brand is changed to a formulation with differing bioavailability When a known interacting drug is introduced or drug interactions are suspected 11 If medico-legal verification of treatment is required TDM in Epilepsy – Why? • Difficult to assess the efficacy of therapy and therefore to tailor the treatment on clinical grounds alone. • Long treatment duration (often for a lifetime) reinforces the importance of TDM to avoid overexposure to potentially toxic drugs, therefore, reducing the risks for chronic adverse effects. • Clinical symptoms and signs of toxicity can be insidious and difficult to detect and interpret, particularly in the many epilepsy patients with additional neurological handicaps. 12 Anticonvulsant Drug Monitoring Objectives • • Avoid blood level related toxicity Attain blood level related effect Special Problems • • • • • • • • Polypharmacy is often necessary (potential for drug interactions) Various drugs have similar effects (beneficial and adverse) Complications may prevent normal clinical assessment Adverse drug effects sometime difficult to distinguish from underlying disease Non-linear pharmacokinetics Big individual differences in dose vs blood level Many AEDs exhibit pronounced inter-individual pharmacokinetic variability. Concurrent disease or physiological changes alter kinetics of many AEDs. 13 Epilepsy Drug Monitoring Specimen Optimisation 1. 2. 3. 4. 5. 6. 7. 8. Ideally trough sample (pre-dose) Best = Pre morning dose Patient should be at steady state (SS) Allow 5 half lives after dose adjustment for new SS When choosing a sampling time other than trough consider PK properties of dosage form Collect at any time if emergency arises Collect adequate sample for total analysis Avoid certain blood tubes Consider non-blood samples 14 Antiepileptic Drugs 1st Generation 2nd Generation 3rd Generation Bromide Phenobarbitone Phenytoin Primidone Ethosuximide Carbamazepine Valproate Clonazepam Clobazam Vigabatrin Lamotrigine Gabapentin Felbamate (US) Topiramate Tiagabine Levetiracetam Oxcarbazepine Fosphenytoin Pregabalin Zonisamide Rufinamide Stiripentol Brivaracetam Eslicarbazepine) Lacosamide Retigabine 1857 1912 1938 1954 1960 1972 1972 1974 1978 1989 1991 1993 1993 1996 1998 2000 2000 2002 2004 2005 2007 2007 2006 2008 15 The Concept of a Therapeutic Range • For several AEDs there is a more or less well-defined therapeutic range of serum levels (for the general population) • Must not be strictly interpretated (in all cases) • In mild epilepsy, seizure control may be attained at ”subtherapeutic” levels • Some patients with severe epilepsy need ”supratherapeutic” levels, often with a difficult balance between clinical effect and side effects • Some individual patients may develop side effects within the therapeutic range • Optimal serum levels may differ with seizure type • Dose should be titrated to the optimal or target serum level for the individual patient • It would therefore be more appropriate to focus on the concept of individualized reference concentrations rather than ”therapeutic” ranges • Dose should not be increased just to reach the defined range 16 First Generation AED’s Phenobarbitone Phenytoin C6H5 NH O O NH C2H5 C6H5 C 6H 5 O O O NH C6 H5 NH NH Primidone NH C2 H5 O O Nitrazepam Ethosuximide Valproic acid H O N O NH O NO2 CH2 C 2 H5 H3C CH2 CH2 CH2 CH3 N Cl CH COOH CH3 17 PK of some First Generation AED’s Drug Phenytoin Oral absorption Rapid & complete – some formulation differences t1/2 (hr) protein binding % Vd (l/kg) Active metabolites Comment Normally quoted as approx 24hr 15-100 observed 90 0.5 None 1. Enzyme inducing 2. Saturation kinetics 3. Fosphenytoin Carbamazepine Slow/incomplete. Many formulations 40 (non-induced) ~24 (induced) 70 1.0 Carbamazepine10,11-epoxide autoinduction Phenobarbitone Slow & nearly complete 50 - 140 45 0.8 None Enzyme inducing Primidone Rapid/complete 5 - 12 25 0.6 Phenobarbitone PEMA Enzyme inducing Ethosuximide Rapid/complete 24 - 60 zero 0.6 None Valproate Rapid/complete 7 - 14 90 0.15 ?? Clonazepam Rapid/complete 20 - 40 82 0.4 None Enzyme inhibiting 18 Zero Order PK of Phenytoin 19 Phenytoin Dose Vs Serum Level Vs Fit Frequency 20 Phenytoin saliva vs free in plasma o = patients with renal failure 21 PLASMA VALPROATE CONCENTRATION vs SEIZURE CONTROL ( patients with tonic-clonic seizures without a focal component) Valproate (mg/L) <30 31-40 41-50 51-60 61-70 71-80 81-90 >91 % seizure freedom 50 50 79 100 100 100 100 100 22 Valproate case • 40year old epileptic patient. Has been taking 3.5g Valproate daily for many years. Had a cadaveric renal TX 8years ago which is failing rapidly with a doubling of his serum creatinine over the last month. Is markedly uraemic (SCr 750, Urea 30) and hypoalbuminaemic (Alb 19g/L). • The patient has a progressive debilitating tremor, has developed thromocytopenia (Plt 49) and pancytopenia. Valproate toxicity is suspected. • A “Total Valproate level" was 45mg/L (reference range 50100mg/L) • A Free Valproate level 48hours post cessation of Valproate was 25 mg/L( Top normal 11 mg/L). Filtrate/adaptable method • Valproate protein binding in this patient is less than 50% and while it is concentration dependent normally is normally in the range 80-95%. 23 Metabolites – Should they be monitored? active CH3 O N N active H2N N Cl Carbamazepine C6 H5 O Clobazam H O active inactive HO OH O O N N N N O active H2N O Carbamazepine Epoxide Desmethylclobazam O NH2 Carbamazepine diol 24 Comparative Value of TDM of Older AEDs Drug Reference Range mg/L Value rating Comments Phenytoin 7 - 20 **** Essential for rational therapy because of saturation kinetics Carbamazepine 1.5 - 9 *** Useful – active metabolite Phenobarbitone 5 – 30 15 – 40 neonates ** Useful, but tolerance – big interindividual differences dose/level Primidone <13 * Ratio phenobarbitone Valproate 50 - 100 *** Useful in certain cases – free level Ethosuximide 40 - 80 *** Good serum level effect relationship Clonazepam 25 – 80 ng/ml ** Useful, particularly in neonates 25 Rational • The rationale for TDM was established with the older AEDs but the principles equally apply to most of the newer drugs. • The goal of TDM is to optimise a patient’s clinical outcome by managing their medication regimen with the assistance of measured drug concentrations. • TDM seeks to optimise the desirable properties of AEDs (anticonvulsant effect), while minimising their undesirable properties of which adverse CNS events may be the primary treatment limiting factor. • The concept is based on the observation that serum drug concentration correlates better with clinical effects than the dose. 26 LAMOTRIGINE • t 1/2……………..20-30hrs. • Bioavailability…....>95% • Protein binding…..55% • Elimination……...Hepatic Subject to many PK interactions with both enhanced clearance (hepatic enzyme inducers) and reduced clearance (hepatic enzyme inhibitors e.g. valproate) 27 Lamotrigine levels vs adverse effects Plasma level lamotrigine vs side effects (unsteadiness +/- vomiting) 16 % subjects with side effects 14 12 10 8 6 4 2 0 0-5 5-10 10-15 15-20 20+ Lamotrigine plasma level (mg/L) 28 Patient with rapid lamotrigine clearance KT - Lamotrigine serum concentration v time following morning dose (350 mg tds) Log drug concn (mg/L) 100 10 t1/2 = 7.95 hrs 1 0 200 400 600 800 1000 1200 Time post dose (mins) 29 Pennell, Epilepsia, 2002 30 Effect of OC on LTG Clearance Black=LTG + OC White=LTG alone Sabers et al., 2003 31 Lamotrigine • THERE IS A GOOD RELATIONSHIP BETWEEN SERUM LEVEL AND CLINICAL EFFECT • POLYTHERAPY: Drug interactions result in extremely wide variation in dosing requirements to achieve target range • MONOTHERAPY: Various reports show large variations in dosing requirement to achieve the reference range • CONCLUSIONS: Unpredictable nature of the dose to serum level relationship makes TDM helpful for guiding treatment 32 GABAPENTIN • • • • • t 1/2…………….5-6 hrs Bioavailability….60-80% Protein binding…..0% Elimination……Renal Target range…2-20 mg/L L-aminoacid transporter – said to limit absorption to approx 3.5 Grm/day. 33 Gabapentin serum level (Mg/L) Serum Gabapentin vs dose in 68 patients 25 20 15 10 5 0 0 20 40 60 80 100 120 Gabapentin dose (Mg/Kg) 34 Gabapentin • POLYTHERAPY: Clearance not affected by other drugs • DISPOSITION: absorption may be variable (L-aminoacid transport system). Excretion depends on renal function • CONCLUSIONS: Unpredictable nature of the dose to serum level relationship makes TDM helpful for guiding treatment. Doses in excess of recommended maximum may be required (and these are absorbed) 35 TOPIRAMATE • • • • • t 1/2…………...20-30 hrs Bioavailability…..80-90% Protein binding….15% Elimination….. .…renal?? Target range…5-20 mg/L 36 Topiramate levels vs Effect MONOTHERAPY 100 90 P80 E70 R60 Sz FREE BETTER WORSE C 50 E 40 N 30 T 20 10 0 0-5 A TROUPIN 5 - 10 10 - 15 15 - 20 20 - 25 25 - 30 Serum concentration mg/L 37 Topiramate side effects 45 P E R C 40 35 SIDE - EFFECTS 30 E 25 GRADE 2 N 20 GRADE 3 T 15 GRADE 4 A 10 G E 5 0 0-5 A TROUPIN 5 - 10 10 - 15 15 - 20 20 - 25 Serum concentration mg/L 25 - 30 38 What’s the Evidence? (for a serum vs concentration effect relationship) • • • • • • OXCARBAZEPINE (10-hydroxy) - levels for seizure control are related to severity:- 10 - 20 mg/L (mild), 20 – 30 mg/L (moderate), > 30 mg/L (severe) LEVETIRACETAM – Despite mainly renal elimination, unpredictable relationship between serum levels and dose. Bilo 2004 – plasma level monitoring increased responder rate. Pennell 2005 – elimination enhanced during pregnancy. TIAGABINE - high serum levels (>400µg/L) cause CNS toxicity, best seizure control with Cmin >40 µg/L (not dose related), Clearance is significantly higher in patients taking hepatic enzyme inducing drugs. FELBAMATE - Leppik’91 showed 18-52 mg/L did not cause severe side effects, Harden et al. ’96 - best seizure control range 55-134 mg/L, but 40% severe side effects. Clearance affected by many other AEDs (both positive and negative). ZONISAMIDE - In 5 animal species, the anticonvulsant effects and the neurotoxic effects of zonisamide were more closely correlated with the plasma concentration than with dose and suggest that zonisamide may be clinically effective at plasma concentrations above 10 mg/L with toxicity occurring above 70 mg/L. Wagner et al. 1984 reported non-linear PK in patients co-medicated with other AED’s. Several reports of AEs increasing significantly with serum level >30 mg/L. 39 Zonisamide Metabolism Sulphonamide – metabolised partly by acetylation. Well known genetic variation with fast & slow acetylators. 40 Assay Methods THE CHALLENGE • To provide a fast reliable assay service for all drugs used in the treatment of epilepsy and related conditions. • The assays must produce accurate results on small samples. METHODS Multidrug V’s Specific Assays • Currently there are 2 main approaches – immunoassay and chromatography. It is important that both the laboratory and the clinician understands the advantages and limitations of these complementary methods. • Metabolites - ? Activity 41 Analytical Methods OLDER DRUGS • Various immunoassays (specific for each drug) • Chromatographic (HPLC/GLC) Specific and able to co-determine active metabolites Capable of multi-drug analysis (and include some of 2nd generation drugs below). NEWER DRUGS • HPLC (RP)/UV – lamotrigine, oxcarbazepine, felbamate, levetiracetam, zonisamide • HPLC (NP) - lamotrigine • HPLC (RP)/deriv – vigabatrin, gabapentin, pregabalin • HPLC (RP)/EC – tiagabine • GC (direct) – lamotrigine, felbamate, levetiracetam, topiramate • GC(deriv) – gabapentin • IA – zonisamide, topiramate, lamotrigine (now available) • LC/MS/MS – everything!! 42 HPLC Chromatogram of some First Generation AED’s 43 Chromatography – screening capacity 44 QMS Assay Principle ® Quantitative Microsphere System – QMS® Rate (mAbs/min) + Antibody + Free Drug No-Inhibition Agglutination Partial Inhibition Partial Agglutination Particle Bound Drug Complete Inhibition No Agglutination g/ml (Calibrators) 45 Precision of Lamotrigine QMS Assay Total Low Control Mid Control High Control Low Patient Pool Mid Patient Pool High Patient pool N 80 80 80 80 80 80 Mean 2.17 15.51 25.57 2.81 10.79 23.93 SD 0.06 0.29 0.52 0.08 0.21 0.58 CV 2.9% 1.9% 2.0% 2.8% 2.0% 2.4% 46 Cross-Reactivity N HN Cl N H OH N OH NH2 N-2 glucuronide (80-90%) Cl Cl O Cl H2 N Cl COOH OH Cl N H2 N HN N H O N H2N N HN NH2 N-2-oxide (0-5%) Concentration Tested (µg/mL) N H N CH3 NH2 N-2-methyl (0-5%) CrossReactivity N-2 oxide 100 500 < 3% N-2 glucuronide 100 500 *ND N-2 methyl 100 500 *ND *ND = Not detected 47 QMS vs HPLC in 94 Clinical samples QMS 40 30 20 10 0 0 10 20 30 HPLC 40 48 Mass Spectrometer Tuning parameters 49 MRMs of Individual AEDs + Retention times 50 Lamotrigine QA 51 TDM and New AEDs • The studies conducted to demonstrate clinical efficacy and tolerability are not designed to evaluate the place of TDM • For several of the new AEDs it is said that TDM is not useful or necessary, and this is used as a promotional tool • The fact is that appropriate studies are lacking • TDM can enhance our use and understanding of new AEDs • More clinical research is required to increase our knowledge about individualized reference concentrations • This research should become more feasible as more patients now receive monotherapy 52 Value of TDM for Antiepileptic Drugs • Clear case when investigating unusual absorption (adherence). • If a plasma concentration/effect relationship is established • If large Inter/Intra individual variations in drug metabolism/disposition occur • SOMETIMES THINGS ARE NOT WHAT THEY SEEM AND TDM REVEALS UNEXPECTED FINDINGS. • METHODOLOGY MAKES A DIFFERENCE. 53 Indications for AED Monitoring • TDM can be useful for all patients, but some situations show greatest clinical value • Once steady state is reached after the onset of therapy or dose adjustment: If fit free = individual therapeutic level If further fit = guide to dose adjustment _______________________________________________________ • Seizures continue despite apparently adequate dose. If serum levels low increase dose accordingly If erratic levels query compliance. Hospitalisation or close supervision will increase levels 54 Indications for AED Monitoring • • • ?? Toxicity – Particularly in multiple therapy where CNS side effects are similar. Patient has unexpected change in drug response while taking constant daily dose Known interacting drug added or withdrawn • Condition known to change PK occurs e.g. Renal disease, Pregnancy etc. • • Childhood – changed PK with growth - to elderly. Emergency 55 AEDs – Best Practice Guidelines for Therapeutic Drug Monitoring A consensus document Prepared by the ILAE Sub-commission on Therapeutic Drug Monitoring under the auspices of the ILAE Commission on Therapeutic Strategies Sub-commission members: Philip Patsalos (Chair), UK David Berry, UK Blaise Bourgeois, USA Jim Cloyd, USA Tracy Glauser, USA Svein Johannessen, N Emilio Perucca, I Torbjörn Tomson, S 56 AEDs used for non-epilepsy indications* • • • • Phenytoin Primidone Carbamazepine Valproate • • • • • • • • Gabapentin Lamotrigine Oxcarbazepine Topiramate Tiagabine Levetiracetam Zonisamide Pregabalin *Trigeminal neuralgia, neuropathic pain, migraine, tremor, bipolar disorders, other psychiatric conditions Spina and Perugi. Epileptic Disord 2004;6:57-75 57 СПАСИБО ЗА ВНИМАНИЕ! 58