Transcript St P AED 101007 - labclinpharm.ru

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
C 2H 5
C6H5
C 6H 5
O
O
O
NH
C6H5
NH
NH
Primidone
NH
C2H5
O
O
Nitrazepam
Ethosuximide
Valproic acid
H
O
N
O
NH
O
NO2
CH2
C 2H 5
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
C6H5 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
H2 N
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