Unexplained Spikes in Lamotrigine Serum Concentration Suggest Nonlinear
Elimination Kinetics in Some Individuals
Patsy Ramey, MSN, RN; Melissa R. Osborn, BSN, RN; Kelly Lowen, CCRP; Bassel W. Abou-Khalil, MD
Department of Neurology, Vanderbilt University, Nashville, TN, USA
INTRODUCTION
METHODS
Lamotrigine (LTG) is one of the most commonly used
antiepileptic drugs. It can be used in monotherapy or in
conjunction with other medicines to help control seizures.
It is reported to have linear kinetics, so that the elimination
rate is linearly proportional to the blood concentration, the
half-life is constant, and a percent change in dose is
accompanied by an equal percent change in serum
concentration. We encountered a number of patients in
whom LTG serum concentration increased dramatically in
response to a minor change or even no change in LTG
dose.
We identified patients who developed clinical LTG toxicity with
LTG serum concentrations greater than 20 mcg/ml, after tolerating
lamotrigine at lower serum concentrations. We reviewed LTG dose
change and other changes that preceded the episode of toxicity. For
qualifying patients we entered relevant information in a web-based
secure database (REDCap). The items recorded included age, race,
AEDs, and changes in LTG or other AEDs preceding toxicity. In
particular, we recorded LTG dose, dose regimen, formulation and
serum concentration prior to, during, and after toxicity. We
investigated the relationship between dose, dose change, and serum
concentration in patients with clinical toxicity and serum
concentrations exceeding 20 mcg/ml at any point in time.
RESULTS
Twenty two patients (12 women) had 25 episodes of LTG clinical toxicity with levels higher than 20 mcg/ml (Table 1). Please refer
to Table 2 for symptoms of clinical toxicity. All patients had drug-resistant epilepsy, but one (patient 22) became seizure-free after
epilepsy surgery prior to the toxicity episodes. Twenty had focal epilepsy, one had idiopathic generalized epilepsy and one
symptomatic generalized epilepsy. Their age ranged from 26 to 66 years (mean 32.5). Five were on lamotrigine monotherapy, 5
were taking one other AED, and the remaining patients were taking two or more adjunctive AEDs. The peak serum concentration
during toxicity varied from 21.1 to 40.3 mcg/ml (mean 29.2).
The increase in level was explained in 2 patients (post-delivery in one patient, and an increase in valproate dose in another).
However, 20 patients developed an increase in LTG level that was not explained by change in dose, or that was disproportionate to
the increase in LTG dose. In these patients the change was also not explained by an interaction. Twelve episodes occurred with no
change in LTG dose; seven occurred after an increase, and three occurred in two patients with a decrease in LTG. The latter were
all explained by the fact that clinical toxicity was already developing at the time of LTG dose reduction, and that the level remained
high despite dose reduction.
CASE STUDIES
Figure 1.
• A 57 year old woman (patient # 9) who had a stable LTG level of 18-20 mcg/ml at a dose of
600 mg per day. After the dose was increased by 25 mg/day (4% change in dose), her level
rose to 40.3 mcg/ml (99.5% increase in level), with associated clinical toxicity (Figure 1).
She became progressively weaker, initially having difficulty holding a glass and then
difficulty holding up her head. She stopped assisting in her transfers and became combative
with her caregivers.
Figure 2.
• A 66 year old woman (patient # 10) had an LTG level of 16.2 mcg/ml on a dose of 600 mg
per day. Her level rose to 37.6 mcg/ml (132% increase) without a change in dose. Clinical
symptoms of toxicity included vomiting and diarrhea, plus agitation and altered mental
status. Her LTG level came back down spontaneously (Figure 2).
Table 1. LTG doses and serum concentrations before and
during toxicity (22 patients/ 25 separate documented episodes)
Patient #/
Gender
1/ F
2/ F
3/ F
4/ F
5/ M
6/ M
7/ M
8/ M
9/ F
10/ F
11/ F
12/ M
13/ M
14/ F
15/ M
16/ M
17/ F
18/ F
19/ F
20/ M
21/ M
22/ F
Age
LTG Dose
Before
Toxicity
(mg/day)
LTG Dose
with
Toxicity
(mg/day)
LTG Level
Before
Toxicity
(mcg/ml)
LTG Level
with
Toxicity
(mcg/ml)
34
28
47
55
39
37
53
32
57
66
35
58
55
47
30
35
26
63
54
49
44
29
26
29
31
700
1550
400
400
400
600
125
1100
600
600
800
1000
400
400
375
400
600
450
800
800
600
400
800
525
300
800
1550
400
400
400
600
75
1200
625
600
700
1000
400
400
450
400
700
450
800
800
700
600
650
500
300
14.2
21
7.4
21.2
23.2
6.9
17.6
9.2
20.2
16.2
11.7
15.2
15.8
18.3
14.7
16
10.3
18.3
11.4
14.8
8
7.4
11.8
15.5
18.3
29.8
32
39.7
29
33.8
29.1
25.2
29.8
40.3
37.6
22.3
24.5
29.7
25.2
23.5
23.6
29.4
25.8
24.9
25.7
21.1
24.2
25.4
32.4
33.4
CONCLUSIONS
• Spikes in LTG levels and associated clinical toxicity may
occur unexpectedly in some individuals, spontaneously
(intra-individual variability) or in response to small dose
change
• The above suggests that LTG elimination kinetics may be
nonlinear in some individuals at serum concentrations in
the upper range.
• Measurement and close monitoring of LTG levels is
warranted for new symptoms that could be consistent
with lamotrigine toxicity, particularly when the baseline
serum concentration has been above 10 mcg/ml.
Table 2. Symptoms of clinical toxicity observed in 22
patients during 25 episodes
Patient Clinical manifestations during toxicity
agitation, aggression, ataxia, increased seizure
1
frequency
2
erratic behavior, increased seizure frequency
3
complex partial status epilepticus
severe
unsteadiness,
stiffening,
combativeness
4
and disorientation
double
vision,
disequilibrium,
word
finding
5
difficulty, difficulty understanding, tremor
Confusion, vertigo, blurry vision, diplopia,
6
imbalance with falling, nausea, sleepiness,
elevated ammonia (133)
7
ataxia, tinnitus, nausea, vomiting, headache
nausea, vomiting, agitation, aggression,
8
combativeness, hallucinations
decreased appetite, could not hold head up,
9
combativeness, would not help with transfers,
increased atonic seizures
vomiting, diarrhea, low-grade fever, agitation,
10
confusion, delirium, headache
word-finding difficulty, severe dizziness, nausea,
11
vomiting
12 unsteadiness, dizziness
13 severe tremor, ataxia, aggression
14 confusion, slurred speech, ataxia
(a) lethargic, prolonged seizure
15
(b) atypical seizures
somnolence, slurred speech, nausea, ataxia,
16
dizziness
17 double vision, vertigo, delusional thinking,
agitation, hallucinations, confusion, aggression
ataxia,
nystagmus,
dizziness,
tremor,
headache,
18
double vision, blurred vision
vertigo, dizziness, imbalance, double vision,
19
blurred vision
dizziness,
imbalance,
blurred
vision,
double
20
vision, nystagmus, ataxia
21 Increased seizure frequency
(a) headache, blurred vision, nausea, vomiting
(b) blurred vision
22
(c) ataxia, nystagmus, dizziness, blurred vision,
tremulousness