Carbamazepine Toxicity Induced by Lopinavir/Ritonavir and

Nelfinavir

Duane E Bates and Robert J Herman

OBJECTIVE: To present a case of carbamazepine toxicity induced by lopinavir/ritonavir and nelfinavir.

CASE SUMMARY: A 50-year-old HIV-positive male developed excessive drowsiness secondary to carbamazepine when an
antiretroviral regimen containing lopinavir/ritonavir was introduced. The carbamazepine serum concentration increased 46%.
Subsequently, the patient developed a possible adverse skin reaction to his antiretrovirals and was hospitalized. The protease
inhibitor was changed to nelfinavir. Within 3 days, the patient again developed excessive drowsiness and became unsteady on his
feet. This time, the carbamazepine serum concentration had increased by 53%. In both instances, the carbamazepine dosage was
decreased by 33%, which resulted in resolution of symptoms.
DISCUSSION: Carbamazepine undergoes extensive hepatic metabolism. The major metabolic pathway involves oxidation of
carbamazepine via CYP3A4 to an active metabolite, carbamazepine-10,11-epoxide. Protease inhibitors are well-known CYP3A4
inhibitors. Other cases of carbamazepine toxicity secondary to protease inhibitors are reviewed. A MEDLINE search (1966–May
2006) revealed 4 cases of carbamazepine toxicity secondary to antiretrovirals. Carbamazepine serum concentrations increased
two- to threefold from baseline. Vertigo, drowsiness, disorientation, ataxia, and vomiting occurred within 12 hours to 2 months, which
resolved with reduction of the carbamazepine dosage.
CONCLUSIONS: An objective causality assessment suggests that our patient became drowsy and unsteady on his feet secondary to
a carbamazepine–protease inhibitor interaction. Lopinavir/ritonavir and nelfinavir may decrease carbamazepine metabolism,
causing an elevation in carbamazepine serum concentrations. Carbamazepine toxicity may be prevented by reducing the
carbamazepine dosage by 25–50% when protease inhibitors are introduced. A carbamazepine serum concentration should be
repeated 3–5 days after the protease inhibitors are started.
KEY WORDS: carbamazepine, lopinavir, nelfinavir, ritonavir.

Ann Pharmacother 2006;40:1190-5.

Published Online, 23 May 2006, www.theannals.com, DOI 10.1345/aph.1G630

he incidence of seizures in HIV-positive patients has
T been reported to be as high as 11%. The elevated seizure
rate is secondary to neurologic manifestations of HIV and
opportunistic infections of the central nervous system
(CNS), CNS lymphoma, and HIV dementia.1 Carba-
mazepine can be used as an anticonvulsant and has many
other indications including treatment of neuropathic pain,
schizophrenia, and bipolar disorder.2 Carbamazepine un-
dergoes oxidation via CYP3A4 to carbamazepine-10,11-
Author information provided at the end of the text.
epoxide which, in addition to possessing anticonvulsant
and analgesic activity, also contributes to toxicity.
Carbamazepine induces the metabolism of other drugs
through its effects on the CYP2C and CYP3A subfamilies
and has been associated with antiretroviral failure.3 HIV-
positive patients treated with protease inhibitor–based regi-
mens are at an increased risk of drug interactions, as protease
inhibitors are both inhibitors and substrates of CYP450
isoenzymes. There have been several reports of carbamaze-
pine toxicity when it is used in combination with protease
inhibitors. We present a case of carbamazepine toxicity in-
duced by lopinavir/ritonavir and nelfinavir.

1190 n The Annals of Pharmacotherapy n 2006 June, Volume 40 www.theannals.com

Case Report
A 50-year-old, HIV-positive white male had his highly active an-
tiretroviral therapy (HAART) changed to tenofovir 300 mg daily,
lamivudine 150 mg twice daily, and lopinavir 133 mg/ritonavir 33 mg 3
capsules twice daily. The patient had been stabilized on carbamazepine
400 mg 3 times daily for 7 months. Carbamazepine serum concentration
one week prior to the change in HAART was 10.3 mg/L (reference
range 4–12). Within 9 days after initiation of the new HAART regimen,
the patient reported feeling very drowsy and the carbamazepine serum
concentration had increased to 15 mg/L. The carbamazepine dosage was
decreased to 400 mg twice daily, which resulted in decreased drowsiness.
A repeat carbamazepine serum concentration on day 11 was 7.4 mg/L.
On day 12 of tenofovir, lamivudine, and lopinavir/ritonavir therapy,
the patient developed fatigue, difficulty swallowing, and diffuse hemor-
rhagic lesions over his extremities, which became confluent over the
trunk. The patient discontinued HAART and his carbamazepine dosage
was increased to 400 mg 3 times daily. Ten days later, he was admitted to
the hospital for evaluation of the rash.
Past medical history included depression, chronic back pain, mi-
graines, complex partial seizures, and prurigo nodularis. He had been di-
agnosed with HIV infection 8 months prior to admission, with a CD4+
count 21 × 106/L and a viral load of 42 000 copies/mL. The presenting
illness at the time of diagnosis was oral candidiasis.
He did not smoke or drink alcohol and denied use of recreational
drugs and over-the-counter medications. There was no history of recent
travel. He had developed Stevens–Johnson syndrome after receiving cot-
rimoxazole and abacavir. Antiretroviral adverse reactions included ane-
mia with zidovudine and decreased energy, confusion, and severe diffi-
culty with attention with efavirenz. Medications on admission included
citalopram 80 mg once daily (for 5 y), dapsone 100 mg once daily (4
mo), and carbamazepine 400 mg 3 times daily (8 mo). Dapsone was dis-
continued on admission.
A diffuse pruritic, blanchable, erythematous macular papular rash was
identified on the upper and lower extremities, trunk, and face. The pa-
tient’s vital signs included temperature 37.2 ˚C, blood pressure 80/59
mm Hg, heart rate 56 beats/min, and respiratory rate 16 breaths/min,
with oxygen saturation 100% on room air. Neurologic examination re-
vealed decreased deep tendon reflexes bilaterally in the upper and lower
limbs (2/5). Paresthesias were noted in his fingers, with decreased pin
prick sensation. Cardiovascular, respiratory, abdominal, and muscu-
loskeletal exams were unremarkable.
On admission, serum electrolytes, creatinine, and glucose levels were
normal. Complete blood cell count and liver function tests are shown in
Table 1. Laboratory evaluation for a macrocytic anemia included a retic-
ulocyte count of 3.1% (reference range 0.2–2), vitamin B12 310 pg/mL
(200 –1000), and folate 1148 ng/mL (140 –960). The carbamazepine
serum concentration was 9.8 mg/L. Rapid plasma reagin for syphilis was
negative. Cytomegalovirus (CMV) immumoglobulin (Ig) M and IgG
were positive, but CMV immediate early antigen was negative, and the
patient did not exhibit clinical signs of CMV disease. Epstein–Barr virus
capsid antigen, antinuclear antibodies, and extractable nuclear antigen re-
sults were negative.
The dermatology service was consulted. The dermatologists thought
that the rash was secondary to HAART and recommended symptomatic
treatment with betamethasone 0.1% cream and hydrocortisone 1%
cream to facial areas. Hydroxyzine 25 mg 3 times daily as needed was
prescribed for pruritus. The rash was biopsied, and the pathology
showed a mild interface dermatitis with occasional necrotic ker-
atinocytes, some vacuolization of basal keratinocytes, and overlying bas-
ket weave orthokeratosis. There was mild perivascular chronic inflam-
matory infiltrate that involved the superficial and deep vessels. There
also was moderate and focal lymphocyte epidermotropism with some
www.theannals.com The Annals of Pharmacotherapy
lymphocytes surrounding the necrotic keratinocytes. No eosinophils
were seen. Periodic acid–Schiff stains did not reveal fungal hyphae or
yeast forms.
A neurologist was consulted, as it was thought the rash and bone mar-
row toxicity were secondary to carbamazepine. The physician suggested
that topiramate 25 mg twice daily be initiated, titrating the dose by
25–50 mg/wk to a target dosage of 200 mg twice daily, and that carba-
mazepine be tapered to discontinuation over 2– 4 weeks.
On hospital day 9, dapsone 100 mg daily was restarted for prophylax-
is of Pneumocystis jiroveci pneumonia, as there was no improvement in
the rash. Dexamethasone 8 mg twice daily was prescribed for possible
immune reconstitution syndrome. Topiramate 25 mg twice daily was
started and the last dose of hydroxyzine was given on day 10. On day 12,
a bone marrow biopsy was done to rule out a myelodysplastic process;
however, bone marrow cytogenetics were normal. Bone marrow, blood,
and stool cultures for mycobacterial organisms were also negative. Mag-
netic resonance imaging of the brain, chest, abdomen, and pelvis were
unremarkable.
On day 17, tenofovir 300 mg daily, lamivudine 150 mg twice daily,
and nelfinavir 1250 mg twice daily were started (viral load 75 000
copies/mL, CD4+ 21 × 106/L). On day 20, the patient began feeling more
tired and unsteady on his feet. A repeat carbamazepine serum concentra-
tion was 15 mg/L. Serum carbamazepine 10,11-epoxide concentrations
were not measured. The carbamazepine dosage was decreased to 400 mg
twice daily and, within 24 hours, symptoms had resolved. On day 21, the
patient was started on fluconazole 100 mg daily for oral candidiasis.
The patient was discharged on day 22; the carbamazepine serum con-
centration at that time was 9.3 mg/L and the dose remained 400 twice
daily. Other medications included fluconazole 100 mg daily for 7 days,
tenofovir 300 mg daily, nelfinavir 1250 mg twice daily, lamivudine 150
mg twice daily, dapsone 100 mg daily, a tapering dose of dexamethasone
beginning at 8 mg twice daily, citalopram 80 mg daily, betamethasone
0.1% twice daily, and hydrocortisone 1% twice daily. The rash had
slightly improved with use of the steroid creams during hospitalization.
Topiramate 75 mg twice daily was increased by 25 mg weekly until a
dosage of 200 mg twice daily was achieved. The carbamazepine 400 mg
twice daily dose was decreased by 100 mg weekly once a topiramate
dose of 100 mg twice daily was attained. A carbamazepine serum con-
centration obtained on day 29 was 8.2 mg/L.
By day 70, the rash had resolved; however, the patient was not adher-
ent to his antiretroviral therapy. A repeat viral load after 4 months was
31 000 copies/mL. Genotype resistance analysis showed nelfinavir resis-
tance and, therefore, nelfinavir was discontinued. The patient was coun-
seled on the importance of adherence to the antiretroviral regimen. Clini-
Table 1. Complete Blood Cell Count and
Liver Function Tests on Admission
Test Value Reference Range
Hemoglobin (g/dL) 6.7 13.7–18
MCV (µm3) 110 82–100
Platelets (103/mm3 ) 112 150–400
WBC (103/mm3) 1.3 4–11
Neutrophils (103/mm3) 0.9 2–9
Lymphocytes (103/mm3) 0.1 0.7–3.5
ALT (U/L) 36 1–60
Alkaline phosphatase (U/L) 57 30–145
GGT (U/L) 71 11–63
Total bilirubin (mg/dL) 0.82 0–1.4
ALT = alanine aminotransferase; GGT = γ-glutamyl transferase;
MCV = mean corpuscular volume; WBC = white blood cell count.
n 2006 June, Volume 40 n 1191
DE Bates and RJ Herman

cians decided to rechallenge him with lopinavir 133 mg/ritonavir 33 mg
3 capsules twice daily. After 2 months, a repeat CD4+ count was 178 ×
106/L and viral load was 33 copies/mL. The patient tolerated the an-
tiretroviral regimen of lopinavir 133 mg/ritonavir 33 mg 3 capsules twice
daily, tenofovir 300 mg daily, and lamivudine 150 mg twice daily.
Discussion
Carbamazepine is extensively metabolized, with less
than 3% excreted unchanged in the urine.2 The major
metabolic pathway involves oxidation of carbamazepine
via CYP3A4 and, to a lesser extent CYP2C8, to the active
metabolite carbamazepine-10,11-epoxide.2,4-7 This metabo-
lite accounts for 25% of the dose in monotherapy and 50%
with concomitant antiepileptic drug therapy.6 Carba-
mazepine-10,11-epoxide is pharmacologically active and
also contributes to toxicity. Three other metabolic path-
ways include hydroxylation of the 6-membered aromatic
rings (25%), N-glucuronidation of the carbamoyl side
chain (15%), and substitution of the 6-membered rings
with sulfur-containing groups (5%).2,7,8 Carbamazepine in-
duces the metabolism of other drugs through its effects on
the CYP2C and CYP3A subfamilies and uridine diphos-
phate glucuronosyltransferase.4-6 Carbamazepine also in-
duces its own metabolism, which is usually complete with-
in 3–5 weeks on a fixed-dose regimen.2,6
HIV protease inhibitors are associated with numerous
drug interactions. Ritonavir is a potent inhibitor of cy-
tochrome P450 isoenzymes, and its inhibition of CYP3A is
dose related.9-11 Indinavir, amprenavir, nelfinavir, and
atazanavir are moderate CYP3A inhibitors, while saquinavir
and lopinavir produce only weak inhibition.10-12 The com-
bination of lopinavir/ritonavir is a weaker inhibitor of
CYP3A-mediated metabolism than ritonavir alone.9 The
Naranjo probability scale suggested a probable interaction
between lopinavir/ritonavir, nelfinavir, and carbamazepine
in our patient.13 A MEDLINE search (1966 –May 2006)
revealed 4 cases of interactions between antiretrovirals and
carbamazepine (Table 2).14-17
Lopinavir/ritonavir and nelfinavir were most likely re-
sponsible for causing carbamazepine toxicity in our pa-
tient. Lopinavir is metabolized by the CYP3A4 isoen-
zyme, while ritonavir is metabolized by both CYP3A and
CYP2D6.18 Four different cytochrome P450 isoenzymes
are involved in nelfinavir metabolism: CYP3A4, CYP2C9,
CYP2C19, and CYP2D6.19-21 Lopinavir/ritonavir acts as a
substrate, inducer, and inhibitor of CYP3A4 and as an in-
hibitor of CYP2D6.9,18 It does not inhibit other CYP iso-
forms at clinically relevant concentrations.22 Nelfinavir pri-
marily inhibits CYP3A4 and does not appear to signifi-
cantly inhibit other CYP isoforms.4,5,10,19 Nelfinavir is also
a substrate for CYP3A4 and CYP2C19.4,5,10 Lopinavir/ri-
tonavir or nelfinavir could inhibit and compete for metabo-
lism of carbamazepine via the CYP3A4 isoenzyme.
Protein binding and P-glycoprotein are not involved in a
lopinavir/ritonavir, nelfinavir, and carbamazepine interac-
tion. The protein binding of carbamazepine is approxi-
mately 75%,23,24 making it unlikely that a clinically signifi-
cant drug interaction would occur.6 Protease inhibitors are
substrates for P-glycoprotein.21 However, carbamazepine
has been shown not to be a substrate of P-glycoprotein,
making an interaction via this mechanism unlikely.25
Topiramate therapy was started 7 days prior to HAART,
suggesting a potential interaction with carbamazepine. To-
piramate has been suggested to be a CYP2C19 inhibitor4,26;
however, carbamazepine is not metabolized by this isoen-
zyme. Topiramate causes a dose-dependent induction of

Table 2. Reported Interactions Between Carbamazepine and Antiretroviral Drugs

Carbamazepine
Serum
Reference Antiretroviral Symptoms Onset Concentration Management
14 a
Mateu-de Antonio (2001) ritonavir 300 mg bid vertigo, drowsiness, 2 days 8.3–16.6 mg/L carbamazepine dose
saquinavir 400 mg bid disorientation, ataxia decreased from 1200 to
nevirapine 200 mg qd 600 mg/day
Garcia (2000)15 lamivudine 150 mg bid dizziness, ataxia 2 mo 6.5–18 mg/Lb carbamazepine 600 mg/day
didanosine 400 mg qd discontinued, replaced
ritonavir 600 mg bid with primidone
saquinavir 400 mg bid
Kato (2000)16 ritonavir 200 mg vomiting, vertigo 12 h 9.5–17.8 mg/Lc ritonavir discontinued,
carbamazepine dose
decreased from 700 to
280 mg/day
Burman (2000)17 ritonavir 400 mg bid ataxia 4 days 6.9–20.4 mg/L carbamazepine dose
saquinavir 400 mg bid decreased from 600 to
efavirenz 600 mg qd 100 mg/day

a
Phenytoin concentration decreased from 10.4 to 7 mg/L; phenobarbital concentration unchanged.
b
Phenytoin concentration essentially unchanged: decreased from 16.5 to 14.7 mg/L.
c
Zonisamide concentration unchanged.

1192 n The Annals of Pharmacotherapy n 2006 June, Volume 40 www.theannals.com


CYP3A4 at doses greater than 400 mg/day.27 Two pharma-
cokinetic studies suggested that topiramate does not signifi-
cantly increase or decrease carbamazepine or carba-
mazepine-10,11-epoxide serum concentrations.28,29 The
Canadian30 and American31 topiramate product monographs
also state that there is essentially no significant change in
carbamazepine or carbamazepine-10,11-epoxide concentra-
tions, defined by a 10–15% difference from baseline.
A MEDLINE search revealed one citation suggesting
an interaction between carbamazepine and topiramate.32
Twenty-five patients had contacted an epilepsy specialist
nursing service. All patients were stabilized on a mean car-
bamazepine dosage of 900 mg twice daily (range 450 mg
to 2.8 g twice daily). Nine patients received carbamazepine
monotherapy, while the remainder were taking 2–3 con-
comitant antiepileptic medications.
Signs of drug intoxication were evident at a mean topir-
amate dose of 160 mg (range 25–800) daily. Symptoms
included drowsiness, lethargy, nausea, dizziness, blurred
vision, diplopia, poor concentration, slurred speech, and
ataxia. Lowering the carbamazepine dose by 100 mg daily
reduced the adverse effects in all cases. There were no car-
bamazepine serum concentrations reported, nor was there
mention of other concomitant drug therapy that could de-
crease carbamazepine metabolism. This case review is
suggestive of a pharmacodynamic interaction between car-
bamazepine and topiramate.32
In our patient, it is unlikely that other medications could
have contributed to the development of carbamazepine
toxicity. He had been taking citalopram for 5 years, and it
has been shown not to affect the pharmacokinetics of carba-
mazepine or the carbamazepine-10,11-epoxide metabolite.33
Dapsone is a substrate for CYP3A4.2,4,10 Dapsone could com-
pete with carbamazepine for the CYP enzyme; however, as
of this writing, there is no documentation of this interaction
in the literature. Our patient had been taking dapsone for 4
months without any increase in the carbamazepine serum
concentration. The likelihood of a drug interaction with
lamivudine is low due to limited metabolism, protein bind-
ing, and almost complete renal clearance.34 Furthermore,
CYP450 isoenzymes are not involved in lamivudine metabo-
lism. In vitro studies have shown that neither tenofovir diso-
proxil fumarate nor tenofovir is a substrate for CYP.35,36 Dex-
amethasone doses of 16 mg/day may induce CYP3A4.37
There is a lack of data evaluating the pharmacokinetic
and pharmacodynamic interaction of anticonvulsants in
patients receiving HAART. Bidirectional drug interactions
involving antiretrovirals and anticonvulsants may result in
decreased efficacy of HAART and increased anticonvul-
sant toxicity. Carbamazepine, phenytoin, and phenobarbi-
tal have been shown to induce CYP3A and may lead to in-
sufficient protease inhibitor serum concentrations resulting
in increased viral replication and resistance.38 Virologic
failure has been reported when carbamazepine was added
www.theannals.com The Annals of Pharmacotherapy
Carbamazepine Toxicity Induced by Lopinavir/Ritonavir and Nelfinavir
to antiretroviral therapy.3 A patient stabilized on indinavir
800 mg every 8 hours, lamivudine 150 mg twice daily, and
zidovudine 200 mg 3 times daily was prescribed carba-
mazepine 200 mg daily for postherpetic neuralgia. Indi-
navir serum concentrations were slightly below the lower
limit of the mean population curve, and the viral load was
less than 400 copies/mL prior to the initiation of carba-
mazepine. After approximately 75 days of treatment, carba-
mazepine was discontinued. The indinavir serum concen-
tration was 4% of the mean population values, and the viral
load had increased to 6000 copies/mL. Carbamazepine
serum concentrations remained within the normal range.
The patient had been adherent to HAART. Viral load, dis-
ease progression, and protease inhibitor and anticonvulsant
serum concentrations must be monitored closely.38,39 The
need for anticonvulsant therapy should be assessed and, if
necessary, an alternative anticonvulsant that does not inter-
act with protease inhibitors would be appropriate.40
Conclusions
Our patient developed carbamazepine toxicity with
lopinavir/ritonavir and nelfinavir, necessitating a 33% re-
duction in his carbamazepine dosage. Resolution of drowsi-
ness and feelings of unsteadiness on his feet occurred with-
in 72 hours of decreasing the carbamazepine dose. Based
on the available information, we suggest a 25–50% reduc-
tion in carbamazepine dosage during protease inhibitor
therapy, with a follow-up carbamazepine serum concentra-
tion obtained in 3–5 days. A viral load may be repeated in
30–60 days to assess viral suppression and monitoring of
protease inhibitor serum concentrations if carbamazepine
therapy is to be continued.
Duane E Bates BSc Pharm, Clinical Pharmacist, Internal Medicine,
Department of Pharmacy, Foothills Medical Centre, Calgary, Alber-
ta, Canada
Robert J Herman MD, Professor, Faculty of Medicine, University
of Calgary; Chief, Division of General Internal Medicine, Calgary
Health Region; Head, Division of General Internal Medicine, Uni-
versity of Calgary, Calgary
Reprints: Mr. Bates, Foothills Medical Centre, 1403 29th St. NW,
Calgary, AB, Canada T2N 2T9, fax 403/944-4893, duane.bates@
calgaryhealthregion.ca
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40. Brooks J, Daily J, Schwamm L. Protease inhibitors and anticonvulsants.
AIDS Clin Care 1997;9:87,90.
EXTRACTO
OBJETIVO: Presentar un caso de toxicidad por carbamazepine precipitado
por lopinavir/ritonavir y nelfinavir.
RESUMEN: Un hombre de 50 anos infectado con el HIV desarrollo
mareos excesivos secundario al uso de carbamazepine cuando fue
comenzado en un regimen antirretroviral que contenia
lopinavir/ritonavir. La concentración serica de carbamazepina aumento
en un 46%. Luego, el paciente desarrollo una posible reacción adversa
en la piel y fue hospitalizado. El inhibidor de proteasa fue descontinuado
y comenzo en nelfinavir. Dentro de los proximos 3 días, el paciente se
quejo de mareos excesivos y pobre estabilidad en los pies. En este
momento, la concentración serica de carbamazepine había aumentado
en un 53%. En ambas ocasiones, la dosis de carbamazepine se
disminuyo en un 33%, lo que resulto en la resolución de los síntomas.
DISCUSIÓN: El carbamazepine es metabolizado extensamente por el
higado. La ruta principal de metabolismo consiste de oxidación por las
isoenzimas del citocromo P-450 a un metabolito activo, el
carbamazepine-10,11-epoxide. Los inhibidores de proteasa son
inhibidores conocidos del sistema de isoenzimas del citocromo P-450.
Se revisan casos reportados de toxicidad por carbamazepine secundarios
a la inhibición de su metabolismo por parte de inhibidores de proteasa.
CONCLUSIONES: Una evaluación objetiva de la causalidad de la reacción
sugiere que el paciente desarrollo mareo e inestabilidad al pararse
debido a la interacción de carbamazepine e inhibidores de proteasa,
evidenciado esto con concentraciones sericas elevadas de
carbamazepine. Tanto lopinavir/ritonavir como nelfinavir pueden
aumentar la concentración serica de carbamazepine. Se puede prevenir
la toxicidad por carbamazepine al reducir la dosis del farmaco en un
25–50% cuando se introducen inhibidores de proteasa en el regimen
terapeutico de un paciente que previamente ha estado recibiendo una
dosis estable de carbamazepine. Es recomendable también, obtener una
concentración serica de carbamazepine luego de 3 a 5 días de haber
comenzado el inhibidor de proteasa.
Wanda T Maldonado
RÉSUMÉ
OBJECTIF: Décrire un cas de toxicité de la carbamazépine induite par le
lopinavir/ritonavir et le nelfinavir.
SOMMAIRE DU CAS: Un homme de 50 ans, infecté par le VIH, a présenté
de la somnolence excessive secondaire à la carbamazépine lorsque
qu’un traitement antirétroviral associant le lopinavir/ritonavir a été
instauré. La concentration sérique de carbamazépine s’est accrue de
46%. Conséquemment, le patient a présenté une réaction indésirable
cutanée aux antirétroviraux et a été hospitalisé. L’association
lopinavir/ritonavir a été cessée et remplacée par le nelfinavir. En moins
de 3 jours, le patient s’est plaint de somnolence excessive et d’être
chancelant en position debout. À ce moment, la carbamazépinémie
s’était élevée de 53%. À chaque changement d’IP, la posologie de la
carbamazépine a été réduite de 33%, ce qui a permis de contrôler les
www.theannals.com
 Carbamazepine Toxicity Induced by Lopinavir/Ritonavir and Nelfinavir

symptômes de toxicité. une interaction médicamenteuse carbamazépine et IP. Le

DISCUSSION: La carbamazépine subit un métabolisme hépatique
important. La principale voie métabolique empruntée est l’oxydation de
la carbamazépine, via le cytochrome P450 3A4, en un métabolite actif,
la carbamazépine-10,11 époxyde. Il est bien connu que les IP sont des
inhibiteurs du cytochrome P450 3A4. Les auteurs décrivent les cas de
toxicité secondaire de la carbamazépine induite par les différents IP de la
protéase.
CONCLUSIONS: Un lien de cause à effet objectivé suggère que ce patient
est devenu somnolent et chancelant en position debout secondairement à
lopinavir/ritonavir ainsi que le nelfinavir peuvent interférer avec le
métabolisme de la carbamazépine causant ainsi une augmentation des
concentrations sériques de cette dernière. La toxicité de la
carbamazépine peut être évitée en diminuant sa posologie de 25 à 50%
lorsqu’un traitement par des IP est instauré. Un dosage plasmatique de la
carbamazépine doit être fait 3 à 5 jours après l’introduction des
inhibiteurs de la protéase.
Denyse Demers

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www.theannals.com The Annals of Pharmacotherapy n 2006 June, Volume 40 n 1195