Here we describe a case of a 24-year-old male patient who had been known
to have tuberous sclerosis complex (TSC) since birth. At the age of 6,
the patient developed a cerebral tumor which was resected successfully,
and had been maintained on oral levetiracetam 500 mg three times daily
and topiramate 100 mg twice daily for several years. At the age of 20,
he was discovered to have malignant multiple bilateral renal epithelioid
angiomyolipomas (EAML), for which the patient underwent right
nephrectomy, selective radiological embolization and cryotherapy for
three EAML of the left kidney. A year later, he was discovered to have a
retro-caecal retroperitoneal mass and a right adrenal mass in which the
patient underwent a surgical intervention for a complete removal of this
retroperitoneal mass and a right adrenalectomy, histopathological
analysis revealed malignant renal EAML. At the age of 22, the patient
underwent an imaging follow-up computer tomography (CT) scan which
showed a retroperitoneal mass (inter aortic-cave) and hepatic lesions;
with a liver punction biopsy result showing EAML metastasis. Treatment
was initiated by everolimus for
8 months, during those 8 months, we noticed stability of the hepatic
metastasis and the renal EAML. Unfortunately, this line of treatment
failed with augmentation of liver metastasis afterwards. Everolimus
trough whole blood concentrations determined by LC/MS² technique were
low but stable, between 1.5 and 4.0 µg.L-1. This led
us to switch to temsirolimus, with a weekly dose administration of 25
mg. This switch did not show any sign of clinical nor radiological
improvement on the patient what so ever leading us to believe that there
might be a possible drug interaction in the equation. Our patient had
been taking carbamazepine 400 mg twice a day for his epilepsy attacks.
Carbamazepine is an antiepileptic drug which is metabolized primarily in
the liver by CYP3A4 and is an inducer of CYP3A4 enzyme, which increases
the clearance of many drugs including everolimus and sirolimus and
decreases their concentration in the blood to sub-therapeutic levels
leading to a reduction in their desired effect. Monitoring of
carbamazepine plasma concentration showed carbamazepine values between
10.4 and 14.9 mg.L-1 (reference values 4-12
mg.L-1). A therapeutic drug monitoring, was proposed
by measuring temsirolimus and sirolimus concentrations in the blood by
LC/MS² techniques. The area under the concentration curve (AUC) for both
molecules was measured. We noticed that with a dose of 25 mg of
temsirolimus, the AUC reached 2.35 h. μg. mL-1,
whereas the AUC described in the literature for temsirolimus was between
2.70 ± 0.72 [2] and 5.03 ± 2.92
h.µg.mL-1 [3]
however no effective therapeutic target is defined. While for sirolimus,
the AUC was 1.37 h.μg.mL-1, however the AUC described
in the literature for sirolimus was between 13.30 ± 3.70
[2] and 14.49 ± 4.94
h.µg.mL-1 [3] for
patients not on enzyme-inducing epileptic drugs (EIAED), whereas
patients receiving EIAED showed a 1.5-fold lower systemic exposure to
temsirolimus and a 2-fold lower exposure to sirolimus
[2,
3]. And on top of that, sirolimus
concentrations in the blood disappeared between the 2nd (6.8 µg.
L-1) and 3rd day (1.7 µg. L-1) after
introduction of carbamazepine, explaining the ineffectiveness on the
hepatic metastasis. As a consequense, we increased the
doses of temsirolimus and sirolimus until reaching an AUC of 6.06
h.μg.mL-1 and 2.51 h.μg.mL-1 for
temsirolimus and sirolimus respectively. Temsirolimus reached an
effective therapeutic zone of 75 mg weekly and was still detected in the
blood at the 7th day postadministration (T168 Hour, 4.1 µg.
L-1). Blood concentrations of sirolimus and
temsirolimus at doses of 25 mg and 75 mg through-out the week are shown
in figure 1. At these specific concentrations, we started noticing
regression of the hepatic metastasis and renal EAML with improvement of
the general state of the patient. Unfortunately, the patient relapsed
one year later and developed an insulinoma going into palliative
treatment and passed away soon after.