CASE REPORT

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.