DISCUSSION
Everolimus is an oral mTOR inhibitor that binds with high affinity to the FK506 binding protein-12 (FKBP-12), and activation of mTOR is inhibited by this complex. Due to several factors could affect its pharmacokinetic profile, TDM is routinely established when everolimus is used in transplant patients to achieve the optimal Cmins, whereas in cancer patients is not established10.
According to product label, in oncology, everolimus is prescribed as an standard fixed oral dose of 10 mg, administered once daily. It is absorbed rapidly and peak concentration is reached after 1.3–1.8 hours. The systemic availability of a single oral 10 mg dose of everolimus is significantly reduced by coadministration with a meal compared with fasting conditions. Maximum concentration (Cmax) and area under the concentration-curve time (AUC) were reduced by 42% and 22% after low-fat meals; this reduction is increased until 54% and 33% after a high-fat meal11. To avoid this variability in absorption we recommended our patient to take everolimus every day in fasting conditions, at least 1-hour before breakfast. Everolimus steady (SS) state is reached within 7-14 days, and steady-state peak and trough concentrations, and AUC are proportional to dosage.
Five studies with 945 patients treated with everolimus (lung, renal and neuroendocrine tumors) were included in a meta-analysis by Ravaud et al where the mean everolimus Cminss was 15.65ng/ml (90%CI 14,79-16.55ng/ml)6. Better response and major reduction in tumour size were observed with a two-fold increase in Cminss. In conclusion, Cminss ≥ 10 ng/mL could be used as target value for optimal response, while Cminss > 26.3 ng/mL was associated with a 4-fold increased risk of toxicity compared to Cminss < 26.3 ng/mL. Only 45% of patients with neuroendocrine tumors achieved optimal everolimus plasmatic concentrations (10-30ng/ml), while in lung and renal cancer were 55.2% and 62.9%, respectively. Administering everolimus with strong CYP3A4 inhibitors increased everolimus Css by 10%. On the other hand, a 7% decrease was observed upon coadministration of CYP3A4 inducers. In another study by Hirabatake et al. median PFS was 13.7 months (1.7-55.8 months) and fifty per cent of breast cancer patients treated with everolimus showed Css below 10ng/ml. PFS was significantly longer in the 10-20ng/ml group (p=0.0078) and the median of Cminss in patients with dose-limiting toxicities was 19ng/ml (11.3-64.6ng/ml)12.
One of the reasons of the interindividual pharmacokinetic variability of everolimus can be explained by different activities of the drug efflux pump P-glycoprotein and of metabolism by cytochrome P450 (CYP) 3A4, 3A5 and 2C88. The critical role of the CYP3A4 system for everolimus biotransformation leads to drug-drug interactions with other drugs metabolised by this cytochrome system and could affect its efficacy or toxicity.
There are some studies and several reports in the literature with single drug-drug interaction with everolimus.
In a study in 16 healthy subjects reported by Kovarik et al., verapamil (a relatively potent inhibitor of P-glycoprotein, and a moderate inhibitor of CYP3A4) administered as 80mg three times daily, during 6 days, was added to a single 2 mg dose of everolimus13. During verapamil co-administration, everolimus Cmax increased 2.3-fold (90% CI, 1.9,2.7) from 21 ± 8 to 47 ± 18 ng ml-1 and AUC increased 3.5-fold (90% CI, 3.1, 3.9) from 115 ± 45 to 392 ± 142 ng ml-1 h. In a case report by Strobbe et al., interaction with verapamil at 120mg every 12 hours, and everolimus at 7.5mg daily was reported in cancer renal patient14. The patient developed a grade 3 oral mucositis and everolimus plasma concentration was 52.4 ng/mL. Administration of everolimus was stopped and then was reintroduced to a 5 mg/daily. The efficacy of everolimus was maintained during more than a year, and a partial tumour response to the 5 mg dose was identified and deemed to be generally well tolerated.
In another study by Kovaric et al., erythromycin 500 mg (a CYP3A inhibitor) administered three times daily, for 9 days and a single 2-mg dose of everolimus were co-administered15. Everolimus  max was rised up 2.0-fold (90% CI, 1.8–2.3) from 20±5 ng/ml to 40±10 ng/ml and AUC was increased 4.4-fold (90% CI, 3.5–5.4) from 116±37 ng h/ml to 524±225 ng h/ml during erythromycin coadministration.
A case of potential interaction in cancer renal patient after three months under everolimus treatment was reported by Miesner et al.16 when clarithromycin was added to his treatment.Helicobacter pylori  infection was suspected and amoxicillin, clarithromycin, and omeprazole therapy was started. Then, 12 days after initiation of this regimen, he was admitted with acute kidney injury, proteinuria and an everolimus trough level of 110 ng/mL (20 hours postdose)
Tran et al. reported a case of a 32- year- old female with relapsed Hodgkin’s lymphoma who was on everolimus for 5 years and developed nephrotic syndrome and everolimus Css found was > 40ng/ml, 2 months after initiation of voriconazole for aspergillus pneumonia17.
Mir et al. described an induction CYP3A4 interaction when fenofibrate was added in a cancer metastatic breast patient who was being treated with everolimus 10mg/daily plus exemestane 25mg/daily18. Everolimus trough plasma concentration was 10.1 ng/ml before introduction of fenofibrate. Two weeks later, everolimus trough concentration had dropped to 4.2 ng/ml. Hence, fenofibrate was withdrawn. Two weeks later, everolimus trough concentration rose to 11.5 ng/mL.
To our knowledge, this is the first case report in the literature with two major interactions which can affect everolimus metabolism through strong induction of CYP3A4. Eerolimus dosing was optimized to achieve optimal Css by using TDM. Carbamazepine and phenytoin are major CYP3A4 inducers and one month after starting treatment, Css everolimus detected was 3.7ng/ml. To achieve optimal Css (10ng/ml) progressive dosage increase from 10mg daily to 15mg daily of everolimus was suggested, and total daily dose was divided into two doses separated 12 hours, 10mg-5mg, in fasting conditions. Pharmacokinetic optimization of everolimus dosing in oncology has been studied, by Verheijen et al., in a crossover trial in 10 patients, that compared everolimus 10 mg once daily with 5 mg twice daily19. Twice daily dosage regimen showed a significantly decrease in Cmax from 61.5ng/ml to 40.3ng/ml (p=0.013), and significantly increase in Css from 9.6ng/ml to 13.7ng/ml (p=0.018), without differences in AUC between them (435ng*h/ml vs 436 ng*h/ml) (p=0.952).
Our patient finally achieved anoptimal Css two months later, after two dose adjustments to increase everolimus dosage to 10mg every 12 hours.