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 C 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.