Everolimus Blood Levels Research Articles

Pulmonary toxicity of mTOR inhibitors. Comparisons of two populations: Solid organ recipients and cancer patients

Mammalian target of rapamycin (mTOR) inhibitors-associated pneumonitis (mTOR-IP) has long been described in solid organ recipients (T) patients but more recently in cancer (K) patients. Its overall characteristics have never been compared between these 2 populations. The aim of this study was to compare them in terms of presentation, severity and outcome in T and in K patients. We carried out a retrospective study in a single French tertiary center. Four databases were used to ensure the exhaustive collection of all mTOR-IP cases between 2001 and 2020. All clinical, biological, radiological, pathological and outcome data were reviewed. Thirty-nine patients with mTOR-IP were diagnosed during this period, 24T and 15K patients. The average dosage of everolimus and sirolimus was 2,65mg (±1,78) and 2,75mg (±0,96) in T patients, respectively, versus 8,75mg (±2,26) for everolimus in K patients. The overall prevalence of mTOR-IP was 6.4% with a median time of occurrence of 7 months [IQR 3-35 months]. mTOR-IP were significantly more frequent (P<0.001) and occurred earlier (P<0.001) in cancer patients. No clinical, functional, radiological, pathological nor outcome differences were otherwise observed between the 2 groups. Average everolimus blood levels at the time of mTOR-IP diagnosis were in the range of recommended therapeutic values. Our study shows that mTOR-IP is comparable in terms of presentation in T and in K patients but that it occurs significantly earlier after drug introduction in the latter. This raises questions as to the potential role of the higher doses used in K patients as well as that of co-treatments in the pathogeny of the disease.

Real-World Evidence Study on the Long-Term Safety of Everolimus in Patients With Tuberous Sclerosis Complex: Final Analysis Results.

The TuberOus SClerosis registry to increase disease Awareness (TOSCA) Post-Authorization Safety Study (PASS) was a non-interventional, multicenter, safety substudy that assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) receiving everolimus for its licensed indications in the European Union (EU). This substudy also aimed to address TSC-associated neuropsychiatric disorders (TAND), sexual development, and male infertility. Eligible patients were enrolled from 39 sites across 11 countries in the EU. Outcomes of interest included the incidence of adverse events (AEs), serious adverse events (SAEs), treatment-related AEs (TRAEs), AEs leading to everolimus discontinuation, AEs of special interest (AESIs), the observed relationship between everolimus blood levels and incidence of AESIs, TAND, and reproductive clinical features. Herein, we present the final analysis results from this substudy (data cutoff date: 22 January 2020). At data cutoff, 179 patients were enrolled (female, 59.2%; age ≥18 years, 65.9%), of which the majority completed the study (76%). Overall, 121 patients (67.6%) had AEs regardless of causality. The most frequent TRAEs (≥5%) were stomatitis (7.8%), aphthous ulcer (6.7%), and hypercholesterolemia (6.1%). The most common treatment-related SAEs (>1%) were pneumonia (3.4%), influenza, pyelonephritis, aphthous ulcer, stomatitis, dyslipidemia, and hypercholesterolemia (1.1% each). Ten patients (5.6%) reported AEs leading to everolimus discontinuation. The common psychiatric disorders (N = 179) were autism spectrum disorder (21.8%), anxiety disorder (12.8%), “other” psychiatric disorders (8.9%), attention-deficit hyperactivity disorder, and depressive disorder (7.8% each). Of 179 patients, 88 (49.2%) had ≥1 behavioral problem. Of these (n = 88), the most common (>20%) were sleep difficulties (47.7%), anxiety (43.2%), mood swings (37.5%), depression mood (35.2%), impulsivity (30.7%), severe aggression (23.9%), and overactivity (22.7%). Of 179 patients, four (2.2%) reported abnormal puberty onset, and three (1.7%) reported other reproductive disorders. Of 106 females, 23 (21.7%) reported menstrual cycle disorders and 10 (9.4%) reported amenorrhea. Available data did not show delays in sexual maturation or an association between sexual development and infertility. The results demonstrate that everolimus has a manageable long-term safety profile in the TSC treatment setting. No new safety signals emerged. This substudy also contributed to the mapping of TAND and reproductive clinical features in patients with TSC.

Phase 0 Clinical Trial of Everolimus in Patients with Vestibular Schwannoma or Meningioma.

Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of patients with neurofibromatosis type 2 (NF2) with vestibular schwannoma. To assess the pharmacokinetics, pharmacodynamics, and potential mechanisms of treatment resistance, we performed a presurgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for vestibular schwannoma or meningiomas. Eligible patients with meningioma or vestibular schwannoma requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately before and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and postoperative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/mL and 9.4 ng/mL, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range, 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared with control tissues from untreated patients (P = 0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited antitumor effect of everolimus observed in clinical studies for patients with NF2 and will inform the design of future preclinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.

ACTR-09. A PHASE 0 PHARMACODYNAMIC AND PHARMACOKINETIC STUDY OF EVEROLIMUS IN VESTIBULAR SCHWANNOMA (VS) AND MENINGIOMA PATIENTS

Abstract BACKGROUND Inhibition of mTORC1 signaling has been shown to diminish growth of NF2 deficient tumors in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of adult and pediatric NF2 patients with VS. To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (“phase 0”) clinical trial of everolimus in patients undergoing surgery for VS or meningiomas. METHODS Eligible patients with meningioma or VS requiring tumor resection received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. RESULTS Ten patients completed protocol therapy, including 5 patients with NF2-related meningioma, 3 patients with sporadic meningioma, and 2 patients with NF2-related VS. Median pre- and post-operative plasma levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 ng/g (range 9.2–169.2), and median tumor tissue to post-operative plasma drug concentration ratio was 0.39. We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to matched control tissues from untreated patients (p = 0.005). Consistent with prior observations that inhibition of mTORC1 may lead to MAPK pathway activation through a PI3K-dependent feedback loop, we observed a statistically significant increase of phospho-ERK (p &lt; 0.03) versus untreated controls. CONCLUSIONS In patients with meningioma or VS, treatment with everolimus leads to incomplete inhibition of mTORC1 signaling and upregulation phospho-ERK. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and identify upregulation of phospho-ERK as a likely resistance mechanism that could be addressed with combination therapies.

Comparison of the everolimus concentrations measured in whole blood with everolimus QMS or sirolimus CMIA

Few years ago, it was proposed that everolimus blood levels could be determined with the commercially available sirolimus chemiluminescence magnetic microparticle immunoassay (CMIA). More recently, a highly specific microsphere system (QMS) has been approved by FDA for therapeutic drug monitoring in humans. Aim of the present study was to compare the results of everolimus assay performed with everolimus QMS and with sirolimus CMIA. The two methods were compared with Passing–Bablok regression and Bland–Altman plot analysis. The Passing–Bablok regression analysis showed that although the results obtained with the two techniques were significantly correlated, CMIA-measured differed from QMS-measured everolimus concentrations by both a systematic and a proportional error. Specifically, at blood levels lower than 5 ng/mL CMIA were lower than QMS-measured everolimus concentrations. On the opposite, at everolimus blood concentrations higher than 10 ng/mL CMIA-estimated values became progressively higher than QMS-measured everolimus concentrations. The analysis of the Bland Altman plot showed a less than optimal agreement of the two tests (5.59% of the data point outside the ±1.96 SD interval). Moreover, the relationship between the difference between EveroQMS and EveroCMIA and their average was clearly concentration dependent with positive and negative values at concentration values lower and higher than 5 ng/mL respectively.In conclusion, our finding showed that the values of everolimus concentrations measured with sirolimus CMIA differ from those detected with the FDA-approved everolimus QMS further suggesting that sirolimus CMIA should not be used anymore for everolimus therapeutic drug monitoring.

The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study.

Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5–21) in combination with azacitidine 75 mg/m2 subcutaneously (days 1–5 and 8–9 every 28 days) in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded (n = 21). Major adverse events (grade > 2) were mostly disease-related: neutropenia (73%), thrombocytopenia (67%), mucositis (24%) and febrile neutropenia (19%). Overall survival (OS) of the entire cohort was 8.5 months, and overall response rate (ORR; including CR/CRi/PR/MLFS) was 22.5%. Furthermore, a landmark analysis beyond cycle 1 revealed superior OS and ORR in patients receiving 2.5 mg everolimus with azoles, compared to those without azoles (median OS 12.8 vs. 6.0 months, P = 0.049, and ORR 50% vs. 16%, P = 0.056), potentially due to achievement of higher everolimus blood levels. This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced AML.

Management of Everolimus and Voriconazole Interaction in Lung Transplant Patients.

To analyze the impact of voriconazole administration on everolimus dose, trough concentrations and concentration/dose (C0/D) ratio in order to determine the appropriate management of this interaction in lung transplant patients. A retrospective study of 16 of consecutive lung transplant patients on a stable everolimus-based regimen to which oral voriconazole was added from January 2013 to February 2014. Everolimus blood levels were measured using the Thermo Scientific QMS Everolimus Immunoassay on an ARCHITECT-C8000 analyzer. The Wilcoxon signed-rank test was used to assess the exposure parameter variations before, during, and after azole withdrawal. A statistical analysis was performed using SPSS version 19.0. P-value < 0.05 was considered statistically significant. Sixteen patients were included. Voriconazole treatment led to a significant 8.7-fold increase in the everolimus C0/D ratio. Although initially the daily dose was reduced to 48.5% ± 20.5%, and subsequently to 79.5% ± 7.1%, the desired therapeutic levels were achieved in all patients when it was decreased to 86.6% ± 3.9%. After its withdrawal, the C0/D ratio returned to values similar to the baseline situation. The comparison of exposure parameters studied at stable moments, before and after the completion of azole treatment with the cotreatment period, revealed significant changes (P < 0.05). Oral voriconazole is a strong inhibitor of everolimus metabolism, requiring a dose reduction of around 87%. At the time of azole withdrawal, the dose should be increased to achieve C0/D ratio values similar to the initial situation. In our clinical practice, for a safe coadministration, a preemptive decrease to 75% of everolimus dose with the first azole prescription is recommended. Close monitoring of the everolimus concentrations and corresponding dosage adjustments are necessary until the target levels are achieved during both periods.

Elevated Everolimus Levels During Severe Diarrhea in Two Children After Heart Transplantation

Minimization of side effects of immunosuppressive therapy after pediatric heart transplantation is an important objective of aftercare. Not only various medications and foods but also gastrointestinal problems can cause increased peak levels of immunosuppressants. Especially, tacrolimus is well known for elevated levels during diarrhea (1–3). In the follow-up care of pediatric heart transplanted patients, the new immunosuppressant everolimus is increasingly used. However, the influence of diarrhea on everolimus blood levels has not been evaluated yet. We report about two patients with elevated everolimus levels during severe diarrhea with at least two watery stools per day. CASE 1 The 3.5-year-old girl with history of heart transplantation in June 2010 because of noncompaction cardiomyopathy was on immunosuppressive therapy with everolimus and tacrolimus. The target value of tacrolimus was 6 ng/mL; the one of everolimus ranged from 4 to 5 ng/mL. Levels were at the lower limits (tacrolimus 5.2 ng/mL and everolimus 2.9 ng/mL) under a daily dosage of 3 mg tacrolimus and 2.5 mg everolimus 1 week before the occurrence of diarrhea. During one episode of severe diarrhea, the patient was admitted to our hospital because of dehydration. The blood trough level of tacrolimus had increased from 5.2 to 21.6 ng/mL, whereas everolimus had increased from 2.9 to 13.4 ng/mL. By pausing both immunosuppressive medications, the levels decreased slowly, so that tacrolimus and everolimus could be continued in a reduced dosage after 2 days (tacrolimus daily dose 2 mg and everolimus daily dose 1.5 mg). Ten days after the onset of diarrhea, the levels of both immunosuppressants returned to normal values under a reduced dosage. Furthermore, there was no need to increase the two immunosuppressive medications to the initial dose before diarrhea within 8 months after diarrhea had occurred. CASE 2 The 13-year-old boy had to undergo heart transplantation 1998 because of dilated cardiomyopathy. Thirteen years later, he was on immunosuppressive therapy with mycophenolic acid (MPA) and everolimus. The target values of MPA were between 0.5 and 4µg/mL and stayed within the target range before, during, and after diarrhea. It was possible to constantly achieve the target values of everolimus (between 5 and 8 ng/mL) under a dosage of 4.75 mg per day. During severe diarrhea, the everolimus level rose to 15.6 ng/mL. Via dose reduction and normalization of the stool, simply under symptomatic therapy, the levels went back to normal in about 1 week. There was no need to change the dosage of MPA. Interestingly, as in the first case, it was not possible to return to the initial dose before diarrhea for more than 1 year. In both cases, a correlation between the elevated values and medication or food was not detectable. There were no changes of medication, the chronological taking of everolimus related to food, or initiation of interacting drugs before the onset of diarrhea. In addition, there was no sign of reduced hepatic function that could have explained the elevated levels of everolimus. It was not possible to identify a specific cause for the diarrhea in the patients. However, a viral infection seems most likely. There are reports on elevated tacrolimus levels during diarrhea (1–3). We detected the same effect with everolimus during diarrhea in two patients after heart transplantation. The immunosuppressant everolimus has a low oral bioavailability of 16% (4). P-glycoprotein and cytochrome P450 are responsible for the absorption and metabolism of everolimus (4) as well as tacrolimus (2). Therefore, the reasons for elevated tacrolimus levels during diarrhea could accordingly apply to everolimus. Possible explanations are decreased activity of cytochrome P450 and P-glycoprotein (2) as well as a decreased hepatic blood flow with reduced hepatic metabolism (1). The apices of the enterocytes in the small intestine carry cytochrome P450. Lysis of the enterocytes by viral diarrhea leads to reduced activity of cytochrome P450 causing decreased intestinal metabolism of immunosuppressants with increased blood levels. In addition, a capacity overload could explain the concordant change of the immunosuppressant levels in case of a simultaneous taking of tacrolimus and everolimus. According to the equivalent hypotheses concerning tacrolimus (2), the lower dosage for almost 1 year after diarrhea could be explained by the time required to normalize the activity of cytochrome P450 and P-glycoprotein. For the evaluation of the concrete mechanism of elevated everolimus levels during diarrhea, further studies are necessary. However, regardless the mechanism responsible, it is important to know about the possible increase of everolimus during diarrhea. A frequent control of everolimus levels is recommended to avoid everolimus-dependent adverse events. Sarah M. Kohler Julia Birnbaum Alexandra Th. Fuchs Roxana Engmann Heinrich Netz Rainer Kozlik-Feldmann Department of Pediatric Cardiology and Intensive Care Medicine Ludwig-Maximilians-University Munich Munich, Germany

Hemodialysis no reason to withhold everolimus

Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) was reported to have anti-tumor activity in neuroendocrine tumors (NET) in phase III studies [1, 2]. These studies excluded patients with major comorbidities. This is not reflecting common practice. Particularly in NETs, often diagnosed in middle-aged or elderly patients, multiple comorbid conditions can coexist [3]. This can pose a challenge in the systemic treatment for a NET. One of the possible comorbidities is renal insufficiency. In Von Hippel–Lindau disease, a disease that predisposes to NET, even up to 25 % of patients develop terminal renal failure due to surgery for renal cell carcinoma. We have treated a 76-year-old lady suffering from a terminal renal insufficiency requiring hemodialysis with everolimus. She had a serotonin producing to the liver metastasized grade 1 ileac carcinoid. The patient had clinical and radiologic progressive disease with diarrhea while on treatment with a somatostatin analog. Comorbidity precluded treatment with interferon or radioactive lutetium. Therefore, treatment with everolimus was considered. Everolimus is in 98 % metabolised by the liver and excreted in the bile and only 2 % is eliminated in the urine [4]. No information is available on everolimus treatment in solid tumor patients on hemodialysis. Given its elimination profile and availability of an everolimus blood level assay, we decided that it was worth to start everolimus in this patient with terminal renal failure. Everolimus was started, under controlled conditions, at 50 % of the starting dose in the phase 3 NET trials, namely 5 mg orally once daily. After 3 weeks, she experienced no side effects and diarrhea was reduced. Whole blood everolimus concentrations at steady state were measured with liquid chromatography–mass spectrometry at two different times to rule out unexpected toxic accumulation. Whole blood everolimus levels were 4.4 and 6.5 lg/l before and 3.3 and 5.8 lg/l after hemodialysis. These values do not exceed the levels measured in solid tumor patients using 5 mg everolimus with normal renal function [5]. After 6 weeks of use, an ongoing decrease in diarrhea and fatigue and a decrease in chromagranin A occurred. Liver metastases were stable on ultrasound of the liver. The dose was increased to 10 mg daily and everolimus blood levels after 1 week did not exceed the previously reported blood values in patients using 10 mg. The patient is currently on everolimus treatment for 9 months without adverse effects. In conclusion, everolimus at a dose of 5–10 mg orally once daily can be used in patients with end-stage renal disease requiring hemodialysis in the treatment for solid tumors. Our findings confirm the recent report about two patients on hemodialysis. Here, hemodialysis did also not influence everolimus blood concentrations in renal cell cancer patients using 10 mg everolimus orally once daily [6]. These findings can help translating the treatment of a selected study population to clinical practice. This is of relevance given the growing number of indications for everolimus, including since recently postmenopausal estrogen positive advanced breast cancer [7]. J. M. van Rooijen (&) E. G. E. de Vries Department of Medical Oncology, University Medical Center Groningen, P.O. Box 30001, Groningen, The Netherlands e-mail: j.m.van.rooijen@umcg.nl

Ultra Fast Liquid Chromatography-Tandem Mass Spectrometry Routine Method for Simultaneous Determination of Cyclosporin A, Tacrolimus, Sirolimus, and Everolimus in Whole Blood Using Deuterated Internal Standards for Cyclosporin A and Everolimus

Specific chromatographic methods for the measurement of cyclosporin A, tacrolimus, sirolimus, and everolimus blood levels in patients with organ transplants are time consuming when large numbers of samples must be processed. The authors developed a robust and fast (1 minute) online solid-phase extraction liquid chromatography/tandem mass spectrometry method for the simultaneous quantification of cyclosporin A, tacrolimus, sirolimus, and everolimus. After protein precipitation of the whole blood with zinc sulphate and methanol, the supernatant was loaded on a wide pore reversed-phase column and cleansed of potential interferences with high flow for 20 seconds. After column switching, the analytes were transferred within 20 seconds in the back-flush mode to a short phenyl-hexyl column. The valve was then returned to its initial position and the chromatographic separation performed within 20 seconds. In the meantime, the loading column was prepared for the next injection. Ammoniated adducts of protonated molecules were used as precursor ions for all analytes. Multiple-reaction mode transitions for each immunosuppressant and the internal standards were used for quantification. The working range of the method was 10-1500 microg/L for cyclosporin A, 1.0-44 microg/L for tacrolimus, 1.0-48 microg/L for sirolimus, and 1.2-48 microg/L for everolimus. Within and between-run assay coefficients of variation ranged from 1.8% to 13.0%. The described liquid chromatography/tandem mass spectrometry method shows best performance using the internal standards cyclosporin A-d4 for cyclosporin A, everolimus-d4 for everolimus and ascomycin for tacrolimus and sirolimus. In conclusion, the authors present a very fast, robust, and economical analytical method for therapeutic monitoring of multiple immunosuppressants in daily clinical practice.

Sotrastaurin and everolimus pharmacokinetics after single-dose coadministration

Sotrastaurin is an immunosuppressant that blocks T-lymphocyte activation via protein kinase C inhibition. The authors determined whether a pharmacokinetic interaction occurs between sotrastaurin and everolimus, both of which are substrates and inhibitors of CYP3A4. This was a randomized, three-period, crossover study in 18 healthy subjects. They received single oral doses of (1) 100 mg sotrastaurin, (2) 2 mg everolimus, and (3) the drug combination. Clinical and pharmacokinetic data were collected to Day 5 after each treatment. Coadministration of everolimus decreased sotrastaurin C(max) from 638 +/- 295 to 539 +/- 211 ng/ml yielding a combination/ monotherapy ratio (90% confidence interval) of 0.87 (0.76 - 1.00). Sotrastaurin total AUC was not altered by everolimus with values of 3660 +/- 1853 versus 3630 +/- 2006 ng*h/ml and a ratio of 1.00 (0.88 - 1.13). Sotrastaurin increased everolimus C(max) from 15 +/- 6 to 16 +/- 6 ng/ml yielding a ratio of 1.15 (0.99 - 1.33) and increased everolimus total AUC from 114 +/- 50 to 137 +/- 56 ng*h/ml yielding a ratio of 1.20 (1.05 - 1.37). The possibility that a higher dose of sotrastaurin than used in this study might further increase everolimus blood levels cannot be excluded. Coadministration of a single 100 mg dose sotrastaurin with a single 2 mg dose everolimus did not alter sotrastaurin pharmacokinetics to a clinically relevant extent. Everolimus AUC was increased 20% by sotrastaurin.

FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo

This study aimed to test whether [18F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg−1 per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses ⩾5 mg kg−1 per day (tumour volume treated vs control (T/C): 51% for 5 mg kg−1 per day and 57% for 15 mg kg−1 per day). Correspondingly, doses ⩾5 mg kg−1 per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg−1 per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg−1 per day and 52% for 15 mg kg−1 per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials.

Differential Pharmacokinetic Interaction of Tacrolimus and Cyclosporine on Everolimus

Objective We characterized the pharmacokinetics of tacrolimus and everolimus in a combined immunosuppressive regimen. Methods This was an open-label exploratory trial in eight maintenance renal transplant patients with calcineurin inhibitor intolerance initially receiving mycophenolate mofetil (MMF) and tacrolimus. At enrollment, MMF was discontinued and replaced with everolimus 1.5 mg twice a day in study period 1 (days 1 to 10). In period 2 (day 11 to month 3), tacrolimus dose was reduced by half. Results At study entry tacrolimus trough level (C0) was 7.9 ± 3.9 ng/mL and area under the curve over a dosing interval (AUC) was 132 ± 56 ng · h/mL. The addition of everolimus in period 1 did not change tacrolimus exposure: C0 8.4 ± 4.0 ng/mL, AUC 134 ± 70 ng · h/mL. Everolimus pharmacokinetics in the presence of tacrolimus in period 1 were: C0 3.3 ± 1.2 ng/mL, Cmax 10.4 ± 5.1 ng/mL, AUC 58 ± 20 ng · h/mL. When compared to pharmacokinetic data from a previous study in 47 renal transplant patients receiving everolimus at the same fixed dose (1.5 mg twice a day) with cyclosporine, everolimus exposure was 2.5-fold higher with cyclosporine relative to the data in this study with tacrolimus. After tacrolimus dose reduction in period 2, there was no clinically relevant change in everolimus exposure: C0 3.0 ± 1.1 ng/mL, Cmax 8.2 ± 1.3 ng/mL, AUC 49 ± 10 ng · h/mL. Conclusions Tacrolimus appears to have a minimal effect on everolimus blood levels compared with the influence of cyclosporine. The dose of everolimus when combined with tacrolimus needs to be higher than when combined with cyclosporine in order to reach a given everolimus blood level.

Effect of multiple-dose erythromycin on everolimus pharmacokinetics

We sought to quantify the influence of the CYP3A inhibitor erythromycin on the pharmacokinetics of everolimus, a CYP3A substrate. This was a two-period, single-sequence, crossover study in 16 healthy subjects. In period 1, subjects received the reference treatment of a single 2-mg dose of everolimus. In period 2, they received the test treatment of erythromycin 500 mg three times daily for a total of 9 days and a single 2-mg dose of everolimus coadministered on the fifth day of erythromycin therapy. The test/reference ratio and 90% confidence interval (CI) were derived for everolimus C (max) and AUC. During erythromycin coadministration, everolimus C (max) increased 2.0-fold (90% CI, 1.8-2.3) from 20+/-5 ng/ml to 40+/-10 ng/ml. Everolimus AUC increased 4.4-fold (90% CI, 3.5-5.4) from 116+/-37 ng h/ml to 524+/-225 ng h/ml. Everolimus half-life was prolonged by 39% from 32+/-6 h to 44+/-6 h. Erythromycin predose concentrations were not changed after single-dose administration of everolimus. Multiple-dose erythromycin increased single-dose everolimus blood levels by an average 4.4-fold (range, 2.0-12.6). During erythromycin treatment, a compensatory everolimus dose reduction should be made guided by everolimus therapeutic drug monitoring.