Pharmacokinetic analysis after implantation of everolimus-eluting self-expanding stents in the peripheral vasculature

Background: A novel self-expanding drug-eluting stent was designed to release everolimus 225 mu g/cm(2) to prevent restenosis following peripheral arterial intervention. The purpose of this study was to measure the pharmacokinetic profile of everolimus following stent implantation. Methods: One hundred four patients with symptomatic peripheral arterial disease underwent implantation of everolimus-eluting stents in the femoropopliteal arteries. In a prespecified subset of 26 patients, blood samples for assay of everolimus content were collected prior to stent implantation, at 1, 4, and 8 hours postprocedure, prior to discharge, and at 1 month postproccdure. Results: A total of 39 stents, ranging from 28 mm to 100 mm in length, were implanted in 26 patients, resulting in a total delivered everolimus dose range of 3.0 to 7.6 mg. Following the procedure, the maximum observed everolimus blood concentrations (C-max) varied from 1.83 +/- 0.05 ng/mL after implantation of a single 80-mm stent to 4.66 +/- 1.78 ng/mL after implantation of two 100-mm stents. The mean time to peak concentration (T-max) varied from 6.8 hours to 35 hours. The pharmacokinetics of everolimus were dose-proportional in that dose-normalized C-max and area under the curve values were constant over the studied dose range. Conclusions: After implantation of everolimus-eluting self-expanding stents in the femoropopliteal arteries, systemic blood concentrations of everolimus are predictable and considerably lower than blood concentrations observed following safe oral administration of everolimus

IGF-I influences everolimus activity in medullary thyroid carcinoma

Context: Medullary thyroid carcinoma (MTC) is a rare tumor originating from thyroid parafollicular C cells. It has been previously demonstrated that insulin-like growth factor I (IGF-I) protects MTC from the effects of antiproliferative drugs. Everolimus, an mTOR inhibitor, has shown potent antiproliferative effects in a human MTC cell line, TT, and in two human MTC primary cultures. Objective: To verify whether IGF-I may influence the effects of everolimus in a group of human MTC primary cultures. Design: We collected 18 MTCs that were dispersed in primary cultures, treated without or with 10 nM-1 mu M everolimus and/or 50 nM IGF-I. Cell viability was evaluated after 48 h, and calcitonin (CT) secretion was assessed after a 6 h incubation. IGF-I receptor downstream signaling protein expression profile was also investigated. Results: Everolimus significantly reduced cell viability in eight MTC [by similar to 20%; P < 0.01 vs. control; everolimus-responders (E-R) MTCs], while cell viability did not change in 10 MTCs [everolimus-non-responders (E-NR) MTCs]. In E-R MTCs, IGF-I blocked the antiproliferative effects of everolimus that did not affect CT secretion, but blocked the stimulatory effects of IGF-I on this parameter. IGF-I receptor downstream signaling proteins were expressed at higher levels in E-NR MTC as compared to E-R MTCs. Conclusion: IGF-I protects a subset of MTC primary cultures from the antiproliferative effects of everolimus and stimulates CT secretion by an mTOR mediated pathway that, in turn, may represent a therapeutic target in the treatment of aggressive MTCs

Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis.

IntroductionEffective treatments for hormone-receptor-positive (HR(+)) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population.MethodsBOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR(+) advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints.ResultsFinal study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38-0.54); log-rank P &lt; 0.0001; central review: 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% confidence interval 0.31-0.48); log-rank P &lt; 0.0001] in the overall population and in all prospectively defined subgroups, including patients with visceral metastases, [corrected] and irrespective of age. The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials.ConclusionThe addition of everolimus to exemestane markedly prolonged PFS in patients with HR(+) advanced BC with disease recurrence/progression following prior NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655

Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy.

BackgroundEverolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety.Patients and methodsData were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately.ResultsThe rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)].ConclusionsStomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines

Everolimus dosing recommendations for tuberous sclerosis complex–associated refractory seizures

ObjectiveThe present analysis examined the exposure-response relationship by means of the predose everolimus concentration (C-min) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target C-min range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target C-min

Cellular antiseizure mechanisms of everolimus in pediatric tuberous sclerosis complex, cortical dysplasia, and non-mTOR-mediated etiologies.

The present study was designed to examine the potential cellular antiseizure mechanisms of everolimus, a mechanistic target of rapamycin (mTOR) pathway blocker, in pediatric epilepsy cases. Cortical tissue samples obtained from pediatric patients (n&nbsp;=&nbsp;11, ages 0.67-6.75&nbsp;years) undergoing surgical resections for the treatment of their pharmacoresistant epilepsy were examined electrophysiologically in ex&nbsp;vivo slices. The cohort included mTOR-mediated pathologies (tuberous sclerosis complex [TSC] and severe cortical dysplasia [CD]) as well as non-mTOR-mediated pathologies (tumor and perinatal infarct). Bath application of everolimus (2&nbsp;μm) had practically no effect on spontaneous inhibitory postsynaptic activity. In contrast, long-term application of everolimus reduced spontaneous excitatory postsynaptic activity, burst discharges induced by blockade of γ-aminobutyric acid A (GABAA) receptors, and epileptiform activity generated by 4-aminopyridine, a K+ channel blocker. The antiseizure effects were more pronounced in TSC and CD cases, whereas in non-mTOR-mediated pathologies, the effects were subtle at best. These results support further clinical trials of everolimus in mTOR pathway-mediated pathologies and emphasize that the effects require sustained exposure over time

Phase I study of everolimus and mitomycin C for patients with metastatic esophagogastric adenocarcinoma

This study aimed at determining the recommended dose of the mammalian target of rapamycin inhibitor everolimus in combination with mitomycin C (MMC) in patients with previously treated metastatic esophagogastric cancer. In this phase I trial, patients received escalated doses of oral everolimus (5, 7.5, and 10 mg/day) in combination with intravenous MMC 5 mg/m2 every 3 weeks. Endpoints were the dose-limiting toxicity (DLT), safety, and response rates. Tumor tissues were tested for HER2-status and mutations in the PTEN, PIK3CA, AKT1, CTNNB1, and E-cadherin type 1 genes. Sixteen patients (12 male, four female) with gastric/gastroesophageal junction cancer were included. All patients were previously treated with a platinum-based chemotherapy. Treatment cohorts were: 5 mg/day, three patients; 7.5 mg/day, three patients; and 10 mg/day, 10 patients. No DLTs occurred during dose escalation. Most frequent grade 3 toxicities were leukopenia (18.8%) and neutropenia (18.8%). All other grade 3 toxicities were below 10%. No grade 4 toxicities occurred. Three (18.8%) patients experienced partial responses and four patients had stable disease (SD). Antitumor activity according to Response Evaluation Criteria In Solid Tumors (RECIST)-criteria was highest in the 10 mg/day cohort. No associations between HER2-status or detected mutations and response were observed. The recommended dose of everolimus combined with MMC is 10 mg/day. Encouraging signs of antitumor activity were seen (http://www.ClinicalTrials.gov; Clinical trial registration number: NCT01042782)