Pharmacokinetics Of Everolimus Research Articles

Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies.

Curcumin, a specific secondary metabolite of Curcuma species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS® immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC0-540 of EVL by 70.6% and 71.5%, respectively, and both dosages reduced the Cmax of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P-gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4.

The effect of CYP3A4*22, CYP3A5*3 and CYP3A combined genotypes on cyclosporine, everolimus and tacrolimus pharmacokinetics in renal transplant recipients

The effect of CYP3A4*22, CYP3A5*3 and CYP3A combined genotypes on cyclosporine, everolimus and tacrolimus pharmacokinetics in renal transplant recipients

FINAL RESULTS OF A PROSPECTIVE MULTI-INSTITUTIONAL PHASE II STUDY OF EVEROLIMUS (RAD001), AN MTOR INHIBITOR, IN PEDIATRIC PATIENTS WITH RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA. A POETIC CONSORTIUM TRIAL

BACKGROUND: Purpose: The ras/raf signaling pathway is crucial in the development of pediatric low-grade gliomas (LGGs). Aberrant ras/raf signaling is involved in tumorigenesis through promotion of cell proliferation, survival, and differentiation in sporadic LGG. Everolimus (RAD001) is a potent and selective inhibitor of mTOR, a downstream element of the ras/raf pathway. The activity, safety and pharmacokinetics of everolimus in pediatric patients with radiographic recurrent/progressive LGG are presented. METHODS: Pediatric patients with radiographic progressive or recurrent LGGs without neurofibromatosis type I were treated with oral everolimus 5mg/m2/dose once daily. Therapy was provided for 28 days (one cycle) and could be repeated for a total of 12 cycles. Response, as determined by standard 2-D MRI criteria, was assessed for all patients. Pharmacokinetics, pharmacogenetics, pharmacodynamic parameters including inhibition of p70s6 kinase activity, 4E-BP1 phosphorylation inhibition and suppression of cMyc expression, as well as the toxicity profile of everolimus were evaluated. RESULTS: Twenty-three patients with a median age of 9 years (range, 3–17 years) were enrolled, all of whom had received prior chemotherapy (average # regimens = 2.7) including progression after a carboplatin-containing regimen. Median number of cycles of therapy was 10 (range, 1-12). Responses were determined by blinded central review and included 4 patients with PR (>50% decrease) and 13 with stable disease. Six patients had progressive disease by one year. Overall therapy was well tolerated; two patients discontinued therapy due to mouth sores (n = 1) and withdrawal of consent (n = 1). Everolimus PK parameters were similar to those previously reported in both adult and pediatric patients and drug trough levels were maintained above 5ng/ml. Pharmacodynamic analysis demonstrated inhibition of downstream targets of mTOR including phospho-S6 kinase, 4E-BP1 phosphorylation and cMyc expression within 14 days of initiation of everolimus therapy and this inhibition was maintained throughout the treatment period. CONCLUSIONS: Everolimus was well tolerated in pediatric patients with progressive or recurrent LGGs and demonstrated activity in this multiply recurrent/progressive patient population. Incorporation of everolimus into frontline LGG therapy is being proposed. SECONDARY CATEGORY: Clinical Neuro-Oncology.

Pharmacokinetics of Everolimus When Combined With Cyclosporine in Japanese De Novo Renal Transplant Recipients

BackgroundCurrently, there are no published data on pharmacokinetics (PK) of everolimus in combination with cyclosporine in Japanese renal transplant patients. We evaluated the PK of everolimus in Japanese de novo renal transplant patients who received everolimus in combination with cyclosporine. MethodsIn this phase 3, multicenter, randomized, open-label study, patients were randomized (1:1) to 1 of the 2 groups: everolimus 1.5 mg (targeted C0 of 3–8 ng/mL) plus reduced-dose cyclosporine or mycophenolate mofetil 2 g/d plus standard-dose cyclosporine. PK assessments for everolimus were performed on day 28 (month 1) in the PK subpopulation. ResultsA total of 11 patients (7 men), mean age 47.5 ± 11.21 years, were enrolled for PK analysis of everolimus. Starting at 1.5 mg (0.75 mg twice a day), the mean dose over a period of 28 days was 0.705 ± 0.1011 mg. Everolimus mean trough concentration was 4.307 ± 1.2459 ng/mL and mean peak concentration was 13.539 ± 3.5330 ng/mL, which peaked at 1 to 2 hours postdose. The average concentration was 7.558 ± 1.4723 ng/mL, area under the concentration-time curve was 90.70 ± 17.667 ng·h/mL, and peak-trough fluctuation was 122.6%. The PK parameters of everolimus were comparable to those in the earlier phase 3 studies (A2306 and A2307). The mean everolimus trough levels were within the target ranges at all time points ranging from 3.4 to 5.5 ng/mL (everolimus 0.75 mg twice a day, safety population). The majority of patients (>85% from day 7 onward) were maintained within the targeted everolimus trough blood levels (safety population). These data were similar to a non-Japanese study (A2309). ConclusionsThe pharmacokinetic characteristics of everolimus in Japanese de novo renal transplant patients did not differ from those previously observed in non-Japanese patients, hence the same dosage of everolimus may be acceptable in Japanese patients.

The impact of genetic polymorphisms, diltiazem, and demographic variables on everolimus trough concentrations in lung transplant recipients

Everolimus (EVR) has inter-individual pharmacokinetic (PK) variability and a narrow therapeutic index. The study objective was to determine whether genetic polymorphisms, co-medications, and/or demographic variables accounted for inter-individual variability in EVR PK in lung transplant recipients (LTxR). LTxR were genotyped for ABCB1 c.1236C>T, ABCB1 c.2677G>T/A, ABCB1 c.3435C>T, CYP3A4*1B, CYP3A5*3, CYP2C8*2/*3/*4, and pregnane X receptor (NR1I2) c.44477T>C, c.63396C>T, c.69789A>G polymorphisms. The primary outcome was the difference in dose-adjusted EVR levels (EVR L/D) between ABCB1 diplotype groups (2 vs. 1 vs. 0 copies of the 1236C/2677G/3435C haplotype). Sixty-five LTxR were included. There was no significant difference in EVR L/D between ABCB1 CGC diplotype groups (CGC/CGC = 2.4 ± 1.1 [n = 9] vs. CGC/XXX = 2.5 ± 1.7 [n = 36] vs. XXX/XXX = 2.7 ± 1.7 ng/mL per mg/d [n = 20]; p = 0.9). CYP3A5*3, CYP3A4*1B, CYP2C8*3/*4, and NR1I2 polymorphisms were not associated with EVR L/D. EVR L/D was 3.4 ± 1.7 in LTxR receiving diltiazem (DILT) vs. 1.8 ± 1.1 ng/mL per mg/d in LTxR not receiving DILT (p <0.001). Demographic variables, including cystic fibrosis, were not associated with EVR PK. DILT use increased EVR L/D, but selected polymorphisms in ABCB1, CYP3A5, CYP3A4, CYP2C8, and NR1I2 did not affect EVR L/D in LTxR. Genotyping LTxR for these polymorphisms is unlikely to aid clinicians in optimizing EVR therapy.

Effects of Atorvastatin on the Pharmacokinetics of Everolimus Among Kidney Transplant Recipients

BackgroundHyperlipidemia occurs in up to 50% of kidney transplant (KT) recipients who take everolimus (EVL). As a result of this, statins are the most commonly prescribed lipid-lowering drugs among these patients. However, we are concerned whether there are any drug interactions between EVL and statins, because both of these drugs use the same pharmacokinetics pathway. Therefore, we assessed the effects of concomitant use of EVL and atorvastatin. MethodsIn this randomized, open-label, crossover study, 20 KT patients were assigned (1:1) to receive EVL with or without 20 mg atorvastatin for 1 month. One-month washout period was used before crossover. Plasma EVL concentrations were measured by homogeneous particle-enhanced turbidimetric immunoassay. Twelve-hour area under the time-concentration curve (AUC0–12) of EVL was calculated with the use of whole-blood EVL concentrations from 10 different time points (0, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 12 hours). ResultsThe mean (SD) AUC0–12 for EVL and EVL plus atorvastatin was 155.9 (41.6) ng·h/mL and 151.3 (51.4) ng·h/mL, respectively (P > .05; paired t test). No difference of EVL Cmax or Tmax was found after atorvastatin coadministration. Even though the EVL AUC0–12 levels were not affected by atorvastatin coadministration in one-half of the subjects, for the rest of the patients, there were unpredictable changes in the EVL AUC0–12 levels. This may be due to the high intrapatient variability of EVL drug concentration (coefficient of variation ranges from 9.8% to 34.1%). ConclusionsCoadministration of atorvastatin with EVL in KT recipients did not affect the pharmacokinetics of EVL.

PKP-011 Pharmacokinetics of everolimus in combination with mycophenolate sodium and clinical outcomes in renal transplant recipients previously treated with calcineurin inhibitors

BackgroundDespite advances in immunosuppressive treatment, long-term renal transplantation outcomes have not improved significantly over the last decade. The nephrotoxicity of calcineurin inhibitors (CNIs) is still associated with chronic allograft loss....

A phase I study of the anti-IGF-1R monoclonal antibody (MoAb), IMC-A12 (I), and everolimus (E) in well-differentiated neuroendocrine tumors (WD NET).

232 Background: Octreotide LAR (LAR) and E have well known anti-cancer effects in WD NETs. Preclinical data also show that inhibition of the insulin like growth factor receptor (IGF-1R) may sensitize NETs to mTOR inhibitors such as E. Methods: Patients (pts) with WD NETs, ECOG performance status ≤ 2 and adequate organ function were treated with LAR 20 mg IM q 21days (d), E 10 mg po daily and escalating doses of I iv q 21 d in 21 d cycles in cohorts of 6 until maximum tolerated dose (MTD). Recommended phase II dose (RP2D) was defined as dose level below MTD. An expansion cohort of 9 pts was planned at RP2D. Plasma samples for everolimus pharmacokinetics (PK), IGF, mTOR pathway pharmacodynamics (PD) in addition to paired tissue biopsies were obtained. Results: 19 pts with previously treated (median prior systemic therapy, 1, range 0-3) WDNET (4 pancreatic NET, 11 carcinoid, 4 unknown primary) were enrolled in this single institution study. Ten pts in dose escalation and 9 in expansion phases received a median of 8.5 cycles (range, 3-19+). Dose limiting toxicities (DLTs) were grade (g) 3 mucositis in 2 pts at 2nddose level of I 15 mg/m2 q 21 d. Most frequent adverse events (AEs) observed while on study were fatigue, hyperlipidemia, weight loss (74%), dysguesia (68%), hyperglycemia and mucositis (63%). Most common g3 AEs were fatigue (21%), mucositis, transaminitis and electrolyte disturbances (all 11%). Other g 3 AEs included anorexia, anemia, injury, retinal detachment, dehydration and thromboembolism. One g 4 AE of hyperglycemia was noted during the expansion phase. One pt with pancreatic NET had confirmed partial response and 17 had stable disease as best response. The median progression free survival was 34+ weeks. Conclusions: The RP2D of this combination is I 10 mg/m2, LAR 20 mg IM q 21 d, E 10 mg po daily. PK, PD and other correlative analyses are ongoing and will be presented at the meeting. Although adequate safety and a sign of activity were noted in this study, these will need to be reconciled with data from larger studies of anti-IGF-1R MoAb in NET and other cancers that have been disappointing. Clinical trial information: NCT01204476.

The pharmacokinetics of everolimus in de novo kidney transplant patients receiving tacrolimus: an analysis from the randomized ASSET study.

Pharmacokinetic data regarding a drug-drug interaction between everolimus and tacrolimus are sparse. In a pharmacokinetic substudy of the randomized ASSET trial, 46 de novo kidney transplant patients receiving very low (1.5-3 ng/mL) or low (4-7 ng/mL) tacrolimus exposure after month 3, both with everolimus and steroids, provided area under the curve (AUC) concentration profiles at day 5 and months 1, 3, and 12. At month 12, mean values for tacrolimus trough concentration (C0), peak concentration (Cmax), and AUC0-12 in the very low tacrolimus group were approximately half that in the low tacrolimus group, but everolimus dose, C0, Cmax, and AUC0-12 were virtually identical in both groups. In a cross-study comparison with data at months 1 and 3 from the pharmacokinetic substudy of the A2307 trial, in which patients received cyclosporine, mean values for everolimus C0, Cmax and AUC0-12 were similar to those in the ASSET trial but the everolimus dose needed to achieve similar exposure was 1.5- to 2-fold higher with concomitant tacrolimus versus cyclosporine. Everolimus exposure is unaffected when tacrolimus exposure is down-titrated within the trough concentration range of 1.5-7 ng/mL. Higher doses of everolimus are needed to achieve a given exposure when combined with tacrolimus versus cyclosporine.

Racial Comparisons of Everolimus Pharmacokinetics and Pharmacodynamics in Adult Kidney Transplant Recipients

There is limited data analyzing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of everolimus (EVR) between African Americans and Caucasians. The purpose of this study was to determine and compare the EVR PKs and concentration-associated efficacy and toxicity in African American and Caucasian adult kidney transplant recipients. This was a retrospective PK and PD analysis of all patients who received EVR at the Medical University of South Carolina Transplant Center between 2006 and 2012. Forty-three patients received EVR (22 African Americans, 21 Caucasians). Baseline demographics, immunosuppression, and immunologic risk were similar between races, except for preexisting hypertension, deceased donor type, and cold ischemic time, which were higher in African American patients. PK analysis revealed that African American patients received higher initial EVR doses (2.1 ± 0.8 versus 1.6 ± 0.6 mg/d, P = 0.036), leading to higher early EVR concentrations (EVR >6 ng/mL during the first 60 days: 36% versus 10%, P = 0.037). Efficacy analysis demonstrated similar EVR effects on acute rejection rates (9% versus 10%, P = 0.961), chronic allograft changes (18% versus 14%, P = 0.729), and renal function, with both groups having improved creatinine clearance with EVR therapy (ΔeGFR: 27 versus 12 mL·min·1.73 m). Toxicity analysis demonstrated that African American patients had a trend toward higher rates of EVR discontinuation (46% versus 19%, P = 0.065) and significantly more diarrhea/gastrointestinal intolerance (73% versus 38%, P = 0.022). These results demonstrate EVR therapy is effective at preventing rejection and improving graft function in both African American and Caucasian adult renal transplant patients. Conflicting with previous mammalian target of rapamycin PK/PD analyses in African American patients, this study cohort demonstrated higher early EVR levels in the African American patients.

Trastuzumab (T) and everolimus (E) pharmacokinetics (PK) in HER2 positive (+) primary breast cancer (BC) patients (pts): Unicancer RADHER trial results.

2599 Background: T has greatly modified the prognosis of HER2+ BC, but few studies have analyzed its PK. The RADHER study evaluated the interest of adding E to T as preoperative therapy for primary HER2+ BC. It also aimed at describing the PK of T and studying the impact of E with T in primary BC. Methods: Eligible pts with HER2+ operable primary BC were randomized to receive T alone (loading dose 4 mg/kg, then 2 mg/kg/week (W)) or T + E (10 mg/day (D)) for a 6-W pre-operative treatment. Blood samples were collected to measure T and E concentrations. For T, plasma samples were collected in all pts before each infusion, and at Hour (H) 1, D1, D3, W1, W2, W4, W8 and W12 after the last infusion. E concentrations were determined on whole blood collected at H0, H0.5, H1, H2, H4, H6, H12 and H24 after the first T infusion, and again after the last E intake. T and E PK were described using population compartment analyses. Results: From 82 pts randomized, 79 were evaluable for T and 22 for E PK. Mean estimated PK parameters of T were (interindividual coefficient of variation %): central (Vc) and peripheral (Vp) volumes of distribution = 2 L (24%) and 1.3 L (39%), systemic (CL) and intercompartment (Q) clearances = 0.22 L/day (19%) and 0.36 L/day, respectively. Vc increased with body weight and decreased with age, while CL increased with body weight and with tumor volume. Elimination half-life was 11 days, a value lower than that previously reported in metastatic BC (28 days). E PK was best described by a two-compartment model. Mean estimated PK parameters (RSE%) of E were: CL = 3.96 L/h (22%), Q = 29.1 L/h (7%), Vc = 119 L (11%), Vp = 1530 L (24%). E did not influence T PK. E PK was similar to that previously reported in other indications. Conclusions: This is the first study describing the PK of T and E in primary BC. Notably, T CL increases with tumor volume and the elimination half-life is only 11 days, lower than expected from previous results in metastatic BC. The differences in PK between primary and metastatic BC might lead to take a second look at trastuzumab dose regimen in primary BC. Clinical trial information: NCT00674414.

The CYP3A Enzyme Inhibitor Diltiazem, Rather Than Genetic Polymorphisms, Is Associated with Everolimus Concentrations in Lung Transplant Recipients

Purpose Everolimus (EVR) has a narrow therapeutic index and large inter-subject variability in pharmacokinetics (PK) following a fixed dose. EVR is a substrate for CYP3A and 2C8 metabolizing enzymes, and the P-glycoprotein ( ABCB1 ) transporter. The objective of this study was to determine if polymorphisms in the genes encoding these proteins account for the inter-subject PK variability of unlabeled EVR in lung transplant recipients (LTxR). Methods and Materials In this cross-sectional study, the primary outcome was the difference in dose-adjusted EVR levels (ng/ml per mg/day, L/D) between ABCB1 diplotype groups (2 vs 1 vs 0 copies of the 1236C/2677G/3435C haplotypes). We also analyzed the effect of CYP3A5 * 3, CYP3A4 * 1B and CYP2C8 * 3 polymorphisms, and concomitant medications, on EVR PK. Mann-Whitney U and Kruskal Wallis tests were used to compare continuous variables between groups. Results The study included 58 LTxR (34 men, 24 women) receiving EVR. The median EVR L/D was 1.9 ng/ml per mg/day (range 0.50, 7.60). There was no significant difference in EVR L/D between ABCB1 1236/2677/3435 diplotype groups. Likewise, CYP3A5 * 3, CYP3A4 * 1B, and CYP2C8 * 3 polymorphisms were not significantly associated with EVR L/D in this population. In contrast, EVR L/D was 98% higher among LTxR on diltiazem (DILT) versus those not on DILT (p Conclusions Polymorphisms in genes responsible for EVR transport and metabolism were not significantly associated with EVR L/D in LTxR. EVR L/D was significantly affected by DILT administration, although this interaction only accounted for a portion of EVR L/D inter-subject variability. Despite max dose EVR, a substantial proportion of LTxR not receiving DILT had a sub-therapeutic EVR level. Supported by Novartis Pharmaceuticals.

Physiologically based pharmacokinetic models for everolimus and sorafenib in mice

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions. Single and multiple oral doses of everolimus and sorafenib were administered alone and in combination in immunocompetent male mice and to severe combined immune-deficient (SCID) mice bearing low-passage, patient-derived pancreatic adenocarcinoma in seven different studies. Plasma and tissue samples including tumor were collected over a 24-h period and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Distribution of everolimus and sorafenib to the brain, muscle, adipose, lungs, kidneys, pancreas, spleen, liver, GI, and tumor was modeled as perfusion rate-limited, and all data from the diverse studies were fitted simultaneously using a population approach. PBPK models were developed for everolimus and sorafenib. PBPK analysis showed that the two drugs in combination had the same PK as each drug given alone. A twofold increase in sorafenib dose increased tumor exposure tenfold, thus suggesting involvement of transporters in tumor deposition of sorafenib. The developed PBPK models suggested the absence of PK interaction between the two drugs in mice. These studies provide the basis for pharmacodynamic evaluation of these drugs in patient-derived primary pancreatic adenocarcinomas explants.

Effects of Hepatic Impairment on the Pharmacokinetics of Everolimus: A Single-Dose, Open-Label, Parallel-Group Study

BackgroundAlthough the pharmacokinetics of everolimus, an oral mammalian target of rapamycin inhibitor, have been characterized in patients with moderate hepatic impairment, they have not been assessed in those with mild or severe hepatic impairment. ObjectiveThe goal of this study was to assess the pharmacokinetics and safety of everolimus in healthy volunteers with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment in otherwise good health to inform dosing in the clinical setting. MethodsA multicenter, open-label, Phase I study in which all enrollees received a single, 10-mg, oral everolimus dose was conducted. Blood samples for pharmacokinetic assessment were collected at predetermined time points up to 168 hours postdosing. Safety was also assessed. Proposed dose recommendations based on Child-Pugh status at baseline and day 8 were calculated based on AUC0–∞ geometric mean ratios and their associated 90% CIs. Post hoc analysis of the relationship between pharmacokinetic parameters and markers of hepatic function was also performed to identify thresholds for dose adjustment. ResultsThirteen subjects with normal hepatic function and 7 patients with mild, 8 patients with moderate, and 6 patients with severe hepatic impairment were enrolled. Compared with normal subjects, everolimus AUC0–∞ for patients with mild, moderate, and severe hepatic impairment increased by 1.60-, 3.26-, and 3.64-fold, respectively. Based on Child-Pugh classification at day 8, the everolimus doses required to adjust the exposure of patients with mild, moderate, and severe hepatic impairment to that of normal subjects were 6.25, 3.07, and 2.75 mg, respectively. Thresholds for 2-fold everolimus dose reduction were 15.0 μmol/L for bilirubin, 43.1 g/L for albumin, and 1.1 for the international normalized ratio; using these thresholds could lead to underdosing or overdosing in some patients. Most adverse events were of grade 1 severity, ≤1 day in duration, and not everolimus related. ConclusionsEverolimus exposure after a single 10-mg dose was influenced by the degree of hepatic impairment. Child-Pugh classification was found to be the most conservative means of guiding dose adjustment in patients with hepatic impairment. Based on these data, as well as previously reported data for patients with moderate hepatic impairment, everolimus once-daily dosing should be 7.5 mg and 5 mg in patients with mild and moderate impairment, respectively. Everolimus is not recommended in patients with severe hepatic impairment unless benefits outweigh risks; in that case, 2.5 mg once daily should not be exceeded. ClinicalTrials.gov identifier: NCT00968591.

Population Pharmacokinetics of Everolimus in Cardiac Recipients

The aim of this study was, using routine drug monitoring data, to identify patient characteristics that may influence everolimus (EVE) pharmacokinetic parameters and to develop a population pharmacokinetic model to predict EVE whole blood concentrations in cardiac recipients. Fifty-nine patients were enrolled in the prospective study. Patient's characteristics were recorded including biological covariates and treatments. CYP3A5 and ABCB1 polymorphisms were determined. Seven hundred seventy-five EVE blood samples were collected for routine drug monitoring. Population pharmacokinetic modeling was carried out using the nonlinear mixed-effects modeling program. Results were analyzed according to a 1-compartment pharmacokinetic model with linear absorption and elimination. The model was evaluated using a bootstrap method and a visual predictive check procedure. The pharmacokinetic of EVE in cardiac recipients was best described by a 1-compartment model. Interindividual variability was best described by an exponential error model and residual error by a proportional plus additive error model. Estimation of EVE apparent clearance (3.33 ± 0.20 L/h) and apparent volume of distribution (146 ± 33 L) were in accordance with previously published data. Bilirubinemia and cyclosporine significantly influenced EVE clearance. Some covariates that were expected to influence EVE clearance, for example, ABCB1 and CYP3A5 polymorphisms, were not evidenced. No covariates influenced the volume of distribution of EVE. This study is the first population pharmacokinetic model of EVE in heart transplantation patients. It allows a better description of the pharmacokinetics of EVE. The present population pharmacokinetic model allows estimating a priori and a posteriori EVE concentrations in cardiac recipients and could limit the over and under drug exposure in this population.

Population Pharmacokinetics and Pharmacogenetics of Everolimus in Renal Transplant Patients

Everolimus is a novel macrolide immunosuppressant used in the prevention of acute and chronic rejection of solid organ transplants. Everolimus is being actively investigated worldwide as a non-nephrotoxic alternative for calcineurin inhibitors. Its highly variable pharmacokinetics and narrow therapeutic window make it difficult to maintain an adequate exposure to prevent serious adverse effects. The primary objective of this study was to improve prediction of everolimus systemic exposure in renal transplant patients by describing the pharmacokinetics of everolimus and identifying the influence of demographic factors and a selection of polymorphisms in genes coding for ABCB1, CYP3A5, CYP2C8 and PXR. The secondary objective of this study was to develop a limited sampling strategy to enable prediction of everolimus exposure in an efficient way and to compare it with the widely used trough blood concentration (C(trough)) monitoring. A total of 783 blood samples were obtained from 53 renal transplant patients who had been switched from a triple therapy of ciclosporin, mycophenolate mofetil and prednisolone to a calcineurin inhibitor-free dual therapy of everolimus (twice daily) and prednisolone. Everolimus blood concentrations were analysed in whole blood using liquid chromatography-tandem mass spectrometry during routine therapeutic drug monitoring targeting an area under the blood concentration-time curve from time zero to 12 hours (AUC(12)) of 120 μg · h/L. A population pharmacokinetic model was developed and demographic factors and genetic polymorphisms in genes coding for ABCB1, CYP3A5, CYP2C8 and PXR were included as covariates. In addition, a limited sampling strategy was developed. Maintaining everolimus systemic exposure at an AUC(12) of 120 μg · h/L resulted in low rejection rates but considerable numbers of adverse events and toxicity. Everolimus pharmacokinetics were best described by a two-compartment model with lag-time (oral clearance = 17.9 L/h; volume of distribution of the central compartment after oral administration [V(1)/F] = 148 L and first-order absorption rate constant [k(a)] = 7.36 h-1). Ideal body weight was significantly related to V(1)/F. None of the selected polymorphisms in genes coding for enzymes involved in distribution and metabolism of everolimus had a significant influence on everolimus pharmacokinetics. The pharmacokinetic limited sampling model (C(trough) and whole blood drug concentration at 2 hours postdose [C(2)]) resulted in a significantly improved prediction of everolimus exposure compared with the widely used C(trough) monitoring. A two-compartment pharmacokinetic model with lag-time describing the concentration-time profile of oral everolimus in renal transplant patients has been developed using pharmacokinetic modelling. Ideal body weight significantly influenced V(1)/F of everolimus; however, the selected polymorphisms in genes coding for ABCB1, CYP3A5, CYP2C8 and PXR had no clinically relevant effect on everolimus pharmacokinetics. Everolimus C(trough) and C(2) as a limited sampling model can be used to accurately estimate everolimus systemic exposure, an improvement over the widely used C(trough) monitoring.

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

A novel self-expanding drug-eluting stent was designed to release everolimus 225 μg/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. 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 postprocedure. 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. 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.

Phase I and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies

Summary Background Everolimus is an oral mTOR-inhibitor. Preclinical data show synergistic effects of mTOR inhibition in combination with 5-fluorouracil-based anticancer therapy. The combination of everolimus with capecitabine seems therefore an attractive new, orally available, treatment regimen. Patients and methods Safety, preliminary efficacy and pharmacokinetics of everolimus in combination with capecitabine were investigated in patients with advanced solid malignancies. Patients were treated with fixed dose everolimus 10 mg/day continuously, plus capecitabine bid for 14 days in three-weekly cycles. Dose escalation of capecitabine proceeded according to the standard 3 × 3 phase I design in four predefined dose levels (500–1,000 mg/m2 bid). Results In total, 18 patients were enrolled. Median (range) treatment duration with everolimus was 70 days (21–414). Capecitabine 1,000 mg/m2 bid combined with 10 mg/day everolimus was declared the maximum tolerated dose, at which level one patient developed dose-limiting toxicity (stomatitis grade 3). Drug-related adverse events were mostly grade ≤2 and included mainly fatigue (56%), stomatitis (50%), and hand-foot syndrome (33%). Partial response was documented in three patients, and four had stable disease. There was no pharmacokinetic interaction between everolimus and capecitabine. Conclusion Everolimus 10 mg/day continuously combined with capecitabine 1,000 mg/m2 bid for 14 days every 3 weeks is a patient-convenient, safe and tolerable oral treatment regimen. This is the first study to demonstrate feasibility of this combination at doses with proven single agent efficacy in a number of tumors. Prolonged clinical benefit was observed in an encouraging 39% of patients with advanced solid malignancies.

Phase I study of everolimus in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).

4074 Background: The PI3K/Akt/mTOR pathway, a key regulator of cellular proliferation and angiogenesis, has emerged as a contributor to hepatocarcinogenesis. Everolimus, an mTOR inhibitor, exhibits antineoplastic activity in preclinical and experimental models of HCC. Sorafenib, a multi-tyrosine kinase (including Raf) inhibitor, is the only targeted therapy demonstrating a survival benefit and approved for first-line treatment in patients with unresectable HCC. Enhanced efficacy may be achieved through dual inhibition of key signaling pathways involved in hepatocarcinogenesis. We evaluated the maximum tolerated dose (MTD) and pharmacokinetics of everolimus in combination with 400 mg bid of sorafenib in patients with advanced HCC. Methods: In this phase I study (NCT00828594) patients ≥18 years of age with measurable, previously untreated, BCLC Stage B or C HCC and ECOG score of 0-1, Child-Pugh’s A (5-6 points) received escalating doses of everolimus starting at 2.5 mg qd + sorafenib 400 mg bid for 28 days. Primary endpoint was MTD. Results: Thirty patients with advanced HCC were enrolled (everolimus 2.5 mg qd, n=16; everolimus 5 mg qd, n=14). Most patients were Asian (73%) and HBsAg positive (63%), with BCLC Stage C HCC (93%). Dose escalation above 5 mg qd was not achieved. Dose-limiting toxicity was grade 3 AST elevation (n=1) in the 2.5 mg group and grade 3/4 thrombocytopenia (n= 5) and hyperbilirubinemia (n=1) in the 5.0 mg group. Drug-related AE rates leading to dose reductions (42.9% vs 0%) and interruptions (71.4% vs 37.5%) were more common in the 5 mg cohort than the 2.5 mg group. Everolimus pharmacokinetics in this population were dose proportional and comparable to that previously reported for monotherapy in non-HCC patients. Disease stabilization occurred in 10 (62.5%) patients and 5 (35.7%) in the 2.5 mg and 5.0 mg groups, respectively. Median time to progression was 3.5 and 3.6 months in the 2.5 mg and 5.0 mg groups, respectively. Conclusions: The MTD of everolimus in combination with sorafenib 400 mg bid was 2.5 mg qd in this population. The inability to achieve what is deemed a biologically effective dose of everolimus in combination with sorafenib will preclude progression to phase II in this study.

Pharmacokinetic (PK) profile of a single dose of everolimus (10 mg) administered with a low- or high-fat meal and under fasting conditions in healthy subjects.

e15080 Background: The mTOR inhibitor everolimus is approved for patients (pts) with metastatic renal cell carcinoma after failure of sunitinib or sorafenib, and for pts with subependymal giant-cell astrocytoma associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgery. Studies in healthy subjects suggest that systemic exposure to everolimus is reduced with a high-fat meal. The effect of fasting conditions and food on everolimus PK after an oral 10 mg dose was evaluated. Methods: In this single-center, open-label study, 24 healthy male and female subjects were randomized to single doses of everolimus in a 3-treatment (low-fat vs high-fat meal vs fasting), 3-period, 6-sequence crossover design. Treatment periods were separated by 14-day washout intervals. PK was assessed at baseline and at 0-12, 24, 36, 48, 72, 96, 120, and 144 hours postdose. Results: All 24 subjects were included in the PK analysis. The geometric mean Cmax decreased by 42% after a low-fat meal and by 54% after a high-fat meal compared with fasting conditions. Total exposure (geometric mean AUC0-t and AUC0-∞) decreased by 22% to 33% after intake of a low- or high-fat meal. A meal had no apparent effect on the post-absorption concentration-time profile. The gastrointestinal absorption rate of everolimus was decreased by food intake: median Tmax was 1 hour in the fasted state, 1.75 hours after a low-fat meal, and 2.50 hours after a high-fat meal. The elimination kinetics in whole blood (T1/2 [35.6 to 40.9 hours] and mean residence time [29.2 to 32.2 hours]) did not appear to be affected by food intake regardless of fasting or nonfasting state. No deaths, serious adverse events (AEs), or significant AEs were reported. Conclusions: The systemic availability of a single oral 10 mg dose of everolimus is significantly reduced by coadministration with a meal (low or high fat) compared with fasting conditions; however, food is not expected to have clinically significant effects on predose trough concentration during daily administration of everolimus. All conditions tested were safe and well tolerated.