Everolimus Blood Concentrations Research Articles

Pharmacokinetic variability of everolimus and impact of concomitant antiseizure medications in patients with tuberous sclerosis complex: A retrospective study of therapeutic drug monitoring data in Denmark and Norway.

The mTOR-inhibitor everolimus is a precision drug with antiepileptogenic properties approved for treatment of epilepsy in persons with tuberous sclerosis complex (TSC) in combination with other antiseizure medications (ASMs). However, the pharmacokinetic variability of everolimus is scarcely described, and the available information on pharmacokinetic interactions is scarce. The purpose of this study was to investigate pharmacokinetic variability of everolimus in patients with TSC, and the impact of age, sex and comedication. In this retrospective observational study we used anonymized data from medical records of patients with TSC using everolimus in Norway and Denmark, 2012 to 2020. Long-term therapeutic drug monitoring (TDM) identified inter-patient and intra-patient variability. The study included 59 patients, (36 females (61%)), median age 22 (range 3-59 years). Polytherapy was used in 50 patients (85%). The most frequently used ASMs were lamotrigine (n = 21), valproate (n = 17), and levetiracetam (n = 13). Blood concentrations of everolimus were measured in all patients. Pharmacokinetic variability of everolimus between patients was extensive, as demonstrated by a 24-fold variability from minimum-maximum concentration/dose (C/D)-ratios. The coefficient of variation (CV) for intra-patient (n = 59) and inter-patient variability (n = 47, ≥3 measurements) was 40% and 43%, respectively. The C/D-ratio of everolimus was 50% lower in 13 patients (22%) using enzyme-inducing ASMs compared to the 30 patients who did not (0.7 vs 1.4 ng/mL mg, P < .05). Age and sex were not significantly associated with changes in C/D-ratios of everolimus. Long-term TDM identified extensive variability in concentrations over time for everolimus both within and between patients, where comedication with enzyme-inducing ASMs was an important contributing factor. The findings suggest a need for TDM in patients with TSC treated with everolimus.

Population pharmacokinetics of everolimus in renal transplant recipients receiving long-term multiple immunosuppressive therapy

Everolimus is used for immunosuppression after renal transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model of everolimus using therapeutic drug monitoring (TDM) data of patients under long-term multiple immunosuppressive therapy, including tacrolimus. To develop the model, 185 renal transplant recipients with 3358 everolimus blood concentrations during a median postoperative period of 35.3 months were included. The PopPK model is described as a one-compartment model with first-order absorption. The population mean of apparent clearance is 8.92 L/h (relative standard error = 3.6%), and this negatively correlated with the dose-normalized concentration (C/D) of tacrolimus and hematocrit value, and positively correlated with a daily dose of everolimus (i.e. TDM effect). The usefulness of dose adjustment using the final popPK model was assessed by a simulation study. The ratio of the first trough measurement within the therapeutic range of 3–8 ng/mL increased from 69.8% in the original dose to 87.9% in the individual dose calculated by the final PopPK model. The tacrolimus C/D ratio before initiating everolimus therapy and the hematocrit value were useful to estimate the initial dose of everolimus and can improve the safety and effectiveness of immunosuppressive therapy involving everolimus.

«Decreased everolimus blood concentration associated with consumption of St. John's wort (Hypericum perforatum) extract sweets»

«Decreased everolimus blood concentration associated with consumption of St. John's wort (Hypericum perforatum) extract sweets»

Pharmacokinetic Drug-Drug Interaction With Coadministration of Cannabidiol and Everolimus in a Phase 1 Healthy Volunteer Trial.

When highly purified cannabidiol (CBD; Epidiolex) and the mammalian target of rapamycin inhibitor everolimus are used concomitantly in the treatment of tuberous sclerosis complex, there is evidence of a pharmacokinetic (PK) interaction, leading to increased everolimus systemic exposure. We evaluated the effect of steady-state CBD exposure following multiple clinically relevant CBD doses on everolimus PK in healthy adult participants in a single-center, fixed-sequence, open-label, phase 1 study. All participants received oral everolimus 5mg on day 1, followed by a 7-day washout. On days 9-17, participants received CBD (100mg/mL oral solution) at 12.5mg/kg in the morning and evening. On the morning of day 13, participants also received a single dose of oral everolimus 5mg. Medications were taken 30 or 45minutes (morning or evening dose) after starting a standardized meal. Maximum concentration and area under the concentration-time curve (AUC) from time of dosing to the last measurable concentration and extrapolated to infinity, of everolimus in whole blood were estimated using noncompartmental analysis, with geometric mean ratios and 90% confidence intervals for the ratios of everolimus dosed with CBD to everolimus dosed alone. A single dose of everolimus 5mg was well tolerated when administered with multiple doses of CBD. Log-transformed everolimus maximum concentration, AUC from time of dosing to the last measurable concentration, and AUC extrapolated to infinity values increased by ≈2.5-fold, and everolimus half-life remained largely unchanged in the presence of steady-state CBD relative to everolimus dosed alone. Everolimus blood concentration monitoring should be strongly advised with appropriate dose reduction when coadministered with CBD.

Effects of NR1I2 and ABCB1 Genetic Polymorphisms on Everolimus Pharmacokinetics in Japanese Renal Transplant Patients.

The purpose of this study was to evaluate the effects of NR1I2 (7635G>A and 8055C>T) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genetic polymorphisms on everolimus pharmacokinetics in 98 Japanese renal transplant patients. On day 15 after everolimus administration, blood samples were collected just prior to and 1, 2, 3, 4, 6, 9, and 12 h after administration. The dose-adjusted area under the blood concentration–time curve (AUC0-12) of everolimus was significantly lower in patients with the NR1I2 8055C/C genotype than in those with other genotypes (p = 0.022) and was significantly higher in male patients than female patients (p = 0.045). Significant correlations between the dose-adjusted AUC0-12 of everolimus and age (p = 0.001), aspartate transaminase (p = 0.001), and alanine transaminase (p = 0.005) were found. In multivariate analysis, aging (p = 0.008) and higher alanine transaminase levels (p = 0.032) were independently predictive of a higher dose-adjusted everolimus AUC0-12. Aging and hepatic dysfunction in patients may need to be considered when evaluating dose reductions in everolimus. In renal transplant patients, management using everolimus blood concentrations after administration may be more important than analysis of NR1I2 8055C>T polymorphism before administration.

Long-term relationship between everolimus blood concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma: a prospective study

BackgroundEverolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Recently, personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. In this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC.MethodsPatients with mRCC were enrolled following treatment with everolimus at Tohoku University Hospital between April 2012 and December 2016. The relationship between everolimus trough blood concentration on day 8 of everolimus therapy and just before discontinuation or dose reduction, and their adverse events were evaluated. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the profiles of adverse events, and efficacy [time to treatment failure (TTF) and progression-free survival (PFS)] were evaluated.ResultsThe median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1–28.0) ng/mL and 14.8 (6.4–58.4) ng/mL, respectively, with no significant difference between these values (P = 0.3594). Patients (n = 6) with discontinuation or dose reduction following adverse events in everolimus therapy had significantly higher blood concentrations than patients (n = 4) with dose maintenance on both day 8 (median, 18.0 vs 8.2 ng/mL; P = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; P = 0.0142). Median TTF and PFS of the total patients (n = 10) were 96 days (95% confidence interval [CI], 26–288) and 235 days (95% CI, 28–291), respectively. Subgroup analysis showed that TTF of the patients with > 15.3 ng/mL (n = 5) was not significantly different from that of the patients with ≤15.3 ng/mL (n = 5; P = 0.5622). Similarly, PFS of the patients with > 15.3 ng/mL was not significantly different from that of the patients with ≤15.3 ng/mL (P = 0.3436).ConclusionsThis study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and adverse events in Japanese patients with mRCC. Thus, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events for Japanese patients with mRCC.

電気化学発光免疫測定法によるエベロリムス血中濃度測定試薬“エクルーシス®試薬エベロリムス”の基礎的検討

電気化学発光免疫測定法によるエベロリムス血中濃度測定試薬“エクルーシス®試薬エベロリムス”の基礎的検討

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.

電気化学免疫測定法（ECLIA法）を用いたeverolimus血中濃度測定に関する臨床的評価

電気化学免疫測定法（ECLIA法）を用いたeverolimus血中濃度測定に関する臨床的評価

Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer.

PurposeMetastatic breast cancer (MBC) progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS) compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs) on outcomes from this treatment through a pharmacogenetic analysis.Patients and methodsBlood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane-everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities), dose reductions or treatment suspensions due to toxicity, progression free survival (PFS) and overall survival.ResultsWe found that CYP3A4 rs35599367 variant (CYP3A4*22 allele) carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019). ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031), while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively). Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006).ConclusionsCYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC.

Circadian pharmacokinetics and limited sampling strategy of everolimus in heart transplant patients .

To evaluate circadian changes in everolimus (EVL) pharmacokinetics and to identify the time point of blood sampling with the strongest correlation with the area under the blood concentration-time curve (AUC) of EVL in heart transplant patients. Heart transplant patients receiving the same dose of EVL twice a day were reviewed. In 28 patients enrolled, whole blood samples were collected before (C0), and 1, 2, 4, 6, 8, and 12 hours after each administration of EVL. Blood concentrations of EVL were compared between active (9:00AM to 9:00PM) and resting periods (9:00 PM to 9:00AM). AUC0-4h, peak concentration (Cmax), Cmax/minimum concentration, and peak-trough fluctuation in the resting period were significantly lower than those in the active period (p=0.008, 0.017, 0.022, and 0.011, respectively). Half-life and mean residence time were significantly longer in the resting period than in the active period (p=0.002 and 0.002, respectively). AUC0-12h in the active period was similar (p=0.154) and correlated with that in the resting period (r²=0.93). Two-point blood samplings, C0 and C2, correlated more strongly with AUC0-12h for EVL, compared with C0 alone (0.92 vs. 0.79, respectively, for r² in the active period). EVL pharmacokinetics showed circadian changes, suggesting delayed absorption and decreased metabolic activity at rest. However, the circadian changes did not affect AUC0-12h. A 2-time-point model that included C0 and C2 was more accurate for predicting the AUC0-12h of EVL than C0 alone in heart transplant patients. .

Population Pharmacokinetics of Everolimus in Relation to Clinical Outcomes in Patients With Advanced Renal Cell Carcinoma

Everolimus has been used for the treatment of unresectable or metastatic renal cell carcinoma (RCC). Here, we measured blood concentrations of everolimus to obtain the population pharmacokinetic parameters and to examine the relationship between blood concentration and clinical outcomes. Twenty-two Japanese patients were enrolled. Blood samples were collected before and 2, 4, 8, and 24 hours after drug administration on days 1 and 8 of everolimus therapy (5 or 10 mg) from inpatients; occasional samples were collected from outpatients. Blood concentrations of everolimus were measured by high-performance liquid chromatography with tandem mass spectrometry. Population pharmacokinetic analysis was conducted using the NONMEM software. Everolimus pharmacokinetics was best described by a 2-compartment model with population mean estimates of apparent oral clearance of 10.0 L/h and an interindividual variability of 42.4%. There was no relationship between overall best responses and the predicted trough concentrations at day 8. The predicted trough concentration in patients who terminated everolimus treatment owing to adverse drug reactions (ADRs) was significantly higher than in patients who stopped the treatment owing to disease progression or other reasons (27.6 ± 3.1 versus 15.7 ± 2.3 ng/mL; mean ± SEM). Patients who terminated the treatment owing to ADRs had significantly shorter time-to-treatment failure than other patients (112 versus 187 days, median). This study reports the first population pharmacokinetic parameters of everolimus in patients with RCC. Individual dose adjustment based on everolimus blood concentrations helps to avoid early drug cessation due to ADRs.

Effect of confounding factors on a phospho-flow assay of ribosomal S6 protein for therapeutic drug monitoring of the mTOR-inhibitor everolimus in heart transplanted patients

Context: Several assays of monitoring immune cell function have been developed to enhance therapeutic drug monitoring.Objective: An in vitro-validated whole-blood assay of phosphorylated ribosomal protein S6 (pS6RP) was evaluated for confounders to monitor the mTOR-inhibitor everolimus (ERL).Materials and methods: Whole blood samples from 87 heart transplant recipients were analyzed for pS6RP-expression in CD3-positive T-cells by phospho-flow analysis.Results: ERL blood concentration, laboratory parameters, co-medications, demographic and clinical data were reviewed.Conclusion: Evaluating the pS6RP-assay revealed that pS6RP is influenced by cyclosporine A (CsA) blood concentration, duration of ERL treatment, co-medication with thiazide diuretics and different metabolic parameters.

De novo everolimus for recipients of kidney transplants from HLA identical donors.

Kidney transplant recipients from HLA-identical living donor have lower risk of acute rejection and greater graft survival compared to other types of kidney transplantation. Immunosuppressive regimens without calcineurin inhibitors (CNI) can further improve these results by reducing cardiovascular, metabolic and toxic events related to this drug class. This study aimed to evaluate efficacy and safety of a new immunosuppressive regimen with planned suspension of CNI. This was a prospective, single center and single treatment arm study to evaluate HLA-identical kidney transplant recipients receiving everolimus (EVR), tacrolimus (TAC) and corticosteroids, followed by TAC discontinuation 30 days after transplantation. TAC discontinuation was later postponed to the third month after an interim efficacy analysis. Thirty-nine patients were included. Although mean TAC and EVR blood concentrations have remained within the proposed therapeutic ranges, five patients had biopsy-proven acute rejection and one patient had an episode of C4D-positive glomerulitis. This result led to the end of the inclusions. Interestingly, the proportion of patients with proteinuria greater than 0.5 g/L has not reached more than 22% of patients in any visit. Adverse events related to EVR use were the most incident in this population: oral ulcers, dyslipidemia and peripheral edema. The proposed scheme was not effective for this population, particularly due to a high incidence of acute rejection. Safety profile showed that prolonged exposure to a high concentration of blood EVR increases the incidence of adverse events related to this drug.

Factors affecting response to everolimus therapy for subependymal giant cell astrocytomas associated with tuberous sclerosis

The aim of the study was to investigate factors affecting response to everolimus, a mammalian-target-of-rapamycin (mTOR) inhibitor, of subependymal giant cell astrocytomas (SEGA) in patients with tuberous sclerosis complex (TSC). The study group consisted of 15 children with a diagnosis of TSC-related SEGA. Median therapy duration was 13 months. Age, sex, previous neurosurgical or mTOR inhibitor treatment, everolimus blood concentration and anticonvulsant therapy were analyzed as potential factors affecting reduction of SEGA tumor volume. Significant reductions in SEGA volumes were noted at 3 and 6 months (median tumor volume 0.97 cm(3) and 0.70 cm(3) , respectively, versus 2.70 cm(3) at baseline, P = 0.001). Responses were observed in 11/15 (73.3%) and 10/12 (83.3%) patients at 3 and 6 months, respectively. The most rapid reduction of SEGA volume (58.6%) was found during the initial 3 months of treatment. There was no statistical difference in the extent of SEGA volume reduction between patients with everolimus trough levels <5 ng/ml and ≥5 ng/ml. Patients treated with ≤1 anticonvulsant had greater tumor reduction after 6 months of treatment. Everolimus is an effective and safe treatment option for TSC-related SEGA. Drug dose titration according to blood concentration did not appear to be crucial to achieve clinical efficacy; however, concomitant anticonvulsant therapy may affect response to mTOR inhibitors.

Impact of everolimus blood concentration on its anti-cancer activity in patients with metastatic renal cell carcinoma

Everolimus has demonstrated its efficacy in metastatic renal cell carcinoma (mRCC). Preliminary studies have shown high variability of everolimus blood concentrations (EBC). In other settings, its activity was correlated with EBC. We therefore decided to monitor EBC in patients treated with mRCC to assess its influence on oncologic outcomes. Our study analyzed first 3 months' trough EBC levels in 42 patients treated in 4 French oncologic centers between March 2010 and August 2013. Patients presented a histologically confirmed diagnosis of mRCC and have failed prior anti-angiogenic (AA) therapies. Median follow-up was 25.9 months. A total of 113 EBC were analyzed. The median trough concentration was 14.1 μg/L (range 2.6-91.5). Fourteen patients (67 %) versus 8 (38 %) patients with median EBC above or below 14.1 μg/L were free from progression at 6 months (p = 0.06). Median progression-free survival was 13.3 versus 3.9 months (HR 0.66 95 % CI 0.33-1.31; p = 0.23), and the median overall survival was 26.2 versus 9.9 months (HR 0.62 95 % CI 0.28-1.37; p = 0.24), for patients above or below the median value of trough concentrations, respectively. Impact of drug exposure for AA tyrosine kinase inhibitors activity has been demonstrated in mRCC setting. Interpatients EBC variability was confirmed in the present study, and the results suggest a relationship between initial EBC within the first 3 months and the drug activity. It underlines the need to prospectively include EBC monitoring in future clinical trials to determine the need of its implementation in routine use.

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

Everolimus and Sirolimus in Combination with Cyclosporine Have Different Effects on Renal Metabolism in the Rat

Enhancement of calcineurin inhibitor nephrotoxicity by sirolimus (SRL) is limiting the clinical use of this drug combination. We compared the dose-dependent effects of the structurally related everolimus (EVL) and sirolimus (SRL) alone, and in combination with cyclosporine (CsA), on the rat kidney. Lewis rats were treated by oral gavage for 28 days using a checkerboard dosing format (0, 3.0, 6.0 and 10.0 CsA and 0, 0.5, 1.5 and 3.0 mg/kg/day SRL or EVL, n = 4/dose combination). After 28 days, oxidative stress, energy charge, kidney histologies, glomerular filtration rates, and concentrations of the immunosuppressants were measured along with 1H-magnetic resonance spectroscopy (MRS) and gas chromatography- mass spectrometry profiles of cellular metabolites in urine. The combination of CsA with SRL led to higher urinary glucose concentrations and decreased levels of urinary Krebs cycle metabolites when compared to controls, suggesting that CsA+SRL negatively impacted proximal tubule metabolism. Unsupervised principal component analysis of MRS spectra distinguished unique urine metabolite patterns of rats treated with CsA+SRL from those treated with CsA+EVL and the controls. SRL, but not EVL blood concentrations were inversely correlated with urine Krebs cycle metabolite concentrations. Interestingly, the higher the EVL concentration, the closer urine metabolite patterns resembled those of controls, while in contrast, the combination of the highest doses of CsA+SRL showed the most significant differences in metabolite patterns. Surprisingly in this rat model, EVL and SRL in combination with CsA had different effects on kidney biochemistry, suggesting that further exploration of EVL in combination with low dose calcineurin inhibitors may be of potential benefit.

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.