sirolimus and Hypophosphatemia

The mammalian target of rapamycin (mTOR) pathway inhibition has emerged as one of the main directions for the development of new targeted agents in renal cell carcinoma (RCC). A prominent member in its class of medications, temsirolimus has already been shown to improve overall survival in advanced kidney cancer, when compared with the previous standard, IFN-alpha.. The aim of this study was to review the most relevant preclinical and clinical data on the mTOR inhibitors, both in clinical use or in current development.. The authors give a comprehensive review of the existing English literature on the role of the mTOR pathway in renal tumorigenesis, as well as a detailed safety and efficacy analysis of older and newer rapamycin analogs.. Rapamycin derivatives temsirolimus and everolimus have significant clinical activity in patients with advanced-stage RCC. Both parenteral and oral formulations of mTOR inhibitors have shown clinical efficacy and are currently being developed. Combinations of mTOR inhibitors with VEGF/VEGFR-blocking agents are also being studied, in an attempt to further enhance the antineoplastic effect.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Hypophosphatemia; Kidney Neoplasms; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Temsirolimus, an inhibitor of the mammalian target of rapamycin, is approved for treatment of patients with advanced renal cell carcinoma in the USA and Europe. Temsirolimus was not yet evaluated in East Asian patients.. This non-randomized Phase II study enrolled 82 patients with advanced renal cell carcinoma [20 (24%) Japanese, 30 (37%) Korean and 32 (39%) Chinese patients; median age (range): 55 (26-83) years]. Most (71%) received prior systemic therapy for metastatic disease; two-thirds were intermediate risk. Six Japanese patients received intravenous temsirolimus 20 mg/m(2) weekly for tolerability assessment (Group A); the remaining 76 received a 25 mg flat dose weekly (Group B). Temsirolimus was dosed once weekly. Primary efficacy end point was the Response Evaluation Criteria in Solid Tumors-defined clinical benefit rate in the intent-to-treat population.. In the entire population, regardless of treatment group, the clinical benefit rate was 48% (95% confidence interval: 36, 59). Objective response rate was 11% (95% confidence interval: 5, 20), median progression-free survival was 7.3 months (95% confidence interval: 4.0, 9.2) and median time to treatment failure was 5.4 months (95% confidence interval: 3.5, 7.4). No patient in Group A demonstrated dose-limiting toxicity. The most frequent Grade 3 or 4 drug-related adverse events were anemia, hyperglycemia, hypophosphatemia and stomatitis (5% each). Serious adverse events reported in ≥ 5% of patients were pneumonia (9%) and interstitial lung disease (7%). Temsirolimus and its major metabolite, sirolimus, were long-lived throughout the dosage interval, with no evidence of accumulation.. Temsirolimus was well tolerated and showed promising activity in Japanese, Korean and Chinese patients with advanced renal cell carcinoma.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Asian People; Carcinoma, Renal Cell; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Hyperglycemia; Hypophosphatemia; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Outpatients; Protein Kinase Inhibitors; Sirolimus; Stomatitis; Treatment Outcome

Temsirolimus (CCI-779) is a novel inhibitor of the mammalian target of rapamycin. This Phase 1 study was aimed at investigating the maximum-tolerated dose, toxicity, pharmacokinetics and antitumor activity in Japanese patients with advanced solid tumors.. Temsirolimus was given as a 30 min intravenous infusion once a week. Patients with solid tumors not amenable to standard forms of treatment were eligible. Dose escalation of temsirolimus was planned from 15, 45, 80 to 165 mg/m(2). The pharmacokinetics of temsirolimus and sirolimus in whole blood were examined for cycles 1, 2, 4 and 5 of treatment.. Ten patients (median age 60.5 years; range 41-69 years) with advanced solid tumors were enrolled. Their primary cancers were renal cell carcinoma (five patients), lung cancer (three patients) and colorectal cancer (two patients). The major toxicities were hypophosphatemia diarrhea, hyperglycemia, stomatitis, pyrexia, elevated aspartate aminotransferase, rash, reduced neutrophil count, elevated alanine aminotransferase, anorexia, hypertriglyceridemia and somnolence. Two of three patients who received temsirolimus 45 mg/m(2) developed dose-limiting toxicities of Grade 3 stomatitis (one patient) and Grade 3 diarrhea (two patients). The maximum-tolerated dose was 15 mg/m(2). The peak blood concentrations of temsirolimus and sirolimus, a major active metabolite, increased in a dose-dependent manner. The area under the concentration-versus-time curve of sirolimus, but not temsirolimus, increased in a dose-dependent manner.. The recommended dose for Phase 2 clinical studies of temsirolimus in Japanese patients with advanced solid tumors is 15 mg/m(2) intravenously once a week.

Topics: Adult; Aged; Anti-Allergic Agents; Antineoplastic Agents; Area Under Curve; Carcinoma, Renal Cell; Colorectal Neoplasms; Diarrhea; Diphenhydramine; Disorders of Excessive Somnolence; Drug Administration Schedule; Drug Eruptions; Fever; Humans; Hyperglycemia; Hypertriglyceridemia; Hypophosphatemia; Infusions, Intravenous; Intestinal Perforation; Kidney Neoplasms; Lung Neoplasms; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Premedication; Sirolimus; Stomatitis; Treatment Outcome

Impaired phosphate handling of the renal allograft is a common problem and of multifactorial origin. The aim of the study was to elucidate whether a rapamycin- or a mycophenolate-based immunosuppressive therapy aggravates the renal phosphate leak in kidney transplant recipients.. Renal phosphate handling was determined in thirty-eight cadaveric allograft recipients, with good renal function at 8, 12, 20 and 28 weeks after transplantation. Nineteen patients (group 1) received triple immunosuppression with rapamycin, cyclosporine and prednisolone, nineteen other transplant recipients received mycophenolate mofetil, cyclosporine and prednisolone immunosuppression (group 2), and six healthy subjects (group 3) served as controls. After 12 weeks of stable graft function, group 1 patients were divided further into two subgroups. Ten patients were kept on their immunosuppressive regimen (group 1A), whereas the remaining nine randomly chosen subjects had their cyclosporine withdrawn; they were thus maintained on a dual immunosuppression regimen with prednisolone and a higher dosage of rapamycin (group 1B).. Renal phosphate reabsorption was significantly lower in group 1 at 8 and 12 weeks after transplantation as compared with groups 2 and 3. At 20 weeks after transplantation, patients with rapamycin-based immunosuppression (groups 1A and 1B) continued to exhibit hypophosphataemia and impaired renal phosphate handling. Group 1B had the lowest TmP/ GFR compared with all groups. At 28 weeks, renal phosphate reabsorption and plasma phosphate levels were no longer different between patient groups and controls.. These data suggest that rapamycin-based immunosuppression prolongs the phosphate leak of the allografted kidney, leading to low serum phosphate levels during the first weeks after transplantation.

Topics: Adult; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Hypophosphatemia; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Phosphates; Sirolimus; Transplantation, Homologous

Transient hypophosphatemia is frequently observed during the first months after renal transplantation and is usually asymptomatic. Phosphate diabetes is defined as inadequate tubular phosphorus reabsorption leading to persistent renal phosphorus wasting, which is an important but overlooked cause of osteodystrophy in the post-renal transplantation population. We report the case of a 58-year-old male who presented with severe multiple osteoarticular pains within 3 months after successful first kidney transplantation. Bone disease was attributed initially to mild hyperparathyroidism secondary to vitamin D deficiency. Despite the correction of the hyperparathyroidism, the withdrawal of corticosteroids, and the reduction of immunosuppressive treatment to tacrolimus-based monotherapy, the osteoarticular pains persisted. Skeletal investigations at month 9 post-transplantation demonstrated a significant bone mineral density loss associated with osteomalacia and osteoporosis on the bone biopsy. Laboratory data showed persistent hypophosphatemia, and phosphate diabetes was then diagnosed explaining the post-transplant bone disease. A tacrolimus-induced renal tubular disorder was suspected to contribute to the excessive renal phosphorus wasting. The replacement of tacrolimus by sirolimus, in addition to oral phosphorus and vitamin D supplementations, led to the disappearance of pains, the normalization of urinary and plasma phosphate level, and a significant improvement of bone mineralization.

Topics: Bone Density Conservation Agents; Humans; Hydroxycholecalciferols; Hypophosphatemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Osteomalacia; Phosphorus; Sirolimus; Tacrolimus

Rapamycin, an immunosuppressive drug used to prevent rejection after kidney transplantation, influences phosphate homeostasis, induces insulin resistance and has been shown to prolong lifespan in animal models. Because Klotho is an aging-suppressor gene controlling phosphate metabolism and insulin sensitivity, we investigated the influence of rapamycin on Klotho expression. A total of 100 kidney transplant recipients, 50 chronically treated with rapamycin and 50 with calcineurin inhibitors, were enrolled; 20 healthy subjects were employed as control. In the rapamycin group, serum phosphate was lower than in the CNI group with an increase in phosphate excretion and a reduction in its reabsorption. In addition, rapamycin increased insulin resistance as shown by HOMA index. Rapamycin treatment of an immortalized proximal tubular cell line induced the expression of Klotho, the phosphorylation of AKT in Ser473, downstream target of mTORC2 and the expression of RICTOR, mTORC2 main component. AKT inhibition reduced the rapamycin-induced expression of Klotho. In vivo rapamycin treatment induced higher degree of RICTOR and AKT Ser(473) expression directly correlating with long-term rapamycin exposure, FE(PO4) and HOMA index. In conclusion, our data would suggest that rapamycin may influence phosphate homeostasis and insulin resistance modulating Klotho expression through mTORC2 activation.

Topics: Adult; Aged; Case-Control Studies; Female; Glucuronidase; Humans; Hypophosphatemia; Immunosuppressive Agents; Insulin Resistance; Klotho Proteins; Male; Sirolimus; Transcription Factors