sirolimus and Hypokalemia

Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination.. Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity.. Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5 mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5 mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91 %), mucositis/stomatitis (75 %), hypomagnesemia (72 %), hypocalcemia (56 %) and hypokalemia (50 %). There were 3 partial responses; an additional 10 subjects had stable disease ≥6 months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40 months.. The recommended phase II dose is everolimus at 5 mg three times weekly plus panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Dose-Response Relationship, Drug; Drug Administration Schedule; Everolimus; Exanthema; Female; Humans; Hypocalcemia; Hypokalemia; Male; Middle Aged; Mucositis; Neoplasms; Panitumumab; Sirolimus; Treatment Outcome; Young Adult

Sirolimus, an antiproliferative immunosuppressant, induces hypomagnesemia and hypokalemia. Rosiglitazone activates renal sodium- and water-reabsorptive pathways. We evaluated whether sirolimus induces renal wasting of magnesium and potassium, attempting to identify the tubule segments in which this occurs. We tested the hypothesis that reduced expression of the cotransporter NKCC2 forms the molecular basis of this effect and evaluated the possible association between increased urinary excretion of magnesium and renal expression of the epithelial Mg2+ channel TRPM6. We then analyzed whether rosiglitazone attenuates these sirolimus-induced tubular effects. Wistar rats were treated for 14 days with sirolimus (3 mg/kg body wt in drinking water), with or without rosiglitazone (92 mg/kg body wt in food). Protein abundance of NKCC2, aquaporin-2 (AQP2), and TRPM6 was assessed using immunoblotting. Sirolimus-treated animals presented no change in glomerular filtration rate, although there were marked decreases in plasma potassium and magnesium. Sirolimus treatment reduced expression of NKCC2, and this was accompanied by greater urinary excretion of sodium, potassium, and magnesium. In sirolimus-treated animals, AQP2 expression was reduced. Expression of TRPM6 was increased, which might represent a direct stimulatory effect of sirolimus or a compensatory response. The finding that rosiglitazone prevented or attenuated all sirolimus-induced renal tubular defects has potential clinical implications.

Topics: Animals; Aquaporin 2; Drug Interactions; Hypoglycemic Agents; Hypokalemia; Immunosuppressive Agents; Kidney; Kidney Function Tests; Magnesium; Male; Polyuria; Rats; Rats, Wistar; Rosiglitazone; Sirolimus; Sodium; Sodium-Potassium-Chloride Symporters; Solute Carrier Family 12, Member 1; Thiazolidinediones; TRPM Cation Channels; Water

Topics: Adult; Antibiotics, Antineoplastic; Humans; Hypertension; Hypokalemia; Kidney Diseases; Male; Sirolimus

Topics: Blood Chemical Analysis; Creatinine; Cyclosporine; Humans; Hypokalemia; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Retrospective Studies; Sirolimus

(1) Sirolimus, an immunosuppressant, is chemically related to tacrolimus but has a different mechanism of action. (2) In a double-blind trial in patients also treated with ciclosporin and a steroid, sirolimus was more effective than azathioprine at preventing acute rejection during the first three months, but caused more adverse effects (especially renal). (3) An unblinded trial compared ciclosporin + steroid + sirolimus with steroid + sirolimus for maintenance treatment. Ciclosporin was withdrawn gradually from the steroid + sirolimus group. Side effects from ciclosporin were therefore reduced (mainly nephrotoxicity and arterial hypertension), but rates of acute rejection, hepatotoxicity, and thrombocytopenia went up. (4) Sirolimus has numerous adverse effects, including hyperlipidemia, thrombocytopenia, hepatic disorders and opportunistic infections. The adverse effects of long term treatment are unknown. Sirolimus is metabolised by the cytochrome P450 isoenzyme CYP3A4, so may induce drug interactions. (5) In practice, sirolimus offers no advantage over existing immunosuppressive treatments for people with renal transplants.

Topics: Azathioprine; Clinical Trials as Topic; Cyclosporine; Drug Approval; Drug Therapy, Combination; Europe; Graft Rejection; Humans; Hyperlipidemias; Hypokalemia; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; Thrombocytopenia; United States; United States Food and Drug Administration