CKD-602 Chong Kun Dang
Chong Kun Dang is developing the camptothecin analog CKD-602 for the potential treatment of cancer. By August 2000, phase II trials of CKD-602 were underway.
Available from: Chang Koo Shim
- "In particular, AUC of belotecan was increased by almost two-fold and the total clearance (CL t ) was reduced by half in FA-ARF rats (Table 3). Because belotecan is known to be substantially excreted via the urinary route (Crul 2003), renal clearance (CL r ) of the two groups was computed for comparison. As expected, CL r was greatly decreased, by almost six-fold, in FA-ARF rats compared with the control group. "
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ABSTRACT: The effects of folic acid-induced acute renal failure on the renal excretion of belotecan were investigated in rats after intravenous administration. Both glomeruli and renal tubules were seriously damaged by folic acid-induced acute renal failure. The renal excretion clearance, CLr, of belotecan was significantly decreased by folic acid-induced acute renal failure. Furthermore, glomerular filtration rate and secretion clearance of the drug were dramatically decreased by folic acid-induced acute renal failure. In vivo renal uptake of belotecan was inhibited by p-aminohippurate, whereas renal excretion was inhibited by GF120918, but not by verapamil and bromosulphalein. This indicates that Oat1/3 and Bcrp are involved in the renal uptake and urinary excretion of belotecan, respectively. Both mRNA and protein levels of Oat1, Oat3 and Bcrp were significantly decreased in folic acid-induced acute renal failure rats. Based on the finding that belotecan is a substrate of OAT1 but not of OAT3, the decrease in CLr of belotecan in folic acid-induced acute renal failure could, therefore, mainly be attributed to the down-regulation of Oat1 and Bcrp, in addition to the decrease in glomerular filtration rate.
Xenobiotica 07/2009; 39(10):711-21. DOI:10.1080/00498250903026458 · 2.20 Impact Factor
Available from: Jong Choon Kim
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ABSTRACT: The subacute toxicity of a new camptothecin anticancer agent, CKD-602, was investigated after 4-week repeated intravenous administration of the chemical in Sprague–Dawley rats. The test chemical was administered intravenously to rats at dose levels of 0, 0.003, 0.013, or 0.067 mg/kg/day for males and 0, 0.004, 0.018, or 0.089 mg/kg/day for females. At the end of the treatment period, 10 rats/sex/group were sacrificed. The remaining 5 rats/sex in the vehicle control and high dose groups continued the study without treatment for 2 weeks (recovery period). During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights, and histopathology were examined. In both sexes of the high dose group, an increase in the incidence of abnormal clinical signs and paleness of the eyes, a reduction in the body weight gain, food consumption and urine protein, and an increase in the water consumption were observed. Hematological investigations revealed a decrease in the red blood cells, hemoglobin and hematocrit and an increase in the mean corpuscular volume, mean corpuscular hemoglobin, platelets, and reticulocytes in a dose-dependent manner. Serum total cholesterol and total protein values were lower in females than those of controls, but not in males. An increase in the heart and liver weights and a decrease in the thymus weight were also found. Histopathological alterations included an increase in the incidence of atrophy of the sternal marrow, atrophy, fibrosis and mast cell hyperplasia of the femoral marrow, atrophy of the white pulp and extramedullary hematopoiesis of the spleen, atrophy of the thymus, auricular hypertrophy of the heart, extramedullary hematopoiesis and centriacinar telangiectasis of the liver, follicular degeneration of the ovary, and inflammation of the tail. The major treatment-related effects were not recovered at the end of 2-week recovery period. There were no adverse effects in the low and middle dose groups of both genders. In the present experimental conditions, the target organs were determined to be bone marrow, blood cells, spleen, liver, thymus, and heart. The no-observed-adverse-effect level was considered to be 0.013 mg/kg/day for males and 0.018 mg/kg/day for females.
Regulatory Toxicology and Pharmacology 01/2005; 40(3-40):356-369. DOI:10.1016/j.yrtph.2004.09.002 · 2.03 Impact Factor
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ABSTRACT: The number of new chemical entities and biologics entering the market in 2004 for therapeutic use was 19, which included five first-in-class therapies. While these numbers were lower than previous years, the emphasis in 2004 was clearly on line extensions comprised of new formulations, new indications and new combinations of existing drugs to provide enhanced value to the patient population [1-5]. For the first time in decades, line extensions accounted for more than half of the drug launches last year. However, it is worth noting that an unusually high number of new molecular entities received approval in the final weeks of the year. Although not in time for launch before year-end, many were projected to appear on the market in the early part of 2005. From the 17 NCEs and two NBEs introduced last year, the US was the most active market with nine new product launches, followed by Europe and Japan with five and four, respectively, and one new drug reached its first market in the Republic of Korea. Of the major pharmaceutical companies, Eli Lilly and Pfizer had a marketing or co-marketing role in two new launches each, followed by AstraZeneca and Novartis, each launching one new product. In addition to the new molecular entities, the year also saw the entry of several new diagnostic agents based on novel technologies. The anticancer field was the most prolific therapeutic area in 2004, with the introduction of seven new entities, including three first-in-class therapies. Avastin™ (bevacizumab), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is the first angiogenesis inhibitor to reach the market, and it is indicated for the treatment of colorectal cancer. In addition, Plenaxis™ (abarelix), the first gonadotropin releasing-hormone (GnRH) receptor antagonist, and Vidaza™ (azacitidine), the first DNA methyltransferase inhibitor, were introduced last year for the treatment of prostate cancer and myelodysplastic syndrome (MDS), respectively. The portfolio of options for the second- and third-line treatment of non-small cell lung cancer (NSCLC) grew considerably with the addition of two NCEs. Tarceva™ (erlotinib), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and Alimta ® (pemetrexed), a multi-targeted antifolate, were launched for this indication. Pemetrexed is also labeled for the treatment of malignant pleural mesothelioma, a rare form of cancer associated with asbestos exposure. The other oncolytic drugs launched last year include Laserphyrin (talaporfin), a photodynamic therapy for early stage lung cancer, and Camtobell ® (belotecan), a new camptothecin analog, for the treatment of ovarian and small cell lung cancer. Belotecan is the third camptothecin derivative to reach the market behind topotecan and irinotecan, which were introduced in previous years. In the area of endocrine and metabolic diseases, three new drugs appeared on the market. Sensipar™ (cinacalcet), the first entry in a new class of therapeutics called the calcimimetics, was launched as an oral treatment for secondary hyperparathyroidism and hypercalcemia. Glufast ® (mitiglinide), a non-sulfonylurea hypoglycemic agent and inhibitor of ATP-dependent potassium channels in beta cells, was introduced in Japan for the treatment of type 2 diabetes. In addition, Protelos ® (strontium ranelate) was launched for the treatment of postmenopausal osteoporosis, specifically to reduce the risk of vertebral and hip fractures. Strontium ranelate is the first osteoporosis drug able to stimulate the formation of new bone as well as prevent loss of existing bone, thereby representing a major advancement in treating the disease. The CNS area was represented by the entry of three new drugs: Cymbalta ® (duloxetine) for the treatment of depression, Lyrica ® (pregabalin) for the treatment of epilepsy and peripheral neuropathic pain, and Sensiron ® (indisetron hydrochloride) for the treatment of chemotherapy-induced nausea and vomiting. Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), is additionally indicated for treating pain caused by diabetic peripheral neuropathy. Pregabalin is the second GABA analog marketed by Pfizer, and it has higher potency and improved pharmacokinetic properties as compared to its predecessor, gabapentin (Neurontin ®). Indisetron is a dual serotonin 5-HT3/5-HT4 receptor antagonist and has proven efficacy in reducing the number and duration of emetic episodes up to 24 hours after the administration of anticancer agents. The anti-infective domain had two new drugs entering the market in 2004. Factive ® (gemifloxacin), a new member of the fluoroquinolone class of antibacterials, was launched for the treatment of community-acquired pneumonia (CAP) caused by multi-drug resistant S. pneumoniae and for the treatment of acute bacterial exacerbations of chronic bronchitis (AECB). Prodif ® (fosfluconazole), a phosphate pro-drug of fluconazole, was also introduced last year in Japan as an intravenous injection for treating Candida and Cryptococcus infections. Fosfluconazole undergoes nearly quantitative hydrolysis in vivo to provide >97% bioavailability of fluconazole, but its improved water-solubility as compared with fluconazole allows a significant reduction in the infusion volume. Unlike in previous years, there were no new drug entities launched in 2004 for HIV and AIDS therapy. Instead, the focus was on combination drugs to simplify the dosing regimens while maintaining efficacy and tolerability, a considerable benefit to patients. Two drugs entering this market were Epzicom™ (abacavir sulfate/lamivudine) and Truvada™ (tenofovir disoproxil fumarate/emtricitabine), and both were based on combinations of previously marketed reverse transcriptase inhibitors. The cardiovascular sector had one NCE and two important combination therapies entering the market in 2004, all of which offer substantial projected value to patients. Exanta ® (ximelagatran) was introduced in Europe as an oral anticoagulant for the prevention of venous thromboembolic events in patients undergoing hip or knee replacement surgery. Vytorin™, a combination of ezetimbe and simvastatin, was launched for the treatment of hypercholesterolemia. Ezetimbe is an inhibitor of cholesterol absorption in the intestine, whereas simvastatin is an inhibitor of cholesterol biosynthesis. Caduet ®, a combination of amlodipine besylate and atorvastatin calcium, also entered the market as a simultaneous treatment for hypertension and high cholesterol, two important risk factors directly associated with cardiovascular mortality. Certican ® (everolimus), a derivative of rapamycin, was launched as an oral immunosuppressant for the prevention of kidney and heart transplant rejection. Everolimus has immunosuppressive properties similar to rapamycin, but with significantly improved oral bioavailability and pharmacokinetic profile. It is indicated for use in combination with Neoral ® (cyclosporine for microemulsion) and corticosteroids. Two new urologic drugs entered their first markets in Europe last year. Vesicare ® (solifenacin), an M3 muscarinic receptor antagonist, was introduced as once-daily oral treatment for treating overactive bladder with symptoms of urge incontinence and increased urinary frequency and urgency. Duloxetine, in addition to being marketed under the trade name Cymbalta ® for treating depression and diabetic peripheral neuropathic pain as mentioned above, was also launched in the UK under the trade name Yentreve ® as a twice-daily oral treatment of stress urinary incontinence in women. Tysabri ® (natalizumab), a humanized monoclonal antibody, was launched in the final days of last year as treatment for relapsing forms of multiple sclerosis. It acts by inhibiting adhesion molecules on the surface of immune cells and preventing the migration of immune cells into the CNS, where they can cause inflammation and potentially damage nerve fibers and their insulation. Finally, several new diagnostic agents were introduced last year, including two heavy metal derivatives: Primovist ® (gadoxate disodium) for the MRI detection and characterization of liver lesions including liver tumors and metastases, and NeutroSpec™ (technetium [Tc 99 m] fanolesomab), an anti CD15 monoclonal antibody, for the diagnosis of appendicitis. Human secretin, a synthetic peptide identical to the natural hormone and a stimulant of pancreatic secretions, was also introduced as an agent to aid in the diagnosis of pancreatic exocrine dysfunction and gastrinoma and in ERCP procedures. Although these diagnostic agents are not considered drug entities for therapeutic use and not covered in this review, they represent significant technological advancements in the field.
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