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The plasma levels of lonidamine have been studied in 24 breast or lung cancer pa tients as part of the Phase II evaluation

of the drug. The pharmacokinetic studi es were performed when the patients had been on oral lonidamine therapy for 27 t o 47 days (mean 32 days) and the studies were conducted over a 24 hour period. L onidamine was administered in three divided doses of 150 mg (t = 0h), 150 mg (t = 7h), and 150 mg or 300 mg (t = 14h). Plasma levels of lonidamine were determin ed by high-performance liquid chromatography (HPLC) with fluorescence detection. Lonidamine was detected in the plasma of all patients studied, and the absolute range for the peak plasma levels of the drug following the first and second dos es were 4.6-33.8 and 4.8-33.3 micrograms/ml, respectively. The range of times af ter administration at which the peak occurred was 0.5 to 4.2 hours for the first dose and 0.5 to 4.1 hours for the second. The absolute range for the trough lev els observed over the 24-hour study period was 1.0 to 12.6 micrograms/ml and in 19 of the patients it was possible to define the apparent half life of lonidamin e that was found to be within the range 2.5 to 11.7 hours. In addition to lonida mine, a number of fluorescent components were detected in the plasma of patients following lonidamine treatment that were not detected in pretreatment plasma sa mples. One component, a compound that eluted from the HPLC more rapidly than lon idamine, was found in some patients to be sensitive to hydrolysis with beta-gluc uronidase. Comparison of the pharmacokinetic data with patient characteristics a nd clinical biochemistry results failed to establish any clear relationship. Sim ilarly there was no relationship between lonidamine pharmacokinetics and either drug-induced myalgia or testicular pain. Insufficient responses were seen in the patient group studied to allow the relationship between lonidamine pharmacokine tics and response to be evaluated. Lonidamine was studied in advanced cancer patients. The drug was given orally by single or repeated administrations. Single doses ranged from 150 to 450 mg. Rep eated administrations were performed with progressively increasing doses: 450-90 0 mg daily. Lonidamine lacked severe toxic effects after both single and prolong ed administrations. The most common side effect was myalgia; gastrointestinal di scomfort was also reported. 1 patient with lung cancer experienced an episode of arrhythmia which subsided upon discontinuation of treatment and did not reoccur r++ when treatment was reinstated. 1 partial and 2 minor responses were observed in the 6 patients with breast cancer. 12 patients with metastatic cancer were treated with the substituted indazole ca rboxylic acid Lonidamine at oral daily doses of 270 mg/m2. Toxicity, consisting mainly of myalgias, somnolence, hyperesthesia, anorexia and vomiting, generally decreased or disappeared over time despite continuing drug administration at unm odified dosage. Myalgias and hyperesthesias were markedly relieved with predniso ne 5 mg twice daily. No laboratory abnormalities were seen. Partial responses we re observed in a patient with hypernephroma and in a patient with breast cancer. Disease-oriented phase II studies with this new anticancer agent are warranted. Lonidamine, a substituted indazole carboxylic acid with unique effects on cellul ar respiration, was studied in 27 patients with advanced malignancies. Of the 18 evaluable patients, 5 had small-cell lung cancer, 3 had non-small-cell lung can cer, 3 sarcoma, 2 breast cancer, and 5 other tumour types. All but 1 had had ext ensive prior treatment. A partial response was seen in 1 patient with metastatic synovial sarcoma, and tumour growth inhibition was demonstrated in 2 other case s. The major toxicity encountered was myalgia (66.6%) which was incompletely ame liorated by prednisone and required dose reduction in 2 patients and cessation o f drug in 3. Other toxicities included auditory changes, anorexia, nausea and vo miting, diarrhoea, skin sensitivity, and conjunctivitis. No added toxicity was s een, when Lonidamine was combined with other chemotherapeutic agents. No correla tion between Lonidamine dose and serum lactate levels was seen, although 4 patie nts showed a progressive increase in lactate levels over time, thought to be rel ated to their increasing tumour burden. 5 patients demonstrated a dramatic fall

in serum testosterone levels 4-8 weeks after starting Lonidamine which was accom panied by an increase in luteinizing hormone levels in 3 patients. In summary, m odest antitumour activity was demonstrated in 3 patients; moderate toxicity was seen in most patients, but was usually tolerable. Further studies of Lonidamine are warranted in less heavily treated patients, alone or in combination with oth er chemotherapeutic agents. The new anticancer agent lonidamine has been recently revisited for the treatmen t of various solid tumors, due to its peculiar and unusual mechanism of action ( ie, interference with energy metabolism of tumor cells, morphologically displaye d by the appearance of "condensed mitochondria"). First generation trials have i n fact demonstrated therapeutic activity and an unusual toxicity profile. Lonida mine is devoid of conventional side effects induced by antiproliferative agents (ie, myelosuppression, stomatitis, cystitis, alopecia, renal, hepatic, and cardi ac toxicity). No serious or life-threatening adverse reactions have been recorde d even over long term treatment periods. Given as a single agent (in daily doses ranging between 300 and 900 mg) lonidamine induces the following side effects: myalgia, testicular pain, asthenia, ototoxicity, nausea and vomiting, gastric pa in, and drowsiness. Hyperesthesia and photophobia have also been reported. In co mbination with radiotherapy (in oral daily doses ranging between 300 and 450 mg) lonidamine was well tolerated, without any reported evidence of additional toxi city. When associated with cytotoxic agents no enhanced toxicity was observed. I n particular, myelosuppression and other conventional nonhematological adverse r eactions were never greater than would be expected with chemotherapy alone. The same applies to toxicity and tolerance of lonidamine when used concurrently with hypertermia. The data collected from large series of cancer patients treated wi th this new agent show that lonidamine is a safe drug whether used alone or in c ombination with other effective anticancer treatments. The reported therapeutic efficacy and the peculiar toxic profile make lonidamine an interesting new drug for future clinical trials

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