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F FIAC and FIAU Preclinical Toxicity Studies

FIAC ACUTE TOXICITY STUDIES

The acute intravenous lethal dose (LD50) of FIAC is reported to range from 500 to 1,000 mg/kg in mice, rats and monkeys. Cardiotoxicity was observed at dosages greater than 500 mg/kg in rats.

Multiple Dose Studies

Mice were treated for 5 days with 500 or 1,000 mg/kg/day, administered intraperitoneally. Half of the animals given 1,000 mg/kg/day died; decreased body weight gain was observed at 500 mg/kg/day. A similar study was performed in rats with analogous results. Cardiotoxicity was observed in rats following 1,000 mg/kg/day.

Dogs were intravenously treated (24, 48 mg/kg/day) with FIAC for 10 days. Decreased food intake, weight loss, intestinal changes and hematopoietic depression were noted at 48 mg/kg/day.

Mutagenicity Studies

FIAC is reported to be devoid of mutagenic activity in an Ames test study.

Comments

FIAC preclinical evaluation studies are not extensive, since interest in this substance waned early. The limited information, however, is of interest since FIAU is reported to be a metabolic product of FIAC. Qualitatively speaking, the studies indicate that the toxic effects of FIAC reported in different laboratory animal species are similar to those obtained with FIAU.



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Review of the Fialuridine (FIAU) Clinical Trials F FIAC and FIAU Preclinical Toxicity Studies FIAC ACUTE TOXICITY STUDIES The acute intravenous lethal dose (LD50) of FIAC is reported to range from 500 to 1,000 mg/kg in mice, rats and monkeys. Cardiotoxicity was observed at dosages greater than 500 mg/kg in rats. Multiple Dose Studies Mice were treated for 5 days with 500 or 1,000 mg/kg/day, administered intraperitoneally. Half of the animals given 1,000 mg/kg/day died; decreased body weight gain was observed at 500 mg/kg/day. A similar study was performed in rats with analogous results. Cardiotoxicity was observed in rats following 1,000 mg/kg/day. Dogs were intravenously treated (24, 48 mg/kg/day) with FIAC for 10 days. Decreased food intake, weight loss, intestinal changes and hematopoietic depression were noted at 48 mg/kg/day. Mutagenicity Studies FIAC is reported to be devoid of mutagenic activity in an Ames test study. Comments FIAC preclinical evaluation studies are not extensive, since interest in this substance waned early. The limited information, however, is of interest since FIAU is reported to be a metabolic product of FIAC. Qualitatively speaking, the studies indicate that the toxic effects of FIAC reported in different laboratory animal species are similar to those obtained with FIAU.

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Review of the Fialuridine (FIAU) Clinical Trials FIAU ACUTE TOXICITY STUDIES After a period of observation of 14 days, the lethal dose after a single oral administration in male rats was estimated to be greater than 3,000 mg/kg. Blood from rats receiving 3,000 mg/kg was analyzed for alanine aminotransferase activity (ALT), hemoglobin concentration, and urea nitrogen concentration up to 1 week post-treatment; all parameters were found to be in the normal range. In addition various clinical signs were also normal. A limited single-dose oral study was conducted in cynomolgus monkeys (1 animal per dose level) with dosages of 50, 250, or 500 mg/kg. The animals were observed for 14 days. Slight to mild elevations in alanine aminotransferase activity were observed in animals given micronized or nonmicronized material (50 and 250 mg/kg) but not in the 3 monkeys treated with lyophilized material at 25, 250, or 500 mg/kg. After a single intravenous administration (10 males, 10 females per group) and a period of observation of 14 days, the lethal dose in mice was estimated to be between 600 and 1,000 mg/kg; in rats (10 males, 10 females per group), between 500 and 800 mg/kg; in monkeys, between 1,000 and 1500 mg/kg. In rats and monkey, only cardiotoxicity (myocardial degeneration) was observed. Multiple Dose Studies Rats (4 males per group) were treated with oral dosages of 1,000-1,500 mg/kg per day for 7 days. No clinical signs of toxicity were observed. Furthermore, no changes in clinicopathology (differential blood counts, alanine aminotransferase activity, urea nitrogen concentration) were detected on days 4 and 7. After intravenous injection (500-750 mg/kg), deaths (3/4) occurred between days 1 and 4 at 600 and 750 mg/kg. Some clinicopathology was observed in the surviving animals on days 4 and 7 (decreased erythrocytes, leukocytosis, lymphocytosis). Changes in alanine aminotransferase or urea nitrogen concentration were not seen. A 1-month subchronic study was performed in cynomolgus monkeys, where 3 or 4 animals per dose level, treated orally twice daily, received 5, 20, or 80 mg/kg/day. Three of four 80-mg/kg/day animals were moribund and sacrificed on days 23, 25, and 27; clinical signs of toxicity included weight loss, diarrhea, hypoactivity, and hypothermia. Stomach erosion and ulceration, as well as hypocellularity of the bone marrow were observed. A decline in white cell counts, decreased uterine weight, and thymus weights were described. At 5 mg/kg/day, no consistent or apparent treatment-related changes were found. In mice (160 mice total), oral treatment with daily dosages of 10, 50, or 250 mg/kg/day for 90 days yielded no adverse effects at 10 or 50 mg/kg/day. At 250 mg/kg/day, 4/50 mice died; renal toxicity was noted, as well as lesions in the testes. No tissue lesions were observed in the 10 mg/kg/day group. Rats (15 males, 15 females per group) were intravenously treated with 10, 25, 50, 250, or 500 mg/kg/day, daily for 1 month. Five of 30 rats given the highest dose died between day 5 and 13. Significantly lower body weight gains were observed at 250 and 500 mg/kg/day. No significant drug-related clinical pathological changes were observed, except for a decreased

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Review of the Fialuridine (FIAU) Clinical Trials leukocyte and reticulocyte count in 1 male rat in the high dose group. Tissue signs indicative of cardiotoxicity were found in the high dose group. The spleen was affected at dosages of 50 mg/kg/day or higher; reduction in nucleated cells in the bone marrow, reduced spermatogenesis, and tubular alterations in the seminiferous tubules occurred at the high dose. Lymphoid and hematopoietic tissues recovered after a 6-week recovery period, while the cardiotoxicity was irreversible. No effects were observed at 10 or 25 mg/kg/day. A pilot multiple dose study was performed in cynomolgus monkeys, where 1 animal per dose level received 300, 400, or 500 mg/kg daily orally for 7 days. Body weight losses were observed. A slight decrease in hemoglobin and erythrocyte count was seen on day 7 in monkeys treated with 300 and 500 mg/kg/day; slight to moderate elevations in alanine aminotransferase were noted on day 4 in the monkey treated with 300 mg/kg/day and on days 3 and 7 in the animal treated with 500 mg/kg/day. A limited study was performed in dogs, where the animals were treated for 10 days orally or intravenously with dosages ranging from 5-25 mg/kg; the lethal dose was estimated to be 14 mg/kg/day. Hematopoietic depression, damage to the intestinal mucosa, and decreased spermatogenesis were observed. A 1-month intravenous study (3 males, 3 females per group) was performed in cynomolgus monkeys, using dosages of 25, 75, or 150 mg/kg/day. With the high dose, 5/6 animals died; 1/6 died at the intermediate dosage level. Body weight losses were observed at all dosage levels. On days 8, 29, and 71, hematologic and serum chemical measurements were obtained; urinalysis was performed on days 29 and 71. Suppression of the hematopoietic tissues occurred in a dose-related manner, being prominent at 150 mg/kg/day and absent at 25 mg/kg/day. At the highest dose, elevated urea nitrogen concentrations were obtained; these were reversible after a 6-week recovery period. Gross examination of organs and tissues revealed marked atrophy of the thymus and watery or gelatinous bone marrow in the high dose animals that died. Drug-related histological changes were observed mostly in the high dose and some of the intermediate-dose groups; these included hematopoietic changes, vacuolation and presence of pigment in hepatocytes, renal cortical tubular dilatation, cytostatic enteropathy of the large intestine and acinar cell atrophy in the salivary gland, giant cell formations in the testes, and myocardial degeneration. All, except the heart, were considered reversible. No changes were observed in the low-dose animals. Chronic Study Mice (20 males, 20 females per group) were treated daily with oral doses of FIAU for 6 months (10, 50, or 150 mg/kg/day), followed by a 1-month reversibility period. At 150 mg/kg, nephropathy was observed in both males and females; testicular toxicity (decreased weight, hypospermatogenesis) was observed in males; 2/20 male mice died, while 10/20 females died. Decreased lymphocytes were observed in female mice given 150 mg/kg; slightly elevated alanine aminotransferase and aspartate transaminase was seen in male mice, but no histological correlates were noted. Kidney lesions were inconsistently observed in female mice at 50 mg/kg. No effects were seen in either sex at 10 mg/kg/day.

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Review of the Fialuridine (FIAU) Clinical Trials Mutagenicity Studies FIAU was assessed for possible mutagenic effects in 7 different in vitro tests (4 Ames tests; mouse lymphoma assay; forward mutation Chinese hamster ovary cells; chromosome aberrations in Chinese hamster ovary cells). The compound was devoid of mutagenic activity in these studies, except for a positive induction of chromosomal aberrations in CHO cells. FIAU was considered active in the in vitro neoplastic transformation assay. In vivo, FIAU was tested for its ability to induce micronuclei in bone marrow of mice and rats. With large oral dosages (1,000 or 2,000 mg/kg), the agent was considered positive in mice, but not in rats. The battery of mutagenicity studies performed indicate that FIAU was negative in many tests, but at high dosages could modify a few specific parameters. This finding is not unusual, considering the biological characteristics of the agent. Reproduction Studies Male rats were orally treated daily (25, 100, or 350 mg/kg/day) with FIAU for 2 weeks, followed by a 2-week recovery period. At the two higher dosages, depression of food consumption and body weight gain were observed, but no apparent adverse effects on sperm production, sperm quality, mating performance, or fertility occurred in this study. The potential to produce developmental toxicity was evaluated in rabbits at dosages of 2, 10, or 50 mg/kg/day on gestation days 6-18. A red discharge of unknown origin was noted with several animals in the high dose group, 2 rabbits in the high dose group aborted. With 10 and 50 mg/kg/day, body weight gain was diminished but food consumption was not affected. Fetal viability was depressed at all dosages. Fetal malformations were observed at all doses, and fetal weight was depressed at 50 mg/kg/day. It was concluded that FIAU was toxic to the developing embryo. Male mice were treated with the agent for 2 weeks (10, 50, 250 mg/kg/day) before cohabitation with females. Females were treated for 2 weeks before cohabitation and until gestation day 17. With 250 mg/kg/day, 2 mice died as a result of treatment. Mating index was slightly diminished at 250 mg/kg. Hypospermatogenesis occurred in all male mice treated with 250 mg/kg, whereas slight effects were seen at 50 mg/kg. Nephropathy was noted in 4 male mice at 250 mg/kg and in 1 male at 50 mg/kg; 5/25 females given 250 mg/kg and 2/25 given 50 mg/kg developed nephropathy. Fetal growth retardation occurred in the groups treated with 50 or 250 mg/kg/day. Comments The preclinical toxicity studies conducted in different species prior to the start of the last PPPC clinical trial indicate that, indeed, the nucleoside FIAU can cause severe toxic effects when administered in large dosages. The major effects include: myocardial degeneration, suppression of the hematopoietic tissues, reduction in spermatogenesis, and nephropathy. Most of the effects, except the cardiotoxicity, were reversible when the animals were observed for

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Review of the Fialuridine (FIAU) Clinical Trials an extended post-treatment period. It is noteworthy, however, that while mild excursions in serum alanine or aspartate aminotransferase activity were observed in some studies, no corresponding morphologic hepatic changes were reported. Furthermore, no mention of pancreatic changes are noted in the reports. The preclinical toxicity data available prior to the PPPC clinical trial was judged to be adequate by the Food and Drug Administration, and, therefore, the clinical trial could proceed as planned. A retrospective evaluation of the material available in 1993 still supports this position. The acute and multiple dose studies performed in different laboratory animals (mice, rats, dogs, and monkeys), a chronic study in one species (mice), a battery of mutagenicity studies, and studies on reproduction yielded patterns of observations that were more or less consistent with the biologic characteristics of FIAU. Furthermore, dose-dependent relationships were generally clear, and the toxic effects usually occurred at dosages near the maximum tolerated range in each species. There was nothing in the preclinical toxicity studies that was suggestive of the tragic episode that transpired in the PPPC clinical trial. Furthermore, unfortunately, there is nothing to indicate that other laboratory animal studies would have been more appropriate or capable of better prediction of the fatal outcome.