Assessment of Potential Oral Activity of IGF1

Two rat gavage studies were carried out to assess the potential oral activity of IGF-1, as requested by the FDA. In the first study, male and female rats were dosed orally with 0, 0.02, 0.2, and 2.0 mg/kg/day IGF-1 for 14 consecutive days.74 The 2-mg/kg oral dose of IGF-1 is several thousand times higher than the potential human dietary exposure from consuming milk. Positive control groups were given either 0.05 or 0.2 mg/kg/day of IGF-1 for 14 days by constant subcutaneous infusion via implanted osmotic minipumps to ensure systemic administration. Another positive control group was given 4.0 mg/kg/day porcine somatotropin (PST), also by subcutaneous infusion. Rats of both sexes in the IGF-1 positive control subcutaneous infusion groups exhibited biological effects consistent with those observed in rats injected with somatotropin [i.e., increased body weights, decreased erythrocyte count and hemoglobin (PST only), decreased BUN and creatinine (IGF-1), increased liver, kidney and spleen weights (females only), increased epiphyseal width, and so forth]. In contrast, rats administered up to 2 mg/kg/day IGF-1 by the oral route did not exhibit these same changes, and it was concluded that IGF-1 was not orally active under the conditions of this study.

Another study was carried out in hypophysectomized rats, which are more sensitive to the anabolic effects of somatotropin and IGF-1 than rats with intact pituitaries.74 In this study, rats were administered IGF-1 by gavage at dosages of 0.01, 0.1, and 1.0 mg/kg/day for 14 consecutive days. A positive control group was given 1.0 mg/kg/ day IGF-1 by subcutaneous infusion via implanted minipumps. Rats that received IGF-1 subcutaneously exhibited increased weight gain, decreased serum BUN, increased kidney and spleen weights — similar to effects described in the previous IGF-1 study. Hypophysectomized rats administered IGF-1 by gavage did not exhibit the changes observed in positive control animals that received IGF-1 by subcutaneous infusion.

The safety review of bST and IGF-1 carried out by international regulatory scientists (JECFA)39 included findings from studies that had been carried out after the FDA approval of bST in 1993. One study was designed to measure the potential therapeutic benefits of IGF-1 administered by the oral route, and the biological halflife of IGF-1 was determined in isolated sections of the rat gastrointestinal tract.104 The biological half-life, as determined by receptor binding assays, was determined to be just a few minutes, which is consistent with the observation that the related protein insulin is not therapeutically active if given by mouth but must be administered to diabetics by injection.66 When casein, a protein normally present in milk, was co-administered with IGF-1, the biological half-life of IGF-1 was increased in the rat digestive tract. The authors acknowledged that the increased biological half-life of IGF-1 could be due to casein competing for the same proteases that degrade IGF-1.

In another study, large doses (1 mg/kg) of IGF-1 labeled with I125 were reported to be slightly bioavailable (9% of the dose), whereas the addition of a protease inhibitor and casein significantly increased the bioavailability of IGF-1.105 However, it was noted in the 1998 JECFA review that the IGF-1 receptor bioassay, which is the most accurate method to confirm the presence of biologically active IGF-1, was not used in this study.39

Other studies referenced in the JECFA review39 have also confirmed the low bio-availability of orally administered IGF-1. Some of these studies were carried out in neonatal animals that have an incomplete mucosal barrier and reduced intestinal protease activity.106 "Studies in neonatal rats and piglets indicated that although 30% of an orally administered dose of 125I-IGF-1 can be recovered in the intestinal mucosa, there is limited absorption into the peripheral circulation.107,108 When suckling transgenic rats ingested 1000-fold higher concentrations of des(1,3) human IGF-1, no des(1,3)-IGF-1 was detected in the plasma of their pups.106 Furthermore, in newborn calves and piglets given a large dose of IGF-1 in milk replacers, no substantial increase in the plasma concentration of this growth factor was found.108-110 In one study with newborn calves fed milk replacer, a small amount of orally administered 125I-IGF-1 was detected in the plasma;111 however, the increase was observed only three days after administration and in only three of six animals. Even in newborns, therefore, IGF-1 is absorbed to only a small extent, and absorption is unlikely in adults."39

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