Summary Basis of Decision for Colesevalam hydrochloride (Lodalis)

3.2.1 Non-Clinical Pharmacology

The non-clinical program for colesevelam hydrochloride tablets was adapted taking into account the physio-chemical properties, clinical use, scientific results and regulatory guidelines. Pharmacological studies were conducted to confirm in vitro and in vivo binding to bile acids. The studies confirmed that colesevelam hydrochloride binds bile acids in man, hamsters and rats, and reduced plasma cholesterol in man and dogs (but not in rats).

Colesevelam hydrochloride is insoluble in aqueous solution. The size distribution of the polymer is controlled and of a size that is essentially not absorbed from the gastrointestinal tract. Absorption and excretion studies with radiolabelled colesevelam were conducted in rats and dogs and the results were consistent with the physiochemical properties. The radiolabelled material was almost completely eliminated via the faeces with only traces of radioactivity in the urine. In none of the studies was there evidence of the radiolabelled material in tissues or plasma.

The lack of oral absorption, the physiochemical properties, the chronic use, and the mechanism of action had a significant impact on the non-clinical pharmacology program.

• The metabolite profile was not characterized. No metabolism or distribution studies were conducted.
• There was no bio-analytical method or monitoring of circulating drug concentrations.
• Safety pharmacology studies to characterize effects on the central nervous system, cardiovascular and respiratory systems were not conducted. The lack of absorption obviated the need for these studies. The lack of absorption is not a justifiable scientific rationale for not conducting safety pharmacology studies to evaluate effects on gastric transit time and renal function in view of the potential for increases in chloride absorption, however, it is recognized that the potential for these effects were assessed in clinical studies.
• Evaluation of potential exaggerated pharmacology and effects of ion exchange were included in the toxicology studies. Since bile acid sequestering may reduce absorption of fat soluble vitamins, effects on circulating vitamin A, D, E and/or K concentrations were monitored and/or diets were supplemented with fat soluble vitamins. As the ion exchange of the polymer involved the release of chloride, particular attention was paid to the monitoring of electrolytes.

3.2.2 Toxicology

The non-clinical safety of colesevelam hydrochloride was evaluated in a toxicology program consisting of repeat-dose oral studies in rats and dogs, genotoxicity evaluations, carcinogenicity studies in rats and mice, and reproductive toxicity studies in rodents in order to support the proposed chronic clinical treatment indication for colesevelam hydrochloride. In addition, there were dedicated toxicology studies to qualify four degradants of colesevelam hydrochloride.

Colesevelam hydrochloride is a non-absorbed polymer intended to reduce the reabsorption of bile acids by ion exchange of chloride for a negatively charged bile acid. The lack of absorption obviates the need to determine circulating concentrations of drug. There is no indication that colesevelam hydrochloride is absorbed in any species and the rats, mice, dogs, and rabbits are appropriate models for the safety evaluation. The route of administration was oral and, in most rodent studies, the test compound was mixed in the diet. The test article is stable and homogeneous in the diet and this route is acceptable for evaluating the non-clinical toxicity.

Single-Dose Toxicity

No acute toxicity studies were conducted. This omission is acceptable in view of the demonstrated lack of oral absorption. In addition, high oral doses were administered in the repeat-dose studies.

Repeat-Dose Toxicity

The results of the toxicology studies show that colesevelam hydrochloride

• induced effects consistent with the pharmacological mechanism of action. In dogs, cholesterol levels were reduced at ≥0.2 g/kg;
• reduced serum levels of fat soluble vitamins in rats at ≥1.2 g/kg and in dogs at ≥0.6 g/kg consistent with a reduction in fat absorption. In the carcinogenicity studies in mice at 3 g/kg/day and rats at 2.4 g/kg/day, vitamin supplementation largely prevented the decrease in serum concentrations of fat soluble vitamins;
• resulted in increased serum chloride levels and urinary chloride excretion consistent with ion exchange of the polymer that included release of chloride;
• was generally tolerated with minimal clinical toxicity after daily oral dosing of up to 2 g/kg/day for 52 weeks in dogs, and in rats after 2.4 g/kg/day for 6 months;
• was associated with quantitative differences in response in rats from two different vendors. With male rats from one vendor, mortality occurred after daily dosing for up to a month at 3 g/kg/day while 2.4 g/kg/day was lethal in male rats from another vendor;
• appeared to induce mortality in male rats secondary to haemorrhage and may be related to reduced vitamin K absorption;
• did not induce any drug-related gross or histopathological changes indicative of overt toxicity at the highest dose tested in dogs (2 g/kg), mice (3 g/kg), or in rats at dose levels not associated with haemorrhage. This analysis included evaluation of the stomach and gastrointestinal tract;
• induced mild/minimal increases in serum transaminases in rats in the 3- and
  6-month studies. The significance of these small increases in the absence of histological liver correlates is uncertain;
• resulted in discoloured/mucoid faeces in dogs at ≥0.67 g/kg/day. Local gastrointestinal effects in some dogs were likely related to the large amount of orally administered compound.

The studies clearly show that repeated oral administration is tolerated at doses up to 2 g/kg in the dog (32 times the human maximal dose on a mg/kg basis) for 52 weeks and 1.2 g/kg (19 times the human dose) in the rat for 26 weeks. It is noteworthy that there were reduced levels of vitamin D and E in rats at 1.2 mg/kg and at 0.6 mg/kg in dogs. Thus for chronic administration, careful attention has to be paid to effects secondary to reduced uptake of fat soluble vitamins.

Genotoxicity

Due to insolubility of colesevelam hydrochloride, in vitro genotoxicity studies were conducted on extracts of colesevelam. The studies showed no indication of in vitro genotoxicity when acid extracts were tested in bacterial cells. The sponsor classified the weak response in the Chinese Hamster Ovary cell chromosomal aberration assay in the presence of metabolic activation as indicative of a positive clastogen. The extract was negative in the absence of metabolic activation.

Carcinogenicity

In a 104-week carcinogenicity study with mice, there was a low incidence of cholangioma (bile duct adenoma) in mice that were administered colesevelam hydrochloride 1 g/kg (one male, drug exposure 16 times the maximum recommended human dose of 4.5 g/day, based on body weight) and 3 g/kg (one male and one female). Cholangioma is an uncommon tumour in mice. Since the mechanism of action of cholestagel is related to bile acid regulation, a relationship to treatment cannot be excluded for cholangioma. The relevance of this finding to humans has not been established.

In a 104-week carcinogenicity study with rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was observed in male rats at doses of >1.2 g/kg/day (approximately 19 times the maximum human dose, based on body weight). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight).

Reproductive and Developmental Toxicity

Colesevelam hydrochloride had no effects on male or female fertility or early embryonic development in male and female rats administered 2 g/kg/day orally prior to and during mating and early pregnancy.

Colesevelam hydrochloride administered orally during organogenesis at doses of 3 g/kg in rats and 1 g/kg in rabbits induced no teratogenic effects or developmental delays.

No effects were reported on pre- and post-natal development in rats that were treated with doses of up to 1 g/kg from gestation Day 6 through lactation Day 20.

Other Toxicology Studies

Dedicated studies were conducted to qualify the four degradants (decylamine hydrochloride, didecylamine hydrochloride, decylamino-6-hexytrimethyl ammonium chloride hydrochloride, and aminohexyltrimethylammonium chloride hydrochloride). The studies adequately qualified these degredants at levels no more than 0.1% each in the drug substance.

3.2.3 Summary and Conclusion

The non-clinical studies for this drug submission are considered acceptable. The results of the non-clinical studies support the proposed clinical use. The toxicology program for colesevelam hydrochloride demonstrated that the compound is relatively safe for humans. Adequate statements are in place in the Product Monograph to address the identified safety concerns.