Toxicity of a novel HMG-CoA reductase inhibitor in the common marmoset (Callithrix jacchus)
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Published on: September 22, 2023
K Owen1, C R Pick, S E Libretto
1Pathology and Toxicology Division, Glaxo Group Research Ltd, Ware, Hertfordshire, UK.
Abstract:
1. GR95030X, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was administered daily to marmosets by gavage. In a Maximum Repeatable Dose (MRD) study, doses of up to 30 mg kg-1 day-1 were administered for 49 days. In a chronic study, animals received dosages equivalent to 0, 1, 2.5, 7.5 and 20 mg kg-1 day-1 for 204 or 205 days. Some animals were maintained without treatment for a recovery period of 29 or 30 days. 2. Clinical signs included poor coat condition, weakness with impaired coordination, lethargy and other behavioural changes. There was also alimentary disturbance, and some deaths occurred at doses of 20 mg kg-1 day-1 and above. 3. Adverse effects upon body weight were seen although some recovery was apparent after the cessation of treatment. 4. Serum cholesterol concentrations were reduced. Very large increases in serum ALT, AST and CK activities were recorded with CK-MM isoenzymes accounting for 80% or more of the total CK enzyme activity. 5. Treatment was associated with muscle fibre atrophy and a sarcolemmal response with little evidence of regeneration. Histological examination revealed vascular changes, glial proliferation and cell death in the brain, with no consistent distribution. Alveolar capillary congestion and alveolar proteinosis indicated that there may have been a reduction in cardiac function. 6. HMG-CoA reductase inhibitors have evident potential to cause myopathy in marmosets. This is believed to be the first report of such an effect.
Insights
This study shows that HMG-CoA reductase inhibitors can cause muscle damage (myopathy) in marmosets, leading to various clinical signs and organ changes. Further research is needed to understand these effects fully.
Area of Science:
- Pharmacology
- Toxicology
- Primate Research
Background:
- 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are widely used to lower cholesterol.
- Potential adverse effects of these drugs, particularly on muscle tissue, require thorough investigation in relevant animal models.
Purpose of the Study:
- To evaluate the toxicological profile of GR95030X, a novel HMG-CoA reductase inhibitor, in marmosets.
- To assess the potential for myopathy and other adverse effects following chronic administration of GR95030X.
Main Methods:
- GR95030X was administered daily to marmosets via gavage in a Maximum Repeatable Dose (MRD) study (up to 30 mg/kg/day for 49 days) and a chronic study (0, 1, 2.5, 7.5, 20 mg/kg/day for 204-205 days).
- Animals underwent a recovery period post-treatment.
- Clinical signs, body weight, serum biochemistry (ALT, AST, CK), and histopathology of various tissues were examined.
Main Results:
- Clinical signs included poor coat, weakness, lethargy, and behavioral changes. Deaths occurred at doses ≥20 mg/kg/day.
- Reduced serum cholesterol and significant increases in ALT, AST, and CK (predominantly CK-MM) were observed.
- Histopathology revealed muscle fiber atrophy, brain changes (vascular, glial proliferation, cell death), and signs of reduced cardiac function (congestion, proteinosis).
Conclusions:
- HMG-CoA reductase inhibitors, exemplified by GR95030X, demonstrate a clear potential to induce myopathy in marmosets.
- This study provides the first report of such drug-induced myopathy in this primate model, highlighting the need for careful monitoring of muscle health in patients receiving these medications.
