Oral repeated-dose toxicity studies of coenzyme Q10 in beagle dogs

Abstract

To support phase III testing of coenzyme Q10 (CoQ₁₀) in humans, we conducted pharmacokinetic and toxicology studies in beagle dogs. Following single gavage administration of CoQ₁₀ at 600, 1200, 1800, or 2400 mg/kg per d no obvious dose response was observed in maximum concentration (C(max)) or area under the curve (AUC) versus time curve at the 3 highest dosages. In a repeated-dose study of CoQ₁₀ at 600, 1200, 1800, or 2400 mg/kg per d for 4 weeks, CoQ₁₀ reached steady state in plasma by 2 weeks at all dosages. Both C (max) and AUC increased with increasing dosage of CoQ₁₀. The highest plasma levels were recorded at 1800 mg/kg per d. In a 39-week chronic toxicity study of CoQ₁₀ at 1200 and 1800 mg/kg per d or placebo, CoQ₁₀ reached steady state in plasma by 13 weeks. Behaviors, blood chemistries, and detailed histopathology were normal. No deaths occurred. These results support the use of a 2400 mg/d dosage of CoQ₁₀ in human clinical trials.

Figure 1. AUC values in dogs administered a single dose of CoQ₁₀ at 600, 1200, 1800 and 2400mg/kg by gavage

Bars denote mean value and dots denote individual values of two animals per dosage group, except in the 600mg/kg dosage group where one animal showed abnormal plasma concentration, likely due to a dosing error (value not shown).

Figure 2. AUC values in dogs administered 600, 1200, 1800 and 2400mg/kg of CoQ₁₀ daily by gavage for 28 consecutive days

Bars denote mean values and dots denote individual values of two animals per dosage group.

Figure 3. C_max Values at Day 1 and at Week 39 in Male and Female Dogs Administered Placebo, 1200mg/kg or 1800mg/kg of CoQ10 daily by gavage for 39 weeks

C_max was greater at Week 39 than at Day 1. Bars denote mean values and dots denote individual values of four animals per dosage group.

Figure 4. T_max Values at Day 1 and at Week 39 in Male and Female Dogs Administered Placebo, 1200mg/kg or 1800mg/kg of CoQ10 daily by gavage for 39 weeks

T_max was shorter at Week 39 than at Day 1 Bars denote mean values and dots denote individual values of four animals per dosage group.

Figure 5. AUC Values at Day 1 and at Week 39 in Male and Female Dogs Administered Placebo, 1200mg/kg or 1800mg/kg of CoQ10 daily by gavage for 39 weeks

AUC was greater at Week 39 than at Day 1. Bars denote mean values and dots denote individual values of four animals per dosage group.