Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties

Abstract

Fibrate drugs are PPARα agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reported associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPARα agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16 th dosage of P1 and 17 th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey #2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly they exhibited a much higher incidence of myotoxicity than that of human. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity.

The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice

“…Interestingly, several studies have documented a deleterious effect of PPARα activation on myocytes. PPARα-induced myotoxicity has been detected in both human and rat cells in vitro and in a primate in vivo model (Johnson et al, 2005; Liu et al, 2009; Liu et al, 2011; Zhao et al, 2010). Similar to the mice in Study I, primates treated with gemfibrozil displayed significant behavioral deficits.…”

Biphasic Regulation of Intracellular Calcium by Gemfibrozil Contributes to Inhibiting L6 Myoblast Differentiation: Implications for Clinical Myotoxicity

“…9 (C) Trough concentrations in cynomolgus monkeys where a high incidence of myotoxicity was observed. 18 (D) EC 50 for PPARα activation by Gemfibrozil. 39 (E) Gemfibrozil inhibits L6 differentiation morphologically between 100 and 400 μ M with maximal effect at a concentration of 400 μ M. (F) Gemfibrozil inhibits L6 CK expression between 20 and 200 μ M with maximal effect at a concentration of 200 μ M. (G) Biphasic regulation of L6 [Ca 2+ ]i by gemfibrozil between 20 and 200 μ M with a reductive effect at 200 μ M. Arrow symbols indicate that higher gemfibrozil concentrations may be applied to produce toxicity or maximal biological effect.…”

“…Interestingly, a high incidence of myotoxicity in cynomolgus monkeys induced by gemfibrozil was reported, where sustained exposure to higher concentrations of gemfibrozil was suggested to be important for the occurrence of myotoxicity. 18…”

Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity

“…Prolonged PPARα activation, as a result of chronic fibrate administration, causes hepatocellular carcinoma in rats and mice (Peters et al 2005; Cunningham et al 2010). Among the fibrates, gemfibrozil is associated with the highest risk of myotoxicity, in monotherapy or combination with statins (Holoshitz et al 2008; Liu et al 2009). In the clinic, gemfibrozil also increases risk of cholestatic jaundice and cholelithiasis (Sabordo and Sallustio 1997; Roglans et al 2004).…”