D. E. Gutstein, R. Krishna, D. Johns, K. Mitra, G. Hartmann, V. Hamilton, J. Cote, F. Gheyas, S. Shah, Y. Mitchel; Merck & Co, Rahway, NJ
BACKGROUND: Anacetrapib (ANA), a highly lipophilic molecule currently in development for dyslipidemia, is characterized by a long plasma terminal half-life in mice and humans. The aim of these investigations was to understand whether the observed long half-life is associated with deposition of ANA in adipose tissue.
METHODS: ANA tissue deposition after multiple dosing was assessed in preclinical and clinical studies. Wild-type lean, obese and CETP-transgenic mice were dosed with 10 mg/kg/day of ANA for 42 days and ANA levels were determined in blood, adipose, liver and brain during dosing and follow-up. Blood and adipose were analyzed for ANA in healthy humans during dosing at 100 mg/d for up to 16 weeks and postdose for 1 year. Adipose drug levels were also characterized after off-drug periods of up to 4 years in a small number of patients previously treated with 100 mg/d ANA in the DEFINE study for durations of up to 3.5 years.
RESULTS: In mice, CETP prolonged the plasma half-life of ANA, but accumulation in adipose depended upon the degree of adiposity, rather than on the presence of CETP. In healthy human subjects, ANA concentration in plasma reached a plateau by ~4 weeks of dosing, but continued to accumulate in adipose to levels ~64-fold higher than plasma by 16 weeks of dosing. ANA concentrations in adipose remain stable for at least 1 year after cessation of dosing. Further emerging data from patients treated chronically with ANA and off drug for extended periods confirms high ANA adipose concentrations with prolonged residence time compared to plasma.
CONCLUSION: ANA accumulates in adipose tissue, with slow release from adipose hypothesized to contribute to the observed long terminal plasma half-life. Studies are ongoing to further characterize accumulation and elimination kinetics of ANA.