P1‐039: LANABECESTAT DOES NOT AFFECT PHARMACOKINETICS OF THE BCRP SUBSTRATE ROSUVASTATIN
Scott A. Monk, Scott W. Andersen, Mosun Ayan‐Oshodi, Yingying Guo, Kathleen M. Hillgren, Douglas E. James, Emily Liffick, Brian A. Willis · Alzheimer s & Dementia · 2018
Lanabecestat (also known as LY3314814 or AZD3293) is a novel beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently being investigated for treatment of Alzheimer's disease in three Phase 3 trials (NCT02245737, NCT02783573, and NCT02972658) at daily doses of 20 and 50 mg. Lanabecestat inhibits breast cancer resistance protein (BCRP) activity in vitro (IC50 = 11.1 μM). To better characterize the clinical effect of lanabecestat on BCRP, the current study evaluated the effect of lanabecestat on pharmacokinetics of the BCRP substrate rosuvastatin. Phase 1, multiple-dose, open-label, fixed treatment sequence, 2-period crossover study was conducted to assess PK of rosuvastatin (20 mg) administered alone or following multiple doses of 50 mg lanabecestat in healthy male and female subjects (NCT02406261). Subjects with polymorphisms associated with impaired OATP1B1 (c.521T>C) or BCRP activity (c.421C>A and c.34G>A) were excluded. Additionally, study was limited to Caucasians as c.421C>A and c.34G>A polymorphisms occur at lower frequency in Caucasians. Genetic analysis was conducted to determine the effect of polymorphisms in transporter genes (BCRP, OATP1B1, OATP1B3, OATP2B1, MRP2, Pgp, and Na+-taurocholate cotransporting polypeptide) on the magnitude of the rosuvastatin-lanabecestat interaction. On Day 8 of the multiple dosing period for lanabecestat, rosuvastatin was coadministered with lanabecestat, and plasma rosuvastatin concentrations were determined up to 120 hr postdose. Lanabecestat PK was evaluated on Days 7 and 8. A total of 26 subjects completed. There were no statistically significant differences in Cmax, AUC(0-∞), or tmax between rosuvastatin administered alone or coadministered with lanabecestat. Additionally, geometric mean t1/2, CL/F, Vz/F, and Vss/F all were similar for rosuvastatin administered alone or with lanabecestat. There were no clinically-meaningful differences in AUCτ,ss or Cmax between lanabecestat administered alone and lanabecestat coadministered with rosuvastatin. Pharmacogenomic analysis indicate no discernible differences in rosuvastatin exposure ratios between subjects with or without the polymorphisms determined. No safety concerns were noted in AEs, clinical laboratory tests, vital signs, or ECGs. Results of this study indicate that coadministration of lanabecestat with rosuvastatin does not meaningfully affect the pharmacokinetics of either compound. Lanabecestat does not meaningfully affect BCRP activity; BCRP substrates do not need to be restricted for individuals receiving lanabecestat.