Assessment of Transporter Polymorphisms as a Factor in a BCRP Drug Interaction Study With Lanabecestat

• Published in: Journal of clinical pharmacology Vol. 60; no. 1; p. 107
• Main Authors: Willis, Brian A, Andersen, Scott W, Ayan-Oshodi, Mosun, James, Douglas E, Liffick, Emily, Hillgren, Kathleen, Guo, Yingying, Monk, Scott A
• Format: Journal Article
• Language: English
• Published: England 01.01.2020
• Subjects: Adult; Amyloid Precursor Protein Secretases - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily G, Member 2 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; Cross-Over Studies; Drug Interactions; Drug-Related Side Effects and Adverse Reactions - genetics; Drug-Related Side Effects and Adverse Reactions - metabolism; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacology; European Continental Ancestry Group; Female; Genotype; Healthy Volunteers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Male; Middle Aged; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Polymorphism, Genetic; Rosuvastatin Calcium - administration & dosage; Rosuvastatin Calcium - adverse effects; Rosuvastatin Calcium - pharmacokinetics; Spiro Compounds - pharmacokinetics; Spiro Compounds - pharmacology; Young Adult; BCRP; lanabecestat; Alzheimer's disease; rosuvastatin; β-site amyloid precursor protein-cleaving enzyme 1
• DOI: 10.1002/jcph.1500

Lanabecestat is a human β-site amyloid precursor protein-cleaving enzyme 1 inhibitor in development to slow disease progression in patients with early Alzheimer's disease. The study evaluated the breast cancer resistance protein (BCRP) inhibition potential of lanabecestat on the pharmacokinetics (PK) of rosuvastatin, a probe for BCRP activity, in healthy white subjects who were not carriers of SLCO1B1 (c.521T>C), not homozygotes for ABCG2 (c.421C>A or c.34G>A), and not heterozygotes of ABCG2 (c.421C>A and c.34G>A). The safety of lanabecestat + rosuvastatin, the effects of rosuvastatin on the PK of lanabecestat, and the effects of multiple genetic polymorphisms on rosuvastatin exposure were assessed. Geometric mean ratios of the maximum observed rosuvastatin concentration (C ), area under the rosuvastatin concentration-versus-time curve (AUC) from time 0 to infinity, and time of maximum observed drug concentration (t ) when rosuvastatin was administered alone and with lanabecestat were contained within 0.8-1.25, as were lanabecestat AUC at steady state and t at steady state when lanabecestat was administered alone or with rosuvastatin. Lanabecestat C at steady state increased 8% in the presence of rosuvastatin. Except for an approximately 80% increase of rosuvastatin AUC (P < .05) in the heterozygotes of ABCG2 c.421C>A relative to the CC genotype, there were no statistically significant associations between rosuvastatin exposure and polymorphisms assessed. Lanabecestat + rosuvastatin was associated with few treatment-emergent adverse events, all of which resolved and were mild. Lanabecestat does not meaningfully impact BCRP activity; therefore, restriction of concomitant administration with BCRP substrates, such as rosuvastatin, may be unnecessary.