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

Brian A. Willis, Scott W. Andersen, Mosun Ayan-Oshodi, Douglas E. James, Emily Liffick, Kathleen Hillgren, Yingying Guo, Scott A. Monk

Research output: Contribution to journalArticle

Abstract

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 (Cmax), area under the rosuvastatin concentration-versus-time curve (AUC) from time 0 to infinity, and time of maximum observed drug concentration (tmax) when rosuvastatin was administered alone and with lanabecestat were contained within 0.8-1.25, as were lanabecestat AUC at steady state and tmax at steady state when lanabecestat was administered alone or with rosuvastatin. Lanabecestat Cmax 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.

Original languageEnglish (US)
JournalJournal of Clinical Pharmacology
DOIs
StateAccepted/In press - Jan 1 2019

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Drug Interactions
Breast Neoplasms
Proteins
Area Under Curve
Rosuvastatin Calcium
Pharmacokinetics
Amyloid beta-Protein Precursor
Homozygote
Enzyme Inhibitors
Genetic Polymorphisms
Heterozygote
Disease Progression
Healthy Volunteers
Alzheimer Disease
Genotype
Safety

Keywords

  • Alzheimer's disease
  • BCRP
  • lanabecestat
  • rosuvastatin
  • β-site amyloid precursor protein-cleaving enzyme 1

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Assessment of Transporter Polymorphisms as a Factor in a BCRP Drug Interaction Study With Lanabecestat. / Willis, Brian A.; Andersen, Scott W.; Ayan-Oshodi, Mosun; James, Douglas E.; Liffick, Emily; Hillgren, Kathleen; Guo, Yingying; Monk, Scott A.

In: Journal of Clinical Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

Willis, Brian A. ; Andersen, Scott W. ; Ayan-Oshodi, Mosun ; James, Douglas E. ; Liffick, Emily ; Hillgren, Kathleen ; Guo, Yingying ; Monk, Scott A. / Assessment of Transporter Polymorphisms as a Factor in a BCRP Drug Interaction Study With Lanabecestat. In: Journal of Clinical Pharmacology. 2019.
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abstract = "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 (Cmax), area under the rosuvastatin concentration-versus-time curve (AUC) from time 0 to infinity, and time of maximum observed drug concentration (tmax) when rosuvastatin was administered alone and with lanabecestat were contained within 0.8-1.25, as were lanabecestat AUC at steady state and tmax at steady state when lanabecestat was administered alone or with rosuvastatin. Lanabecestat Cmax 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.",
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AU - Hillgren, Kathleen

AU - Guo, Yingying

AU - Monk, Scott A.

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