Background: LY500307 is a highly selective estrogen receptor β (ERβ) agonist, which loses its selectivity at high dose and leads to undesirable suppression of total testosterone (TT) concentration. The objective of the present analysis was to define the LY500307 dose with minimal effect on TT METHODS: LY500307 and TT concentrations were obtained from a single ascending-dose study in a total of 30 healthy male subjects. LY500307 (in the range of 0.5 to 500 mg) or placebo was administered orally as a single dose on 2 occasions with a 3-week washout period. A population pharmacokinetics/pharmacodynamics (PK/PD) model that integrated Fourier series in an indirect response model was developed to describe the circadian rhythm of TT and the exposure-response relationship of LY500307 on TT.
Results: The maximum TT suppression (Emax ) was approximately 28.6%. The potency (EC50 ) of LY500307 on TT suppression was approximately 1.69 ng/mL with a 95%CI of 0.871 to 4.44 ng/mL. This model could provide inferences on LY500307 dose levels that would result in various magnitudes of TT suppression.
Conclusions: Population PK/PD modeling is a highly sensitive tool to detect exposure-response relationships on top of the complicated and highly variable circadian rhythm of TT.
Keywords: LY500307; PK/PD; Phase 1; circadian rhythm; estrogen receptor beta agonist; pharmacodynamics; pharmacokinetics; testosterone.
© 2015, The American College of Clinical Pharmacology.