PI‐70

BACKGROUND Asoprisnil (J867) is a novel selective progesterone receptor modulator (SPRM) with partial or mixed agonist/antagonist effects depending on the biological action studied. Previous studies using human liver microsomes have shown that the metabolism of asoprisnil to its active metabolite J912 involves CYP2C8 and CYP3A. The objective of this study was to evaluate the effect of a moderate inhibitor of CYP3A, erythromycin, on the pharmacokinetics (PK) of asoprisnil and J912. METHOD In this open‐label sequential drug‐drug interaction study, 24 healthy female subjects received a single 10 mg oral dose of asoprisnil before and after multiple oral doses of 500 mg erythromycin 3 times daily for 5 days. Serial blood samples were obtained over 23 hours to determine the PK of both asoprisnil and J912. Plasma concentrations of asoprisnil and J912 were determined using a validated LC/MS/MS assay. RESULTS The 90% confidence intervals (CI) for the ratios of the central values of asoprisnil or J912 C max and AUC were above the no effect boundaries of 0.80–1.25 when asoprisnil was coadministered with erythromycin. There were no serious adverse events. (See Table)C max AUC t AUC 0‐∞Analyte Ratio 90% CI Ratio 90% CI Ratio 90% CIAsoprisnil 3.790 3.195–4.497 4.405 3.601–5.389 4.371 3.582–5.334 J912 1.473 1.302–1.667 2.433 2.151–2.752 2.583 2.276–2.931CONCLUSION Concomitant administration of erythromycin with asoprisnil resulted in increases of C max and AUC ∞ of 279% and 337% for asoprisnil and 47% and 158% for J912. Based on these findings, erythromycin inhibited the metabolism of asoprisnil and to a lesser extent of J912. Therefore, caution should be taken if erythromycin is coadministered with asoprisnil. Clinical Pharmacology & Therapeutics (2005) 79 , P25–P25; doi: 10.1016/j.clpt.2005.12.091