title: Activity-based exposure comparisons among humans and nonclinical safety testing species in an extensively metabolized drug candidate.
abstract: 1. Extensive metabolism of a drug candidate can complicate the interpretation of comparative safety and efficacy data from humans and preclinical species. 2. The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, AMG 221 underwent extensive oxidative metabolism to structurally similar but differentially active primary and secondary metabolites. Relative potency data from synthetic metabolites enabled a stepwise quantitative assessment of AMG 221 in vivo metabolism that compared relative exposure to metabolites in plasma across species and discerned which active metabolites to monitor in preclinical and clinical safety and efficacy studies. 3. Pooled plasma samples from AMG 221-dosed human subjects were profiled using high-resolution liquid chromatography-mass spectrometry (LC-MS) with a mass-defect-filter. The most abundant peak, M1 accounted for 47%-59% of peaks followed by AMG 221 at 27%-40%. Other metabolites were each less than 7%. Activity-normalized data indicated both M1 and AMG 221 should be monitored to assist pharmacokinetic-pharmacodynamic (PK-PD) modeling. 4. Rat and dog area under the plasma concentration time curve (AUC) exposures to M1 at preclinical no observable adverse effect level (NOAEL) doses were 2-42-fold higher than human, indicating M1 was not a disproportionate metabolite, as defined by International Committee on Harmonization (ICH) M3(R2) guidance. 5. Development decisions regarding active metabolite monitoring and potentially disproportionate metabolites in extensively metabolized drug candidates are enabled by metabolite synthesis and liquid chromatography high-resolution mass spectrometry (LC-HRMS)-based assessment of potency-normalized plasma metabolite AUCs.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA 91320, USA.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Zhu
authors.forename: J Greg
authors.initials: JG
authors.lastname: Slatter
authors.forename: Maurice G
authors.initials: MG
authors.lastname: Emery
authors.forename: Molly R
authors.initials: MR
authors.lastname: Deane
authors.forename: Anna
authors.initials: A
authors.lastname: Akrami
authors.forename: Xiping
authors.initials: X
authors.lastname: Zhang
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.forename: Gary L
authors.initials: GL
authors.lastname: Skiles
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D002853:Chromatography, Liquid; D004285:Dogs; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D053719:Tandem Mass Spectrometry; D013844:Thiazoles / Q000493:pharmacokinetics*
chemical_list: C541878:AMG 221; D013844:Thiazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1