Background: Somapacitan is a reversible albumin-binding growth hormone (GH) derivative developed for once-weekly administration in patients with GH deficiency (GHD). It consists of a human GH backbone, similar to endogenous human GH, with one amino acid substitution, attached to an albumin binder via a linker chain.
Objective: Absorption, metabolism and excretion (AME) of somapacitan were investigated in a Phase 1 trial (NCT02962440). Absorption and excretion data have been reported previously. Here we report on the metabolic fate of somapacitan, its linker chain and albumin binder.
Methods: Metabolites were identified and quantified in plasma and urine collected from seven healthy males aged 4562 years, following a single s.c. administration of 6 mg somapacitan containing 20 MBq [3H]-somapacitan radiolabel. The pharmacokinetics (Cmax and AUC) of the plasma components were determined and the radioactive peaks of the most abundant plasma metabolites (>10% of total AUC of the somapacitan-related material) and urine metabolites were selected for HPLC fractionation with reversed phase chromatography and UPLC-mass spectrometry (MS) analysis. Fractions with individual plasma and urine components were analysed with liquid chromatography-MS and liquid chromatography-radioactivity monitoring for structure identification.
Results: Three abundant plasma metabolites (P1, M1 and M1B) and two abundant urine metabolites (M4 and M5) were identified. In plasma samples, somapacitan was the principal component up to 168 hours after dosing. P1, M1 and M1B were the most abundant and the only plasma components at 336 and 504 hours. The AUC of intact somapacitan accounted for 59% of the total AUC of all somapacitan-related material, P1 accounted for 21%, and M1 plus M1B accounted for 12%. M4 and M5 were the most abundant urine metabolites and accounted for 37% and 8%, respectively, of the administered somapacitan radioactivity. M1, M1B, M4 and M5 were identified as metabolites formed after extensive degradation of the peptide backbone of somapacitan, leaving a tetrapeptide attached to the linker and albumin binder (M1). Deamidation of asparagine to aspartate in M1 forms M1B and further degradation of M1 or M1B forms M5 and M4. P1 was not structurally identified, but is likely to be identical to M4 or a conjugate thereof. No intact somapacitan was found in excreta, suggesting full degradation of somapacitan prior to excretion of small residual fragments.
Conclusion: These data describe the metabolic fate of somapacitan, its linker chain and albumin binder in human subjects, and demonstrate that somapacitan is extensively degraded prior to excretion of small residual fragments.
19 Sep 2019 - 21 Sep 2019