PMID- 34601071
OWN - NLM
STAT- MEDLINE
DCOM- 20211117
LR  - 20220531
IS  - 1879-0720 (Electronic)
IS  - 0928-0987 (Linking)
VI  - 167
DP  - 2021 Dec 1
TI  - Absorption, metabolism and excretion of once-weekly somapacitan, a long-acting 
      growth hormone derivative, after single subcutaneous dosing in human subjects.
PG  - 106030
LID - S0928-0987(21)00333-X [pii]
LID - 10.1016/j.ejps.2021.106030 [doi]
AB  - Somapacitan is a reversible albumin-binding growth hormone (GH) derivative in 
      clinical development for once-weekly administration in patients with adult GH 
      deficiency (AGHD) and children with GH deficiency (GHD). To date, the use of 
      somapacitan in AGHD or severe AGHD has been approved in the USA and Japan, 
      respectively. This study (ClinicalTrials.gov, NCT02962440) investigated the 
      absorption, metabolism and excretion, as well as the pharmacokinetics (PK), of 
      tritium-labelled somapacitan ([(3)H]-somapacitan). Seven healthy males received a 
      single subcutaneous dose of 6 mg somapacitan containing [(3)H]-somapacitan 20 
      MBq. Blood, serum, plasma, urine, faeces, and expired air were collected for 
      radioactivity assessment. Metabolites were identified and quantified in plasma 
      and urine collected. The PK of plasma components were determined, and the 
      radioactive peaks of the most abundant plasma metabolites and urine metabolites 
      were selected for analysis. Twenty-eight days after dosing, 94.0% of the 
      administered dose was recovered as [(3)H]-somapacitan-related material, most of 
      which was excreted in urine (80.9%); 12.9% was excreted in faeces, and an 
      insignificant amount (0.2%) was exhaled in expired air. PK properties of 
      [(3)H]-somapacitan-related material appeared to be consistent across plasma, 
      serum and blood. Three abundant plasma metabolites (P1, M1 and M1B) and two 
      abundant urine metabolites (M4 and M5) were identified. The total exposure of 
      intact somapacitan accounted for 59% of the total exposure 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% of the dosed [(3)H]-somapacitan radioactivity, respectively. No intact 
      somapacitan was found in excreta. Two subjects had six adverse events (AEs); all 
      were mild in severity and unlikely to be related to trial product. The majority 
      of dosed [(3)H]-somapacitan (94%) was recovered as excreted metabolites. Urine 
      was the major route for excretion of somapacitan metabolites, followed by faeces, 
      and exhalation in expired air was negligible. The low molecular weights of 
      identified urine metabolites demonstrate that somapacitan was extensively 
      degraded to small residual fragments that were excreted (fully biodegradable). 
      The extensive metabolic degradation and full elimination of metabolites in 
      excreta were the major clearance pathways of somapacitan and the key elements in 
      its biological fate. A single dose of 6 mg somapacitan (containing 
      [(3)H]-somapacitan) in healthy male subjects was well tolerated with no 
      unexpected safety issues identified.
CI  - Copyright (c) 2021. Published by Elsevier B.V.
FAU - Helleberg, Hans
AU  - Helleberg H
AD  - Global Discovery and Development Sciences, Novo Nordisk A/S, Malov, Denmark. 
      Electronic address: hhll@novonordisk.com.
FAU - Bjelke, Mads
AU  - Bjelke M
AD  - Global Discovery and Development Sciences, Novo Nordisk A/S, Malov, Denmark. 
      Electronic address: msbp@novonordisk.com.
FAU - Damholt, Birgitte Bentz
AU  - Damholt BB
AD  - Stem Cell Development, Novo Nordisk A/S, Malov, Denmark.
FAU - Pedersen, Palle Jacob
AU  - Pedersen PJ
AD  - Isotope Chemistry, Novo Nordisk A/S, Bagsvaerd, Denmark. Electronic address: 
      pjcp@novonordisk.com.
FAU - Rasmussen, Michael Hojby
AU  - Rasmussen MH
AD  - Stem Cell Development, Novo Nordisk A/S, Malov, Denmark; Clinical Drug 
      Development, Novo Nordisk A/S, Soborg, Denmark. Electronic address: 
      mhr@novonordisk.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT02962440
PT  - Clinical Trial
PT  - Journal Article
DEP - 20211001
PL  - Netherlands
TA  - Eur J Pharm Sci
JT  - European journal of pharmaceutical sciences : official journal of the European 
      Federation for Pharmaceutical Sciences
JID - 9317982
RN  - 0 (Albumins)
RN  - 0 (somapacitan)
RN  - 12629-01-5 (Human Growth Hormone)
RN  - 339NCG44TV (Phenol)
RN  - 3OWL53L36A (Mannitol)
RN  - 4QD397987E (Histidine)
SB  - IM
MH  - Administration, Cutaneous
MH  - Administration, Oral
MH  - Adult
MH  - Albumins
MH  - Child
MH  - Feces
MH  - Histidine/*administration & dosage/*pharmacokinetics/urine
MH  - Human Growth Hormone/*administration & dosage/*pharmacokinetics/urine
MH  - Humans
MH  - Male
MH  - Mannitol/*administration & dosage/*pharmacokinetics/urine
MH  - Phenol/*administration & dosage/*pharmacokinetics/urine
MH  - Research Subjects
OTO - NOTNLM
OT  - AME
OT  - Absorption
OT  - Excretion
OT  - Growth hormone derivative
OT  - Metabolism
OT  - Somapacitan
EDAT- 2021/10/04 06:00
MHDA- 2021/11/18 06:00
CRDT- 2021/10/03 20:41
PHST- 2021/04/21 00:00 [received]
PHST- 2021/08/31 00:00 [revised]
PHST- 2021/09/29 00:00 [accepted]
PHST- 2021/10/04 06:00 [pubmed]
PHST- 2021/11/18 06:00 [medline]
PHST- 2021/10/03 20:41 [entrez]
AID - S0928-0987(21)00333-X [pii]
AID - 10.1016/j.ejps.2021.106030 [doi]
PST - ppublish
SO  - Eur J Pharm Sci. 2021 Dec 1;167:106030. doi: 10.1016/j.ejps.2021.106030. Epub 
      2021 Oct 1.