Sensitive quantification of the somatostatin analog AP102 in plasma by ultra-high pressure liquid chromatography-tandem mass spectrometry and application to a pharmacokinetic study in rats.

Details

Serval ID
serval:BIB_31A6C2CA0D23
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Sensitive quantification of the somatostatin analog AP102 in plasma by ultra-high pressure liquid chromatography-tandem mass spectrometry and application to a pharmacokinetic study in rats.
Journal
Drug testing and analysis
Author(s)
Eugster P.J., Boyle C.N., Prod'hom S., Tarasco E., Buclin T., Lutz T.A., Harris A.G., Grouzmann E.
ISSN
1942-7611 (Electronic)
ISSN-L
1942-7603
Publication state
Published
Issued date
09/2018
Peer-reviewed
Oui
Volume
10
Number
9
Pages
1448-1457
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
AP102 is a di-iodinated octapeptide somatostatin agonist (SSA) designed to treat acromegaly and neuroendocrine tumors. A sensitive and selective method was validated for the quantification of AP102 in plasma following the European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines. Sample preparation was performed using solid-phase extraction microplates. Chromatographic separation was achieved on an ultra-high pressure liquid chromatography (UHPLC) C18 column in 6.0 minutes. The compounds were quantified using multiple reaction monitoring on a tandem quadrupole mass spectrometer with <sup>13</sup> C, <sup>15</sup> N-labeled AP102 as internal standard. Calibration ranged from 50 to 10000 pg/mL. The lower limit of quantification (LLOQ) was measured at 20 pg/mL, and robust analytical performances were obtained with trueness at 99.2%-100.0%, intra-assay imprecision at 2.5%-4.4%, and inter-assay imprecision at 8.9%-9.7%. The accuracy profiles (total error) built on the 3 concentrations levels showed accuracy within the 70%-130% range. AP102 is remarkably stable since no proteolytic fragments were detected on plasma samples analyzed by Orbitrap-MS. Pharmacokinetic studies were conducted in rats, after single dose (1, 3, and 10 μg/kg, sc) and continuous subcutaneous administration (osmotic minipumps for 28 days, 3.0 or 10.0 μg/kg/h). AP102 showed a rapid absorption by the subcutaneous route (T <sub>max</sub> : 15-30 minutes) and a fast elimination (t <sub>1/2</sub> : 33-86 minutes). The PK profile of AP102 exhibited a mean clearance of 1.67 L/h and a mean distribution volume at steady state of 7.16 L/kg, about 10-fold higher than those observed with other SSA or non- and mono-iodinated AP102. LogD <sub>7.4</sub> determination confirmed the lipophilic properties of AP102 that might influence its distribution in tissues.
Keywords
Animals, Calibration, Chromatography, High Pressure Liquid, Injections, Subcutaneous, Male, Peptides, Cyclic/blood, Peptides, Cyclic/chemistry, Peptides, Cyclic/pharmacokinetics, Peptides, Cyclic/pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Somatostatin/agonists, Reproducibility of Results, Solid Phase Extraction, Somatostatin/analogs & derivatives, Somatostatin/blood, Somatostatin/chemistry, Somatostatin/pharmacokinetics, Somatostatin/pharmacology, Tandem Mass Spectrometry, AP102, Acromegaly, UHPLC-MS/MS, quantification, somatostatin
Pubmed
Web of science
Create date
17/05/2018 18:40
Last modification date
20/08/2019 13:17
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