Metabolism and Excretion of Therapeutic Peptides: Current Industry Practices, Perspectives, and Recommendations.

Humans Drug Industry Drug Development Peptides

Journal

Drug metabolism and disposition: the biological fate of chemicals
ISSN: 1521-009X
Titre abrégé: Drug Metab Dispos
Pays: United States
ID NLM: 9421550

Informations de publication

Date de publication:
11 2023
Historique:
received: 23 06 2023
accepted: 15 08 2023
medline: 23 10 2023
pubmed: 18 8 2023
entrez: 17 8 2023
Statut: ppublish

Résumé

Therapeutic peptides (TPeps) have expanded from the initial endogenous peptides to complex modified peptides through medicinal chemistry efforts for almost a century. Different from small molecules and large proteins, the diverse submodalities of TPeps have distinct structures and carry different absorption, distribution, metabolism, and excretion (ADME) properties. There is no distinct regulatory guidance for the industry on conducting ADME studies (what, how, and when) for TPeps. Therefore, the Peptide ADME Working Group sponsored by the Translational and ADME Sciences Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) was formed with the goal to develop a white paper focusing on metabolism and excretion studies to support discovery and development of TPeps. In this paper, the key learnings from an IQ industry survey and U.S. Food and Drug Administration/European Medicines Agency submission documents of TPeps approved between 2011 and 2022 are outlined in detail. In addition, a comprehensive assessment of in vitro and in vivo metabolism and excretion studies, mitigation strategies for TPep metabolism, analytical tools to conduct studies, regulatory status, and Metabolites in Safety Testing considerations are provided. Finally, an industry recommendation on conducting metabolism and excretion studies is proposed for regulatory filing of TPeps. SIGNIFICANCE STATEMENT: This white paper presents current industry practices for metabolism and excretion studies of therapeutic peptides based on an industry survey, regulatory submission documents, and expert opinions from the participants in the Peptide Absorption, Distribution, Metabolism, and Excretion Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development. The group also provides recommendations on the Metabolites in Safety Testing considerations and metabolism and excretion studies for regulatory filing of therapeutic peptides.

Identifiants

DOI: 10.1124/dmd.123.001437 PMID: 37591731
pubmed: 37591731
pii: dmd.123.001437
doi: 10.1124/dmd.123.001437
doi:

Substances chimiques

Peptides 0

Types de publication

Journal Article Review

Langues

eng

Sous-ensembles de citation

IM

Pagination

1436-1450

Informations de copyright

Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.

Auteurs

Minxia Michelle He (MM)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.) he_michelle_minxia@lilly.com xiaochun.zhu@takeda.com.

Sean Xiaochun Zhu (SX)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.) he_michelle_minxia@lilly.com xiaochun.zhu@takeda.com.
ORCID: 0009-0006-7937-812X

Joe R Cannon (JR)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

Jesper Kammersgaard Christensen (JK)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

Ruchia Duggal (R)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

Mithat Gunduz (M)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

Constanze Hilgendorf (C)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).
ORCID: 0000-0001-9445-4692

Adam Hughes (A)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

Ivy Kekessie (I)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

Maximilian Kullmann (M)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

Dennis Leung (D)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

Carsten Terjung (C)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

Kai Wang (K)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

Frank Wesche (F)

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.M.H.); Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc., Cambridge, Massachusetts (S.X.Z.); Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, Princeton, New Jersey (J.R.C.); Development ADME, Novo Nordisk A/S, Måløv, Denmark (J.K.C.); Preclinical Development ADME, Merck & Co., Boston, Massachusetts (R.D.); PK Sciences/Global Biotransformation, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (M.G.); DMPK, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Sweden (C.H.); Discovery Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Stevenage, United Kingdom (A.H.); Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California (I.K.); Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany (M.K., C.T.); Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California (D.L.); Translational PK/PD and Investigative Toxicology, Janssen Research & Development, San Diego, California (K.W.); and Department of Drug Discovery Sciences, Discovery Science Technology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach a.d. Riss, Germany (F.W.).

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Classifications MeSH

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questionsmedicales.fr › Technologie, industrie et agriculture › Industrie › Secteur secondaire › Industrie pharmaceutique › Metabolism and Excretion of Therapeutic...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Metabolism and Excretion of Therapeutic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Metabolism and Excretion of Therapeutic...