Doses Evaluated in Clinical Pharmacology Studies Investigating the Effect of Intrinsic and Extrinsic Factors on PK and Safety: Case Examples from Approved Drug Development Programs.
Humans
Drug Development
/ methods
Dose-Response Relationship, Drug
Drug Approval
Drug Interactions
Pharmacology, Clinical
/ methods
Pharmacokinetics
Clinical Trials as Topic
/ methods
Drug-Related Side Effects and Adverse Reactions
/ prevention & control
Food-Drug Interactions
Pharmaceutical Preparations
/ administration & dosage
QT
drug interaction
extrinsic
food effect
hepatic impairment
intrinsic
pharmacokinetics
phase I
renal impairment
therapeutic dose
Journal
The AAPS journal
ISSN: 1550-7416
Titre abrégé: AAPS J
Pays: United States
ID NLM: 101223209
Informations de publication
Date de publication:
17 Jun 2024
17 Jun 2024
Historique:
received:
15
02
2024
accepted:
18
05
2024
medline:
18
6
2024
pubmed:
18
6
2024
entrez:
17
6
2024
Statut:
epublish
Résumé
Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug's safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.
Identifiants
pubmed: 38886275
doi: 10.1208/s12248-024-00935-5
pii: 10.1208/s12248-024-00935-5
doi:
Substances chimiques
Pharmaceutical Preparations
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
71Informations de copyright
© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.
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