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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

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Abstract

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.

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  1. Rudiger Kaspera and Yoshihisa Shitara contributed equally to this work.

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  1. Clinical Pharmacology, Drug Development Services, ICON plc, Van Swietenlaan 6, P.O.Box 8144, 9702, KC, Groningen, The Netherlands

    Rudiger Kaspera

  2. Pharmacokinetics, Dynamics and Metabolism, Translational Medicine and Early Development, R&D, Sanofi K.K., 3 Chome-20-2, Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan

    Yoshihisa Shitara

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Kaspera, R., Shitara, Y. 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. AAPS J 26, 71 (2024). https://doi.org/10.1208/s12248-024-00935-5

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