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Review
. 2022 Jun;12(6):2751-2777.
doi: 10.1016/j.apsb.2022.03.009. Epub 2022 Mar 17.

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Yurong Lai  1 , Xiaoyan Chu  2 , Li Di  3 , Wei Gao  2 , Yingying Guo  4 , Xingrong Liu  5 , Chuang Lu  6 , Jialin Mao  7 , Hong Shen  8 , Huaping Tang  9 , Cindy Q Xia  10 , Lei Zhang  11 , Xinxin Ding  12
Affiliations
Review

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Yurong Lai et al. Acta Pharm Sin B. 2022 Jun.

Abstract

Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

Keywords: ADME; Biologics license application; Drug discovery and development; Micro-physiological systems; Model-informed drug development; New drug application; New modalities; Pharmacokinetics.

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Conflict of interest statement

The views expressed are those of authors and do not necessarily reflect FDA's views or policy. The authors declare no conflicts of interest.

Figures

Image 1
Graphical abstract
Fig. 1
Figure 1
Overview of DMPK related activities in drug discovery and development. The overall process can be divided into six stages: hit to lead, lead optimization, candidate selection, preclinical development, clinical development and registration and launch. Key DMPK related activities at each of the six stages are listed in the text boxes separated by small molecule and biologics.
Fig. 2
Figure 2
Multi-phase kinetics of CAR-T cell and model structure. (a) A typical multi-phase kinetics of CAR-T cell: distribution, expansion, contraction and persistence phase; (b) model structure for CAR-T kinetics; (c) schematic diagram of a three-step workflow for modeling and analysis. ALL, acute lymphocytic leukemia; CAR-T, chimeric antigen receptor-T; CLL, chronic lymphocytic leukemia; Cmax, peak plasma concentration; CR/PD, complete response/progressive disease; DLBCL, diffuse large-B cell lymphoma; MM, multiple myeloma. Reproduced with permission from Ref. . Copyright © 2020 The authors and American Society for Clinical Pharmacology and Therapeutics.
Fig. 3
Figure 3
FDA DDI Guidance History (1997–2020). Major CYP enzymes recommended for routine assessment to identify potential metabolism-mediated interactions include: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Transporter-mediated DDI was first recommended in 2006 draft FDA DDI guidance, focusing on P-glycoprotein. Evolving knowledge on roles of transporters in DDI, safety and efficacy, and collaborative work led by the International Transporter Consortium has led to more transporters being studied,, , . To date, nine clinically important transporters are recommended in FDA DDI guidance documents for routine evaluations of DDI potential for investigational drugs, which include four efflux transporters (P-gp, BCRP, MATE1 and MATE2-K) and five uptake transporters (OATP1B1, OATP1B3, OAT1, OAT3, and OCT2),. Basic and more mechanistic models and decision criteria have been developed and refined over the past decade. The international harmonization efforts on DDI evaluation are being pursued at the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). An ICH M12 guideline on DDI is being developed to provide a consistent approach in designing, conducting, and interpreting DDI studies during the development of a therapeutic product (https://www.ich.org/page/multidisciplinary-guidelines).
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