Emerging Role of Organ-on-a-Chip Technologies in Quantitative Clinical Pharmacology Evaluation

Abstract

The recently enacted Prescription Drug User Fee Act (PDUFA) VI includes in its performance goals "enhancing regulatory science and expediting drug development." The key elements in "enhancing regulatory decision tools to support drug development and review" include "advancing model-informed drug development (MIDD)." This paper describes (i) the US Food and Drug Administration (FDA) Office of Clinical Pharmacology's continuing efforts in developing quantitative clinical pharmacology models (disease, drug, and clinical trial models) to advance MIDD, (ii) how emerging novel tools, such as organ-on-a-chip technologies or microphysiological systems, can provide new insights into physiology and disease mechanisms, biomarker identification and evaluation, and elucidation of mechanisms of adverse drug reactions, and (iii) how the single organ or linked organ microphysiological systems can provide critical system parameters for improved physiologically-based pharmacokinetic and pharmacodynamic evaluations. Continuous public-private partnerships are critical to advance this field and in the application of these new technologies in drug development and regulatory review.

Figure 1

Quantitative clinical pharmacology models.6, 7 (a) Disease models that quantify disease progression under placebo based on relevant clinical end points or biomarkers to inform clinical trial design and are typically used at the end of phase 2a or phase 2 to help sponsors design phase 3 trials. (b) Drug models that describe the relationship between exposure (or pharmacokinetics) and/or response (or pharmacodynamics) for both desired and undesired effects, and individual patient characteristics. (c) Clinical trial models describe the inclusion/exclusion criteria, patient discontinuation and adherence, and attempt to quantify the patient population covariates important for product safety and efficacy. Figure reproduced from public domain.6

Figure 2

Potential role of microphysiological systems to inform quantitative clinical pharmacology models. Better understanding of physiology, pathology, and pharmacology is critical for developing systems biology and systems pharmacology models. Microphysiological systems can be viewed as an innovative technology that has the potential to enhance the understanding of physiology, pathology, and pharmacology. Specific applications of the microphysiological systems in the areas of biomarker development; demonstrating proof‐of‐concept, elucidating the mechanism of drug toxicity, and characterizing the complex physiologic changes that occur in disease states can provide the necessary information to advance the role of quantitative clinical pharmacology models in drug development.

Figure 3

Physiologically‐based pharmacokinetic (PBPK) model use (a) in regulatory submissions to the US Food and Drug Administration (FDA) and (b) in peer reviewed literature. The figure shows the numbers of drugs and specific PBPK model applications used in a and the numbers of individual papers and the numbers of specific applications reported in b. For the FDA submissions, some PBPK models were used for multiple applications and, hence, the total numbers of applications cannot be directly compared with the number of drug submissions. The data in a are adapted from Grimstein et al.5, 46 and personal communication with Yaning Wang. The data in b are adapted from Sager et al.47 PK, pharmacokinetic.

Figure 4

Overall structure of a simple physiologically‐based pharmacokinetic (PBPK) model and the incorporation of data from microphysiological systems into the model. The potential role of microphysiological systems in informing drug PBPK model parameters are indicated by colored boxes. CL, clearance; GFR, glomerular filtration rate; HA, hepatic artery; PV, portal vein; Q, blood flow rate.