PK/PD Studies Prove Critical for mAb Development

An understanding of the pharmacokinetics (PK) of monoclonal antibodies (mAbs) is important so that potential patient responses to treatment can be predicted. Both PK and pharmacodynamic (PD) studies are necessary in the development of a new mAb drug candidate.

PKPK/PD modelling is already widely used in pre-clinical and clinical drug development; these studies are important for characterizing drug candidates quantitatively as well as aiding go/no-go decisions and informing future trial design and optimal dosing regimens (1). However, what is less well known is that PK/PD modelling can also be an effective tool in the earliest stages of drug development, such as in target selection and lead candidate selection. The same modelling techniques can be used to predict and illuminate the drug candidates that have the necessary characteristics for potentially successful development, or, conversely, can help pinpoint which drug development programmes may be less successful, before too much time and cost are accrued on that specific programme.

In particular, mAbs, which are an important therapeutic class, have complex pharmacology and interdependent PK/PD properties. Understanding the PK and PD of mAbs and their biological activity as well as their mechanisms of action are crucial factors in enabling their design and selection. Understanding these factors allows for the design of appropriate studies to characterize the mAb’s efficacy and toxicity, the translation of PK/PD parameters to humans, and the optimization of a dose and regimen for maximizing success in clinical development (2).

Meanwhile, the practice of characterizing the relationship between PK and PD is an important tool in the drug discovery phase. PK/PD strategies should be implemented in the early phases of research during drug discovery projects because these studies can enable a successful transition from discovery phase to development phase (3). An effective PK/PD study design, as well as proper analysis and interpretation can help researchers characterize the PK–PD relationship. Understanding the relationship would enable understanding of the mechanism of drug action and help identify PK properties that can help improve and optimize the design of the drug compound (3).

To learn more about the necessity of PK/PD studies in early mAb development and the most reliable ways to conduct these studies to generate data compliant with investigational new drug application (IND) filings, Pharmaceutical Technology Europe spoke with Maotian Zhou, PhD, Principal Scientist—DMPK Services Department, at WuXi AppTec.

PK in early development

PTE: In the early development of a new mAb, what role does PK play in the development lifecycle?

Zhou (WuXi AppTec): PK plays an important role in the early development of mAb therapeutics. This is even more apparent when the antibody is designed against a novel target, or if the antibody aims to be a ‘best in class’ drug in an already competitive arena with well-studied targets (i.e., HER2, PD1 [programmed cell death protein 1]/PDL1 [programmed cell death ligand 1], etc.).

This may differ from past views on mAb drug development. It is usually assumed that, for humanized monoclonal antibodies, the in-vivo/in-vitro absorption, distribution, metabolism, and excretion (ADME) characteristics share more significant commonality than small-molecule drugs. Thus, the importance of PK studies in the early phase of mAb development is diminished. The efficacy (or pharmacodynamics) appears to be more significant in the leading-candidate mAb selection.

The importance of PK studies increases with a better understanding of mAb drug mechanisms. Many factors can affect mAb exposure–response relationships in vivo, the affinity between the mAb and its ligand, the association between the mAb and different Fc receptors, and the modifications and physicochemical characteristics of the mAb. These factors form the basis for the continuous refinement of current mAb drugs. The mAb PK properties act as a bridge between its design philosophy and ultimate efficacy and safety. Fully understanding candidate mAb PK parameters can provide support for leading-mAb drug selection.

In summary, the PK studies significantly impact whether a mAb moves forward, and should happen early in discovery. Pushing a mAb toward an IND submission without fully understanding its PK could waste time and resources and/or result in programme failure.

Pairing PK and PD

PTE: I always see the terms PK and PD together when discussing drug candidate screening or in drug discovery. What is the importance of both in mAb development, and is it necessary to have both PK data and PD data (can you have one without the other)?

Zhou (WuXi AppTec): Simply put, PK is ‘what the body does to the drug’, whereas PD is ‘what the drug does to the body’.Explicitly, PK quantitatively describes the process of absorption and disposition of the drug in the body. PD evaluates the time course of the pharmacological effects of drugs.

For mAb drug development, the PK and PD always communicate, because mAb drugs generally have long-acting PD effects, and PD will have a direct impact on PK. PK and PD are mechanistically linked (unlike small-molecule drugs). Having both PK and PD data for mAb development is strongly recommended. PK/PD studies serve distinct roles at different stages of mAb drug development.

PTE: What is a ‘best practice’ approach to conducting PK/PD studies, and do these studies necessarily need to be compliant with regulatory standards?

Zhou (WuXi AppTec): PK/PD studies should adapt to the different requirements of each research stage. In the discovery phase, the PK/PD assessments facilitate an understanding of the biology by validating and confirming target engagement. For the leading-mAb selection stage, PK/PD studies should help to select the most ‘potential’ mAb, along with efficacy and toxicity evaluations, to minimize the risk of off-targeting. At the IND stage, systematic PK/PD studies, along with safety studies, play a vital role in translating pre-clinical knowledge to first-in-human clinic studies. In the clinical phase, further in-depth PK/PD studies can identify the covariates and potential sources of population variability, establishing exposure–response relationships in different cohorts. And finally, these studies support proper dose selection, regimen optimization, and biomarker tools establishment.

PK/PD studies must comply with regulatory guidance, both during and after the IND phase of mAb drug development. It is also helpful to reference the regulatory standards in the early phase of drug development. Given that regulations are often adapted based on the lessons learned from many actual drug development cases, items rooted in regulatory guidance are often representative of key points in drug development. For example, a mAb PK bioanalysis in the discovery phase, using a partially validated method (validating specific parameters such as selectivity and stability) will make the mAb quantification more reliable in an unconventional matrix.

Data challenges

PTE: What role or impact do PK/PD studies have on an IND filing for a new mAb?Are they even relevant at that stage?

Zhou (WuXi AppTec): PK/PD studies are essential materials for an IND filing. PK/PD studies serve the following purpose in the IND phase for mAb development: integrate pharmacology and toxicology data and help correlate pre-clinical knowledge to first-in-human clinical study; bridge toxicology studies to define maximum tolerated dose (MTD) and select first-in-human dose; design a dose escalation scheme; and project efficacious dose in clinical.

PTE: What currently are the major analytical/technical challenges in conducting PK/PD studies on new mAbs?

Zhou (WuXi AppTec): Several challenges currently exist within PK/PD studies for mAb drugs. First, the assumptions used to simplify the exposure–response relationships in PK/PD modelling may not always be appropriate. For example, in the past, the PK/PD model assumed the drug concentration in tumor cells was related to the cell-killing effect. However, in the absence of an actual measurement of the distribution cascade, the validity of this assumption is uncertain.

Second, the translation from animals (pre-clinical) to humans (clinical) based on PK/PD modelling is also challenging. Furthermore, existing PK/PD modelling assumptions are usually based on prior experience, as such studies are needed to understand the applicability of new mAbs.

Third, the reliability of PK/PD data depends on the selection of a proper analytical method/platform, which may be a challenge in some instances. The bioanalysis should always follow a fit-for-purpose principle. Based on the ligand properties (such as solubility and endogenous concentrations), the availability of critical reagents, and desired sensitivity, a suitable assay format needs to be designed.

There is an ongoing effort regarding PK/PD analytical strategy optimization. The ability to accelerate research and develop safe and effective mAbs rely less on tools and more on an investigator’s skills, knowledge, and expertise. Drug developers and sponsors that do not have the time, capacity, or expertise to conduct these investigations in-house should consider working with a testing partner.

References

1. M. Penney and B. Agoram, Br J Clin Pharmacol. 77 (5) 740–745 (2014).
2. A.V. Kamath, Drug Discovery Today: Technologies 21–22, 75–83 (2016).
3. T. Tuntland, et al., Frontiers in Pharmacology 5 (2014).

About the author

Feliza Mirasol is the science editor for Pharmaceutical Technology.