Determining the delivery, exposure, and disposition of a therapeutic agent in nonclinical species is a critical consideration in any early drug development program to enable success in the clinic. Understanding these key pharmacokinetic elements are essentially captured in the classical areas of Absorption, Distribution, Metabolism and Excretion (ADME). It is not uncommon for Sponsors to attempt to solely rely on toxicokinetic (TK) data to describe the relationship between dose and exposure for all dose levels. However, this is not the goal of the toxicokinetic analysis which is intended to demonstrate adequate exposure in animal toxicology species, in order to determine toxicity and any dose-dependency thereof. There are some important differences between the ADME information that can be determined at high dose levels intended to assess the safety and toxicity of a product, i.e., the Toxicokinetics as compared to that determined in the pharmacologically / therapeutically active dose range i.e., the Pharmacokinetics (PK). Toxicology dose levels are often too high to fully define the PK of the drug, especially in the dose range relevant to pharmacodynamic effect or clinical efficacy. Dedicated pharmacokinetic studies in parallel to or as part of the pre-clinical pharmacodynamic studies are a pivotal part of understanding the potential effectiveness of a molecule and defining the anticipated pharmacologically active clinical dose level and target exposure.
Pharmacokinetics vs. Toxicokinetics
As described in “What is Toxicokinetics?”, toxicokinetic data are intended “to correlate findings of toxicity (not therapeutic efficacy) with a corresponding level of exposure to an experimental drug compound.” Pharmacokinetics, on the other hand, are focused on defining the key ADME components of drug delivery, exposure, and disposition in the well-tolerated and pharmacologically active dose range. It is not uncommon for the exposure (AUC or Cmax) for a drug to increase in a dose-dependent manner across the pharmacologically active dose range, often linearly to the dose level. But as dose levels increase many of the key ADME processes can become saturated, significantly changing the exposure profile at higher dose levels in different ways.
Absorption
Saturation of absorption may distinctly prolong drug delivery, lowering peak exposure (Cmax), which is often the key parameter tied to pharmacodynamics. Depending on clearance from the delivery site before being absorbed (e.g. passing through the gut), either the same AUC or a diminished total exposure might be achieved.
Metabolism
Saturation of metabolic processes at high doses would clearly produce prolonged exposure and potentially indicate a much higher steady-state exposure than would be achieved at pharmacologically active dose levels. On the other hand, induction of metabolic processes by higher doses could result in more rapid clearance.
Distribution
The shape of the exposure-time curve can be substantially altered at higher dose levels if the high circulating drug concentrations provide a driving force for distribution to tissues not accessed by the lower pharmacologically active drug levels. The re-circulation of drug to plasma from these compartments can significantly extend the plasma half-life of a drug well beyond that achieved at pharmacologically active dose levels.
Excretion
Saturation of excretion mechanisms at higher doses would impact the steady state exposure in a similar fashion to saturated metabolism. Induction of an alternate excretion pathway due to excess drug at higher dose levels could substantially impact the entire exposure-time profile.
Understanding Exposure Parameters in the Pharmacologically-active Dose Range
As indicated above, different aspects of the exposure-time profile for a drug are critical to different outcomes. Beneficial and adverse effects can be either dose-dependent or activated once exposure passes a threshold level depending on the target and mechanism of action. Some effects wane with continued activation of the target, while others continue to increase in severity with continued target engagement. As such, while both pharmacodynamics and toxicity can be impacted by peak exposure (Cmax) and total exposure (AUC), it is important to also understand the other pharmacokinetic parameters in order to determine the potential effectiveness and optimal dosing regimen for a novel therapeutic. A vital part of defining the dosing regime, achieving suitable available drugs for target engagement, and achieving beneficial pharmacodynamic activity is the achievement of steady-state drug levels. This is defined as the dosing conditions wherein exposure is reproducible following each subsequent new dose administration (where the amount in is equal to the amount out). However, the achievement of steady state and the exposure parameters at each dose level are greatly impacted by the ADME factors described above and must be defined in the dose range relevant to clinical use, not just the toxicologically active dose range.
Using Pre-clinical Pharmacokinetics in Clinical Study Planning
The primary goal of the pre-clinical program is to support the estimation of a safe and effective dose range for testing in clinical studies. The toxicology studies provide definition of the No Adverse Effect Level (the highest dose that does not produce adverse effects) in the most sensitive nonclinical species. This dose level is then converted to a Human Equivalent Dose (HED) on a comparative body-surface area basis, in the absence of either broader clinical pharmacokinetic data or a specific mechanistic or pharmacokinetic justification for an alternate conversion factor. Utilizing a 10x or 100x safety factor, the Maximum Safe Starting Dose is defined for the First-in-Human (FIH) study of safety and pharmacokinetics (the Phase 1 healthy volunteer study). Meanwhile, the understanding of what dose level and exposure profile will be beneficial in patients requires a more sophisticated algorithm built around understanding the following:
- the efficacious dose level in pre-clinical pharmacodynamic models
- the related exposure and pharmacokinetics in the pre-clinical species in this dose range
- the necessary elements to convert these dose and exposure parameters to humans
Defining the effective dose range in an in vivo pre-clinical model of the disease is a standard component of candidate selection for most organizations. While the suitability of, and various forms of validity for, these models isn’t within the scope of this article, understanding the exposure and pharmacokinetics of the drug in these models at doses that produce clinically relevant pharmacodynamic outcomes is also critical. This pharmacokinetic profile is somewhat unique to the dose range tested in the test species (and occasionally the strain of animal used) and must be translated to a clinically relevant exposure measure. Firstly, the known interspecies differences related to the drug must be accommodated. Primarily, this relates to the differences in drug affinity and potency for the targets expressed by different species (target orthologs) and provides the basis for an adjustment in target drug concentrations based on the potency shift. Secondly, metabolic differences between species also need to be taken into account. These range from the more detailed differences in plasma protein binding and metabolic stability to the broader integrated pharmacokinetic considerations utilized in allometric scaling between species. The main goal of the pharmacokinetic investigation in pre-clinical studies is to define the anticipated pharmacologically active drug level in the target compartment (eg. plasma or CSF). With this estimate, the safe starting dose and dose escalation scheme for the Phase 1 study can then be properly justified. This anticipated pharmacologically active concentration is also vital in determining the appropriate dose levels and exposure targets for safety pharmacology assessments which, unlike toxicology studies, are not required to be dosed to effect but rather to demonstrate a 10x or greater exposure margin between the target pharmacodynamic effect and the secondary pharmacologic action on the central nervous system (CNS), respiratory, or cardiovascular systems. Alongside the regulatory aspects of the early development program that are supported by pre-clinical pharmacokinetic data, a key risk assessment step for any program is to determine the potential therapeutic window. The simplest form of which is often predicated on the toxic dose divided by the efficacious dose (ideally in the same species). However, as discussed, the dose level achieving toxicity may have a very distinct exposure-time profile compared to the pharmacologically active dose level. Furthermore, the pharmacokinetic parameters responsible for the dose-limiting toxicity may be distinct from those responsible for efficacy. For example, many gastrointestinal (GI) and CNS side effects related to a rapid rise in drug levels in specific compartments or tissues, while the efficacy may be related to continuous occupation of the target receptor for multiple weeks (eg. re-uptake inhibitors for depression) or phasic activation of the target (eg. PYY or GLP-1 agonists in type 2 diabetes mellitus). As such the therapeutic window, and thus the development risks for a program, are better defined by relative exposure-time profiles for both pharmacodynamic and adverse effects than straight dose-level comparisons.
Conclusions
The ICH requirements on pre-clinical pharmacokinetics are fairly open as described in M3 (R2), which states: “Further information on pharmacokinetics (PK) (e.g., absorption, distribution, metabolism, and excretion) in test species and in vitro biochemical information relevant to potential drug interactions should be available before exposing large numbers of human subjects or treating for long duration (generally before phase 3).” This might lead a Sponsor to the conclusion that toxicokinetics are sufficient to support IND-filing and Phase 1 clinical studies. However, a detailed understanding of the pharmacokinetics of the drug in pre-clinical models and dose ranges relevant to pharmacodynamic activities is necessary to determine early development risk (therapeutic window), to support a safe and appropriate Phase 1 dosing strategy (dose levels and escalation), and to ensure that the Phase 1/2 program investigates pharmacologically appropriate dose levels. Visit our services page to learn more about our capabilities and find out how Allucent’s nonclinical drug development experts can help you with designing and conducting pre-clinical studies.
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