Dose Optimization: How to Get it Right

At the heart of dose optimization is a mandate to safeguard the health of study participants. From unwanted side effects to reduced efficacy and toxicity, the pharmacological effect of administered doses for any potential drug candidate must always be carefully vetted for safety and efficacy.  

Let’s take a closer look at dose optimization – what it is and how to get it right.

What is dose optimization?

Dose optimization, sometimes also referred to as dose selection, refers to the process of determining the most favorable dose of a drug. This typically occurs before drug approval, as the drug is being studied in humans during clinical trials. The primary aim of dose optimization is to identify the dose amount which preserves clinical benefit while maintaining optimal tolerability.

Dose optimization typically begins quantitatively, by choosing a “safe” initial dose of an investigational drug. This doesn’t mean selecting a dose that holds zero risk, but rather, identifying a dose selection strategy that balances overall benefit with a favorable risk assessment.

Why dose optimization matters

When it comes to getting dose optimization right, the stakes are quite high. In the worst case scenario, poor dose optimization could put the lives of study participants in danger. It could also curtail a study – sinking years of development and related costs.

Dose optimization can have a huge impact on a patient’s quality of life. A dose that’s too high can make patients feel unnecessarily ill or lead to other unwanted side effects, sometimes even precluding patients from taking a necessary treatment.

There’s also evidence that some dose optimization strategies and interventions can lead to significant cost savings for patients. For example, switching patients from multiple unit medications to once-daily medication with parity in efficacy and tolerability.

How does dose optimization work?

Unwanted side effects and/or toxicity are a risk of all pharmacological activity. Dose optimization, therefore, seeks to quantify the relationships between dose, exposure, and response in order to help predict those pharmacological effects.

This means considering how the drug is linked to the engagement of a target, whether intended or unintended.

‍Primary pharmacology – the drug’s effect on the intended target in the intended location

Secondary pharmacology – the drug’s effect on the intended target in an unintended location

Tertiary pharmacology – the drug’s effect on an unintended target

What is the current process for establishing doses?

Because drug development is so highly regulated, national guidelines provide a conceptual framework for establishing the initial dose selection in entry-into-human studies. This typically consists of four parts: non-clinical profiling, predicting human exposure, predicting human effect, and mitigating risk.

• Non-clinical profiling – Non-clinical toxicology and pharmacology studies are essential to dose selection within drug development programs. Traditionally, before giving an investigational drug compound to human subjects, the in vivo toxicity profile must first have been established in animals in at least one pharmacologically-relevant species. However, today, new in vitro methods and technologies (e.g. “organ-on-a-chip”) are being used increasingly, and can be incorporated alongside standard toxicology and pharmacology studies. In all methods, experiments must include the measurement of drug concentrations to determine the level of drug exposure that results in a pharmacological effect.
• Predicting human exposure – There are a few different accepted methods for predicting human exposure. One is allometric scaling, which uses of mathematical relationships to predict human pharmacokinetic parameters from corresponding animal parameters. Another is in vitro-in vivo extrapolation, where in vivo parameters are predicted from in vitro studies. Physiologically-based pharmacokinetic modeling (PBPK) uses mechanistic models to allow simulation of time course profiles for drug concentrations in plasma and tissue. PBPK modeling has been shown to predict with great accuracy human pharmacokinetics very early on in a drug discovery program.‍
• Predicting human effect – In dose selection, predicting exposure vs. response relationship in animals is not enough, meaning an explicit prediction of pharmacodynamic effects in humans is also required. Methods need to include attributes of the biological system and of the drug and pharmacologically-active metabolites.‍
• Mitigating risk – After human effect and response is predicted, a subjective risk assessment which considers everything from mechanism of action, to seriousness of potential side effects, is conducted. Based on this risk assessment, an appropriate exposure target can be selected. 

What is the maximum tolerated dose (MTD)?

Dose-finding trials for oncology drugs are traditionally designed in order to determine the maximum tolerated dose (MTD). Particularly with cytotoxic chemotherapy drugs, patients and providers are willing to accept a significant amount of toxicity to treat very serious, life-threatening diseases. In these cases, the MTD is identified by increasing doses in a small number of patients over short periods of time, until a prespecified rate of severe or life-threatening dose-limiting toxicities (DLTs) is observed. 

More recent cancer therapies, however, are targeted therapies, which are quite different from  cytotoxic chemotherapy drugs. These targeted therapies may be able to achieve efficacy at much lower doses than the MTD. As a result, the MTD approach is generally no longer applicable to these new, targeted treatments like immunotherapies and molecular targeted agents (MTAs). 

What is the FDA’s latest guidance on dose optimization? 

New draft guidance from the FDA outlines dose optimization for drugs and biologics specifically to treat oncologic diseases. The guidelines are aimed to help sponsors of prescription drugs and biologics identify the optimal doses of their products during the development process, and before regulatory submission for approval. Considerations for evaluating safety and tolerability of doses, in addition to general recommendations, are included.

What’s next for dose optimization?

Increasingly, the MTD approach has resulted in dosing regimens that result in interruptions or discontinuations. Emerging immunotherapies and targeted agents, some of which may be taken for the duration of a patient’s life, are precipitating the need for a reconsidered approach to dose optimization, particularly in oncology.

The race toward drug approval can create significant pressure to rush through the dose optimization process. However, a considered approach that leverages technological advancements and follows the most current regulatory guidelines can help save patients from unnecessary exposures and adverse effects, and ensure the full clinical benefit of a treatment.