The main objective of first-in-human (FIH) trials is to determine the starting dose of a new drug, one that is low enough to provide minimal to no safety and toxicity risks and allows the highest dosage/benefit for the intended trial.

The manufacture of the drug product for clinical trials is of critical importance, as the formulation, manufacturing, and assessment of a drug candidate during FIH trials can be contributing factors in whether the drug safely provides the correct dosage and, ultimately, gains regulatory approval. Decisions made during early phase development, when the compound is being used in a clinical research setting, provide significant learnings for its progression through later phase research. Integration is key — ensuring that information gathered at the clinic is efficiently incorporated into the manufacturing process is a major contributor to the goal of achieving marketing approval.

In Issue 17 of The Altascientist, we review:

• the role of formulation in drug development
• the impact of formulation on subject safety
• meeting regulatory requirements
• Pharmacy case study: Supporting Regulatory Approval
• Manufacturing case study: Mission Impossible to Possible

The Importance of Drug Formulation in First-in-Human Trials

The first step on the pathway to FIH clinical trials is formulation development. Generally, it is advisable to develop a dosage form that can be produced efficiently and cost effectively, to established quality specifications; simpler dosage forms like oral liquids, powders, tablets, or capsules are favored. Among the favored dosage forms, there are advantages and disadvantages to each. For example, tablets can have a longer shelf life and can accommodate a higher dose of active ingredient than capsules, while capsules are fast acting and can provide a higher drug absorption rate. Some advanced drug delivery systems, such as nanoparticles, require more complex formulations and manufacturing processes, and thus involve increased manufacturing costs, particularly in later development stages and commercialization.

Many of the drugs that enter development fail, even if they make it through FIH studies. Some of the high attrition rate can be attributed to the fact that key performance characteristics — such as solubility and bioavailability — are easily achieved in simple FIH formulations but challenging to replicate in more complex dosage forms for late-stage trials and commercial use. When creating a FIH formulation, it is important to keep in mind the rigors of later stage development and eventual market availability.

The Impact of Drug Formulation on Subject Safety in First-in-Human Trials

Subject safety is always a primary concern in planning clinical studies, and particularly with novel drug products entering FIH trials. The use of single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, as well as the employment of adaptive protocols and sentinel dosing are part of the established safety protocols for Phase I studies.

If the candidate drug is considered high risk based on data from preclinical trials, it is preferable to formulate for intravenous administration. A slow intravenous infusion can easily be stopped if serious/severe adverse reactions occur. Likewise, dose escalation needs to be considered during manufacturing to fit the planned dose levels in the FIH study and the data gathered from sentinel dosing. If adjustments are needed based on data from the initial dose plan between cohorts, it is important to be prepared with a plan to titrate dosage, or reformulate the product to ensure maximum effectiveness with minimal safety concerns.

How Altasciences Can Help With Drug Formulation for Your First-in-Human Trials

Significant benefits can be realized with Altasciences’ Proactive Drug Development approach of integrating Good Manufacturing Practice (GMP) manufacturing and clinical testing. Shorter timelines, reduced costs, and improved flexibility are achieved with real-time drug product manufacture, as the development team can evaluate and optimize new formulations in the clinic, based on human data. When clinical trial teams work closely with those involved in formulation and manufacturing process development, collaboration and data sharing minimize risk and help reduce delays. Product development can be started when a quality active pharmaceutical ingredient (API) is ready, the clinical study can start as soon as regulatory approvals are received, and the product is released.

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Microsampling significantly lessens the volume of blood and plasma/serum that is collected and analyzed to determine circulating concentrations of therapeutic drugs, metabolites, and biomarkers in preclinical and clinical research.

In preclinical research, microsampling technology supports the 3Rs of animal research, and allows for less intrusive blood collection procedures.

By definition, clinical microsampling reduces sample volume to less than or equal to 50 microlitres (μL) compared to conventional venipuncture wherein millilitres (mL) of blood volume is collected. In Altasciences’ experience, microsample volumes being analyzed are less than or equal to 20 μL, with some microsampling techniques as low as 5 μL.

In Issue 16 of The Altascientist, we explore the benefits, applications, and considerations of microsampling in preclinical, clinical, and bioanalytical research, including:

• Regulatory considerations
• Case study: Anti-Epileptic Drug Monitoring – Sample Preparation Using Impact-Assisted Extraction
• Case study: Large Molecule – Determination of Rituximab Using a Surrogate Peptide Approach

Benefits of Microsampling in Preclinical Research

Microsampling addresses two of the 3Rs (replacement and reduction) of preclinical research. By eliminating or greatly reducing the use of satellite animals, microsampling can reduce the number of rodents in certain preclinical studies by 30 to 40 percent. Decreasing the number of animals required can have an added benefit of reducing R&D costs related to animals and housing, particularly for toxicokinetic (TK) studies that use satellite animals to minimize repeated conventional blood sampling procedures.

Lower-volume blood draws, from both rodents and non-rodents, taken from less disruptive locations, allow lab animals to recover more quickly, and have fewer sampling-related adverse events compared to conventional sampling. Refinement of the bleeding technique also translates to less animal handling, minimizing stress.

The elimination of satellite animals improves the quality of research data, as scientists conduct all TK analysis using main study animals. This enables direct correlation of exposure with pharmacodynamic and toxicological outcomes.

Benefits of Microsampling in Clinical Research

Microsampling in clinical research reduces patient burden, improves enrollment and engagement, and reduces drop-out. Self-administration facilitates the data collection during studies related to unpredictable clinical episodes, such as acute migraine or epilepsy attacks, and allows episodic sampling to relate efficacy with bioavailability. The dried blood samples can be stored and transported at ambient temperature, eliminating the costly cryopreservation and shipment that conventional wet blood samples demand.

Microsampling also provides a convenient, low-cost way to collect blood and plasma/serum from patients remotely. Individuals in remote geographic locations are able to participate in clinical trials, as they can conduct their blood draws at home.

Bioanalytical Considerations for Microsampling

The accurate analysis of dried blood microsamples requires equipment with high sensitivity and specificity, such as that offered by triple-stage quadrupole mass spectrometry systems paired with liquid chromatography front ends to optimize signal-to-noise ratio. When additional selectivity is required, this can be addressed by accurate mass filtering (e.g., time-of-flight or orbitrap mass spectrometer) or the use of differential ion mobility spectrometry to separate analyte from interference prior to mass selection.

Is Microsampling the Right Option for Your Preclinical or Clinical Study?

Microsampling is not appropriate for all studies and should be considered on a case-by-case basis. In a microsampling drug development program, it is critical to establish the appropriate pharmacokinetic/ statistical considerations to enable correlation/concordance between microsampling and standard blood sampling techniques.

How Altasciences Can Help

Altasciences’ scientific acumen and experience with different microsampling devices, supporting numerous programs, has led to unparalleled expertise in the development of assays and processes for all your drug candidates, from the straightforward to the most complex.

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