Over 80% of new chemical entities (NCEs) today have poor solubility (BCS Class II or IV). Preclinical animal safety study formulation is often widely different from first-in-human formulation, as preclinical scientists often use strong solvents and/or surfactants to solubilize insoluble drug candidates to achieve a maximum exposure level in animals. However, these formulations may not be suitable for human clinical trials due to the toxicity associated with the high level of strong solvents and excipients. Due to the high failure rate of Phase 1 clinical trials which measure pharmacokinetics and biopharmaceutical properties of drugs, many companies use rudimentary fit-for-purpose simple formats, such as liquid formulations, powder-in-bottle or powder-in-capsules. A major benefit of this strategy is to minimize the upfront CMC investment, which will reduce the time and cost of generating initial clinical data, but it could lead to failed first-in-human studies due to solubility limiting dose escalation or high food effects. If a company decided to move forward with the suboptimal FIH data or, more likely, to form an alliance to advance to Phase 2 proof of concept (POC) trial, this “kicking the CMC can down the road” will be met with delays and risks in obtaining successful POC data. The attrition rate of Phase 1 and Phase 2 trials are 38% and 60%, respectively. Addressing the solubility challenges up front during the preclinical stage can lead to using the optimized formulation in all three critical stages of drug development: animal safety studies, FIH clinical trials, and POC trials. Breaking the silos of preclinical, FIH, and POC formulations and spending some time and effort during the preclinical and pre-FIH trials can shorten the overall development time and R&D cost and increase the probability of achieving an accelerated POC milestone. NanoTransformer™ technology can help NCE development by accelerating POC timeline while managing risks of formulation translation errors between preclinical and FIH as well as POC clinical phases. With rapid development timelines and no added harsh solvents and surfactants, this scalable nanoformulation is amenable to be dosed as oral gavage for small animals, encapsulated for large animals and FIH dosing, and compressed as tablets for POC trials and beyond. Using essentially the same nanoformulation for definitive safety studies, FIH trials, and POC studies can accomplish this goal of achieving POC milestones with seamless development timelines for clinical trial material.
Learning Objectives:
Consider ways to incorporate solubility enhancing formulation of NCE during the preclinical stage.
Evaluate human relevant NanoTransformer formulation for preclinical animal safety studies as either oral gavage or capsule dosage form.
Propose to the team leader and/or CSO to consider engaging solubility enhancing technology during the preclinical stage to use human-relevant formulation in animal safety studies.
Bridge the silo mentality between preclinical DMPK group and CMC group (clinical formulation development group) and work together as a team.
