(M1230-11-62) Formulation and Taste Assessments in First in Human Studies–Evolving beyond Safety, Tolerability, and Pharmacokinetics

Purpose: First-in-human studies (FIH) traditionally have provided safety, tolerability and pharmacokinetic (PK) data to support Phase 1b/2 dosing in patients. Over the past decade, there has been an evolution of FIH studies to include additional assessments to compress development timelines. Industry is tending to have greater foresight with starting with the end goal in mind. Inclusion of pharmacodynamic (PD) markers if relevant and continuous Holter monitoring to provide potential TQTc waivers, have become commonplace. Further benefits are achieved through Translational Pharmaceutics platforms which integrate drug substance and drug product GMP manufacturing and clinical testing platforms. These approaches allow formulation assessment, optimization, and selection within a FIH study, enabling an exit from the FIH study with a formulation suitable for patient studies. For example, performing a FIH adult study with a pediatric/geriatric-friendly formulation acts as a catalyst to progress straight into a pediatric/geriatric patient study for proof of concept (POC). The current abstract provides a review of recent FIH studies incorporating formulation assessment and describes two alternative designs for taste assessment.

Methods: Formulation Assessment in FIH - Flexible, multi-part FIH protocols can be developed to allow assessment of multiple solution/suspension formulations during SAD, progression of the selected formulation in multiple ascending dose (MAD) and then an optional part to assess a solid dosage form. Alternative formulations are normally assessed during the SAD part, typically at dose level 3, either in a new cohort of subjects, or the same cohort of subjects returning to have additional formulations after an appropriate washout (Figure 1). Careful consideration needs to be given to the dose level of the alternative formulations, especially if they are enhanced formulations that may yield higher exposure. It is usually advised to dose all the formulations at the same dose level to allow direct comparison of the formulation performance. When comparing different formulation technologies, suspension formulations are usually advised, e.g. spray dried dispersion (SDD), hot melt extrusion (HME) versus crystalline suspension, since this will provide gold standard exposure data as the API is pre-wetted. Once a technology is selected, then formulation development work can begin on a solid dosage form if required for patient studies, with performance being assessed (optionally as a separate part of the same study) in a relative bioavailability assessment. Date from 25 FIH were analyzed to establish the frequency of including formulation evaluation in FIH protocols and assessed the types of formulation flexibility and assessments conducted. The model of testing different formulations during SAD can also be applied to solid dosage forms. Taste Assessments in FIH - FIH studies often use liquid drug products and will apply an external taste blind to the placebo formulation, e.g. Listerine strip or Bitrex mouthwash. If the drug is likely to have a pediatric or geriatric indication in the future, assessing palatability of the solution/suspension formulation early in development provides information to guide future taste masking approaches and avoids the need for a separate clinical taste assessment study. Taste assessment can be included in a FIH protocol without breaking the blind for the primary objective. Either subjects from a SAD cohort can return for an extended follow up visit or a new group of subjects can be recruited. Subjects are trained in ‘sip and spit’ tasting technique before evaluating palatability of placebo and active formations at 2 concentrations. Immediately after each taste assessment subjects complete a taste questionnaire assessing palatability attributes ranked on a 9-point Likert scale. Multiple vehicles containing flavors and sweeteners can also be assessed to provide additional information. For both methods, subjects remain resident overnight for safety observations. Taste feedback from this provides an indication if taste optimization is required for the future formulation strategy.

Results: 25 FIH studies conducted over 3 years were evaluated. Analysis of the formulations tested, composition and flexibility within these studies, found that more than 50 % of studies have investigated more than 1 formulation with up to 5 formulations being assessed in a single FIH study. Figure 2 shows the breakdown of the formulations dosed. 15 different types of formulation have been assessed within these studies: 4 simple fit for purpose formulations, 8 solubility enhanced formulations and 3 different tablet types; immediate release (IR), modified release (MR) and delayed release (DR). 23 of the 25 studies had flexibility to alter composition (dose and/or functional excipients) based on emerging data, which was facilitated by real time GMP manufacturing. 17 of the 25 studies incorporated a liquid formulation and so would have been suitable for incorporation of the taste evaluation methodology described herein.

Conclusion: Recent years have seen FIH study design evolve to assess more than just safety, tolerability, and PK. Assessment of alternative formulations, allowing formulation selection/optimization within FIH and taste assessment during this phase can provide additional information to accelerate clinical development and timelines.

Figure 1 FIH design allowing formulation assessment



Figure 2 Assessment of different types of formulations tested during FIH studies