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Entrectinib is a potent and selective tyrosine kinase inhibitor (TKI) of TRKA/B/C, ROS1, and ALK with both systemic and CNS activities, which has recently received FDA approval for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. This paper describes the application of a physiologically based biophamaceutics modeling (PBBM) during clinical development to understand the impact of food and gastric pH changes on absorption of this lipophilic, basic, molecule with reasonable permeability but strongly pH-dependent solubility. GastroPlus™ was used to develop a physiologically based pharmacokinetics (PBPK) model integrating in vitro and in silico data and dissolution studies and in silico modelling in DDDPlus™ were used to understand the role of self-buffering and acidulant on formulation performance. Models were verified by comparison of simulated pharmacokinetics for acidulant and non-acidulant containing formulations to clinical data from a food effect study and relative bioavailability studies with and without the gastric acid-reducing agent lansoprazole. A negligible food effect and minor pH-dependent drug-drug interaction for the market formulation were predicted based on biorelevant in vitro measurements, dissolution studies, and in silico modelling and were confirmed in clinical studies. These outcomes were explained as due to the acidulant counteracting entrectinib self-buffering and greatly reducing the effect of gastric pH changes. Finally, sensitivity analyses with the verified model were applied to support drug product quality. PBBM has great potential to streamline late-stage drug development and may have impact on regulatory questions.

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Standard compendia dissolution apparatus are the first choice for development of new dissolution methods. Nevertheless, limitations coming from the amount of material available, analytical sensitivity, lack of discrimination or biorelevance may warrant the use of non compendial methods. In this regard, the use of small volume dissolution methods offers strong advantages. The present study aims primarily to evaluate the dissolution performance of various drug products having different release mechanisms, using commercially available small volume USP2 dissolution equipment.The present series of tests indicate that the small volume dissolution is a useful tool for the characterization of immediate release drug product. Depending on the release mechanism, different speed factors are proposed to mimic common one liter vessel performance. In addition, by increasing the discriminating power of the dissolution method, it potentially improves know how about formulations and on typical events which are evaluated during pharmaceutical development such as ageing or scale–up. In this regard, small volume dissolution is a method of choice in case of screening for critical quality attributes of rapidly dissolving tablets, where it is often difficult to detect differences using standard working conditions.

The study aimed to characterise the mechanism of release and absorption of Basmisanil, a biopharmaceutics classification system (BCS) class 2 compound, from immediate-release formulations via mechanistic absorption modelling, dissolution testing, and Raman imaging. An oral absorption model was developed in GastroPlus® and verified with single-dose pharmacokinetic data in humans. The properties and drug release behaviour of different oral Basmisanil formulations were characterised via biorelevant dissolution and Raman imaging studies. Finally, an in vitro-in vivo correlation (IVIVC) model was developed using conventional and mechanistic deconvolution methods for comparison. The GastroPlus model accurately simulated oral Basmisanil exposure from tablets and granules formulations containing micronized drug. Absorption of oral doses below 200 mg was mostly dissolution rate-limited and thus particularly sensitive to formulation properties. Indeed, reduced exposure was observed for a 120-mg film-coated tablet and the slower dissolution rate measured in biorelevant media was attributed to differences in drug load. This hypothesis was confirmed when Raman imaging showed that the percolation threshold was exceeded in this formulation. This biorelevant dissolution method clearly differentiated between the formulations and was used to develop a robust IVIVC model. The study demonstrates the applicability and impact of mechanistic absorption modelling and biopharmaceutical in vitro tools for rational drug development.

The anaplastic lymphoma kinase (ALK) inhibitor alectinib is an effective treatment for ALK-positive non-small-cell lung cancer. This bioequivalence study evaluated the in vivo performance of test 3 formulations with the reduced wetting agent sodium lauryl sulfate (SLS) content. This randomized, 4-period, 4-sequence, crossover study compared alectinib (600 mg) as 25%, 12.5%, and 3% SLS hard capsule formulations with the reference 50% SLS clinical formulation in healthy subjects under fasted conditions (n = 49), and following a high-fat meal (n = 48). Geometric mean ratios and 90% confidence intervals (CIs) for C , AUC , and AUC of alectinib, its major active metabolite, M4, and alectinib plus M4 were determined for the test formulations versus the reference formulation. Bioequivalence was concluded if the 90%CIs were within the 80% to 125% boundaries. The 25% SLS formulation demonstrated bioequivalence to the reference 50% SLS formulation for C , AUC , and AUC of alectinib, M4, and alectinib plus M4 under both fasted and fed conditions. Further reductions in SLS content (12.5% and 3% SLS) did not meet the bioequivalence criteria. Cross-group comparisons showed an approximately 3-fold positive food effect. Reducing SLS to 25% resulted in a formulation that is bioequivalent to the current 50% SLS formulation used in alectinib pivotal trials.

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