(W0930-02-12) A High Throughput In Vitro Screening Method for Cocrystal Food Effect Evaluation

Purpose: This study aimed to develop a high-throughput in vitro method to identify critical parameters influencing food effect for different solid forms of basic drugs, using posaconazole (PSZ) and posaconazole–4-aminobenzoic acid (PSZ-4ABA) cocrystal as model compounds.

Methods: The PSZ-4ABA cocrystal was prepared by reaction crystallization in acetonitrile at room temperature and characterized by X-ray Powder Diffraction. Dissolution studies were performed in Pion MicroDISS with Rainbow Dynamic Dissolution UV System fitted with UV-fiber optic probes. Dissolution behavior was assessed under biorelevant conditions (FaSSGF, FaSSIF, FeSSGF, and FeSSIF) in 1-stage and 2-stage dissolution. Standard gastrointestinal (GI) parameters were varied and assessed in the in vitro experiment including, the effect of bile salts, pH, gastric emptying time, buffer capacity and gastrointestinal volume (Table 1). Area under the concentration-time curve (AUC) and steady-state concentration (Css) were used to evaluate the fed/fasted ratio and to calculate the food effect risk.

Results: A positive food effect was observed for PSZ under standard GI conditions, with increases of 2.1-fold in AUC and 2.5-fold in Css in the fed state compared to the fasted state. In contrast, the PSZ-4ABA cocrystal did not exhibit a significant food effect under the same conditions, with food effect ratios of 0.9 for AUC and 1.4 for Css. The primary critical parameters contributing to a positive food effect for PSZ were volume and gastric emptying time. In contrast, buffer capacity, pH, and bile salts were associated with a negative food effect. For PSZ-4ABA, the key parameters identified were gastric emptying time and pH, both of which had a positive impact on food effect (Figure 1).

Conclusion: This in vitro screening method is a valuable tool to estimate the magnitude of food effect for basic drugs and the risk of observing a food effect in clinical studies. Understanding these critical parameters can support and accelerate drug development and guide the design of early-phase clinical trial studies on food effect.

References: [1] Kuminek, G.; Cavanagh, K.L.; Piedade, M.F.M.; Rodríguez-Hornedo, N. Crystal Growth & Design, 2019 19 (11), 6592-6602.
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[3] Mathias, N.; Xu, Y.; 1, Vig, B.; Kestur, U.; Saari, A.; Crison, J.; Desai, D.; 1, Vanarase, A.; Hussain, M. Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models. The AAPS Journal, 2015 17 (4), 988–998.
[4] Hens, B.; Talattof, A.; Paixão, P.; Bermejo, M.; Tsume, Y.; Löbenberg, R.; Amidon, G.L. Measuring the Impact of Gastrointestinal Variables on the Systemic Outcome of Two Suspensions of Posaconazole by a PBPK Model. The AAPS Journal, 2018 (20) 57, 1-14.

Table 1. Established conditions to determine the critical parameters affecting dissolution of PSZ and PSZ-4ABA.

Figure 1. Food effect radar plot for (A) PSZ-4ABA and (B) PSZ.