Utility of physiologically based modeling and preclinical in vitro/in vivo data to mitigate positive food effect in a BCS class 2 compound

Abstract

Physiologically based pharmacokinetic (PBPK) modeling has become a useful tool to estimate the performance of orally administrated drugs. Here, we described multiple in silico/in vitro/in vivo tools to support formulation development toward mitigating the positive food effect of NVS123, a weak base with a pH-dependent and limited solubility. Administered orally with high-fat meal, NVS123 formulated as dry filled capsules displayed a positive food effects in humans. Three alternative formulations were developed and assessed in in vitro and in vivo preclinical and/or clinical studies. By integrating preclinical in vitro and in vivo data, the PBPK model successfully estimated the magnitude of food effects and the predicted values were within ± 30% of the observed results. A model-guided parameter sensitivity analysis illustrated that enhanced solubility and longer precipitation times under fed condition were the main reason for enhanced NVS123's exposure in presence of food. Eventually, exposure after an amorphous formulation was found to be not significantly altered because of remarkably enhanced intestinal solubility and reduced precipitation. Gastroplus population simulations also suggested that the amorphous formulation is promising in mitigating a clinically significant food effect. Overall, these efforts supported the rationale of clinical investigation of the new formulation, and more importantly, highlighted a practical application of PBPK modeling solving issues of undesirable food effects in weakly basic compounds based on preclinical in vitro/in vivo data.

Fig. 1

In vitro two-step dissolution/precipitation profiles of three formulations of NVS123, including F1 (a), F2 (b), and F3 (c) formulations in SGF/FaSSIF or SGF/FeSSIF media

Fig. 2

Observed and simulated mean plasma concentrations after a single administration of 50 mg of NVS123 given as F1 (a), F2 (b), F3 (c), or F4 (d) formulation in dogs under fasted and fed state. Symbol annotation: open triangles observed fasted concentration with standard deviation; open circles observed fed concentration with standard deviation; dotted curve simulated mean fasted concentration; and solid curve simulated fed concentration

Fig. 3

Comparison of in vitro dissolution, adjusted Weibull input dissolution, and predicted in vivo dissolution as well as deconvoluted and predicted systemic availability for F1 (a, b), F2 (c, d), and F3 (e, f) formulation under fasted (a, c, d) and fed (b, d, f) state

Fig. 4

Observed and simulated mean plasma concentrations after a single administration of 200 mg of NVS123 given as F1-arm 1 (a), F1-arm 2 (b), F2 (c), or F3 (d) formulation in humans under fasted and fed state. Symbol annotation: open triangles observed fasted concentration with standard deviation; open circles observed fed concentration with standard deviation; dotted curve simulated mean fasted concentration, and solid curve simulated fed concentration. Insert panel: observed and simulated mean plasma concentrations of each formulation from 0 to 12 h

Fig. 5

Sensitivity analysis displayed as contour plot of fraction absorbed (F _a) as a function of precipitation time and duodenum solubility under fasted state (200 mg)

Fig. 6

a Comparison of in vitro dissolution and adjusted Weibull input dissolution for F4. b Simulated plasma concentration with 90% confidence interval (CI) after a single dose of F4 formulation (200 mg) under fasted and fed state