Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound—The Venetoclax Story

Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement

“…The percentage of CSF concentration to plasma concentration was 0.1%, corresponding to the free drug present as unbound fraction in plasma, which is the fraction of the drug which can be distributed into the CNS. 8 The trough drug level of 1.5 ng/mL found in the CSF, which is the lowest concentration reached by the drug before the next dose, was close to the IC50 (1.9 nM, 1.6 ng/mL) established in vitro in a cultured CLL cell line exposed for 24 h to venetoclax. 9 It is reasonable to suggest that this amount can effectively inhibit tumor growth at the CNS site, also considering that chronic treatment will induce continuous exposure of cancer cells to active venetoclax concentrations.…”

Combining biorelevant in vitro and in silico tools to investigate the in vivo performance of the amorphous solid dispersion formulation of etravirine in the fed state

“…The same conclusion was reached by Emami-Riedmaier et al who combined biorelevant in vitro data with PBPK modeling to predict the in vivo performance of the ASD of the BCS Class IV venetoclax. [46] Similar results have also been observed by Wilson et al for the ASD of enzalutamide in rats. [2] The authors opined that the absence of crystallization of enzalutamide along with the interplay of in vivo permeation, diffusion and dissolution creates a continuous sink for an amorphous compound and thus facilitates its in vivo absorption.…”

“…[2,3,43] To date, there has been limited application of PBPK / absorption models in predicting the in vivo performance of ASDs due to the complex in vitro and in vivo dissolution process. [44][45][46] However, some early attempts have already been published and more, relevant studies are needed to advance our understanding in this field. [44][45][46] As demonstrated in the current study, the use of biorelevant in vitro tools in combination with modeling and simulation techniques provides a way forward to better understand the in vivo performance of such formulations.…”

“…[44][45][46] However, some early attempts have already been published and more, relevant studies are needed to advance our understanding in this field. [44][45][46] As demonstrated in the current study, the use of biorelevant in vitro tools in combination with modeling and simulation techniques provides a way forward to better understand the in vivo performance of such formulations.…”

Biopharmaceutic IVIVE—Mechanistic Modeling of Single- and Two-Phase In Vitro Experiments to Obtain Drug-Specific Parameters for Incorporation Into PBPK Models

“…11 The underlying principle of biopharmaceutical IVIV_E and its application in PBPK prediction sciences have already been explained in detail elsewhere. [20][21][22] The SIVA toolkit thus assists with the analysis of complex data generated from biopharmaceutic experiments for solubilitydsimple buffers and simulated intestinal fluidsdand dis-solutiondUSP II, USP IV, transfer models, media change experiments, 2-phase, mDiss etc. These modules thus provide a mechanistic framework permitting the assessment of the accuracy of the model parameters and validity of the mechanistic models, and their assumptions, in a controlled and well-defined in vitro dissolution environment; if required, unknown or uncertain parameters of the model can be estimated using parameter estimation tools.…”