Utilizing Physiologically Based Pharmacokinetic Modeling to Inform Formulation and Clinical Development for a Compound with pH-Dependent Solubility

Predictive Performance of Physiologically Based Pharmacokinetic Models for the Effect of Food on Oral Drug Absorption: Current Status

“…The “true” in vivo precipitation behavior of a drug strongly depends on the drug characteristics, formulation, and physiology, and is technically difficult to measure . Therefore, precipitation time under fasted and fed conditions were adjusted to best fit the in vivo human PK profiles in some literatures because no feasible in vitro method is currently available to quantitatively determine the precipitation time. Especially for highly permeable weak bases, in vitro setups to measure precipitation, such as the transfer model, were demonstrated to overpredict the extent of precipitation in vivo .…”

Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development—Industry Case Studies

“…We have attempted in Table 1 to also list some of the most commonly available data relevant to development of the absorption PBPK models in each development phase; however, it is worth clarifying that depending on the specific compound activities and development paradigms in each organization, these activities may shift between phases; for example, if dissolution data are generated before FIH, these may be used instead of API PSD based models. 23 Understanding of formulation behavior in preclinical studies FIH dose prediction [8][9][10] Impact of physiological variability (e.g., stomach pH) [20][21][22] Food effect assessment 14 Verify understanding of oral absorption and disposition in different preclinical species IVIVE evaluation in preclinical species Estimate of precipitation time in vivo from preclinical data 17 pKa, LogP/LogD Solubility data (screening vs. more definitive experiments)…”

“…In vitro metabolism data Permeability estimate Preclinical species IV PK data Stability in biorelevant fluids FIH formulation characterization PSD for FIH formulation FIH, phase IIB/III Impact of changes in dissolution profile, formulation related Impact of changes in dissolution profile, process and /or stability related Impact of release rate for MR formulations 22 Impact of API PSD 22,24 Physiologically based IVIVC 31 Impact of physiological variability (e.g., stomach pH) 20,21 Food effect assessment [16][17][18] Estimate of precipitation time in vivo from clinical data Verification of understanding of oral absorption and disposition in healthy volunteers and patients PBPK-PD…”

“…[14][15][16][17][18] More recently, a few publications have also focused on understanding stomach pH-related interactions. [19][20][21][22] A few literature reports have demonstrated the potential applicability of PBPK modeling to study active pharmaceutical ingredient (API) properties [22][23][24] or understand the impact of dissolution differences during manufacturing changes. 22,[25][26][27] In the meantime, publications, primarily by Regulatory Authorities, have clearly indicated the potential utility of such models to support Quality-by-Design arguments and gain biopharmaceutical understanding.…”

“…22,[28][29][30] Despite the relatively few publications, the available published drug development examples do clearly demonstrate the potential use of these models to drive biopharmaceutics decisions. 17,18,[20][21][22][23][24][25][26][27] Although not always published, biopharmaceutical/absorption modeling is nowadays used within the pharmaceutical industry to make a broad range of development decisions often starting from the pre-FIH phase throughout the different phases of development. The intent of this report is to present case studies of use of such models across different pharmaceutical companies.…”