Dataset Information

Combining "Bottom-up" and "Top-down" Approaches to Assess the Impact of Food and Gastric pH on Pictilisib (GDC-0941) Pharmacokinetics.

ABSTRACT: Pictilisib, a weakly basic compound, is an orally administered, potent, and selective pan-inhibitor of phosphatidylinositol 3-kinases for oncology indications. To investigate the significance of high-fat food and gastric pH on pictilisib pharmacokinetics (PK) and enable label recommendations, a dedicated clinical study was conducted in healthy volunteers, whereby both top-down (population PK, PopPK) and bottom-up (physiologically based PK, PBPK) approaches were applied to enhance confidence of recommendation and facilitate the clinical development through scenario simulations. The PopPK model identified food (for absorption rate constant (Ka )) and proton pump inhibitors (PPI, for relative bioavailability (Frel ) and Ka ) as significant covariates. Food and PPI also impacted the variability of Frel . The PBPK model accounted for the supersaturation tendency of pictilisib, and gastric emptying physiology successfully predicted the food and PPI effect on pictilisib absorption. Our research highlights the importance of applying both quantitative approaches to address critical drug development questions.

SUBMITTER: Lu T

PROVIDER: S-EPMC5702897 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Combining "Bottom-up" and "Top-down" Approaches to Assess the Impact of Food and Gastric pH on Pictilisib (GDC-0941) Pharmacokinetics.

Lu Tong T Fraczkiewicz Grazyna G Salphati Laurent L Budha Nageshwar N Dalziel Gena G Smelick Gillian S GS Morrissey Kari M KM Davis John D JD Jin Jin Y JY Ware Joseph A JA

CPT: pharmacometrics & systems pharmacology 20171017 11

Pictilisib, a weakly basic compound, is an orally administered, potent, and selective pan-inhibitor of phosphatidylinositol 3-kinases for oncology indications. To investigate the significance of high-fat food and gastric pH on pictilisib pharmacokinetics (PK) and enable label recommendations, a dedicated clinical study was conducted in healthy volunteers, whereby both top-down (population PK, PopPK) and bottom-up (physiologically based PK, PBPK) approaches were applied to enhance confidence of r ...[more]

PMID: 28748626

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Project description:Background and objectivesWe propose a strategy for studying ethnopharmacology by conducting sequential physiologically based pharmacokinetic (PBPK) prediction (a 'bottom-up' approach) and population pharmacokinetic (popPK) confirmation (a 'top-down' approach), or in reverse order, depending on whether the purpose is ethnic effect assessment for a new molecular entity under development or a tool for ethnic sensitivity prediction for a given pathway. The strategy is exemplified with bitopertin.MethodsA PBPK model was built using Simcyp(®) to simulate the pharmacokinetics of bitopertin and to predict the ethnic sensitivity in clearance, given pharmacokinetic data in just one ethnicity. Subsequently, a popPK model was built using NONMEM(®) to assess the effect of ethnicity on clearance, using human data from multiple ethnic groups. A comparison was made to confirm the PBPK-based ethnic sensitivity prediction, using the results of the popPK analysis.ResultsPBPK modelling predicted that the bitopertin geometric mean clearance values after 20 mg oral administration in Caucasians would be 1.32-fold and 1.27-fold higher than the values in Chinese and Japanese, respectively. The ratios of typical clearance in Caucasians to the values in Chinese and Japanese estimated by popPK analysis were 1.20 and 1.17, respectively. The popPK analysis results were similar to the PBPK modelling results.ConclusionAs a general framework, we propose that PBPK modelling should be considered to predict ethnic sensitivity of pharmacokinetics prior to any human data and/or with data in only one ethnicity. In some cases, this will be sufficient to guide initial dose selection in different ethnicities. After clinical trials in different ethnicities, popPK analysis can be used to confirm ethnic differences and to support dose justification and labelling. PBPK modelling prediction and popPK analysis confirmation can complement each other to assess ethnic differences in pharmacokinetics at different drug development stages.

Dataset Information

Combining "Bottom-up" and "Top-down" Approaches to Assess the Impact of Food and Gastric pH on Pictilisib (GDC-0941) Pharmacokinetics.

Publications

Combining "Bottom-up" and "Top-down" Approaches to Assess the Impact of Food and Gastric pH on Pictilisib (GDC-0941) Pharmacokinetics.

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