Hao Helen Hou1, Wei Jia2, Lichuan Liu3, Sravanthi Cheeti3, Jane Li2, Ewa Nauka2, Karthik Nagapudi4. 1. Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. hou.hao@gene.com. 2. Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. 3. Clinical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. 4. Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. nagapudi.karthik@gene.com.
Abstract
PURPOSE: The purpose of this work is to investigate the effect of microenvironmental pH modulation on the in vitro dissolution rate and oral absorption of GDC-0810, an oral anti-cancer drug, in human. METHODS: The pH-solubility profile of GDC-0810 free acid and pHmax of its N-Methyl-D-glucamine (NMG) salt were determined. Precipitation studies were conducted for GDC-0810 NMG salt at different pH values. GDC-0810 200-mg dose NMG salt tablet formulations containing different levels of sodium bicarbonate as the pH modifier were tested for dissolution under the dual pH-dilution scheme. Three tablet formulations were evaluated in human as a part of a relative bioavailability study. A 200-mg dose of GDC-0810 was administered QD with low fat food. RESULTS: Intrinsic solubility of GDC-0810 free acid was found to be extremely low. The pHmax of the NMG salt suggested a strong tendency for form conversion to the free acid under GI conditions. In vitro dissolution profiles showed that the dissolution rate and extent of GDC-0810 increased with increasing the level of sodium bicarbonate in the formulation. The human PK data showed a similar trend for the geometric mean of Cmax and AUC0-t for formulations containing 5%, 10%, and 15% sodium bicarbonate, but the difference is not statistically significant. CONCLUSION: Incorporation of a basic pH modifier, sodium bicarbonate, in GDC-0810 NMG salt tablet formulations enhanced in vitro dissolution rate of GDC-0810 via microenvironmental pH modulation. The human PK data showed no statistically significant difference in drug exposure from tablets containing 5%, 10%, and 15% sodium bicarbonate.
PURPOSE: The purpose of this work is to investigate the effect of microenvironmental pH modulation on the in vitro dissolution rate and oral absorption of GDC-0810, an oral anti-cancer drug, in human. METHODS: The pH-solubility profile of GDC-0810free acid and pHmax of its N-Methyl-D-glucamine (NMG) salt were determined. Precipitation studies were conducted for GDC-0810NMGsalt at different pH values. GDC-0810 200-mg dose NMGsalt tablet formulations containing different levels of sodium bicarbonate as the pH modifier were tested for dissolution under the dual pH-dilution scheme. Three tablet formulations were evaluated in human as a part of a relative bioavailability study. A 200-mg dose of GDC-0810 was administered QD with low fat food. RESULTS: Intrinsic solubility of GDC-0810free acid was found to be extremely low. The pHmax of the NMGsalt suggested a strong tendency for form conversion to the free acid under GI conditions. In vitro dissolution profiles showed that the dissolution rate and extent of GDC-0810 increased with increasing the level of sodium bicarbonate in the formulation. The human PK data showed a similar trend for the geometric mean of Cmax and AUC0-t for formulations containing 5%, 10%, and 15% sodium bicarbonate, but the difference is not statistically significant. CONCLUSION: Incorporation of a basic pH modifier, sodium bicarbonate, in GDC-0810NMGsalt tablet formulations enhanced in vitro dissolution rate of GDC-0810 via microenvironmental pH modulation. The human PK data showed no statistically significant difference in drug exposure from tablets containing 5%, 10%, and 15% sodium bicarbonate.
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