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Effect of Microenvironmental pH Modulation on the Dissolution Rate and Oral Absorption of the Salt of a Weak Acid – Case Study of GDC-0810

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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.

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Abbreviations

API:

Active pharmaceutical ingredient

AUC:

Area under the curve

FaSSIF:

Fasted-state simulated intestinal fluid

HPLC:

High performance liquid chromatography

IDR:

Intrinsic dissolution rate

NMG:

N-Methyl-D-glucamine

PXRD:

Powder x-ray diffraction

SGF:

Simulated gastric fluid

ssNMR:

Solid-state nuclear magnetic resonance

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Acknowledgments and Disclosures

The authors would like to thank Dr. Po-Chang Chiang, Genentech Inc., for valuable scientific discussion. We would like to acknowledge Dr. Ching-Wei Chang, Genentech Inc., for assistance in statistical analysis.

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Authors and Affiliations

  1. Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Hao Helen Hou, Wei Jia, Jane Li, Ewa Nauka & Karthik Nagapudi

  2. Clinical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Lichuan Liu & Sravanthi Cheeti

Authors
  1. Hao Helen Hou
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  2. Wei Jia
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  3. Lichuan Liu
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  4. Sravanthi Cheeti
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  5. Jane Li
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  6. Ewa Nauka
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  7. Karthik Nagapudi
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Corresponding authors

Correspondence to Hao Helen Hou or Karthik Nagapudi.

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Hou, H.H., Jia, W., Liu, L. et al. Effect of Microenvironmental pH Modulation on the Dissolution Rate and Oral Absorption of the Salt of a Weak Acid – Case Study of GDC-0810. Pharm Res 35, 37 (2018). https://doi.org/10.1007/s11095-018-2347-z

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  • DOI: https://doi.org/10.1007/s11095-018-2347-z

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