Overcoming Bioavailability Challenges of Very Weak Acid for Oral Delivery – A Case Study of HCV Drug Dasabuvir

26 September 2022 16:15 - 16:45

  • Dasabuvir is a BCS II compound posing a significant barrier to achieving sufficient human bioavailability. Its substantially weak acidity (pKa > 8) made salt approach challenging and risky due to disproportionation.
  • Identification of effective crystallization inhibitors captured the dissolution advantage of dasabuvir sodium salt and provided a path forward for formulation development.
  • The comprehensive evaluation of solid-state properties, biopharmaceutical properties, in-vivo pharmacokinetics, and manufacturability of dasabuvir monosodium monohydrate ensured the selection of this solid form for successful formulation development and clinical studies.
  • Oral delivery of dasabuvir via salt approach ultimately helped enable the triple combination direct acting antiviral HCV regimen Viekira Pak.
Dasabuvir is a non-nucleoside polymerase inhibitor for the treatment of hepatitis C virus (HCV) infection. It is an extremely weak diacidic drug (pKa = 8.2 and 9.2) and a prolific solvate former. Due to its exceedingly low aqueous solubility (≤ 0.127 µg/mL at pH 1 ‒ 6.8, dose number of 1.31 × 104), crystalline dasabuvir free acid exhibited poor oral bioavailability in animal PK assessment. While salt formation has been widely used to enhance solubility and dissolution rate of solids, this approach has rarely been applied to develop oral solid dosage forms for acidic drugs as weak as dasabuvir due to concerns of rapid disproportionation and crystallization of free acid. In this presentation, we highlight our efforts in identifying dasabuvir monosodium monohydrate as drug substance that is stable, manufacturable, and significantly enhances dissolution and oral absorption of this poorly soluble drug. The oral delivery of dasabuvir through salt approach has enabled the commercialization of triple combination direct acting antiviral HCV regimen Viekira Pak. The methodologies and solutions identified in targeted studies to overcome technical challenges (i.e., incorporation of polymers to inhibit crystallization and disproportionation and species mapping to enable salt manufacturing process, etc.) can be applied to other insoluble compounds.

Shuang Chen, Ph.D., Sr. Principal Research Scientist Solid State Chemistry, Process R&D, AbbVie