Various approaches have been developed to enhance the solubility or dissolution rate for the delivery of poorly water-soluble molecules. In this work, guided by an in silico solubility sensitivity analysis for oral absorption, a comparative assessment of the biopharmaceutical performance of a jet-milled free base, a tosylate salt, and a 50:50 (w/w) amorphous solid dispersion (ASD) with hydroxypropyl methylcellulose acetate succinate (HPMCAS) of a weak base drug candidate, GDC-3280, was conducted. Successful particle size reduction without amorphization or form change was confirmed for the jet-milled free base. The potential of solubility enhancement and desupersaturation risk were identified for tosylate salt and ASD formulation by measurements of tosylate salt solubility product constant (Ksp) and amorphous solubility of GDC-3280. In vitro dissolution testing demonstrated dissolution rate improvement for the jet-milled free base when compared with the unmilled free base and confirmed solubility enhancement followed by desupersaturation for GDC-3280 tosylate salt and ASD formulation. A crystallization inhibitor, hydroxypropyl methylcellulose (HPMC), was found to slow down the desupersaturation of tosylate salt solution, providing general insights for the development of pharmaceutical salts with disproportionation risks. Finally, a pharmacokinetic study in dogs showed that the in vivo exposure increased by 1.7- to 2-fold for the tosylate salt and ASD formulation compared with the jet-milled free base, consistent with the in silico solubility sensitivity analysis for the fraction of drug absorbed. Overall, this work provides insights into the evaluation of multiple formulation approaches for enhancing the biopharmaceutical performance of poorly water-soluble drugs.