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In this paper, a special case for bioequivalence evaluation of oral formulations is discussed. Drug formulations with different forms of active moieties (e.g., free base and salt) may yield different dissolution characteristics and, thus, differ in absorption at elevated gastric  pH . However, routine bioequivalence trials using subjects with normal gastric  pH  (i.e., ~ 1) may fail to identify these differences because dissolution/absorption profiles of the two formulations at normal gastric  pH  are similar. In the case of palbociclib, it is confirmedthat the free base and salt formulations showed different absorption in patients with different gastric  pH . Significant reduction in drug absorption was observed only in patients with elevated gastric  pH  using free base formulation. The discovery that the free base had significantly reduced absorption hinged on the inclusion of enough patients with elevated gastric  pH  to detect a difference in a bioequivalence trial. This raises a concern, as demonstrated through simulation, that dissolution/absorption differences in other formulations could be missed in routine bioequivalence trials. Aside from differences in active pharmaceutical ingredients ( API s), other factors, such as changes in excipients or manufacturing methods, may also lead to exposure differences between formulations at elevated gastric  pH . For formulations containing different forms of the same active moiety or the same  API  and showing different dissolution profiles at elevated  pH  (i.e.,  pH  ~ 4–6.8), evaluation of bioequivalence with gastric  pH  modulators (e.g., a H 2  blocker) in addition to routine bioequivalence assessments may help to ensure therapeutic equivalence in patients with elevated gastric  pH .

clinical and translational science

A Proposal of Conducting Bioequivalence Trials with Gastric  pH  Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated  pH