Medicinal products with pH-dependent solubility-A problem for BA/BE assessment?

Area of Science:

• Pharmacokinetics and Drug Development
• Regulatory Science

Background:

• The International Council for Harmonisation (ICH) M13A draft guideline proposes specific criteria for bioequivalence studies.
• Current draft regulations address exclusion of very low plasma profiles and additional studies for pH-dependent drugs.

Purpose of the Study:

• To critically evaluate the scientific rationale and practical implications of proposed ICH M13A draft guideline regulations.
• To propose necessary specifications for the exclusion of very low plasma profiles and requirements for additional bioequivalence studies.

Main Methods:

• Scientific literature review and critical analysis of proposed ICH M13A draft guideline provisions.
• Assessment of bioavailability challenges associated with poorly soluble compounds and gastric pH modification.

Main Results:

• Very low plasma profiles can arise from formulation disintegration issues, not solely subject non-compliance.
• Limiting exclusions to one case per study may be scientifically unjustifiable for certain compounds.
• Additional bioequivalence studies for pH-dependent drugs require clearer specifications.

Conclusions:

• The ICH M13A draft guideline's provisions on very low plasma profiles and additional studies need further scientific clarification and refinement.
• Recommendations are made for a more scientifically sound approach to bioequivalence evaluations, considering formulation-dependent bioavailability issues.