Biowaiver monographs for immediate-release solid oral dosage forms: Lemborexant

Area of Science:

• Pharmaceutical Sciences
• Biopharmaceutics
• Drug Development

Background:

• Lemborexant, a dual orexin receptor antagonist, is classified as Biopharmaceutics Classification System (BCS) class II.
• This classification prevents immediate-release (IR) solid oral dosage forms from BCS-based biowaivers per ICH M9 Guideline.
• The refined Developability Classification System (rDCS) classifies lemborexant as class I, indicating minimal biopharmaceutics risks.

Purpose of the Study:

• To explore alternative strategies for establishing bioequivalence (BE) for lemborexant formulations.
• To address the limitations of the BCS-based approach for lemborexant IR solid oral dosage forms.
• To propose a virtual BE assessment pathway for lemborexant and similar compounds.

Main Methods:

• Utilized the refined Developability Classification System (rDCS) for lemborexant classification.
• Conducted customized rDCS investigations to identify critical bioavailability attributes.
• Employed biorelevant dissolution testing to assess dissolution behavior.
• Proposed a four-step pathway involving rDCS, biorelevant dissolution, Physiologically Based Biopharmaceutics Modeling (PBBM), and virtual BE assessment.

Main Results:

• rDCS analysis identified dissolution as the primary risk factor for lemborexant, not solubility or permeability.
• Clinical data in humans supports that lemborexant absorption is not limited by solubility or permeability.
• The proposed four-step pathway offers a method to mitigate risks associated with formulation changes or generic introductions.
• This approach facilitates virtual bioequivalence assessment when BCS-based justification is not feasible.

Conclusions:

• The refined Developability Classification System (rDCS) provides a more nuanced risk assessment for lemborexant than BCS.
• Dissolution is the critical attribute to monitor for lemborexant formulation development and generic substitution.
• A virtual bioequivalence assessment pathway combining rDCS, biorelevant dissolution, and PBBM is a viable strategy for lemborexant and similar drugs.
• This strategy can streamline drug development and generic approval processes by reducing reliance on clinical bioequivalence studies.