Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Isavuconazonium Sulfate

Area of Science:

• Pharmaceutical Sciences
• Drug Development
• Regulatory Science

Background:

• Isavuconazonium sulfate is a prodrug of isavuconazole, an antifungal medication.
• The prodrug (BCS Class III) and parent drug (BCS Class II) exhibit distinct Biopharmaceutics Classification System (BCS) properties.
• In vivo, isavuconazonium sulfate behaves as a BCS Class I drug, indicating high solubility and permeability.

Purpose of the Study:

• To evaluate the feasibility of a BCS-based biowaiver monograph for isavuconazonium sulfate immediate-release oral dosage forms.
• To assess the suitability of isavuconazonium sulfate for regulatory approval using in vitro data in place of in vivo bioequivalence studies.
• To review risks associated with biowaivers for prodrugs and analyze formulation-specific dissolution limitations.

Main Methods:

• Evaluation of experimental and literature solubility and dissolution data for isavuconazonium sulfate.
• Comparison of data against regulatory guidelines (FDA, EMA, ICH) for BCS-based biowaivers.
• Analysis of the dissolution profile of the commercial capsule formulation (Cresemba).

Main Results:

• Isavuconazonium sulfate exhibits high solubility but instability in aqueous media.
• Dissolution of the active pharmaceutical ingredient (API) from capsule contents is rapid.
• The capsule shell material limits the release of isavuconazonium sulfate, hindering biowaiver approval.

Conclusions:

• Current regulatory guidelines for BCS-based biowaivers are restrictive, especially for prodrugs.
• Formulation factors, specifically the capsule shell, present a significant impediment to generic approval of isavuconazonium sulfate via the BCS-Biowaiver approach.
• Despite rapid API dissolution, the overall drug product performance may not meet biowaiver criteria due to formulation limitations.