Guiding the Molnupiravir Tablet Formulation Using Physiologically Based Biopharmaceutics Modeling and Successfully
Thomas Morrow1, Nicole Jarvi1, Madeline Halota1
1Development Sciences and Clinical Supply , MRL, Merck & Co., Inc., Rahway, NJ, 07065, USA.
The AAPS Journal
|June 8, 2026
Summary
Physiologically Based Biopharmaceutics Models (PBBMs) aid drug development by defining bioequivalence safe spaces. This approach enhances regulatory flexibility and supports clinically relevant specifications for products like molnupiravir.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Pharmaceutical Sciences
- Regulatory Science
Background:
- Physiologically Based Biopharmaceutics Models (PBBMs) are increasingly accepted regulatory tools.
- PBBMs assist in establishing drug product quality specifications.
- Molnupiravir development utilized PBBMs for formulation and bioequivalence studies.
Purpose of the Study:
- To demonstrate the application of PBBMs in molnupiravir drug product development.
- To calculate bioequivalence safe spaces for capsule and tablet formulations.
- To inform regulatory strategies and define clinically relevant specifications.
Main Methods:
- PBBM data inputs, model development, and validation using clinical study data.
- Calculation of bioequivalence safe space and dissolution knowledge space.
- Utilizing predictive error analysis for Cmax and AUC, and z-factor for dissolution.
Main Results:
- Predictive errors for Cmax and AUC were less than 25%.
- PBBM successfully informed bioequivalence studies and formulation selection for molnupiravir.
- A wider dissolution space was established, allowing for greater post-approval flexibility.
Conclusions:
- PBBMs are valuable for drug product development, formulation selection, and regulatory flexibility.
- The use of PBBMs can lead to the approval of clinically relevant specifications.
- Widening the dissolution knowledge space through PBBMs offers significant advantages for scale-up and post-approval changes.
Related Concept Videos
01:28Factors Influencing Drug Absorption: Pharmaceutical Parameters
Solid dosage forms such as tablets and capsules undergo rigorous manufacturing processes to ensure stability and effectiveness. Their dissolution and absorption properties are influenced significantly by the choice of excipients (inactive ingredients that serve various roles in the formulation), and the methodology applied during production. The manufacturing parameters, such as compression force and granulation techniques, significantly affect dissolution rates. Elevated compression forces...
01:13In Vitro Drug Dissolution: Compendial Testing Models I
Compendial dissolution methods are standardized procedures defined by pharmacopeias to evaluate the rate at which a drug dissolves in a specific medium. These methods ensure batch-to-batch consistency, enable quality control, and support the prediction of drug bioavailability. They are critical for both immediate and modified-release drug products.The apparatuses used for dissolution testing differ in their design and mechanical function, but all aim to simulate the physiological environment of...
01:17In Vitro Drug Dissolution: Alternative Methods
Alternative drug dissolution methods include the rotating bottle, intrinsic dissolution test, peristalsis, and the Franz diffusion cell method. The rotating bottle method involves meticulously rotating tightly capped controlled-release beads in a temperature-controlled bath. Periodic decanting of samples allows for residue assay, followed by refilling with fresh medium and testing at various pH levels to emulate the gastrointestinal tract conditions.In contrast, the intrinsic dissolution test...
01:09In Vitro Drug Dissolution: Compendial Testing Models II
Various dissolution methods are utilized to assess a drug’s dissolution rate, including the flow-through cell, paddle-over-disk, cylinder, and reciprocating disk methods.The flow-through cell apparatus (USP (United States Pharmacopeia) method 4) comprises a reservoir for the dissolution medium and a pump that propels the medium through the cell containing the test sample. This method is crucial for assessing modified-release dosage forms with minimally soluble active ingredients, maintaining...
01:20Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
Orally administered drugs primarily enter the systemic circulation via passive diffusion through the intestinal membranes. The drug's absorption is influenced by drug stability in the gastrointestinal GI tract, membrane permeability, the surface area available for absorption, luminal drug concentration, and residence time in the lumen. Drug permeability can be enhanced by adjusting the lipophilicity, polarity, or molecular size of the drug, promoting its passive transport across intestinal...
01:27Factors Influencing Drug Absorption: Drug Dissolution
The pharmacokinetic journey of drugs from solid oral dosage forms into systemic circulation is multifaceted. It begins with disintegration, a prerequisite ensuring a solid dosage form's subdivision into minute particles. Dissolution occurs next as these granulated entities solubilize in gastrointestinal fluids. This solubilization is crucial for the succeeding stage, permeation, which describes the traversal of the drug across the intestinal membrane and its subsequent entry into the blood...