| Autor: |
Amaral Silva D; Simulations Plus, Incorporated, 42505 10th Street West, Lancaster, CA 93534, USA., Le Merdy M; Simulations Plus, Incorporated, 42505 10th Street West, Lancaster, CA 93534, USA., Alam KD; Division of Quantitative Methods and Modeling, Office of Research and Standards (ORS), Office of Generic Drugs (OGD), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, MD 20993, USA., Wang Y; Division of Quantitative Methods and Modeling, Office of Research and Standards (ORS), Office of Generic Drugs (OGD), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, MD 20993, USA., Bao Q; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA., Malavia N; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA., Burgess D; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA., Lukacova V; Simulations Plus, Incorporated, 42505 10th Street West, Lancaster, CA 93534, USA. |
| Abstrakt: |
Long-acting injectable (LAI) formulations provide sustained drug release over an extended period ranging from weeks to several months to improve efficacy, safety, and compliance. Nevertheless, many challenges arise in the development and regulatory assessment of LAI drug products due to a limited understanding of the tissue response to injected particles (e.g., inflammation) impacting in vivo performance. Mechanism-based in silico methods may support the understanding of LAI-physiology interactions. The objectives of this study were as follows: (1) to use a mechanistic modeling approach to delineate the in vivo performance of DepoSubQ Provera ® and formulation variants in preclinical species; (2) to predict human exposure based on the knowledge gained from the animal model. The PBPK model evaluated different elements involved in LAI administration and showed that (1) the effective in vivo particle size is potentially larger than the measured in vitro particle size, which could be due to particle aggregation at the injection site, and (2) local inflammation is a key process at the injection site that results in a transient increase in depot volume. This work highlights how a mechanistic modeling approach can identify critical physiological events and product attributes that may affect the in vivo performance of LAIs. |
