FDA Approval Summary: Dabrafenib in Combination with Trametinib for BRAFV600E Mutation-Positive Low-Grade Glioma.

On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V).

Regulatory utility of physiologically-based pharmacokinetic modeling to support alternative bioequivalence approaches and risk assessment: A workshop summary report.

This report summarizes the proceedings for day 2 sessions 1 and 3 of the 2-day public workshop entitled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches," a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG). The aims of this workshop were: (1) to discuss how mechanistic modeling, including physiologically-based pharmacokinetic (PBPK) modeling and simulation, can support product development, and regulatory submissions; (2) to share the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (3) to establish a consensus on best practices for using PBPK modeling for BE assessment to help drive further investment by the generic drug industry into mechanistic modeling and simulation; and (4) to introduce the concept of a Model Master File to improve model-sharing. The theme of day 2 covered PBPK absorption model for oral products as an alternative BE approach and a tool for supporting risk assessment and biowaiver (session 1), oral PBPK for evaluating the impact of food on BE (session 2), successful cases, and challenges for oral PBPK (session 3).

Nanoparticles and the immune system.

Today nanotechnology is finding growing applications in industry, biology, and medicine. The clear benefits of using nanosized products in various biological and medical applications are often challenged by concerns about the lack of adequate data regarding their toxicity. One area of interest involves the interactions between nanoparticles and the components of the immune system.

Regulatory perspective on the importance of ADME assessment of nanoscale material containing drugs.

The promise of nanoscale material containing drug products to treat complex diseases is mounting. According to the literature, in addition to the liposomes, micelles, emulsions, there are novel drug delivery systems such as dendrimers and metal colloids at different stages of pre-clinical and clinical development. With the anticipation that more nanoscale material containing drug products will be submitted to the Food and Drug Administration (FDA) for approval in the future, FDA formed a Nanotechnology Task Force in 2006 to determine the critical regulatory issues regarding nanomaterials.

Induction of autophagy in porcine kidney cells by quantum dots: a common cellular response to nanomaterials?

Quantum dots (QDs) are being investigated as novel in vivo imaging agents. The leaching of toxic metals from these QDs in biological systems is of great concern. This study compared the cytotoxic mechanisms of two QD species made of different core materials (cadmium selenide [CdSe] vs.

Rapid distribution of liposomal short-chain ceramide in vitro and in vivo.

Ceramide, an endogenous sphingolipid, has demonstrated antieoplastic activity in vitro and in vivo. However, the chemotherapeutic utility of ceramide is limited because of its insolubility. To increase the solubility of ceramide, liposomal delivery systems have been used.

In situ fiber optic method for long-term in vitro release testing of microspheres.

The objective of this study was to develop an in vitro release method for relatively unstable drugs in long-term modified release (MR) formulations, such as microspheres. Drug stability in the release medium can complicate in vitro release testing of such delivery systems. To overcome this problem, a method has been developed where the model drug, cefazolin, and its degradation products are monitored simultaneously, using UV fiber optic probes, to account for cumulative drug release from poly(lactic-co-glycolic) acid (PLGA) microspheres.

Evaluation of in vivo-in vitro release of dexamethasone from PLGA microspheres.

Two poly(lactic-co-glycolic acid) (PLGA) microsphere formulations, with different polymer molecular weights were investigated to determine whether an in vitro and in vivo relationship could be established for dexamethasone release. A USP apparatus 4 was used for in vitro testing. The in vivo release kinetics and pharmacodynamic effects of dexamethasone were evaluated using a Sprague Dawley rat model.

Effect of acidic pH on PLGA microsphere degradation and release.

Polymer degradation and drug release kinetics from PLGA microspheres were investigated under neutral and acidic pH conditions. Two different Mw formulations (Mw: 25,000 and 70,000) were investigated and both exhibited a triphasic release profile at pH 7.4 as well as at pH 2.

Elevated temperature accelerated release testing of PLGA microspheres.

Drug release from four different poly(lactic-co-glycolic) acid (PLGA) microsphere formulations was evaluated under "real-time" (37 degrees C) and accelerated release testing conditions of elevated temperature (45, 53, 60 and 70 degrees C) and increase in flow rate (4-35 ml/min) using United States Pharmacopeia (USP) apparatus 4. Formulation 5 K (composed of low Mw PLGA) exhibited diffusion-controlled kinetics in "real-time". Whereas, formulations 25 K, 28 K and 70 K (composed of medium and high Mw PLGA) followed erosion-controlled kinetics at 37 degrees C.