In vitro dissolution testing is commonly performed to ensure that oral solid dosage medicines are of high quality and will achieve their targeted in vivo performance. However, this testing is time and material consuming. Therefore, pharmaceutical companies have been developing predictive dissolution models (PDMs) for drug product release based on fast at- and/or on-line measurements, including real-time release testing of dissolution (RTRT-D). Recently, PDMs have seen acceptance by major regulatory bodies as release tests for the dissolution critical quality attribute. In this paper, several methodologies are described to develop and validate a fit-for-purpose model, then to implement it as a surrogate release test for dissolution. These approaches are further exemplified by real-life case studies, which demonstrate that PDMs for release are not only viable but more sustainable than in vitro dissolution testing and can significantly accelerate drug product release. The rise of continuous manufacturing within the pharmaceutical industry further favors the implementation of real-time release testing. Therefore, a steep uptake of PDMs for release is expected once this methodology is globally accepted. To that end, it is advantageous for global regulators and pharmaceutical innovators to coalesce around a harmonized set of expectations for development, validation, implementation, and lifecycle of PDMs as part of drug product release testing.
- MeSH
- aplikace orální MeSH
- farmaceutická chemie metody MeSH
- léčivé přípravky chemie aplikace a dávkování MeSH
- lidé MeSH
- příprava léků MeSH
- rozpustnost MeSH
- schvalování léčiv MeSH
- uvolňování léčiv * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Fibroblast activation protein (FAP) has been extensively studied as a cancer biomarker for decades. Recently, small-molecule FAP inhibitors have been widely adopted as a targeting moiety of experimental theranostic radiotracers. Here we present a fast qPCR-based analytical method allowing FAP inhibition screening in a high-throughput regime. To identify clinically relevant compounds that might interfere with FAP-targeted approaches, we focused on a library of FDA-approved drugs. Using the DNA-linked Inhibitor Antibody Assay (DIANA), we tested a library of 2667 compounds within just a few hours and identified numerous FDA-approved drugs as novel FAP inhibitors. Among these, prodrugs of cephalosporin antibiotics and reverse transcriptase inhibitors, along with one elastase inhibitor, were the most potent FAP inhibitors in our dataset. In addition, by employing FAP DIANA in the quantification mode, we were able to determine FAP concentrations in human plasma samples. Together, our work expands the repertoire of FAP inhibitors, analyzes the potential interference of co-administered drugs with FAP-targeting strategies, and presents a sensitive and low-consumption ELISA alternative for FAP quantification with a detection limit of 50 pg/ml.
- MeSH
- cefalosporiny chemie farmakologie MeSH
- endopeptidasy * metabolismus MeSH
- knihovny malých molekul farmakologie chemie MeSH
- lidé MeSH
- membránové proteiny * antagonisté a inhibitory metabolismus MeSH
- molekulární struktura MeSH
- rychlé screeningové testy * MeSH
- schvalování léčiv MeSH
- serinové endopeptidasy * metabolismus MeSH
- Úřad Spojených států pro potraviny a léky MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- želatinasy * antagonisté a inhibitory metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Spojené státy americké MeSH
