Dataset Information

Uptake carriers and oncology drug safety.

ABSTRACT: Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics in multiple tissues. Many of these transporters are highly expressed in the gastrointestinal tract, liver, and kidney and are considered to be of particular importance in governing drug absorption, elimination, and cellular sensitivity of specific organs to a wide variety of oncology drugs. Although the majority of studies on the interaction of oncology drugs with SLC have been restricted to the use of exploratory in vitro model systems, emerging evidence suggests that several SLCs, including OCT2 and OATP1B1, contribute to clinically important phenotypes associated with those agents. Recent literature has indicated that modulation of SLC activity may result in drug-drug interactions, and genetic polymorphisms in SLC genes have been described that can affect the handling of substrates. Alteration of SLC function by either of these mechanisms has been demonstrated to contribute to interindividual variability in the pharmacokinetics and toxicity associated with several oncology drugs. In this report, we provide an update on this rapidly emerging field.

SUBMITTER: Sprowl JA

PROVIDER: S-EPMC3965905 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Uptake carriers and oncology drug safety.

Sprowl Jason A JA Sparreboom Alex A

Drug metabolism and disposition: the biological fate of chemicals 20131230 4

Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics in multiple tissues. Many of these transporters are highly expressed in the gastrointestinal tract, liver, and kidney and are considered to be of particular importance in governing drug absorption, elimination, and cellular sensitivity of specific organs to a wide variety of oncology drugs. Although the majority of studies on the interaction ...[more]

PMID: 24378324

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Project description:ContextThe illicit drug supply is rapidly evolving. Equally important to gathering drug supply data for monitoring is timely sharing of information with people who use drugs, the providers who care for them, law enforcement partners, and public health stakeholders so that efforts to avoid harmful substances, take preventive actions, and better target interventions can occur.ProgramThe Massachusetts Drug Supply Data Stream (MADDS) is the country's first statewide community drug checking program. Founded on public health-public safety partnerships, MADDS collects remnant drug packaging and paraphernalia with residue from people who use drugs and noncriminal samples from partnering police departments. MADDS tests samples using simultaneous immunoassay fentanyl test strips, Fourier-transform infrared spectrometry (FTIR), and off-site laboratory testing by gas chromatography-mass spectrometry (GC/MS). Results are accessible to community programs and municipalities, while trend analyses inform public health for cross-site alerts and informational bulletins.ImplementationMADDS was launched statewide in 2020 and rapidly expanded to a multisite program. Program staff approached communities and met with municipal police and community partners to secure written agreements to host drug checking. Community partners designed sample collection consistent with their pandemic era workflows. Consultations with stakeholders gathered feedback on design and deliverables.EvaluationThe program tests sample donations on-site from community agencies and police departments, incorporates review by a medical toxicologist for health and safety concerns, crafts stakeholder-specific communications, and disseminates English, Spanish, and Portuguese language materials. For 2020, a total of 427 samples were tested, of which 47.1% were positive for fentanyl. By early 2021, MADDS detected shifts in cocaine purity, alerted communities of a new toxic fentanyl analogue and a synthetic cannabinoid contaminant, and confirmed the increase of xylazine (a veterinary sedative) in Massachusetts.DiscussionCommunity drug checking programs can be collaboratively designed with public health and public safety to generate critical health and safety information for people who use drugs and the communities where they live.

Project description:Background/aimsThe Food and Drug Administration's final rule on investigational new drug application safety reporting, effective from 28 March 2011, clarified the reporting requirements for serious and unexpected suspected adverse reactions occurring in clinical trials. The Clinical Trials Transformation Initiative released recommendations in 2013 to assist implementation of the final rule; however, anecdotal reports and data from a Food and Drug Administration audit indicated that a majority of reports being submitted were still uninformative and did not result in actionable changes. Clinical Trials Transformation Initiative investigated remaining barriers and potential solutions to full implementation of the final rule by polling and interviewing investigators, clinical research staff, and sponsors.MethodsIn an opinion-gathering effort, two discrete online surveys designed to assess challenges and motivations related to management of expedited (7- to 15-day) investigational new drug safety reporting processes in oncology trials were developed and distributed to two populations: investigators/clinical research staff and sponsors. Data were collected for approximately 1?year. Twenty-hour-long interviews were also conducted with Clinical Trials Transformation Initiative-nominated interview participants who were considered as having extensive knowledge of and experience with the topic. Interviewees included 13 principal investigators/study managers/research team members and 7 directors/vice presidents of pharmacovigilance operations from 5 large global pharmaceutical companies.ResultsThe investigative site's responses indicate that too many individual reports are still being submitted, which are time-consuming to process and provide little value for patient safety assessments or for informing actionable changes. Fewer but higher quality reports would be more useful, and the investigator and staff would benefit from sponsors'"filtering" of reports and increased sponsor communication. Sponsors replied that their greatest challenges include (1) lack of global harmonization in reporting rules, (2) determining causality, and (3) fear of regulatory repercussions. Interaction with the Food and Drug Administration has helped improve sponsors' adherence to the final rule, and sponsors would benefit from increased communication with the Food and Drug Administration and educational materials.ConclusionThe goal of the final rule is to minimize uninformative safety reports so that important safety signals can be captured and communicated early enough in a clinical program to make changes that help ensure patient safety. Investigative staff and sponsors acknowledge that the rule has not been fully implemented although they agree with the intention. Clinical Trials Transformation Initiative will use the results from the surveys and interviews to develop new recommendations and educational materials that will be available to sponsors to increase compliance with the final rule and facilitate discussion between sponsors, investigators, and Food and Drug Administration representatives.

Dataset Information

Uptake carriers and oncology drug safety.

Publications

Uptake carriers and oncology drug safety.

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