Dataset Information

Preclinical and Healthy Volunteer Studies of Potential Drug-Drug Interactions Between Tenapanor and Phosphate Binders.

ABSTRACT: Tenapanor (RDX5791, AZD1722), a first-in-class small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3. Tenapanor acts locally in the gut, where it reduces absorption of sodium and phosphate. It is being studied in patients with chronic kidney disease requiring dialysis, who are often administered phosphate binders such as sevelamer to help control hyperphosphatemia. We investigated whether coadministration of tenapanor with phosphate binders (sevelamer or calcium-based binders) impacts the pharmacodynamic effects of tenapanor. In vitro studies suggested a binding interaction between tenapanor and sevelamer, but this did not translate into altered pharmacodynamic effects in rats. An open-label, 2-way crossover study was then conducted in healthy volunteers (NCT02346890). This showed that 4 days' treatment with tenapanor hydrochloride (15 mg twice daily) with or without sevelamer carbonate (800 mg 3 times daily) resulted in comparable 24-hour stool and urinary sodium and phosphorus levels. Stool frequency, consistency, and weight were also comparable between the treatments. These results suggest that the binding between sevelamer and tenapanor observed in vitro does not translate into altered pharmacodynamic effects in humans.

SUBMITTER: Johansson S

PROVIDER: S-EPMC5599948 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Preclinical and Healthy Volunteer Studies of Potential Drug-Drug Interactions Between Tenapanor and Phosphate Binders.

Johansson Susanne S Leonsson-Zachrisson Maria M Knutsson Mikael M Spencer Andrew G AG Labonté Eric D ED Deshpande Desiree D Kohler Jill J Kozuka Kenji K Charmot Dominique D Rosenbaum David P DP

Clinical pharmacology in drug development 20161026 5

Tenapanor (RDX5791, AZD1722), a first-in-class small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3. Tenapanor acts locally in the gut, where it reduces absorption of sodium and phosphate. It is being studied in patients with chronic kidney disease requiring dialysis, who are often administered phosphate binders such as sevelamer to help control hyperphosphatemia. We investigated whether coadministration of tenapanor with phosphate binders ...[more]

PMID: 27654985

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Project description:BACKGROUND:With the exception of genotoxic oncology drugs, first-in-human, Phase 1 clinical studies of investigational drugs have traditionally been conducted in healthy volunteers (HVs). The primary goal of these studies is to investigate the pharmacokinetics and pharmacodynamics of a novel drug candidate, determine appropriate dosing, and document safety and tolerability. MAIN BODY:When tailored to specific study objectives, HV studies are beneficial to manufacturers and patients alike and can be applied to both non-oncology and oncology drug development. Enrollment of HVs not only increases study accrual rates for dose-escalation studies but also alleviates the ethical concern of enrolling patients with disease in a short-term study at subtherapeutic doses when other studies (e.g. Phase 2 or Phase 3 studies) may be more appropriate for the patient. The use of HVs in non-oncology Phase 1 clinical trials is relatively safe but nonetheless poses ethical challenges because of the potential risks to which HVs are exposed. In general, most adverse events associated with non-oncology drugs are mild in severity, and serious adverse events are rare, but examples of severe toxicity have been reported. The use of HVs in the clinical development of oncology drugs is more limited but is nonetheless useful for evaluating clinical pharmacology and establishing an appropriate starting dose for studies in cancer patients. During the development of oncology drugs, clinical pharmacology studies in HVs have been used to assess pharmacokinetics, drug metabolism, food effects, potential drug-drug interactions, effects of hepatic and renal impairment, and other pharmacologic parameters vital for clinical decision-making in oncology. Studies in HVs are also being used to evaluate biosimilars versus established anticancer biologic agents. CONCLUSION:A thorough assessment of toxicity and pharmacology throughout the drug development process is critical to ensure the safety of HVs. With the appropriate safeguards, HVs will continue to play an important role in future drug development.

Dataset Information

Preclinical and Healthy Volunteer Studies of Potential Drug-Drug Interactions Between Tenapanor and Phosphate Binders.

Publications

Preclinical and Healthy Volunteer Studies of Potential Drug-Drug Interactions Between Tenapanor and Phosphate Binders.

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