Regulatory guidelines do not accurately predict tolvaptan and metabolite interactions at BCRP, OATP1B1, and OAT3 transporters.

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  • Additional Information
    • Source:
      Publisher: WileyBlackwell Pub Country of Publication: United States NLM ID: 101474067 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1752-8062 (Electronic) Linking ISSN: 17528054 NLM ISO Abbreviation: Clin Transl Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Malden, MA : WileyBlackwell Pub., 2008-
    • Subject Terms:
      ATP Binding Cassette Transporter, Subfamily G, Member 2/*antagonists & inhibitors ; Drug Approval/*statistics & numerical data ; Liver-Specific Organic Anion Transporter 1/*antagonists & inhibitors ; Neoplasm Proteins/*antagonists & inhibitors ; Organic Anion Transporters, Sodium-Independent/*antagonists & inhibitors ; Tolvaptan/*pharmacology; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Adult ; Clinical Trials as Topic/standards ; Cross-Over Studies ; Drug Interactions ; Female ; Furosemide/pharmacology ; Furosemide/therapeutic use ; Guidelines as Topic ; HEK293 Cells ; Half-Life ; Humans ; Liver-Specific Organic Anion Transporter 1/metabolism ; Male ; Neoplasm Proteins/metabolism ; Organic Anion Transporters, Sodium-Independent/metabolism ; Rosuvastatin Calcium/pharmacology ; Rosuvastatin Calcium/therapeutic use ; Tolvaptan/metabolism ; Tolvaptan/therapeutic use ; United States ; United States Food and Drug Administration/standards ; Young Adult
    • Abstract:
      Tolvaptan (TLV) was US Food and Drug Administration (FDA)-approved for the indication to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease in 2018. In vitro, TLV was a breast cancer resistance protein (BCRP) inhibitor, whereas the oxobutyric acid metabolite of TLV (DM-4013) was an inhibitor of organic anion transport polypeptide (OATP)1B1 and organic anion transporter (OAT)3. Based on the 2017 FDA guidance, potential for clinically relevant inhibition at these transporters was indicated for the highest TLV regimen. Consequently, two postmarketing clinical trials in healthy subjects were required. In trial 1, 5 mg rosuvastatin calcium (BCRP and OATP1B1 substrate) was administered alone, with 90 mg TLV or 48 h following 7 days of once daily 300 mg TLV (i.e., in the presence of DM-4103). In trial 2, 40 mg furosemide (OAT3 substrate) was administered alone and in presence of DM-4103. For BCRP, rosuvastatin geometric mean ratios (90% confidence intervals [CIs]) for maximum plasma concentration (C max ) were 1.54 (90% CI 1.26-1.88) and for area under the concentration-time curve from time 0 to the time of the last measurable concentration (AUC t ) were 1.69 (90% CI 1.34-2.14), indicating no clinically significant interaction. DM-4103 produced no clinically meaningful changes in rosuvastatin or furosemide concentrations, indicating no inhibition at OATP1B1 or OAT3. The BCRP prediction assumed the drug dose is completely soluble in 250 ml; TLV has solubility of ~0.01 g/250 ml. For OATP1B1/OAT3, if fraction unbound for plasma protein binding (PPB) is less than 1%, then 1% is assumed. DM-4103 has PPB greater than 99.8%. Use of actual drug substance solubility and unbound fraction in plasma would have produced predictions consistent with the clinical results.
      (© 2021 Otsuka Pharmaceutical Developmental & Commercialization, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
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    • Grant Information:
      Otsuka Pharmaceutical Development & Commercialization, Inc.
    • Accession Number:
      0 (ABCG2 protein, human)
      0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
      0 (Liver-Specific Organic Anion Transporter 1)
      0 (Neoplasm Proteins)
      0 (Organic Anion Transporters, Sodium-Independent)
      0 (SLCO1B1 protein, human)
      0 (organic anion transport protein 3)
      21G72T1950 (Tolvaptan)
      7LXU5N7ZO5 (Furosemide)
      83MVU38M7Q (Rosuvastatin Calcium)
    • Publication Date:
      Date Created: 20210320 Date Completed: 20220214 Latest Revision: 20220214
    • Publication Date:
      20221213
    • Accession Number:
      PMC8301576
    • Accession Number:
      10.1111/cts.13017
    • Accession Number:
      33742787