title: Brincidofovir Is Not a Substrate for the Human Organic Anion Transporter 1: A Mechanistic Explanation for the Lack of Nephrotoxicity Observed in Clinical Studies.
abstract: Brincidofovir (BCV) is an orally bioavailable lipid conjugate of cidofovir (CDV) with increased in vitro potency relative to CDV against all 5 families of double-stranded DNA viruses that cause human disease. After intravenous (IV) administration of CDV, the organic anion transporter 1 (OAT1) transports CDV from the blood into the renal proximal tubule epithelial cells with resulting dose-limiting nephrotoxicity.
  
  
  
  To study whether OAT1 transports BCV and to evaluate the pharmacokinetic and renal safety profile of oral BCV compared with IV CDV.
  
  
  
  The cellular uptake of BCV and its major metabolites was assessed in vitro. Renal function at baseline and during and after treatment in subjects in BCV clinical studies was examined.
  
  
  
  In OAT1-expressing cells, uptake of BCV and its 2 major metabolites (CMX103 and CMX064) was the same as in mock-transfected control cells and was not inhibited by the OAT inhibitor probenecid. In human pharmacokinetic studies, BCV administration at therapeutic doses resulted in detection of CDV as a circulating metabolite; peak CDV plasma concentrations after oral BCV administration in humans were <1% of those observed after IV CDV administration at therapeutic doses. Analysis of renal function and adverse events from 3 BCV clinical studies in immunocompromised adult and pediatric subjects indicated little to no evidence of associated nephrotoxicity. Over 80% of subjects who switched from CDV or foscarnet to BCV experienced an improvement in renal function as measured by maximum on-treatment estimated glomerular filtration rate.
  
  
  
  The lack of BCV uptake through OAT1, together with lower CDV concentrations after oral BCV compared with IV CDV administration, likely explains the superior renal safety profile observed in immunocompromised subjects receiving BCV compared with CDV.
authors.affiliation: Chimerix, Durham, North Carolina.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Tippin
authors.forename: Marion E
authors.initials: ME
authors.lastname: Morrison
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Brundage
authors.forename: Hervé
authors.initials: H
authors.lastname: Momméja-Marin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D002648:Child; D003596:Cytosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004285:Dogs; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008875:Middle Aged; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D063065:Organophosphonates / Q000009:adverse effects* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; C525733:brincidofovir; D003596:Cytosine