{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T16:09:58Z","timestamp":1790438998065,"version":"4.1.0"},"reference-count":49,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2015,4,1]],"date-time":"2015-04-01T00:00:00Z","timestamp":1427846400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Ribavirin, a guanosine analog, is a broad-spectrum antiviral agent. Ribavirin has been a fundamental component of the treatment of hepatitis C virus (HCV) infection for decades, but there is a very limited understanding of the clinical pharmacology of this drug. Furthermore, it is associated with a major dose-limiting toxicity, hemolytic anemia. Ribavirin undergoes intracellular phosphorylation by host enzymes to ribavirin monophosphate (RMP), ribavirin diphosphate (RDP), and ribavirin triphosphate (RTP). The intracellular forms have been associated with antiviral and toxic effects\n                    <jats:italic>in vitro<\/jats:italic>\n                    , but the kinetics of these phosphorylated moieties have not been fully elucidated\n                    <jats:italic>in vivo<\/jats:italic>\n                    . We developed a model to characterize the plasma pharmacokinetics of ribavirin and the difference between intracellular phosphorylation kinetics in red cells (nonnucleated) and in peripheral blood mononuclear cells (nucleated). A time-independent two-compartment model with first-order absorption described the plasma data well. The cellular phosphorylation kinetics was described by a one-compartment model for RMP, with the formation rate driven by plasma concentrations and the first-order degradation rate. RDP and RTP rapidly reached equilibrium with RMP. Concomitant telaprevir use, inosine triphosphatase genetics, creatinine clearance, weight, and sex were significant covariates. The terminal ribavirin half-life in plasma and phosphorylated anabolites in cells was approximately 224 h. We found no evidence of time-dependent kinetics. These data provide a foundation for uncovering concentration-effect associations for ribavirin and determining the optimal dose and duration of this drug for use in combination with newer direct-acting HCV agents. (This study has been registered at ClinicalTrials.gov under registration no. NCT01097395.)\n                  <\/jats:p>","DOI":"10.1128\/aac.04618-14","type":"journal-article","created":{"date-parts":[[2015,2,3]],"date-time":"2015-02-03T01:04:54Z","timestamp":1422925494000},"page":"2179-2188","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":31,"title":["Population Pharmacokinetic Modeling of Plasma and Intracellular Ribavirin Concentrations in Patients with Chronic Hepatitis C Virus Infection"],"prefix":"10.1128","volume":"59","author":[{"given":"Liviawati S.","family":"Wu","sequence":"first","affiliation":[{"name":"University of Southern California, Biomedical Engineering, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph E.","family":"Rower","sequence":"additional","affiliation":[{"name":"University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"James R.","family":"Burton","sequence":"additional","affiliation":[{"name":"University of Colorado School of Medicine, Division of Gastroenterology and Hepatology, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L.","family":"Anderson","sequence":"additional","affiliation":[{"name":"University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle P.","family":"Hammond","sequence":"additional","affiliation":[{"name":"University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fafa","family":"Baouchi-Mokrane","sequence":"additional","affiliation":[{"name":"Denver Health Medical Center, Denver, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory T.","family":"Everson","sequence":"additional","affiliation":[{"name":"University of Colorado School of Medicine, Division of Gastroenterology and Hepatology, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Urban","sequence":"additional","affiliation":[{"name":"Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Z.","family":"D'Argenio","sequence":"additional","affiliation":[{"name":"University of Southern California, Biomedical Engineering, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Kiser","sequence":"additional","affiliation":[{"name":"University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00281a014"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.177.4050.705"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.109309"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1315722"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1316145"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402338"},{"key":"e_1_3_2_8_2","volume-title":"Abstr 49th Annu Meet Eur Assoc Study Liver (EASL)","author":"Gane EJ","year":"2014","unstructured":"Gane EJ, Hyland RH, An D, Pang PS, Symonds WT, Hutchison JG, Stedman CA. 2014. 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