{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T01:44:05Z","timestamp":1784079845664,"version":"3.55.0"},"reference-count":27,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T00:00:00Z","timestamp":1579651200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Microdose studies are exploratory trials to determine early drug pharmacokinetics in humans. In this trial we examined whether the pharmacokinetics of gemcitabine at a therapeutic dose could be predicted from the pharmacokinetics of a microdose. In this prospective, open\u2010label microdosing study, a gemcitabine microdose (100 \u00b5g) was given intravenously to participants on day 1, followed by a therapeutic dose (1250 mg\/m<jats:sup>2<\/jats:sup>) on day 2. Gemcitabine and its metabolite 2\u2019,2\u2019\u2010difluorodeoxyuracil (dFdU) were quantified in plasma and intracellularly by using liquid chromatography\u2010mass spectrometry). Noncompartmental pharmacokinetic analysis was performed. Ten patients participated in this study. The mean area under the plasma concentration\u2010time curve (AUC<jats:sub>0\u20108<\/jats:sub>) of gemcitabine after microdosing was 0.00074 h\u00b7mg\/L and after therapeutic dosing was 16 h\u00b7mg\/L. The mean AUC<jats:sub>0\u20108<\/jats:sub> of dFdU following the microdose and therapeutic dose were 0.022 h\u00b7mg\/L and 169 h\u00b7mg\/L, respectively. Exposure to gemcitabine after the therapeutic dose was within 2\u2010fold of the exposure following a microdose, when linearly extrapolated to 1250 mg\/m<jats:sup>2<\/jats:sup>. However, the shape of the concentration\u2010time curve was different, as reflected by poor scalability in volume of distribution (939 L versus 222 L). Furthermore, intracellularly phosphorylated gemcitabine and phosphorylated dFdU levels could not be predicted from the microdose. The AUC<jats:sub>0\u20108<\/jats:sub> of gemcitabine at therapeutic dose was accurately predicted by the pharmacokinetics of a microdose, when linearly extrapolated to 1250 mg\/m<jats:sup>2<\/jats:sup>. Volume of distribution, elimination rate constant, and intracellular pharmacokinetics of the therapeutic dose could not be predicted from the microdose, which demonstrates limitations of the microdose approach in this case.<\/jats:p>","DOI":"10.1002\/cpdd.774","type":"journal-article","created":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T07:25:51Z","timestamp":1579764351000},"page":"929-937","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pilot Study to Predict Pharmacokinetics of a Therapeutic Gemcitabine Dose From a Microdose"],"prefix":"10.1002","volume":"9","author":[{"given":"M.","family":"Van Nuland","sequence":"first","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Rosing","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Thijssen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.A.","family":"Burgers","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology The Netherlands Cancer Institute  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.D.R.","family":"Huitema","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute  Amsterdam the Netherlands"},{"name":"Division of Clinical Pharmacology The Netherlands Cancer Institute  Amsterdam the Netherlands"},{"name":"Department of Clinical Pharmacy University Medical Center Utrecht Utrecht University  the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology The Netherlands Cancer Institute  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.H.M.","family":"Schellens","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences, Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.H.","family":"Beijnen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology The Netherlands Cancer Institute  Amsterdam the Netherlands"},{"name":"Division of Clinical Pharmacology The Netherlands Cancer Institute  Amsterdam the Netherlands"},{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences, Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6603925"},{"key":"e_1_2_7_3_1","unstructured":"European Medicines Agency (EMA). Position paper on non\u2010clinical safety studies to support clinical trials with a single microdose.http:\/\/www.iaa-ams.co.jp\/img_bsnss\/MD1.pdfPublished 2004. Accessed May 10 2019."},{"key":"e_1_2_7_4_1","unstructured":"US Food and Drug Administration (FDA). Guidance for industry investigators and reviewers: Exploratory IND studies.https:\/\/www.fda.gov\/media\/72325\/downloadPublished 2006. Accessed May 10 2019."},{"key":"e_1_2_7_5_1","unstructured":"European Medicines Agency (EMA). ICH M3 (R2): Note for guidance on non\u2010clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals.https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/ich-m-3-r2-non-clinical-safety-studies-conduct-human-clinical-trials-marketing-authorization_en.pdfPublished 2009. 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