title: The Use of Dried Blood Spots for Pharmacokinetic Monitoring of Vemurafenib Treatment in Melanoma Patients.
abstract: Pharmacokinetic monitoring is increasingly becoming an important part of clinical care of tyrosine kinase inhibitor treatment. Vemurafenib is an oral tyrosine kinase inhibitor that inhibits mutated serine/threonine protein kinase B-Raf (BRAF) and is approved for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The aim of this study was to establish the relationship between dried blood spot (DBS) and plasma concentrations of vemurafenib to enable the use of DBS sampling, which is a minimally invasive form of sample collection. In total, 43 paired plasma and DBS samples (in duplicate) were obtained from 8 melanoma patients on vemurafenib therapy and were analyzed using high-performance liquid chromatography-tandem mass spectrometry. Plasma concentrations were predicted from the DBS concentrations using 2 methods: (1) individual hematocrit correction and blood cell-to-plasma partitioning and (2) the calculated slope explaining the relationship between DBS and plasma concentrations (without individual hematocrit correction). Vemurafenib DBS concentrations and plasma concentrations showed a strong correlation (r = 0.964), and the relationship could be described by ([vemurafenib]plasma = [vemurafenib]DBS /0.64). The predicted plasma concentrations were within ±20% of the analyzed plasma concentrations in 97% and 100% of the samples for the methods with and without hematocrit correction, respectively. In conclusion, DBS concentrations and plasma concentrations of vemurafenib are highly correlated. Plasma concentrations can be predicted from DBS concentration using the blood cell-to-plasma partition and the average hematocrit value of this cohort (0.40 L/L). DBS sampling for pharmacokinetic monitoring of vemurafenib treatment can be used in clinical practice.
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands. cynthianijenhuis@gmail.com.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Nijenhuis
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Serena
authors.initials: S
authors.lastname: Marchetti
authors.affiliation: Division of Immunology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Blank
authors.affiliation: Division of Immunology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.affiliation: Division of Immunology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Johannes V
authors.initials: JV
authors.lastname: van Thienen
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D059788:Dried Blood Spot Testing / Q000379:methods*; D016903:Drug Monitoring; D006400:Hematocrit; D006801:Humans; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib
keywords: bioanalysis; dried blood spot; pharmacokinetics; therapeutic drug monitoring; vemurafenib