title: Biases affecting injected doses of an experimental drug during clinical trials.
abstract: During clinical trials, researchers rarely question nominal doses specified on labels of investigational products, overlooking the potential for inaccuracies that may result when calculating pharmacokinetic and pharmacodynamic parameters. This study evaluated the disparity between nominal doses and the doses actually administered in two Phase I trials of a biosimilar drug.
  
  
  
  In Trial A, 12 healthy volunteers received various doses of an interferon β-1a biosimilar via either subcutaneous or intravenous injection, prepared by partially emptying 0.53 ml syringes supplied by the manufacturer. In Trial B, 12 volunteers received three different formulations of the drug via intravenous injection (biosimilar with and without albumin and a comparator), followed by multiple subcutaneous injections. In both trials, the dose administered was calculated as D = C × V - losses, where C is the drug concentration assessed using ELISA, V is the volume administered calculated using syringe weighing and losses are deduced from in-vitro experiments. Interferon binding to added albumin and infusion lines was evaluated using a (125)I-interferon tracer with gel-filtration chromatography.
  
  
  
  In Trial A, measured concentrations were close to the nominal strength indicated by the manufacturer (median bias: -6 %), whereas in Trial B they differed significantly for all three formulations (median biases: +67 %, +73 % and +31 % for the biosimilar with albumin, the biosimilar without albumin and the comparator, respectively). In Trial A, the doses actually administered showed large variability and biases, especially at the lowest doses. Indeed, actually injected volumes differed by as much as 74 % from theoretical volumes - a phenomenon mainly attributed to unnoticed fluid re-aspiration through the syringe needle. This was corrected in Trial B. Interferon was not significantly adsorbed on the infusion lines used for intravenous administration. Its binding to albumin was slow, reaching 50 % after a 16 h incubation.
  
  
  
  These examples illustrate the importance of assessing the actual doses administered in clinical trials, to ensure accuracy in the determination of clearance, distribution volume, bioavailability and dose-response relationships.
  
  
  
  Clinicaltrials.gov NCT02515695 (Trial A) and NCT02517788 (Trial B). Registered on 24 July and 5 August 2015, respectively.
authors.affiliation: Service of Pharmacy, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Nancy
authors.initials: N
authors.lastname: Perrottet
authors.affiliation: Brunner Naga, Health Science Consulting, Pfäffikon-ZH, Switzerland.
authors.forename: Françoise
authors.initials: F
authors.lastname: Brunner-Ferber
authors.affiliation: Division of Clinical Pharmacology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Grouzmann
authors.affiliation: Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Spertini
authors.affiliation: Division of Clinical Pharmacology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Biollaz
authors.affiliation: Division of Clinical Pharmacology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.affiliation: Division of Clinical Pharmacology, Lausanne University Hospital, Lausanne, Switzerland. Nicolas.Widmer@chuv.ch.
authors.forename: Nicolas
authors.identifier: 0000-0001-7392-2418
authors.initials: N
authors.lastname: Widmer
mesh_terms: D000418:Albumins / Q000378:metabolism; D015982:Bias; D001682:Biological Availability; D059451:Biosimilar Pharmaceuticals / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004339:Drug Compounding; D054796:Drug Dosage Calculations; D004348:Drug Labeling; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D000068556:Interferon beta-1a / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design
chemical_list: D000418:Albumins; D059451:Biosimilar Pharmaceuticals; D000068556:Interferon beta-1a
keywords: Bias; Clinical trials; Drug dose; Drug evaluation; Pharmacokinetics; Phase I as topic