title: Multivariate evaluation of pharmacological responses in early clinical trials - a study of rIL-21 in the treatment of patients with metastatic melanoma.
abstract: OBJECTIVE
  Evaluation of the utility of multivariate data analysis in early clinical drug development.
  
  
  METHODS
  A multivariate chemometric approach was developed and applied for evaluating clinical laboratory parameters and biomarkers obtained from two clinical trials investigating recombinant human interleukin-21 (rIL-21) in the treatment of patients with malignant melanoma. The Phase I trial was an open-label, first-human dose escalation safety and tolerability trial with two separate dosing regimens; six cycles of thrice weekly (3/w) vs. three cycles of daily dosing for 5 days followed by 9 days of rest (5+9) in a total of 29 patients. The Phase II trial investigated efficacy and safety of the '5+9' regimen in 24 patients.
  
  
  RESULTS
  From the Phase I trial, separate pharmacological patterns were observed for each regimen, clearly reflecting distinct properties of the two regimens. Relations between individual laboratory parameters were visualized and shown to be responsive to rIL-21 dosing. In particular, novel systematic pharmacological effects on liver function parameters as well as a bell-shaped dose-response relationship of the overall pharmacological effects were depicted. In validation of the method, multivariate pharmacological patterns discovered in the Phase I trial could be reproduced by the dataset from the Phase II trial, but not from univariate exploration of the Phase I trial.
  
  
  CONCLUSIONS
  The new data analytical approach visualized novel correlations between laboratory parameters that points to specific pharmacological properties. This multivariate chemometric data analysis offers a novel robust, comprehensive and intuitive tool to reveal early pharmacological responses and guide selection of dose regimens.
authors.affiliation: Department of Food Science, University of Copenhagen, Frederiksberg C, Novo Nordisk A/S, Denmark.
authors.forename: Morten Arendt
authors.initials: MA
authors.lastname: Rasmussen
authors.forename: Morten
authors.initials: M
authors.lastname: Colding-Jørgensen
authors.forename: Lasse Tengbjerg
authors.initials: LT
authors.lastname: Hansen
authors.forename: Rasmus
authors.initials: R
authors.lastname: Bro
mesh_terms: D015703:Antigens, CD / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D015415:Biomarkers / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D007378:Interleukins / Q000009:adverse effects / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy*; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D000098546:Interleukin-21
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D015415:Biomarkers; D007378:Interleukins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000098546:Interleukin-21
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