Multivariate evaluation of pharmacological responses in early clinical trials - a study of rIL-21 in the treatment of patients with metastatic melanoma.
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.
Rasmussen
Morten Arendt
MA
Department of Food Science, University of Copenhagen, Frederiksberg C, Novo Nordisk A/S, Denmark.
Colding-Jørgensen
Morten
M
Hansen
Lasse Tengbjerg
LT
Bro
Rasmus
R
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
D015703:Antigens, CD; D000970:Antineoplastic Agents; D015415:Biomarkers; D007378:Interleukins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000098546:Interleukin-21
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