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Population PK/PD analysis of DX‐8951F when administered to cancer patients
Author(s) -
Seng Yue C.,
Lavigne J.,
Colucci P.,
Kamida M.,
De Jager R.,
Yamaguchi M.,
Ducharme M. P.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.239
Subject(s) - dosing , medicine , population , cmax , pharmacokinetics , neutropenia , nonmem , concomitant , pharmacology , toxicity , environmental health
Aim Evaluate the population PK‐PD of DX‐8951. Methods Results from a population PK analysis of DX‐8951 (presented separately) were used as a foundation for a population PK‐PD analysis using NONMEM® where absolute neutrophil counts (ANC) were co‐modeled. Design Six non‐comparative dose‐escalation studies were analyzed retrospectively. Settings PK samples were taken in hospitals. Participants 153 Intervention Dosing schemes varied from 30‐min infusions to 21‐day continuous infusions at varying frequencies. Initial doses ranged from 0.05 to 4 mg/m 2 . Results An indirect model with inter‐occasion variability best described the PD of ANC. Clinical covariates found to explain significantly the PD of DX‐8951 were the concomitant use of G‐CSF or antibiotics, the Cmax of DX‐8951, prior treatment (tx) and frequency of DX‐8951 tx. Results indicate that pts whose AUC above 1.57μg/L exceeded 1610μg·h/L (area above a threshold concentration[CTX]) and whose concentrations exceeded 6.25μg/L for over 75h (time above CTX) are likely to demonstrate severe toxicity (neutropenia). Conclusions A model for DX‐8951 dosing will be presented taking into account the PK‐PD of the drug and clinical characteristics of patients. Clinical Pharmacology & Therapeutics (2005) 77 , P91–P91; doi: 10.1016/j.clpt.2004.12.239