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- Bauer, D. C., et al.
(författare)
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Classification of osteoarthritis biomarkers: a proposed approach
- 2006
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Ingår i: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 14:8, s. 723-727
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Forskningsöversikt (refereegranskat)abstract
- Objective: Osteoarthritis (OA) biomarkers are needed by researchers and clinicians to assist in disease diagnosis and assessment of disease severity, risk of onset, and progression. As effective agents for CA are developed and tested in clinical studies, biomarkers; that reliably mirror or predict the progression or amelioration of CA will also be needed. Methods: The NIH-funded CA Biomarkers Network is a multidisciplinary group interested in the development and validation of CA biomarkers. This review summarizes our efforts to characterize and classify CA biomarkers. Results: We propose the "BIPED" biomarker classification (which stands for Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic), and offer suggestions on optimal study design and analytic methods for use in CA investigations. Conclusion. The BIPED classification provides specific biomarker definitions with the goal of improving our ability to develop and analyze OA biomarkers, and to communicate these advances within a common framework. (C) 2006 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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| 2. |
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| 3. |
- Joerger, Markus, et al.
(författare)
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Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients : a study by the EORTC-PAMM-NDDG
- 2007
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Ingår i: Clinical Pharmacokinetics. - 0312-5963 .- 1179-1926. ; 46:12, s. 1051-1068
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients. Patients and methods: Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m(2) over 15 minutes followed by cyclophosphamide 600 mg/m(2) over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling. Relationships were explored between drug exposure (the area under the plasma concentration-time curve [AUC]), toxicity and tumour response. Results: Fifty-nine patients had complete pharmacokinetic and toxicity data. In 50 patients with measurable disease, the objective response rate was 60%, with complete responses in 6% of patients. Both doxorubicin and cyclophosphamide pharmacokinetics were associated with neutrophil toxicity. Cyclophosphamide exposure (the AUC) was significantly higher in patients with at least stable disease (n = 44) than in patients with progressive disease (n = 6; 945 mu mol . h/L [95% CI 889, 1001] vs 602 mu mol . h/L [95% CI 379, 825], p = 0.0002). No such correlation was found for doxorubicin. Body surface area was positively correlated with doxorubicin clearance; AST and patient age were negatively correlated with doxorubicin clearance; creatinine clearance was positively correlated with doxorubicinol clearance; and occasional concurrent use of carbamazepine was positively correlated with cyclophosphamide clearance. Conclusions: The proposed inhibitory population pharmacokinetic-pharmacodynamic model adequately described individual neutrophil counts after administration of doxorubicin and cyclophosphamide. In this patient population, exposure to cyclophosphamide, as assessed by the AUC, might have been a predictor of the treatment response, whereas exposure to doxorubicin was not. A prospective study should validate cyclophosphamide exposure as a predictive marker for the treatment response and clinical outcome in this patient group
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| 4. |
- Joerger, Markus, et al.
(författare)
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Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients : a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group.
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:21, s. 6410-6418
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 μmol/L (tC > 0.05−0.2) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m2) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel tC > 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel tC > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel tC > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel tC > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (Cmax and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10−4). Conclusions: In this group of patients, paclitaxel tC > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.
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| 5. |
- Williams, Frances M. K., et al.
(författare)
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The heritable determinants of cartilage oligomeric matrix protein
- 2006
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 54:7, s. 2147-2151
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Cartilage oligomeric matrix protein (COMP) is a cartilage matrix macromolecule. The protein is detectable in serum and has been investigated as a biomarker of osteoarthritis (OA). An association between COMP and OA has been shown, yet the precise factors governing serum levels of COMP remain unclear. The aim of this study was to determine whether genetic factors influence serum levels of COMP. Methods. A classic twin study was conducted using COMP levels in serum obtained from healthy female twin volunteers. COMP levels were determined by an inhibition enzyme-linked immunosorbent assay method. The heritability of COMP was determined by comparing correlation among 160 monozygotic and 349 dizygotic twin pairs. Data on potential confounding factors, including age, body mass index, and the presence of OA as assessed by hand, hip, and knee radiographs, were included in the analysis. Results. Serum levels of COMP showed a correlation of 0.72 (95% confidence interval [95% CI] 0.650.80) among monozygotic twin pairs and 0.47 (95% CI 0.39-0.55) in dizygotic pairs. This equated to an estimated heritability for COMP of 40% (95% CI 20-60%). Although age and body mass index were found to be significantly associated with COMP in regression analysis, taking the effects of these factors into account did not influence the estimate of heritability. Conclusion. This study showed that heritable factors influence serum levels of the cartilage matrix biomarker COMP. Together with other published data, the results suggest that genetic factors operate at an early stage in the etiologic pathways that influence the development of radiographically discernible OA.
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