Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.
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PMID:First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies. 2339 98

A mathematical model component that extends an existing physiologically based multiscale systems pharmacology model (MSPM) of calcium and bone homeostasis was developed, enabling prediction of nonlinear changes in lumbar spine bone mineral density (LSBMD). Data for denosumab, a monoclonal antibody osteoporosis treatment, dosed at several levels and regimens, was used for fitting the BMD component. Bone marker and LSBMD data extracted from the literature described on/off-treatment effects of denosumab over 48 months [Miller, P.D. et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43, 222-229 (2008)]. An indirect model linking bone markers to LSBMD was embedded in the existing MSPM, reasonably predicting nonlinear increases in LSBMD during treatment (24 months); LSBMD declines following discontinuation and increases upon treatment reinstitution. This study demonstrates the utility of MSPM extension to describe a phenomena of interest not originally in a model, and the ability of this updated MSPM to predict nonlinear longitudinal changes in the clinically relevant endpoint, LSBMD, with denosumab treatment.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e14; doi:10.1038/psp.2012.15; advance online publication 14 November 2012.
CPT Pharmacometrics Syst Pharmacol 2012 Nov 14
PMID:Predicting nonlinear changes in bone mineral density over time using a multiscale systems pharmacology model. 2383 96