Population pharmacokinetics of ABT-767 in BRCA1 or BRCA2 mutation carriers with advanced solid tumors or in subjects with high grade serous ovarian, primary peritoneal or fallopian tube cancer

Abstract

Purpose

The objective of the manuscript is to describe the development of a population pharmacokinetic model for ABT-767, a potent and orally bioavailable inhibitor of poly (ADP-ribose) polymerase enzyme, and to evaluate the potential influence of patient demographics and baseline covariates on the pharmacokinetics of ABT-767.

Methods

A total of 1809 plasma ABT-767 concentrations from 90 subjects were used for population pharmacokinetic modeling. Covariates screened for influence on pharmacokinetic parameters were body weight, lean body weight, body surface area, albumin, creatinine clearance, serum creatinine, liver function tests, and age. The effect of food on absorption and bioavailability were also evaluated. Model validation was performed using bootstrap analysis and visual predictive check.

Results

A two-compartment model with firstorder absorption adequately described the pharmacokinetics of ABT-767. The population estimates of apparent clearance from central compartment (CL/F), volume of central compartment (V c/F), and absorption rate constant (k a) were 7.34 L/h, 25.8 L, 1.45 h−1, respectively. The estimates of interindividual variabilities (%CV) in CL/F, V c/F, and k a were 40.4, 40.5, and 53.8%, respectively. The k a was influenced by food. Albumin on CL/F was a statistically significant covariate; however, it explained only 8% of the variability in the pharmacokinetics of ABT-767.

Conclusions

Albumin on CL/F was the only statistically significant baseline covariate affecting ABT-767 pharmacokinetics, but it only explained a fraction of the pharmacokinetic variability. Dosage adjustments based on body size, age, or mild renal impairment are not needed for ABT-767. The developed model will be used to evaluate ABT-767 exposure–response analyses and to perform simulations for different dose and dosing regimens.

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Population pharmacokinetics of ABT-767 in BRCA1 or BRCA2 mutation carriers with advanced solid tumors or in subjects with high grade serous ovarian, primary peritoneal or fallopian tube cancer

Articles DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial

Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts.

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Articles DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial

Comment Mercaptopurine in childhood acute lymphoblastic leukaemia

Unlike other cancers, acute lymphoblastic leukaemia requires prolonged therapy, consisting of induction (about 1 month), post-induction intensification (about 6 months), and maintenance or continuation therapy (18–30 months). Two decades ago, findings from a large meta-analysis1 showed a small, but significant, advantage of a third year of maintenance therapy despite more deaths from pneumocystis, varicella, and measles, which are rarely seen today, compared with shorter treatment groups. In the Tokyo Children’s Cancer Study Group L92-13 study,2 maintenance therapy was terminated at 1 year from diagnosis and resulted in an event-free survival of 57% at 12 years.

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Comment Mercaptopurine in childhood acute lymphoblastic leukaemia

Physical activity and lung cancer risk in men and women

Abstract

Purpose

Although evidence has accumulated that recreational physical activities (PA) may reduce lung cancer risk, there is little evidence concerning the possible role of a potentially more important source of PA, namely occupational PA. We investigated both recreational and lifetime occupational PA in relation to lung cancer risk in a population-based case–control study in Montreal, Canada (NCASES = 727; NCONTROLS = 1,351).

Methods

Unconditional logistic regression was used to estimate odds ratios (OR), separately for men and women, adjusting for smoking, exposure to occupational carcinogens, and sociodemographic and lifestyle factors.

Results

In both sexes, increasing recreational PA was associated with a lower lung cancer risk (ORMEN = 0.66, 95% confidence interval (CI) 0.47–0.92; ORWOMEN = 0.55, 95% CI 0.34–0.88, comparing the highest versus lowest tertiles). For occupational PA, no association was observed among women, while increasing occupational PA was associated with increased risk among men (ORMEN = 1.96, 95% CI 1.27–3.01). ORs were not modified by occupational lung carcinogen exposure, body mass index, and smoking level; results were similar across lung cancer histological types.

Conclusions

Our results support the previous findings for recreational PA and lung cancer risk. Unexpectedly, our findings suggest a positive association for occupational PA; this requires replication and more detailed investigation.

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Physical activity and lung cancer risk in men and women

Breast cancer milestones 2007–2016

Summary

Over the past 10 years, enormous progress has been made in breast cancer (BC) treatment, leading to a substantial decline in BC mortality in Western countries. Although the following short review is necessarily incomplete, the discussion will highlight major achievements in the field.

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Breast cancer milestones 2007–2016

Metallothionein 1H (MT1H) functions as a tumor suppressor in hepatocellular carcinoma through regulating Wnt/β-catenin signaling pathway

Metallothionein 1H (MT1H) expression level is downregulated in several kinds of tumors, including hepatocellular cancer (HCC). However, its biological functions and underlying mechanisms in HCC is largely unknown…

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Metallothionein 1H (MT1H) functions as a tumor suppressor in hepatocellular carcinoma through regulating Wnt/β-catenin signaling pathway

In search of druggable targets for GBM amino acid metabolism

Amino acid (AA) pathways may contain druggable targets for glioblastoma (GBM). Literature reviews and GBM database (http://​r2.​amc.​nl) analyses were car…

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In search of druggable targets for GBM amino acid metabolism