Lack of a pharmacokinetic interaction between trastuzumab and carboplatin in the presence of docetaxel: results from a phase Ib study in patients with HER2-positive metastatic or locally advanced inoperable solid tumors.

The objective of this study was to evaluate the potential for a pharmacokinetic (PK) drug-drug interaction (DDI) between trastuzumab and carboplatin and to evaluate the potential effect of trastuzumab on the electrocardiogram QT interval. Here, we report the results of the PK DDI assessment and an interim safety analysis. Patients with metastatic or locally advanced, inoperable, human epidermal growth factor receptor 2-positive cancer received docetaxel and carboplatin on cycle 1, day 1 and then on day 1 of each subsequent 3-weekly treatment cycle. Trastuzumab was administered by intravenous infusion, with an accelerated loading dose on cycle 1, day 2 and cycle 1, day 8, and then a maintenance dose on day 1 of each subsequent 3-weekly treatment cycle. Blood was collected at various time points to assess free (unbound) plasma carboplatin and serum trastuzumab PK. The study enrolled 59 patients. Carboplatin concentrations in the presence and absence of trastuzumab were similar, as demonstrated by the geometric mean ratios for PK parameters, which were close to 1.0 (no effect). The observed trastuzumab concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, computed using the actual sampling time. In this interim safety analysis, 84.5% of patients had experienced adverse events of grade three or higher, the most common of which were hematologic and as expected. The results suggest that there is no clinically relevant PK DDI between carboplatin and trastuzumab. The safety profile of trastuzumab plus carboplatin and docetaxel was consistent with the known safety profile of this combination.

Comparison of a dietary intervention promoting high intakes of fruits and vegetables with a low-fat approach: long-term effects on dietary intakes, eating behaviours and body weight in postmenopausal women.

The aim of the present study was to compare the long-term effects of two dietary approaches on changes in dietary intakes, eating behaviours and body weight: (1) approach using restrictive messages to limit high-fat foods (low-fat intake; LOFAT); (2) approach emphasising non-restrictive messages directed towards the inclusion of fruits and vegetables (high intake of fruits and vegetables; HIFV). A total of sixty-eight overweight or obese postmenopausal women were randomly assigned to one of the two dietary approaches. The 6-month dietary intervention included three group sessions and ten individual sessions with a dietitian. Dietary intakes, eating behaviours and anthropometrics were measured at baseline, at the end of the dietary intervention (T = 6) and 6 months and 12 months after the end of the intervention (T = 12 and T = 18). In the LOFAT group, energy and fat intakes were lower at T = 6 when compared with baseline and remained lower at T = 12 and T = 18. In the HIFV group, fruit and vegetable intakes increased significantly at T = 6 but were no longer significantly different from baseline at T = 12 and T = 18. Dietary restraint increased at T = 6 and remained higher than baseline at T = 18 in the LOFAT group while no significant change was observed in the HIFV group. At T = 6, body weight was significantly lower than baseline in both groups (LOFAT: - 3.7 (SD 2.8) kg; HIFV: - 1.8 (SD 3.0) kg) and no significant difference in body-weight change from baseline was found between groups at T = 18. We concluded that weight loss was similar at 1-year follow-up in both dietary approaches. Despite relatively good improvements in the short term, the adherence to a 6-month dietary intervention promoting high intakes of fruits and vegetables was difficult to maintain.

A single administration of recombinant human interleukin-12 is associated with increased expression levels of interferon-gamma and signal transducer and activator of transcription in healthy subjects.

The objectives of this study were to assess the safety and tolerability of single doses of 1, 4, and 8 mug of recombinant human interleukin-12 (rhIL-12) administered subcutaneously to healthy subjects. The pharmacokinetics, pharmacodynamics, and pharmacogenomics of rhIL-12 were evaluated. Recombinant human IL-12 was well tolerated in these healthy male and female subjects. The most frequently reported adverse events were flu-like symptoms, which exhibited a dose-response relationship. Pharmacokinetic analysis suggested that serum IL-12 levels increased with dose. Analysis of serum levels indicated that interferon-gamma increased with the dose of rhIL-12, whereas IL-6 levels showed no changes with rhIL-12 treatment. The messenger ribonucleic acid expression of signal transducer and activator of transcription was significantly increased 24 hours after the administration of rhIL-12 for all dose groups versus placebo, and results indicated that the magnitude of increase may be dose dependent. This study suggests that interferon-gamma and signal transducer and activator of transcription are biomarkers of rhIL-12 activity.

Trastuzumab, in combination with carboplatin and docetaxel, does not prolong the QT interval of patients with HER2-positive metastatic or locally advanced inoperable solid tumors: results from a phase Ib study.

PURPOSE: This study evaluated the potential effect of trastuzumab on the electrocardiogram (ECG) QT interval and assessed the potential pharmacokinetic interaction between trastuzumab and carboplatin. Here, we report the QT and safety results. METHODS: Patients with metastatic or inoperable HER2-positive solid tumors received docetaxel and carboplatin on Day 1 of each 3-week (q3w) cycle. Trastuzumab was administered intravenously, as an accelerated loading dose regimen, on Cycle 1, Day 2 and Cycle 1, Day 8, and then on Day 1 of each subsequent q3w cycle. ECG assessments were performed pre- and posttrastuzumab infusion in the first two cycles. Fridericia's correction was applied to QT intervals (QTcF). Baseline-adjusted QTcF intervals (the change from baseline) and their 90 % confidence intervals (CIs) were calculated. RESULTS: The study enrolled 59 patients. At all time points, the 90 % CI upper bound for the mean baseline-adjusted QTcF was <10 ms. At steady-state serum trastuzumab concentrations, the mean baseline-adjusted QTcF interval was -8.4 ms (90 % CI -11.1, -5.7). No patient exhibited an absolute QTcF interval of >480 ms. No relationship was observed between trastuzumab concentration and baseline-adjusted QTcF interval. At data cutoff, 84.5 % of patients had experienced grade ≥3 adverse events, the most common of which were hematologic and as expected. Left ventricular ejection fraction remained ≥45 % in all patients during the study. CONCLUSIONS: The results suggest that trastuzumab had no clinically relevant effect on QTcF interval. The safety profile of trastuzumab in combination with carboplatin and docetaxel was consistent with the known safety profile of this combination.

Using dynamic N-mixture models to test cavity limitation on northern flying squirrel demographic parameters using experimental nest box supplementation.

Dynamic N-mixture models have been recently developed to estimate demographic parameters of unmarked individuals while accounting for imperfect detection. We propose an application of the Dail and Madsen (2011: Biometrics, 67, 577-587) dynamic N-mixture model in a manipulative experiment using a before-after control-impact design (BACI). Specifically, we tested the hypothesis of cavity limitation of a cavity specialist species, the northern flying squirrel, using nest box supplementation on half of 56 trapping sites. Our main purpose was to evaluate the impact of an increase in cavity availability on flying squirrel population dynamics in deciduous stands in northwestern Québec with the dynamic N-mixture model. We compared abundance estimates from this recent approach with those from classic capture-mark-recapture models and generalized linear models. We compared apparent survival estimates with those from Cormack-Jolly-Seber (CJS) models. Average recruitment rate was 6 individuals per site after 4 years. Nevertheless, we found no effect of cavity supplementation on apparent survival and recruitment rates of flying squirrels. Contrary to our expectations, initial abundance was not affected by conifer basal area (food availability) and was negatively affected by snag basal area (cavity availability). Northern flying squirrel population dynamics are not influenced by cavity availability at our deciduous sites. Consequently, we suggest that this species should not be considered an indicator of old forest attributes in our study area, especially in view of apparent wide population fluctuations across years. Abundance estimates from N-mixture models were similar to those from capture-mark-recapture models, although the latter had greater precision. Generalized linear mixed models produced lower abundance estimates, but revealed the same relationship between abundance and snag basal area. Apparent survival estimates from N-mixture models were higher and less precise than those from CJS models. However, N-mixture models can be particularly useful to evaluate management effects on animal populations, especially for species that are difficult to detect in situations where individuals cannot be uniquely identified. They also allow investigating the effects of covariates at the site level, when low recapture rates would require restricting classic CMR analyses to a subset of sites with the most captures.

Dietary intervention promoting high intakes of fruits and vegetables: short-term effects on eating behaviors in overweight-obese postmenopausal women.

OBJECTIVE: To compare changes in eating behaviors in response to two dietary interventions: one focusing on restrictive messages to limit consumption of high-fat foods (LOFAT) and the other one based on non-restrictive messages to increase consumption of fruits and vegetables (HIFV). METHODS: Sixty-eight overweight-obese postmenopausal women were randomly assigned to one of the two 6-month dietary interventions that included three group sessions and ten individual sessions with a dietitian. Anthropometric variables and eating behaviors were measured at baseline, 3months and 6months. RESULTS: Body weight decreased significantly in both groups at 6months compared to baseline (LOFAT: -3.5±2.9kg; HIFV: -1.6±2.9kg). At 6months, dietary restraint score was higher in the LOFAT group compared to the HIFV group (12.7±4.2 vs 10.5±4.9; p<0.05). Disinhibition and hunger decreased significantly in the HIFV group after 6months while only hunger decreased in the LOFAT group. CONCLUSION: A weight loss approach based on increasing fruit and vegetable consumption leads to a significant weight loss and is associated with a decrease in disinhibition and hunger without any increase in dietary restraint.