Predictors of care-giver stress in families of preschool-aged children with developmental disabilities

Background This study examined the predictors, mediators and moderators of parent stress in families of preschool-aged children with developmental disability. Method One hundred and five mothers of preschool-aged children with developmental disability completed assessment measures addressing the key variables. Results Analyses demonstrated that the difficulty parents experienced in completing specific caregiving tasks, behaviour problems during these caregiving tasks, and level of child disability, respectively, were significant predictors of level of parent stress. In addition, parents’ cognitive appraisal of care-giving responsibilities had a mediating effect on the relationship between the child’s level of disability and parent stress. Mothers’ level of social support had a moderating effect on the relationship between key independent variables and level of parent stress. Conclusions Difficulty of care-giving tasks, difficult child behaviour during care-giving tasks, and level of child disability are the primary factors which contribute to parent stress. Implications of these findings for future research and clinical practice are outlined

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort

Introduction and Objective:Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥ 20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing. Methods: A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications.Results: A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%). Conclusion: TDM reduced the proportion of patients with subtherapeutic exposure levels by ~ 50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥ 20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.</p

Sunitinib for the treatment of metastatic gastrointestinal stromal tumors:the effect of TDM-guided dose optimization on clinical outcomes

Background: Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an exposure–response relationship at the standard dose, and minimum target levels of drug exposure have been defined above which better treatment outcomes are observed. Therapeutic drug monitoring (TDM) could be used as a tool to optimize the individual dose, aiming at sunitinib trough concentrations ≥37.5 ng/ml for continuous dosing. Nonetheless, data on the added value of TDM-guided dosing on clinical endpoints are currently lacking. Therefore, we evaluate the effect of TDM in patients with advanced and metastatic GIST treated with sunitinib in terms of efficacy and toxicity.Patients and methods: A TDM-guided cohort was compared to a non-TDM-guided cohort in terms of median progression-free survival (mPFS) and overall survival (mOS). Also, mPFS between patients with and without dose-limiting toxicities (DLTs) was compared. Patients in the prospective cohort were included in two studies on TDM-guided dosing (the DPOG-TDM study and TUNE study). The retrospective cohort consisted of patients from the Dutch GIST Registry who did not receive TDM-guided dosing.Results: In total, 51 and 106 patients were included in the TDM-guided cohort and non-TDM-guided cohort, respectively. No statistical difference in mPFS was observed between these two cohorts (39.4 versus 46.9 weeks, respectively; P = 0.52). Patients who experienced sunitinib-induced DLTs had longer mPFS compared to those who did not (51.9 versus 28.9 weeks, respectively; P = 0.002).Conclusions: Our results do not support the routine use of TDM-guided dose optimization of sunitinib in patients with advanced/metastatic GIST to improve survival.</p

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort

Introduction and Objective: Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥ 20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing. Methods: A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications. Results: A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%). Conclusion: TDM reduced the proportion of patients with subtherapeutic exposure levels by ~ 50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥ 20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients

Delayed exciton emission and its relation to blinking in CdSe quantum dots

The efficiency and stability of emission from semiconductor nanocrystal quantum dots (QDs) is negatively affected by "blinking" on the single-nanocrystal level, that is, random alternation of bright and dark periods. The time scales of these fluctuations can be as long as many seconds, orders of magnitude longer than typical lifetimes of exciton states in QDs. In this work, we investigate photoluminescence from QDs delayed over microseconds to milliseconds. Our results prove the existence of long-lived charge-separated states in QDs. We study the properties of delayed emission as a direct way to learn about charge carrier separation and recovery of the exciton state. A new microscopic model is developed to connect delayed emission to exciton recombination and blinking from which we conclude that bright periods in blinking are in fact not characterized by uninterrupted optical cycling as often assumed

Phase I study of weekly oral docetaxel (ModraDoc001) plus ritonavir in patients with advanced solid tumors.

2550 Background: ModraDoc001 is a novel oral formulation containing docetaxel as a solid dispersion. Oral administration of docetaxel is feasible in combination with the CYP3A4 inhibitor ritonavir. Objectives were to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of weekly oral docetaxel (as ModraDoc001) in combination with ritonavir. Methods: Patients with advanced solid tumors, WHO PS ≤ 2, no concomitant use of MDR or CYP3A modulating drugs, adequate bone marrow (ANC ≥ 1.5x109 /L), liver (bilirubin ≤ 1.5xULN, ALAT/ASAT ≤ 2.5xULN) and renal function (creatinine ≤ 1.5xULN or clearance ≥ 50 ml/min) were eligible. Docetaxel (ModraDoc001 10mg capsule) and ritonavir (Norvir 100mg) were simultaneously given once weekly in a ‘3+3 cohort’ dose escalation design. MTD was defined as the highest dose resulting in &lt;1/6 probability of causing a dose limiting toxicity in the first 4 weeks of treatment. This cohort was expanded with 6 patients. PK was determined on days 1 and 8. Results: 40 patients (25 male, 35 evaluable for safety) were enrolled in 6 dose levels (30/100, 40/100, 60/100, 80/100, 60/200 and 80/200 mg docetaxel/ritonavir). Common treatment related adverse events in the 4 highest dose levels were diarrhea (68%), nausea (62%) and fatigue (62%), mostly CTC grade 1-2 (80%, 95% and 73% respectively). Five patients experienced a DLT (grade 3 diarrhea (4), elevated ASAT/ALAT (1), grade 4 dehydration and grade 3 mucositis (1), grade 3 fatigue (2)). The MTD was 60 mg/200 mg docetaxel/ritonavir. Partial remission was seen in 4 patients (CUP, NSCLC, gastric and mamma ca) and sustained stable disease in 15 patients (6x NSCLC). Both drugs were rapidly absorbed after oral administration. Mean Tmax was 2.0 hours (CV=73%) for docetaxel. Cmax and AUC of docetaxel increased less than proportionally with dose to 162 ng/ml (CV= 67%) and 1615 ng/ml*hr (CV= 81%), respectively, in 15 patients at the MTD. Conclusions: At the MTD (once weekly 60 mg docetaxel and 200 mg ritonavir) ModraDoc001 is safe, well tolerated and shows encouraging antitumor activity. The exposure of docetaxel with this regimen is comparable to weekly intravenous administration of 35 mg/m2 docetaxel. Phase II studies in solid tumors are planned. </jats:p

A Phase I Dose Escalation Study of Once-Weekly Oral Administration of Docetaxel as ModraDoc001 Capsule or ModraDoc006 Tablet in Combination with Ritonavir

Abstract Purpose: Oral bioavailability of docetaxel is poor. Absorption could be improved by development of pharmaceutical formulations based on docetaxel solid dispersions, denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg) and coadministration of ritonavir, an inhibitor of CYP3A4 and P-glycoprotein. In this study, the safety, MTD, recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of oral docetaxel combined with ritonavir in a once-weekly continuous schedule was investigated. Patients and Methods: Patients with metastatic solid tumors were included. Dose escalation was performed using a classical 3+3 design. Pharmacokinetic sampling was performed for up to 48 hours after drug administration. Safety was evaluated using CTCAE v3.0. Antitumor activity was assessed according to RECIST v1.0. Results: Sixty-seven patients were treated at weekly docetaxel dosages ranging from 30 to 80 mg in combination with 100- or 200-mg ritonavir. Most common toxicities were nausea, vomiting, diarrhea and fatigue, mostly of grade 1–2 severity. No hypersensitivity reactions were observed. The area under the plasma concentration–time curve (AUC0–48) of docetaxel at the RP2D of once-weekly 60-mg ModraDoc001 capsule with 100-mg ritonavir was 1,000 ± 687 ng/mL/hour and for once-weekly 60-mg ModraDoc006 tablet with 100-mg ritonavir, the AUC0–48 was 1,790 ± 819 ng/mL/hour. Nine partial responses were reported as best response to treatment. Conclusions: Oral administration of once-weekly docetaxel as ModraDoc001 capsule or ModraDoc006 tablet in combination with ritonavir is feasible. The RP2D for both formulations is 60-mg ModraDoc with 100-mg ritonavir. Antitumor activity is considered promising. </jats:sec