Effect of capmatinib on the pharmacokinetics of substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with MET-dysregulated solid tumours.

BACKGROUND: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal-epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety. METHODS: This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two-drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator. RESULTS: A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (Cmax ) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUCinf ) and area under the plasma concentration-time curve from time zero to the last measurable point (AUClast ), respectively, with no change in Cmax . Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study. CONCLUSION: The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.

Estimating Shelf Life Through Tolerance Intervals Extended to Nonlinear Response Trends.

Methods for estimating pharmaceutical shelf life based on tolerance intervals are proposed by Schwenke, et al. AAPS PharmSciTech. 2020;21:290, [1] where a critical quality attribute that follows a simple linear (straight line) response trend across storage time is presented as the traditional example. A random coefficient mixed linear regression model is used to characterize the between batch and within batch variation. These methods are further discussed for various stability study scenarios, number of stability batches, and levels of assumed risk in Schwenke, et al. AAPS PharmSciTech. 2021;22:273, [4] through a simulation study, again based on a critical quality attribute assuming a simple linear response. However, in practice, not all stability response profiles conveniently follow straight line or linear trends. The purpose of this paper is to extend the proposed tolerance interval and random coefficient mixed regression methods for estimating pharmaceutical shelf life to critical quality attributes that follow more complex stability response profiles. As an example, a nonlinear response is typically characterized by either an increasing or decreasing response, starting from an initial concentration, trending with storage time towards some limiting response or asymptote. Nonlinear responses cannot be statistically analyzed with linear model methods. Practical information supported by simulation results based on a pharmaceutical stability study are discussed to allow for appropriate statistical analyses and shelf life estimates through random coefficient mixed nonlinear regression and tolerance interval methods.

Pharmacokinetics of capmatinib in participants with hepatic impairment: A phase 1, open-label, single-dose, parallel-group study.

AIMS: Capmatinib, a mesenchymal-epithelial transition factor tyrosine kinase inhibitor, is metabolized by cytochrome P450 (CYP) 3A4 and aldehyde oxidase. In individuals with hepatic impairment, alterations in hepatobiliary excretion and metabolism could lead to higher capmatinib exposure. We compared the pharmacokinetics of a single oral dose of capmatinib 200 mg administered to participants with varying degrees of hepatic impairment vs. matched controls with normal hepatic function. METHODS: This phase 1, multicentre, open-label, parallel-group study enrolled adult participants with normal hepatic function and mild, moderate and severe hepatic impairments. Eligible participants received a single oral dose of 200 mg capmatinib. The pharmacokinetic parameters of capmatinib were analysed and compared across participants with impaired and normal hepatic function. RESULTS: Of 31 enrolled participants, 29 had an evaluable pharmacokinetic profile: normal (n = 9); mild (n = 6); moderate (n = 8); severe (n = 6). Compared with the normal group, geometric mean (GM) maximum (peak) observed plasma drug concentration after single-dose administration decreased by 27.6% in the mild group (GM ratio [GMR] = 0.724; 90% confidence interval [CI]: 0.476-1.10), by 17.2% in the moderate group (GMR = 0.828; 90% CI: 0.563-1.22) and remained unchanged in the severe group (GMR = 1.02; 90% CI: 0.669-1.55). Compared with the normal group, GM area under the plasma concentration-time curve from time zero to infinity decreased by 23.3% in the mild group (GMR = 0.767; 90% CI: 0.532-1.11), by 8.6% in the moderate group (GMR = 0.914; 90% CI: 0.652-1.28) and increased by 24% in the severe group (GMR = 1.24; 90% CI: 0.858-1.78). CONCLUSION: Mild, moderate and severe hepatic impairment did not have a clinically relevant impact on capmatinib pharmacokinetics. No new safety findings are reported in this study.

Effect of capmatinib on the pharmacokinetics of digoxin and rosuvastatin administered as a 2-drug cocktail in patients with MET-dysregulated advanced solid tumours: A phase I, multicentre, open-label, single-sequence drug-drug interaction study.

AIMS: Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic nonsmall cell lung cancer with METex14 skipping mutations. The study investigated the effect of capmatinib on the pharmacokinetics of a single oral dose of digoxin and rosuvastatin in patients with MET-dysregulated advanced solid tumours. METHODS: This was a multicentre, open-label, single-sequence study. An oral drug cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin was administered to adult patients with MET-dysregulated advanced solid tumours on Day 1, and then on Day 22 with capmatinib. Between Days 11 and 32, capmatinib 400 mg was administered twice daily to ensure the attainment of steady state for drug-drug interaction assessment. Pharmacokinetics of cocktail drugs and safety of capmatinib were evaluated. RESULTS: Thirty-two patients were enrolled. Compared to digoxin alone, the geometric mean ratios (90% confidence interval) of area under the concentration-time curve from time zero to infinity and maximum concentration for digoxin plus capmatinib were 1.47 (1.28, 1.68) and 1.74 (1.43, 2.13), respectively. Compared to rosuvastatin alone, the geometric mean ratios (90% confidence interval) of area under the curve to infinity and maximum concentration for rosuvastatin plus capmatinib were 2.08 (1.56, 2.76) and 3.04 (2.36, 3.92), respectively. Most frequent adverse events (≥25% for all grades) were nausea, asthenia, constipation, vomiting, peripheral oedema and pyrexia. Most frequent Grade 3/4 adverse events (≥5%) were anaemia, pulmonary embolism, asthenia, dyspnoea, nausea and vomiting. CONCLUSION: This study demonstrated that capmatinib is an inhibitor of P-gp and BCRP transporters, with clinically relevant drug-drug interaction potential. Capmatinib was well-tolerated and no unexpected safety concerns were observed.

A Practical Discussion on Estimating Shelf Life Through Tolerance Intervals.

This paper is a companion article to the research originally presented in "Estimating Shelf Life through Tolerance Intervals" (Schwenke et al., 21:290, 2020) published in AAPS PharmSciTech where tolerance intervals are introduced as an alternative methodology for estimating pharmaceutical shelf life. An industry stability shelf life example data set was used to demonstrate the proposed methods. Although using industry data does give relevance to examples demonstrating shelf life estimation, measures of how well the proposed methods accurately and effectively estimate shelf life cannot be obtained because the true shelf life values are not known for example data sets. In this current paper, the results of a computer simulation are reported where the tolerance interval estimates of shelf life are compared to theoretically known true shelf life values. Various factors that affect a tolerance interval estimate of pharmaceutical shelf life are investigated. A critical decision factor is the choice of the proportion of the stability distribution allowed out of specification at expiry to define the pharmaceutical risk. The number of stability batches available for shelf life estimation and the storage time at which the estimate is made are also considered in this simulation study. The industry example data are again used as the basis for the simulation study to give relevance to this research.

Estimating Shelf Life Through Tolerance Intervals.

This paper is a continuation of the research published by the Stability Shelf Life Working Group as chartered under the Product Quality Research Institute. The Working Group was formed in 2006 and disbanded in late 2019. Following the philosophy presented by the Working Group on how to characterize the stability shelf life paradigm (Capen et al., 2012), shelf life is estimated here in terms of defining risk as a specified proportion of the pharmaceutical stability distribution of interest being out of specification. Shelf life can be defined for the batch mean distribution for regulatory issues, as well as for the product distributions for patient interests. Estimates of shelf life are proposed corresponding to each stability distribution through the use of statistical tolerance intervals. Appropriate estimates of the between-batch and within-batch variance components are obtained through a random coefficient mixed regression model analysis based on the best fit to batch stability response data. Tolerance interval estimates are computed as part of the mixed model analysis and computed directly using the statistical definition of the stability distributions. A proposed rationale is offered on how to select an appropriate proportion allowed out of specification to define a meaningful shelf life. Examples of the proposed shelf life estimates are presented using industry stability batch data. For each example, the traditional ICH shelf life estimate is given for comparison.

Evaluating Current Practices in Shelf Life Estimation.

The current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) methods for determining the supported shelf life of a drug product, described in ICH guidance documents Q1A and Q1E, are evaluated in this paper. To support this evaluation, an industry data set is used which is comprised of 26 individual stability batches of a common drug product where most batches are measured over a 24 month storage period. Using randomly sampled sets of 3 or 6 batches from the industry data set, the current ICH methods are assessed from three perspectives. First, the distributional properties of the supported shelf lives are summarized and compared to the distributional properties of the true shelf lives associated with the industry data set, assuming the industry data set represents a finite population of drug product batches for discussion purposes. Second, the results of the ICH "poolability" tests for model selection are summarized and the separate shelf life distributions from the possible alternative models are compared. Finally, the ICH methods are evaluated in terms of their ability to manage risk. Shelf life estimates that are too long result in an unacceptable percentage of nonconforming batches at expiry while those that are too short put the manufacturer at risk of possibly having to prematurely discard safe and efficacious drug product. Based on the analysis of the industry data set, the ICH-recommended approach did not produce supported shelf lives that effectively managed risk. Alternative approaches are required.

Effect of esomeprazole, a proton pump inhibitor on the pharmacokinetics of sonidegib in healthy volunteers.

AIMS: This study aimed to evaluate the impact of esomeprazole on the pharmacokinetics of sonidegib. METHODS: This Phase I study evaluated the impact of the proton pump inhibitor (PPI) esomeprazole on the oral absorption and pharmacokinetics (PKs) of a single dose of sonidegib under fasted conditions. A total of 42 healthy subjects were enrolled to receive either sonidegib alone (200 mg single dose) or sonidegib in combination with esomeprazole (40 mg pre-treatment 5 days and combination were given on day 6). Primary PK parameters assessed in the study were area under the concentration-time curve (AUC) from 0-14 days and 0-7 days and maximum observed plasma concentration (Cmax ). RESULTS: The plasma exposure (AUC0-14d, AUC0-7d and Cmax ) of a single 200 mg oral dose of sonidegib was decreased by 32-38% when sonidegib was co-administered with esomeprazole compared with sonidegib alone, with no apparent change in elimination slope and tmax . Baseline gastric pH was similar between the two arms. CONCLUSIONS: These results suggest a modest reduction in the extent of sonidegib absorption by esomeprazole. There was no obvious metabolic drug-drug interaction between the two agents. Both sonidegib and esomeprazole were well tolerated in the study population.

Exposure-QT analysis for sonidegib (LDE225), an oral inhibitor of the hedgehog signaling pathway, for measures of the QT prolongation potential in healthy subjects and in patients with advanced solid tumors.

PURPOSE: Sonidegib prevents activation of the Hedgehog signal transduction pathway. This PK-QT analysis has been performed to test for potential prolongation of the QT/QTc interval during extended use, and to understand the exposure-QT relationship for sonidegib in patients and in healthy volunteers (HV). METHODS: A pooled analysis of the change in QT interval corrected for heart rate according to Fridericia's formula was conducted across four patient studies from a total of 341 patients (n = 211, 102, 21, and 7 from the phase II pivotal study A2201, study X2101, study X1101, and study B2209, respectively), and across four healthy volunteer studies from a total of 204 healthy volunteers (n = 146, 36, 16, and 6 from study A2114, study A1102, study A2108, and study A2110, respectively). A PK/ECG subgroup of 62 patients from the pivotal study A2201 was also analyzed to assess the QT prolongation risk at steady-state exposures. Sonidigib PK and ECG data were matched to determine the change from baseline in QTcF using a linear mixed-effect model. RESULTS: Clinical data indicate sonidegib does not cause QTc prolongation. ΔQTcF at steady-state concentrations for both 200 and 800-mg doses were all below 5 ms. The highest mean ΔQTcF at steady state was -3.9 ms at week 17 pre-dose in the sonidegib 200-mg group and 2.7 ms at 2-h post-dose in the sonidegib 800-mg group. The upper one-sided 95 % confidence interval of the estimated ΔQTcF at steady-state concentrations from the linear mixed-effect models were all <10 ms. No cases of ventricular arrhythmia or torsades de pointes and no deaths associated with QT prolongation have been reported in the sonidegib clinical development program. CONCLUSIONS: Based on these analyses, there is no evidence of QT prolongation associated with sonidegib 200 or 800 mg in solid tumor patients and HV.

Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer.

Ribociclib is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6 inhibition by ribociclib leads to retinoblastoma tumor suppressor protein (Rb) reactivation, thereby restoring Rb-mediated cell cycle arrest. Ribociclib is approved for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced breast cancer (ABC), at the dose of 600 mg once daily (QD) during cycles of 21 days on/7 days off, with optional dose reduction to 400 mg and 200 mg. Ribociclib is rapidly absorbed with a median time to reach maximum plasma concentration of 2.4 h, mean half-life of 32.0 h and oral bioavailability of 65.8% at 600 mg. It is eliminated mainly by hepatic metabolism (~ 84% of total elimination), mostly by cytochrome P450 (CYP) 3A4. Age, body weight, race, baseline Eastern Cooperative Oncology Group status, food, mild hepatic impairment, mild-to-moderate renal impairment, proton pump inhibitors, and combination partners (non-steroidal aromatase inhibitors or fulvestrant) have no clinically relevant impact on ribociclib exposure. Ribociclib inhibits CYP3A at 600 mg leading to increased exposure of CYP3A substrates. Strong CYP3A inhibitors or inducers increase or decrease, respectively, ribociclib exposure. Exposure-safety and exposure-efficacy analyses support the clinical benefit of the 600 mg QD starting dose, with potential individualized dose reductions to 400 mg and 200 mg for effective management of the adverse events neutropenia and QTcF interval prolongation, while maintaining efficacy, in patients with HR+/HER2- ABC. Overall, these clinical pharmacology data informed ribociclib dose justification and clinical development, as well as its prescribing information for clinical use in advanced breast cancer patients.

Interdependence of baseline correction method and covariance structure for crossover TQT studies.

Thorough QT/QTc (TQT) trials are conducted to assess a drug's risk potential for prolonging the QT interval. In a randomized crossover, multiple postdose electrocardiograph (ECG) readings are collected over time, within each period leading to a repeated-measures scenario. Additionally, baseline readings at single or multiple time points are collected prior to treatment. Two active, yet seemingly separate, areas of statistical research for TQT crossover studies concern the method of baseline correction and the specified covariance structure for repeated measures analysis. Due to interdependence of the covariance structure of baseline-corrected QTc values and the definition of baseline, these two research areas cannot be considered separately. We illustrate how the covariance structure for baseline-corrected QTc values differs under various definitions of baseline and provide recommendations on the choice of baseline: Time-matched baseline averaged over periods and time-matched baseline from the first period only are preferable in terms of efficiency; in case a period-specific correction is required to account for the treatment carryover effect, period-specific time-averaged baseline with multiple measurements taken predose in each period offers greater efficiency than a single predose baseline. This research on the interdependence of baseline correction method and covariance structure enables statisticians to use observed data from previous TQT studies to plan design and analysis for future studies.

Evaluating the performance of the ICH guidelines for shelf life estimation.

The goal of shelf life estimation is to determine the storage time during which the entire product meets specification with acceptably high probability. The estimated shelf life should be "applicable to all future batches" (ICH Q1E, International Conference on Harmonization, 2003b). There is compelling evidence of issues with the International Conference on Harmonization (ICH) guidelines for shelf life estimation. Issues include fixed batch effects, poolability tests, and confidence intervals for the mean. Two conclusions from evaluating the ICH procedure are that batch effects should be random and that focus should be on a quantile. A procedure is needed that combines random batches with the ICH objective of estimating the minimum batch shelf life.

On the distribution of batch shelf lives.

Implicit in ICH Q1E (International Conference on Harmonization [ICH], 2003b ) are definitions of batch shelf life (the time the batch mean crosses the acceptance limit) and product shelf life (the minimum batch shelf life). The distribution of batch means over time projects to a distribution of batch shelf lives on the x-axis. Assuming multivariate normality, shelf life is the ratio of correlated Gaussian variables. Using Hinkley ( 1969 ), we describe the relationship between quantiles of the distributions of batch shelf lives and batch means. Exploiting this relationship, a linear mixed model is used to estimate a target quantile of batch shelf lives to address the ICH objective.

Exploratory Food Effect Assessment in Patients in Early Clinical Development of Oncology Drugs.

Instructions for administration with regard to food are a key aspect of how patients experience oral drugs. Through potential effects on pharmacokinetics, the food condition can influence safety and efficacy, and thereby is one of many dimensions of dose optimization. Regulatory guidance from major health authorities advocates for the early investigation of food effect (FE) in clinical development. In oncology, exploratory FE (eFE) evaluation is often incorporated into the first-in-human (FIH) studies in patients to inform food condition of later clinical studies. However, the design aspects of such exploratory assessments are generally under-reported and barely described, and yet complex, due to uniqueness of FIH study design and drug development process in oncology. Herein, we review literature of eFE assessment study design in oncology in patients, and present the Novartis experience in the design, execution, and impact of eFE in FIH oncology studies from 2014 to 2021. Based on this, we propose a roadmap for eFE assessment in early clinical drug development for oncology drugs in patients, including a framework for common study design options with a focus on study- and patient-level timing for typical scenarios. We also provide a broad spectrum of decision-making factors which should be evaluated to drive the design and implementation of eFE assessment, spanning from clinical development strategy, FIH study design, to compound-specific features.

Justifying Ribociclib Dose in Patients with Advanced Breast Cancer with Renal Impairment Based on PK, Safety, and Efficacy Data: An Innovative Approach Integrating Data from a Dedicated Renal Impairment Study and Oncology Clinical Trials.

BACKGROUND AND OBJECTIVE: Renal impairment is common in patients with cancer and can alter the PK and thus the safety and efficacy of drugs. We assessed the impact of renal impairment during treatment with ribociclib, a cyclin-dependent kinase 4/6 inhibitor, and determined dose recommendations for patients with advanced breast cancer with renal impairment. METHODS: A comprehensive assessment integrating pharmacokinetic, safety, and efficacy data from a phase I dedicated renal impairment study in non-cancer subjects and six phase I-III trials in patients with cancer was performed. RESULTS: Ribociclib showed higher pharmacokinetic exposure in subjects with renal impairment than those with normal renal function following a single 400-mg dose in the dedicated renal impairment study. However, in patient trials, both single-dose and steady­state ribociclib exposure was comparable between patients with cancer with mild/moderate renal impairment and those with normal renal function following the recommended starting dose of 600 mg. Model-predicted steady­state exposure in patients with advanced breast cancer was also similar across the renal function groups. Progression-free survival was similar and safety profiles were generally consistent across the renal cohorts (normal/mild/moderate) in patients with advanced breast cancer, with low-grade and manageable adverse events, demonstrating a positive benefit-risk profile. CONCLUSIONS: From the collective evidence and considering a real-world clinical setting, no dose adjustment is recommended for patients with mild/moderate renal impairment, whereas a reduced dose is recommended for patients with severe renal impairment. This report presented a holistic and innovative strategy to determine dose in patients with renal impairment and demonstrated the effectiveness of integrating the data of both a clinical pharmacology study and patient trials to justify doses in patients with renal impairment. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT02431481, NCT01958021, NCT02422615, NCT02278120, NCT01237236, NCT01898845, NCT01872260.

Investigating the value of glucodensity analysis of continuous glucose monitoring data in type 1 diabetes: an exploratory analysis.

Introduction: Continuous glucose monitoring (CGM) devices capture longitudinal data on interstitial glucose levels and are increasingly used to show the dynamics of diabetes metabolism. Given the complexity of CGM data, it is crucial to extract important patterns hidden in these data through efficient visualization and statistical analysis techniques. Methods: In this paper, we adopted the concept of glucodensity, and using a subset of data from an ongoing clinical trial in pediatric individuals and young adults with new-onset type 1 diabetes, we performed a cluster analysis of glucodensities. We assessed the differences among the identified clusters using analysis of variance (ANOVA) with respect to residual pancreatic beta-cell function and some standard CGM-derived parameters such as time in range, time above range, and time below range. Results: Distinct CGM data patterns were identified using cluster analysis based on glucodensities. Statistically significant differences were shown among the clusters with respect to baseline levels of pancreatic beta-cell function surrogate (C-peptide) and with respect to time in range and time above range. Discussion: Our findings provide supportive evidence for the value of glucodensity in the analysis of CGM data. Some challenges in the modeling of CGM data include unbalanced data structure, missing observations, and many known and unknown confounders, which speaks to the importance of--and provides opportunities for--taking an approach integrating clinical, statistical, and data science expertise in the analysis of these data.

Quantitative Assessment of Ribociclib Exposure-Response Relationship to Justify Dose Regimen in Patients with Advanced Breast Cancer.

Ribociclib in combination with endocrine therapy (ET) is a globally approved treatment option for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) and has demonstrated significantly improved overall survival (OS) in 3 phase 3 clinical trials. To justify the dose regimen and dose modification scheme for patients with ABC, the pharmacokinetic (PK), safety, and efficacy data of ribociclib were analyzed. The data of several phase 1-3 clinical studies were pooled and analyzed to characterize the relationship between exposure (dose or PK) and efficacy (progression-free survival (PFS), time to response, and OS) or safety (neutropenia and QT interval prolongation). The exposure-efficacy analysis showed no apparent relationship between ribociclib exposure and efficacy (PFS and OS), and efficacy analysis by dose reduction showed that patients with ABC continued to benefit from the treatment following dose reduction, supporting the starting dose of 600 mg as well as dose reductions to 400 and 200 mg. The exposure-safety analysis showed that neutropenia and QT prolongation are related to ribociclib exposure that can be effectively managed by individualized dose modification (dose reduction/interruption). Collective evidence from the exposure-response analyses for efficacy and safety support the use of ribociclib in combination with ET partners at the starting dose of 600 mg, and also the effectiveness of individualized dose reductions in managing safety, while maintaining efficacy, in patients with HR+/HER2- ABC. This analysis illustrates the utility of quantitative assessment in justifying dose selection and dose modification for oncology medicines.

Identifying research priorities with children, youth, and families: A scoping review.

Increased patient advocacy has resulted in a shift toward more active patient engagement in the research. A scoping review was conducted to explore the literature on healthcare research priority settings wherein children, youths, or their families were involved in the priority-setting process. Six databases including MEDLINE, CINAHL, PsycINFO, Embase, Web of Science, and Global Health and the James Lind Alliance website were searched up until September 2019. All primary studies involving children (<18 years of age) or families in developing research priorities in health care were included. All retrieved references were uploaded into Covidence, and two independent reviewers screened the search results. Descriptive thematic analysis was used to identify common themes. A total of 30 studies with 4247 participants were included. Less than half of the participants (n = 1237, (33%) were pediatric patients and their families. A total of 455 research priorities were identified. Three common themes emerged: (i) quality of care delivery, (ii) self-efficacy in health behaviors, and (iii) community engagement in care. This scoping review revealed priority research health topics from the perspectives of children, youths, or their families. The findings may be used as a foundation for future research to improve the health outcomes of children, youths, or their families according to their identified priorities.

On the shelf life of pharmaceutical products.

This article proposes new terminology that distinguishes between different concepts involved in the discussion of the shelf life of pharmaceutical products. Such comprehensive and common language is currently lacking from various guidelines, which confuses implementation and impedes comparisons of different methodologies. The five new terms that are necessary for a coherent discussion of shelf life are: true shelf life, estimated shelf life, supported shelf life, maximum shelf life, and labeled shelf life. These concepts are already in use, but not named as such. The article discusses various levels of "product" on which different stakeholders tend to focus (e.g., a single-dosage unit, a batch, a production process, etc.). The article also highlights a key missing element in the discussion of shelf life-a Quality Statement, which defines the quality standard for all key stakeholders. Arguments are presented that for regulatory and statistical reasons the true product shelf life should be defined in terms of a suitably small quantile (e.g., fifth) of the distribution of batch shelf lives. The choice of quantile translates to an upper bound on the probability that a randomly selected batch will be nonconforming when tested at the storage time defined by the labeled shelf life. For this strategy, a random-batch model is required. This approach, unlike a fixed-batch model, allows estimation of both within- and between-batch variability, and allows inferences to be made about the entire production process. This work was conducted by the Stability Shelf Life Working Group of the Product Quality Research Institute.

Phase 1 Study Evaluating Pharmacokinetics and Tolerability of Ofatumumab Combined With Bendamustine in Patients With Indolent B-Cell Non-Hodgkin's Lymphoma.

The pharmacokinetics (PK) and safety of ofatumumab and bendamustine alone and in combination were evaluated in patients with treatment-naive or relapsed indolent B-cell non-Hodgkin lymphoma (iNHL). Patients were randomly assigned to ofatumumab and bendamustine or ofatumumab alone. Ofatumumab PK concentration profiles and parameters were similar, alone or in combination with bendamustine. A decrease of 14% in the maximum observed plasma concentration (Cmax ) and 15% in the area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration sampling time (AUClast ) was observed for ofatumumab coadministered with bendamustine, which was not considered clinically relevant. Bendamustine PK concentration profiles and parameters were similar with or without ofatumumab. The most frequent treatment-related adverse event was infusion-related reaction in 53% in the combination arm and 47% in the ofatumumab arm. No relevant drug-drug interaction was observed between ofatumumab and bendamustine. Ofatumumab alone or in combination with bendamustine had a manageable safety profile.