Abstract In pediatric drug development, large amounts of adult data are often available before the start of a pediatric study. It is believed that borrowing this information will improve the efficiency. However, when adult information is not sufficiently similar to that of pediatrics, incorporating adult data will introduce bias and consequently result in efficiency loss. A Bayesian alternative—namely, commensurate prior approach where the level of information borrowing is based on the concordance of adult and pediatric data—was investigated. Simulation results indicate that the commensurate prior approach, in general, provides a balanced and robust trade‐off between bias and efficiency gain. The benefit of this approach was quantified in terms of sample size savings, and recommended sample sizes are provided.
Summary Bortezomib is a first‐in‐class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib’s benefit–risk profile. Here, we performed exposure–response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6‐week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42·2 vs. 38·5 mg/m 2 ) and ALCYONE patients stayed on treatment longer (mean: 7·2 vs. 5·8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with ≥ 39·0 versus < 39·0 mg/m 2 cumulative dose (hazard ratio, 0·119; P < 0·0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions.
Suboptimal health status (SHS) is characterized by ambiguous health complaints, general weakness, and lack of vitality, and has become a new public health challenge in China. It is believed to be a subclinical, reversible stage of chronic disease. Studies of intervention and prognosis for SHS are expected to become increasingly important. Consequently, a reliable and valid instrument to assess SHS is essential. We developed and evaluated a questionnaire for measuring SHS in urban Chinese.Focus group discussions and a literature review provided the basis for the development of the questionnaire. Questionnaire validity and reliability were evaluated in a small pilot study and in a larger cross-sectional study of 3000 individuals. Analyses included tests for reliability and internal consistency, exploratory and confirmatory factor analysis, and tests for discriminative ability and convergent validity.The final questionnaire included 25 items on SHS (SHSQ-25), and encompassed 5 subscales: fatigue, the cardiovascular system, the digestive tract, the immune system, and mental status. Overall, 2799 of 3000 participants completed the questionnaire (93.3%). Test-retest reliability coefficients of individual items ranged from 0.89 to 0.98. Item-subscale correlations ranged from 0.51 to 0.72, and Cronbach's alpha was 0.70 or higher for all subscales. Factor analysis established 5 distinct domains, as conceptualized in our model. One-way ANOVA showed statistically significant differences in scale scores between 3 occupation groups; these included total scores and subscores (P<0.01). The correlation between the SHS scores and experienced stress was statistically significant (r=0.57, P<0.001).The SHSQ-25 is a reliable and valid instrument for measuring sub-health status in urban Chinese.
Prothrombin time ( PT ) is a measure of coagulation status and was assessed in the majority of patients in the rivaroxaban phase II and III clinical trials as a pharmacodynamic marker. In the absence of sufficient phase III pharmacokinetic ( PK ) data to provide individual exposure measures for input into rivaroxaban exposure–response analyses, the aim of the present study was to investigate the use of PT ‐adjustment approaches (i.e., the use of observed individual PT measurements) to enhance the prediction of individual rivaroxaban exposure metrics (derived using a previously developed integrated population PK model) based on the observed linear relationship between PT and rivaroxaban plasma concentrations. The PT ‐adjustment approaches were established using time‐matched PK and PT measurements, which were available from 1,779 patients across four phase II trials and one phase III trial of rivaroxaban. PT ‐adjusted exposure estimates improved the identification of statistically significant effects when compared with covariate‐only exposure estimates.
Daratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes. Four clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (n = 3), 4 mg/kg (n = 3), 8 mg/kg (n = 4), and 16 mg/kg (n = 34). A total of 650 patients in EQUULEUS (n = 128), POLLUX (n = 282), and CASTOR (n = 240) received daratumumab 16 mg/kg. The exposure–efficacy and exposure–safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively. Pharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events. These data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies. Janssen Research & Development.
The aim of this study was to assess the effect of moderate or severe renal impairment on the pharmacokinetic (PK) properties of milvexian. This open-label, parallel-group study assessed the PK, safety, and tolerability of a single oral 60 mg dose of milvexian in participants with normal renal function (n = 8; estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2) and participants with moderate (n = 8; eGFR ≥ 30 to ≤ 59 mL/min/1.73 m2) or severe (n = 8; eGFR < 30 mL/min/1.73 m2) renal impairment. Regression analysis was performed using linear regression of log-transformed PK parameters versus eGFR. Milvexian was well tolerated, with no deaths, serious adverse events, or serious bleeding reported. The maximum milvexian concentration (Cmax) was similar for all groups. Based on a regression analysis of milvexian concentration versus eGFR, participants with eGFR values of 30 and 15 mL/min/1.73 m2, respectively, had area under the curve (AUC) values that were 41% and 54% greater than in participants with normal renal function. Median time to maximum concentration (Tmax) was similar for the three groups (4.5–5.0 h). The half-life increased for participants with moderate (18.0 h) or severe (17.7 h) renal impairment compared with those with normal renal function (13.8 h). A single dose of milvexian 60 mg was safe and well tolerated in participants with normal renal function and moderate or severe renal impairment. There was a similar increase in milvexian exposure between the moderate and severe renal groups. This study was registered with ClinicalTrials.gov (NCT03196206, first posted 22 June 2017).
This study explored the efficacy and safety of rivaroxaban in elderly patients, at different doses and age of patients, and analyzed risk factors of bleeding. A retrospective analysis was conducted of 299 patients aged 60 years or older who were admitted to the First Hospital of Jilin University between January 2016 and August 2018. It was found that the rate of bleeding events (but not embolism) significantly increased as the dose of oral rivaroxaban increased ( P < .001), and with age, especially in patients aged ≥80 years ( P = .001, both). The multivariate logistic regression analysis indicated that age (odds ratio [OR]: 2.963, 95% CI: 1.627-5.396) and the daily dose of rivaroxaban (OR: 2.325, 95% CI: 1.483-3.645) were independent risk factors for bleeding. The study determined that rivaroxaban anticoagulant therapy is effective in the elderly patients, but the risk of bleeding increases with age, and is a concern especially in the most old patients. The recommended daily dose of rivaroxaban is effective, but a lower dose is safer for the elderly patients.
In a recent issue of Blood Advances, Yoshioka et al 1 performed a model-based meta-analysis (MBMA) to evaluate the optimal dose of rivaroxaban, apixaban, and edoxaban in patients with atrial fibrillation (AF).To develop the model, they used reported population pharmacokinetic (PK) and pharmacodynamic models to estimate time profiles of changes in the prothrombin time (PT) in 5 randomized controlled trials (RCTs) that evaluated the efficacy and safety of oral factor Xa (FXa) inhibitors in AF patients.After assay normalization, the authors calculated the model-based relationships between the simulated PT ratio profiles and the rates of ischemic stroke or systemic embolism and major bleeding, and used this information to determine the dose of each oral FXa inhibitor that would achieve minimal simulated mortality.
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