Impact of dosing schedules on performance of rotavirus vaccines in Ghana.

Background: Available live-oral rotavirus vaccines are associated with low to moderate performance in low- and middle-income settings. There is limited evidence relating to how the vaccine dosing schedule might be adjusted to improve vaccine performance in these settings. Methods: We used mathematical models fitted to rotavirus surveillance data for children <5 years of age from three different hospitals in Ghana (Korle-Bu Teaching Hospital in Accra, Komfo Anokye Teaching Hospital in Kumasi and War Memorial Hospital in Navrongo) to project the impact of rotavirus vaccination over a 10-year period (April 2012-March 2022). We quantified and compared the impact of the previous vaccination program in Ghana to the model-predicted impact for other vaccine dosing schedules across the three hospitals and the entire country, under different assumptions about vaccine protection. To project the rotavirus vaccine impact over Ghana, we sampled from the range of model parameters for Accra and Navrongo, assuming that these two settings represent the "extremes" of rotavirus epidemiology within Ghana. Results: For the previously implemented 6/10-week monovalent Rotarix vaccine (RV1) schedule, the model-estimated average annual incidence of moderate-to-severe rotavirus-associated gastroenteritis (RVGE) ranged between 1,151 and 3,002 per 100,000 people per year over the 10-year period for the three sites. Compared to no vaccination, the model-estimated median percentage reductions in RVGE ranged from 28-85% and 12-71% among children <1 year and <5 years of age respectively, with the highest and lowest percentage reductions predicted using model parameters estimated for Accra and Navrongo, respectively. The median predicted reductions in RVGE for the whole country ranged from 57-66% and 35-45% among children <1 year and <5 years of age, respectively. The 1/6/10- and 6/10/14-week schedules provided the best and comparable reductions in RVGE compared to the original 6/10-week schedule, whereas there was no improvement in impact for the 10/14-week schedule. Conclusions: We found that administering an additional dose of RV1 might be an effective strategy to improve rotavirus vaccine impact, particularly in settings with low vaccine effectiveness. The results could be extrapolated to other countries using a 2-dose vaccine schedule with low to moderate vaccine performance.

Efficacy, effectiveness and immunogenicity of reduced HPV vaccination schedules: A review of available evidence.

Background: Current National Advisory Committee on Immunization (NACI) guidance recommends human papillomavirus (HPV) vaccines be administered as a two or three-dose schedule. Recently, several large clinical trials have reported the clinical benefit of a single HPV vaccine dose. As a result, the World Health Organization released updated guidance on HPV vaccines in 2022, recommending a two-dose schedule for individuals aged 9-20 years, and acknowledging the use of an alternative off-label single dose schedule. Objective: The objective of this overview is to provide a detailed account of the available evidence comparing HPV vaccination schedules, which was considered by NACI when updating recommendations on HPV vaccines. Methods: To identify relevant evidence, existing systematic reviews were leveraged where possible. Individual studies were critically appraised, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence. Results: Available evidence suggests that a one, two, or three-dose HPV vaccine schedule may provide similar protection from HPV infection. While antibody levels against HPV vaccine types were statistically significantly lower with a single dose schedule compared to two or three doses, titres were sustained for up to 16 years. The clinical significance of lower antibody titres is unknown, as there is no established immunologic correlate of protection. Conclusion: While the available evidence on single-dose HPV vaccination schedules shows a one-dose schedule is highly effective, continued follow-up of single-dose cohorts will be critical to understanding the relative duration of protection for reduced dose schedules and informing future NACI guidance on HPV vaccines.

A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors.

BACKGROUND: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. RESULTS: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56-62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. CONCLUSIONS: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

Cetuximab every 2 weeks versus standard weekly dosing administration schedule.

Cetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule. Cetuximab Q2W can be administered with a Q2W dose of chemotherapy, making it a more convenient option to the Q1W schedule, potentially resulting in reduced costs for administration, increased flexibility for clinical staff and improved patient adherence.

Cetuximab is a drug for patients with colorectal cancer or cancer of the head and neck. It is usually administered once a week. However, studies have shown that cetuximab given once every 2 weeks instead has similar clinical benefits and side effects. Based on this evidence, the every 2 weeks dosing schedule has been approved for use in USA and Japan. The every 2 weeks dosing schedule is a convenient alternative to the weekly schedule. It may result in fewer hospital visits, improved patient quality of life, reduced healthcare costs and more flexibility for medical staff. This review summarizes the current evidence and benefits for the every 2 weeks dosing schedule.

Comparison of clinical safety between standard versus extended interval dosing of immune checkpoint inhibitors: a real-world retrospective cohort study.

BACKGROUND: Extended interval dosing (ED) for inhibitors of programmed cell death protein 1 (anti-PD-1) (nivolumab, pembrolizumab) or its ligand (anti-PD-L1) (durvalumab) were recently approved based on pharmacokinetic model results that predicted a benefit-risk profile comparable with the standard dosing (SD) regimen. However, safety data in real-world condition of use are lacking. The objective was to compare the incidence and the risk factors of serious immune-related adverse events (irAEs) and any-grade irAEs between the SD and ED regimens in patients treated with anti-PD-1 or anti-PD-L1. MATERIALS AND METHODS: IrAEs were assessed from medical records in all new users of nivolumab, pembrolizumab, or durvalumab between 1 January 2019 and 31 December 2020 across two oncology centers in France. The incidence of irAEs was compared between both dosing regimens using Cox proportional hazards models adjusting for the main available confounders. RESULTS: Among 686 patients included, 63% were new users of an SD regimen, 14% of ED regimen, and 23% started with SD and switched to ED regimen during follow-up. Overall, 34.6% of patients experienced at least one irAE of any grade and 11.4% presented at least one serious grade ≥3 irAE. No statistical difference was found between the SD and ED regimen on the risk of grade ≥3 irAEs [adjusted hazard ratio (HR) 1.40, 95% confidence interval (CI) 0.71-2.76] but our results suggest an increased risk of any-grade irAEs with the ED regimen (adjusted HR 1.46, 95% CI 1.00-2.12, P = 0.048). IrAEs resolved without sequelae in 46.4% of cases, and they were fatal for three patients (0.4%). Autoimmune pre-existing condition was confirmed as a risk factor for grade ≥3 irAEs (HR 2.56, 95% CI 1.53-4.27) and for all-grade irAEs (HR 1.60, 95% CI 1.17-2.20). CONCLUSIONS: In a real-world setting, according to the regimen chosen by the oncologist based on clinical characteristics, we did not observe an increase in grade ≥3 irAE incidence between the SD and ED regimens.

Evaluation of the effect of reduced-dose pneumococcal conjugate vaccine schedules on vaccine serotype carriage in children and their caretakers in a naïve population in Vietnam: Protocol for a cluster randomized non-inferiority trial.

Introduction: The WHO currently recommends giving pneumococcal conjugate vaccines (PCVs) as three doses - either three doses in infancy with Pentavalent vaccine (3p+0), or two doses in infancy followed by a booster around 12 months (2p+1). However, their high price is a barrier to introduction and sustainability in low and middle-income countries. We hypothesize that a schedule with a single priming and a booster dose (1p+1) may maintain similar levels of protection for the community by sustaining herd immunity, once circulation of vaccine types has been controlled. Methods and analysis: We will conduct a cluster randomized trial with four intervention arms (1p+1, 0p+1, 2p+1, 3p+0) and three unvaccinated clusters in the 27 communes of Nha Trang, central Vietnam. A PCV catch-up vaccination campaign to all children under three years of age will be performed at the start of the trial. The primary endpoint is non-inferiority of the1p+1 schedule if compared to the WHO standard 2p+1 and 3p+0 schedules in reducing vaccine serotype carriage prevalence in infants. We will also explore impact of 0p+1 schedule. A baseline and annual pneumococcal carriage surveys of 6480 participants per survey covering infants, toddlers and their mothers will be conducted. Ethics and dissemination: Ethical approvals were obtained from the ethical review committees of Institute of Tropical Medicine, Nagasaki University (151203149-2) and the Ministry of Health, Vietnam (1915/QD-BYT). The results, interpretation and conclusions will be presented at national and international conferences, and published in peer-reviewed open access journals. Trial registration number: NCT02961231.

Second International Consensus Study of Antipsychotic Dosing (ICSAD-2).

BACKGROUND: Expert consensus-based clinically equivalent dose estimates and dosing recommendations can provide valuable support for the use of drugs for psychosis in clinical practice and research. AIMS: This second International Consensus Study of Antipsychotic Dosing provides dosing equivalencies and recommendations for newer drugs for psychosis and previously reported drugs with low consensus. METHODS: We used a two-step Delphi survey process to establish and update consensus with a broad, international sample of clinical and research experts regarding 26 drug formulations to obtain dosing recommendations (start, target range, and maximum) and estimates of clinically equivalent doses for the treatment of schizophrenia. Reference agents for equivalent dose estimates were oral olanzapine 20 mg/day for 15 oral and 7 long-acting injectable (LAI) agents and intramuscular haloperidol 5 mg for 4 short-acting injectable (SAI) agents. We also provide a contemporary list of equivalency estimates and dosing recommendations for a total of 44 oral, 16 LAI, and 14 SAI drugs for psychosis. RESULTS: Survey participants (N = 72) from 24 countries provided equivalency estimates and dosing recommendations for oral, LAI, and SAI formulations. Consensus improved from survey stages I to II. The final consensus was highest for LAI formulations, intermediate for oral agents, and lowest for SAI formulations of drugs for psychosis. CONCLUSIONS: As randomized, controlled, fixed, multiple-dose trials to optimize the dosing of drugs for psychosis remain rare, expert consensus remains a useful alternative for estimating clinical dosing equivalents. The present findings can support clinical practice, guideline development, and research design and interpretation involving drugs for psychosis.

Randomized phase II study of zoledronate dosing every four versus eight weeks in patients with bone metastasis from lung cancer (Hanshin Cancer Group0312).

BACKGROUND: Zoledronic acid (ZA) reduces the incidence of skeletal-related events (SREs) in patients with bone metastases from solid tumors. However, the optimal dosing interval of ZA for patients with lung cancer is uncertain. METHODS: We conducted a randomized, open-label, feasibility phase 2 trial at eight Japanese hospitals. Patients with bone metastases from lung cancer were randomly assigned to receive either 4 mg of ZA every four weeks (4wk-ZA) or every eight weeks (8wk-ZA). The primary endpoint was the time to the first SRE and the rate and types of SREs after one year. SREs were defined as pathologic bone fracture, bone radiation therapy or surgery, and spinal cord compression. Secondary endpoints were the SRE incidence at six months, pain assessment, changes in analgesic consumption, serum N-telopeptide, toxicity, and overall survival. RESULTS: Between November 2012 and October 2018, 109 patients were randomly assigned to the 4wk-ZA group (54 patients) and the 8wk-ZA group (55 patients). The number of patients who received chemotherapy or molecular-targeted agents was 30 and 23 and 18 and 16 in the 4wk-ZA and 8wk-ZA groups, respectively. The median time to the first SRE could not be calculated because of a low SRE. The time to the first SRE of all patients did not differ between the groups (P = 0.715, HR = 1.18, 95% CI = 0.48, 2.9). The SRE rate of all patients after 12 months was 17.6% (95% CI = 8.4, 30.9%) in the 4wk-ZA and 23.3% (95% CI = 11.8, 38.6%) in the 8wk-ZA group, without significant differences between the groups. There was no difference in any secondary endpoint between groups, and these endpoints did not differ among treatment modalities. CONCLUSIONS: An eight-week ZA interval does not increase the SRE risk for patients with bone metastasis from lung cancer and could be considered clinically.

Impact of COVID-19 Pandemic on Non-Small Cell Lung Cancer Care.

We assessed the impact of COVID-19 on healthcare visits, timing of stage IV NSCLC diagnosis and immunotherapy initiation, and rates of switching to extended dosing schedules of immunotherapies among patients with stage IV NSCLC. This retrospective study examined electronic health record data of adult patients receiving treatment for stage IV NSCLC within The US Oncology Network and Onmark. Endpoints were compared for February-July 2019 (before COVID) vs. February-July 2020 (during COVID). The study found rapid decreases in numbers of patients with clinic/vital visits, immunotherapy initiations, and new diagnoses of stage IV NSCLC during April-May 2020 vs. April-May 2019. The rate of delays of immunotherapy administrations and proportions of patients with such delays increased from February to March of 2020. These patterns may have resulted from the increase in COVID-19 cases during this period and the corresponding quarantine and lockdowns. However, when comparing pre COVID-19 and during COVID-19 for May and after, the differences in delay of immuno-oncology administrations became less marked, likely due to lifting of lockdowns. The rate of switching from shorter to longer dosing schedules increased from May-July 2020. This was mainly attributed to pembrolizumab, likely due to FDA approval of the pembrolizumab 6W dosing schedule in April 2020.

Alternate Pembrolizumab Dosing Interval in Advanced NSCLC with PD-L1 TPS ≥ 50%: 3 Weekly Compared to 6 Weekly Dosing.

BACKGROUND: A fixed dose of 200 mg of pembrolizumab every 3 weeks (Q3W) is the standard of care for patients with stage IV non-small cell lung cancer (NSCLC) and PDL1 ≥50%. In April 2020, based on pharmacokinetic modeling without formal comparative studies, the FDA approved 400 mg every 6 weeks (Q6W). Pharmacokinetic studies also suggested comparable target engagement with weight-based and flat dosing for the respective schedules. The objective of this study was to determine if overall survival (OS) differs based on the Q3W vs. Q6W dosing schedule of pembrolizumab. METHODS: BC Cancer patients with stage IV NSCLC and PDL1 ≥50% treated with pembrolizumab were retrospectively reviewed. Patients were treated with weight-based dosing, per institution standard, of pembrolizumab 2 mg/kg Q3W or 4 mg/kg Q6W. Patient demographics, treatment and outcome were recorded. Patients were assigned to Q3W or Q6W according to the schedule that was used for the majority of treatment (greater than 50%). RESULTS: 718 patients with NSCLC and PDL1 ≥50% received first-line pembrolizumab between 2017 and2021, Q3W/Q6W dosing 677/41 patients. Baseline characteristics with respect to age, sex, smoking status, histology and performance status (PS) were similar between groups. In the multivariate model, including age, sex, PS and dosing schedule, the hazard ratio for death (HR) for OS Q3W vs. Q6W was 0.759 (p = 0.230). A 2:1 case-matched analysis for OS was performed, controlling for sex, age ± 5 years, PS and duration on pembrolizumab ± 2 months for Q3W vs. Q6W (n = 113) with a HR 0.834 (p = 0.500). CONCLUSIONS: There was no OS difference demonstrated with pembrolizumab dosing Q3W compared to Q6W in a multivariate analysis that included age, sex and PS. A case-matched analysis that controlled for these variables and for duration of treatment confirmed these findings. This study supports the use of Q6W pembrolizumab dosing, allowing for less frequent interactions with the medical system.

Five-day versus 7-day treatment regimen with azacitidine in lower risk myelodysplastic syndrome: A phase 2, multicenter, randomized trial.

BACKGROUND: Low-dose azacitidine (AZA) regimens, primarily 5-day AZA, have been used in lower risk myelodysplastic syndrome (LrMDS) but they have yet to be directly compared to the standard 7-day, uninterrupted dosing schedule. METHOD: In this phase 2, multicenter, randomized trial, 55 patients with adult LrMDS (low and intermediate-1 risk by international prognostic scoring system [IPSS]) were randomly assigned and received either 5-day (n = 26) or 7-day (n = 29) AZA between March 2012 and August 2020. The trial was stopped prematurely because of the slow accrual of patients. The primary end point was the overall response rate (ORR) of the 5-day AZA as compared to that of the 7-day regimen. RESULTS: Median patient age was 59 years, and IPSS intermediate-1 risk comprised the majority (81.8%). The median number of cycles in both arms was six. In the ITT subset (n = 53), in each of the 5-day and 7-day arms, the ORR of 48.0% and 39.3%, hematologic improvement of 44.0% and 39.3%, and RBC transfusion independence of 35.3% and 40.0% were observed respectively, and none of these findings were significantly different between the two arms. A cytogenetic response rate was significantly higher in the 7-day arm (8.3% and 53.8%, p = .027). Survival and adverse events were similar between the groups, although gastrointestinal toxicities, grade ≥3 thrombocytopenia, and febrile neutropenia were less frequent in the 5-day arm. CONCLUSION: The 5-day AZA in LrMDS showed comparable efficacy to a 7-day regimen in terms of similar overall response and other outcomes, despite significantly higher rates of cytogenetic responses in the 7-day regimen. LAY SUMMARY: Azacitidine (75 mg/m2 /day for 7 consecutive days per 28-day cycle) has shown survival benefit in patients with higher risk myelodysplastic syndrome (MDS). Although the use of azacitidine is less-well studied for lower risk MDS, it is generally accepted as a feasible option for lower risk MDS (LrMDS).

Adherence to the Recommended HPV Vaccine Dosing Schedule among Adolescents Aged 13 to 17 Years: Findings from the National Immunization Survey-Teen, 2019-2020.

The 9-valent human papillomavirus (9-vHPV) vaccine uptake rate among adolescents has improved over the years; however, little is known about the adherence to the recommended dosing schedule. This study examines the prevalence and factors associated with adherence to the recommended 9vHPV vaccination dosing schedule among adolescents aged 13 to 17 years. The cross-sectional study was conducted using the 2019-2020 National Immunization Survey-Teen. The parents of 34,619 adolescents were included in our analyses. The overall up-to-date (UTD) prevalence was 57.1%. The UTD prevalence was 60.0% among females and 54.2% among males. Adolescents aged 16 years had the highest UTD prevalence of 63.0%. The UTD prevalence was 61.6% among Hispanics and 54.7% among non-Hispanic Whites. Overall, compared to females, males had 14% lower odds of UTD. The odds of UTD were 1.91 times, 2.08 times, and 1.98 times higher among adolescents aged 15-17 years, respectively, compared to those aged 13 years. Moreover, region, poverty, insurance status, mothers' educational level, and provider recommendation were associated with UTD. Our findings show that adherence to the recommended 9vHPV vaccine schedule is low in the US. Targeted public health efforts are needed to improve the rates of adherence to the recommended 9vHPV dose schedule.

Association of sunitinib concentration and clinical outcome in patients with metastatic renal cell carcinoma treated with a 2-week-on and 1-week-off schedule.

WHAT IS KNOWN AND OBJECTIVE: Sunitinib is used as a first-line therapy for metastatic renal cell carcinoma. The primary aim of this study was to determine the optimal total sunitinib (sunitinib plus N-desethyl sunitinib) trough concentration for the alternative dosing schedule: 2-week-on and 1-week-off schedule (2/1 schedule). METHODS: Patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib, whose total sunitinib concentrations were available, were recruited for this study. Out of 19 patients, 17 whose sunitinib dosage was not changed until the measurement of drug concentration were eligible for the analysis of the relationship between total sunitinib concentration and clinical outcome. Individual pharmacokinetic parameters in 19 patients were estimated via the Bayesian analysis. RESULTS: The onset of severe (grade ≥3) adverse effects among 17 patients during 3 weeks as a first course of sunitinib therapy was observed in 7 (41.2%) patients. The median total sunitinib concentration in patients with severe adverse effects was significantly higher compared with that in patients without severe adverse effects [median: 119 (113-131) vs. 87.8 (77.4-102) ng/mL, p = 0.01]. According to the receiver operating characteristic analysis of the onset of severe adverse effects, the cut-off value of the total sunitinib concentration was 108 ng/mL. Patients with a total sunitinib concentration lower than 108 ng/mL had a longer time to first dose reduction or withdrawal due to adverse effects compared with those with a total sunitinib concentration of 108 ng/mL or higher (p = 0.03). The probability without treatment failure was not significantly different between the two concentration groups. In addition, the estimated sunitinib apparent oral clearance (CL/F) was significantly lower in the severe adverse effects group. Our simulation demonstrated that 0.67-time dose is needed for patients with approximately 90.0 ng/mL of sunitinib concentration on day 7 to maintain the concentration at the same level as the patients with higher CL/F. WHAT IS NEW AND CONCLUSION: Maintaining the total sunitinib trough concentrations of less than 108 ng/mL is safe to avoid the onset of serious adverse effects without increasing the treatment failure in patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib.

Dynamics of Acquired Resistance to Nivolumab Therapies Varies From Administration Strategies.

PURPOSE: The identification of optimal drug administration schedules to overcome the emergence of resistance that causes treatment failure is a major challenge in cancer research. We report the outcomes of a computational strategy to assess the dynamics of tumor progression as a function of time under different treatment regimens. METHODS: We developed an evolutionary game theory model that combined Lotka-Volterra equations and pharmacokinetic properties with 2 competing cancer species: nivolumab-response cells and Janus kinase (JAK1/2) mutation cells. We selected 3 therapeutic schemes that have been tested in the clinical trials: 3 mg/kg Q2w, 10 mg/kg Q2w, and 480 mg Q4w. The simulation was performed under the intervals of 75, 125, and 175 days, respectively, for each regimen. The data sources of the pharmacokinetic parameters used in this study were collected from previous published clinical trials. Other parameters in the evolutionary model come from the existing references. FINDINGS: Predictions under various dose schedules indicated a strong selection for nivolumab-independent cells. Under the 3 mg/kg dose strategy, the reproduction rate of JAK mutation cells was highest, with strongest tumor elimination ability at a 75-day interval between treatments. Prolonged drug intervals to 125 or 175 days delayed tumor evolution but accelerated tumor recurrence. Although 10 mg/kg Q2w had an obvious clinical effect in a short time, it further promotes the progress of resistant population compared with the 3 mg/kg dose. Our model suggests that 480 mg Q4w would be more valuable in terms of clinical efficacy, but complete resistant occurs earlier regardless the interval. IMPLICATIONS: The results of this study emphasize that increasing the dose or shortening the interval between doses accelerates the evolution of heterogeneous populations, although the short-term effect is significant. In practice, the therapeutic regimen should be balanced according to the evolutionary principle.

Impact of Split Dosing the First Rituximab Infusion in Patients with High Lymphocyte Count.

The most common adverse reactions to rituximab are infusion-related reactions (IRR). We evaluated the efficacy of split dosing the first rituximab infusion over two days to reduce IRR incidence in patients with hematological cancer and a high lymphocyte count. This is a retrospective observational study conducted in two healthcare centers in Quebec, Canada. The study enrolled patients with white blood cell counts ≥25.0 × 109/L who received their first rituximab dose for hematological cancer between December 2007 and May 2020. One healthcare center used asymmetrical split dosing, while the other used symmetrical split dosing. A total of 183 treatment episodes were collected from 143 patients. Among patients who received a fractionated dosing schedule, 42% developed an IRR from the first rituximab infusion compared with 50% for the standard protocol (adjusted relative risk, 0.89; p = 0.540). No significant difference was observed in IRR severity between either groups. However, 24% of patients who received the asymmetrical protocol developed an IRR compared to 68% for the symmetrical protocol (adjusted relative risk, 0.32; p = 0.003). These results suggest that an asymmetrical split dosing could be effective in reducing the incidence of IRR and is preferable to a symmetrical one.

Drug delivery strategies in maximizing anti-angiogenesis and anti-tumor immunity.

Metronomic chemotherapy has been shown to elicit anti-tumor immune response and block tumor angiogenesis distinct from that observed with maximal tolerated dose (MTD) therapy. This review delves into the mechanisms behind anti-tumor immunity and seeks to identify the differential effect of dosing regimens, including daily low-dose and medium-dose intermittent chemotherapy (MEDIC), on both innate and adaptive immune populations involved in observed anti-tumor immune response. Given reports of VEGF/VEGFR blockade antagonizing anti-tumor immunity, drug choice, dose, and selective delivery determined by advanced formulations/vehicles are highlighted as potential sources of innovation for identifying anti-angiogenic modalities that may be combined with metronomic regimens without interrupting key immune players in the anti-tumor response. Engineered drug delivery mechanisms that exhibit extended and local release of anti-angiogenic agents both alone and in combination with chemotherapeutic treatments have also been demonstrated to elicit a potent and potentially systemic anti-tumor immune response, favoring tumor regression and stasis over progression. This review examines this interplay between various cancer models, the host immune response, and select anti-cancer agents depending on drug dosing, scheduling/regimen, and delivery modality.

Pneumococcal vaccine implementation in the African meningitis belt countries: the emerging need for alternative strategies.

Introduction: Besides meningococcal disease, the African meningitis belt (AMB) region is also affected by pneumococcal disease. Most AMB countries have introduced pneumococcal conjugate vaccines (PCV) following a schedule of three primary doses without a booster or a catch-up campaign. PCV is expected to help control pneumococcal disease through both direct and indirect effects. Whether and how fast this will be achieved greatly depends on implementation strategies. Pre-PCV data from the AMB indicate high carriage rates of the pneumococcus, not only in infants but also in older children, and a risk of disease and death that spans lifetime. Post-PCV data highlight the protection of vaccinated children, but pneumococcal transmission remains important, resulting in a lack of indirect protection for unvaccinated persons.Areas covered: A non-systematic literature review focused on AMB countries. Relevant search terms were used in PubMed, and selected studies before and after PCV introduction were summarized narratively to appraise the suitability of current PCV programmatic strategies.Expert opinion: The current implementation strategy of PCV in the AMB appears suboptimal regarding the generation of indirect protection. We propose and discuss alternative programmatic strategies, including the implementation of broader age group mass campaigns, to accelerate disease control in this high transmission setting.

Overview of lithium's use: a nationwide survey.

BACKGROUND: Lithium is considered the gold standard treatment for bipolar disorder (BD). Current clinical guidelines and scientific evidence support its use as a first-line treatment in BD. However, over the last two decades, there has been a downward tendency in lithium's use in several developed countries. Based on a nationwide survey, this study's objective is to analyze in a large sample of psychiatrists relevant issues of the use of lithium salts in BD. METHODS: Data were collected through an anonymous survey sent by email among 500 psychiatrists who belong to a National Society of Psychiatry (Spanish Society of Biological Psychiatry). The survey is a self-administered questionnaire consisting of 21 items on the most key aspects of lithium's use (indication, dosage, monitoring, and information for patients). RESULTS: 212 psychiatrists completed the survey. 70% of psychiatrists prescribe lithium to more than 50% of patients diagnosed with BD. Adverse effects are the main reason not to use lithium salts. Over 75% of the participants consider lithium salts the treatment of choice for the maintenance phase of BD, both in women and men. Most of the participants (> 50%) start lithium after the first affective episode, use conservative plasma concentrations (0.6-0.8 mmol/L), and generally prescribe it twice a day. 57% of psychiatrists who treat patients under 18 do not use lithium in this population. About 70% of the survey respondents use official protocols to inform and monitor patients on lithium treatment. CONCLUSIONS: From the results of the present study, it can be concluded that the use of lithium in Spain is in line with the recommendations of the main international clinical guidelines and current scientific literature. The first reason not to prescribe lithium in our country is the perception of its adverse effects and not the aspects related to its practical use or its effectiveness. Considering that BD is a chronic disease with a typical onset in adolescence, the low rate of prescription of lithium salts in patients under 18 must be thoroughly studied.

Once-weekly (70 mg/m2 ) vs twice-weekly (56 mg/m2 ) dosing of carfilzomib in patients with relapsed or refractory multiple myeloma: A post hoc analysis of the ENDEAVOR, A.R.R.O.W., and CHAMPION-1 trials.

Combination of carfilzomib with dexamethasone (Kd) is approved for use in relapsed and/or refractory multiple myeloma (RRMM), with carfilzomib administered twice weekly at 56 mg/m2 (Kd56 BIW) or once weekly at 70 mg/m2 (Kd70 QW). Post hoc cross-trial comparisons were performed to compare efficacy and safety profiles of Kd70 QW vs Kd56 BIW dosing schedules using data from three trials of patients with RRMM: A.R.R.O.W., CHAMPION-1, and ENDEAVOR. To select for comparable patient populations, side-by-side efficacy and safety comparisons were performed in subgroups of patients with 2-3 prior lines of therapy who were not refractory to bortezomib. The overall response rate (ORR) was 69.9% (95% confidence interval [CI], 61.7-77.2) for Kd70 QW and 72.4% (95% CI, 65.9-78.2) for Kd56 BIW. Median progression-free survival (PFS) was 12.1 months (95% CI, 8.4-14.3) for Kd70 QW and 14.5 months (95% CI, 10.2-not evaluable) for Kd56 BIW. Frequency of grade ≥ 3 adverse events (AEs) was 67.6% for Kd70 QW and 85.3% for Kd56 BIW. Regression analyses (adjusting for prognostic factors) of all patients in the trials who received Kd70 QW vs Kd56 BIW estimated a PFS hazard ratio of 0.91 (95% CI, 0.69-1.19; P = .47) and an ORR odds ratio of 1.12 (95% CI, 0.74-1.69; P = .61). These results suggest that Kd70 QW has a comparable efficacy profile compared with Kd56 BIW and represents a convenient and well-tolerated treatment for patients with RRMM.

Optimization of clinical dosing schedule to manage neutropenia: learnings from semi-mechanistic modeling simulation approach.

Neutropenia is a common side-effect of oncology drugs. We aimed to study the impact of exposure and dosing schedule on neutropenia to guide selection of dosing schedules that minimize neutropenia potential while maintaining the desired minimum concentration (Cmin) required for target engagement. Dose, frequency and PK parameters were chosen for five hypothetical drugs of various half-lives to (1) achieve same exposure with continuous dosing and evaluate impact of 4 intermittent dosing schedules; and (2) achieve same nadir for continuous and intermittent dosing and evaluate impact on % time above Cmin, a surrogate assumed to indicate target engagement. Absolute neutrophil count (ANC) profiles were simulated using Friberg model, a widely used semi-mechanistic myelosuppression model, assuming drug concentration directly reduce the proliferation rate of stem cells and progenitor cells in proliferation compartment. The correlations between different PK measures and neutropenia metrics were explored. In (1), when the same daily dose was used, intermittent schedules offered better management of ANC nadir. The reduced average drug exposure with intermittent dosing led to lower% time above Cmin. In (2), when the dose was adjusted to achieve the same nadir, drugs with moderate half-life (8-48 h) showed similar % time above Cmin regardless of schedule, while continuous dosing was better for a short half-life (4 h). Area under the concentration curve (AUC) was highly correlated with neutropenia. In summary, continuous dosing, with the dose selected correctly, is most effective to maintain % time above Cmin while providing similar tolerability as intermittent dosing with a higher dose. But dose interruptions could be required to manage individual toxicities. Intermittent schedules, on the other hand, allow recovery of ANC, enabling more orderly schedules.