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The cost-effectiveness of adding bevacizumab biosimilar with or without chemotherapy (CT) and drug wastage in treating platinum-resistant recurrent ovarian cancer (PRrOC) was assessed. A three-state partitioned-survival model to compare the clinical and economic outcomes in the treatment of patients with PRrOC from a Taiwan healthcare prospective, extrapolated to two years based on data obtained from the JGOG3023 clinical trial. The primary outcomes of the model were incremental cost-effectiveness ratios (ICERs). In the base-case scenario, using vials of bevacizumab biosimilar (Bevbiol) plus chemotherapy, the ICER was (new Taiwan dollar) NT$ 4,555,878 per QALY gained. The incremental cost savings of an incremental 2.02 QALYs were NT$ 1,605,828 if weight-based Bevbiol plus chemotherapy were used, but the ICER remained high at the willingness-to-pay (WTP) threshold. If the cost of Bevbiol were reduced to 50% per vial, adding it to CT would be cost-effective at an acceptable WTP threshold of NTD 2,994,200, with an ICER of NT$ 2,975,484. Bevacizumab biosimilars in mg/kg dosage form with chemotherapy are still not cost-effective in Taiwan, but using weight-based dosing will reduce drug waste and save treatment costs. [ABSTRACT FROM AUTHOR]

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

Abstract Background In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. Methods The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen. Results The proposed weight-based regimen has 5 dosing bands: (i) 5–7 kg, 5 mg, resulting in 0.71–1.0 mg/kg/day; (ii) 8–16 kg, 7.5 mg, 0.47–0.94 mg/kg/day; (iii) 17–40 kg, 15 mg, 0.38–0.88 mg/kg/day; (iv) 41–80 kg, 30 mg, 0.37–0.73 mg/kg/day; and (v) 81–100 kg, 45 mg, 0.45–0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6–11 months, 5 mg, 0.43–1.0 mg/kg/day; (ii) 1–5 years, 7.5 mg, 0.35–1.25 mg/kg/day; (iii) 6–14 years, 15 mg, 0.30–1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35–1.07 mg/kg/day. Conclusion The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.

Background: In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. Methods: The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen. Results: The proposed weight-based regimen has 5 dosing bands: (i) 5–7 kg, 5 mg, resulting in 0.71–1.0 mg/kg/day; (ii) 8–16 kg, 7.5 mg, 0.47–0.94 mg/kg/day; (iii) 17–40 kg, 15 mg, 0.38–0.88 mg/kg/day; (iv) 41–80 kg, 30 mg, 0.37–0.73 mg/kg/day; and (v) 81–100 kg, 45 mg, 0.45–0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6–11 months, 5 mg, 0.43–1.0 mg/kg/day; (ii) 1–5 years, 7.5 mg, 0.35–1.25 mg/kg/day; (iii) 6–14 years, 15 mg, 0.30–1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35–1.07 mg/kg/day. Conclusion: The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens. [ABSTRACT FROM AUTHOR]

This study aimed to characterize rasburicase dosing and duration. Secondary objectives included characterizing the indication of rasburicase and identifying the utilization of prophylactic therapy for tumor lysis syndrome (TLS).This retrospective review included patients 0 to 89 years old admitted between 1 January 2021 and 31 December 2021, and received at least one dose of rasburicase. Patients were excluded if they were >89 years old, pregnant, lactating, or received rasburicase outpatient.A total of 192 patients, 176 adults and 16 pediatric patients were included in the retrospective review. Of the total population, 184 received a fixed dose of rasburicase and 8 patients received a weight-based dose (0.15 mg/kg/dose) of rasburicase. The average dose administered was 3.4 mg for fixed and 2.99 mg for weight-based dosing. Nearly half (49.5%) the patients received rasburicase for an elevated uric acid but did not meet Cairo-Bishop criteria for TLS. Only 42.2% received at least one dose of allopurinol within 5 days prior to rasburicase and 18.8% received aggressive hydration within 72 h prior to rasburicase.The majority of rasburicase administered was ordered as fixed dose for a uric acid level ≥7.5 mg/dL. Most patients did not meet criteria for laboratory or clinical TLS and less than half the patients received prophylactic allopurinol and/or aggressive hydration. These study results are supported by recent literature for fixed dose rasburicase as a safe and economical dosing strategy compared to weight-based dosing. [ABSTRACT FROM AUTHOR]

Introduction: This study outlined cemiplimab intravenous (IV) dosing strategy to move from body weight (BW)-based 3 mg/kg every-2-week (Q2W) dosing in first-in-human study (study 1423; NCT02383212) to fixed 350 mg every-3-week (Q3W) dosing, utilizing population pharmacokinetics (PopPK) modeling and simulations, and supported by a limited dataset from a phase 2 study (study 1540; NCT02760498).Methods: Cemiplimab concentration data from a total of 505 patients were pooled from study 1423 in advanced malignancies and study 1540 in advanced cutaneous squamous cell carcinoma (CSCC). All patients received weight-based cemiplimab dose (1, 3, 10 mg/kg Q2W or 3 mg/kg Q3W) except 4% who received 200 mg Q2W. A linear two-compartment PopPK model incorporating covariates that improved goodness-of-fit statistics was developed to compare cemiplimab exposure at 350 mg Q3W versus 3 mg/kg Q2W. Upon availability, observed cemiplimab concentration at 350 mg Q3W in study 1540 was then compared with the simulated values.Results: Post hoc estimates of cemiplimab exposure and variability (505 patients; weight range 30.9-156 kg; median 76.1 kg) at steady state were found to be similar at 350 mg Q3W and 3 mg/kg Q2W. Effect of BW on cemiplimab exposure was described by exposure versus BW plots and at extreme BW. Overlay of individual observed cemiplimab concentrations in 51 patients with metastatic CSCC on simulated concentration-time profiles in 2000 patients at 350 mg Q3W confirmed cemiplimab exposure similarity and demonstrated the robustness of dose optimization based on PopPK modeling and simulations.Conclusions: Cemiplimab 350 mg Q3W is being further investigated in multiple indications. [ABSTRACT FROM AUTHOR]

Four-factor prothrombin complex concentrate (4F-PCC) is widely used for urgent reversal of anticoagulation with warfarin, but the optimal 4F-PCC dosing approach is unknown. Herein, we sought to determine the efficacy of a novel fixed, weight-based dosing nomogram. We retrospectively studied consecutive adult patients receiving fixed, weight-based 4F-PCC dosing for warfarin reversal between 30 April 2009 and 31 December 2010. The primary outcome was reversal of warfarin anticoagulation, defined as INR ≤1.5 within 6 h. Secondary outcome was the occurrence of thromboembolic events. A total of 227 patients (56% male), with a median age of 74 years and a median weight of 76kg were evaluated. The most common indications for 4F-PCC were active bleeding (37.4%: 12.7% intracranial, 12.3% gastrointestinal, 4.0% trauma, 8.4% other), reversal for a procedure (22.0%), reversal for surgery (29.5%) or other (11.1%). 66.1% of patients achieved an INR ≤1.5 within 6 h of 4F-PCC administration. 95.0% (57/60) of patients completed a planned procedure and 95.7% (67/70) of patients completed a planned surgery. The median baseline INR was 2.9 (1.5–10) and decreased significantly to a median of 1.3 (1.0–3.7) (p <.001) post-4F-PCC administration. There was no statistically significant difference in response to a fixed, weight-based dose of 4F-PCC based on pre-PCC INR, as long as the pre-treatment INR was ≤ 4.5. Although the majority of patients in our study (99%) received doses over 1000IU, rates of thrombosis were low (1.8%). Fixed, weight-based dosing of 4F-PCC is effective for reversing warfarin anticoagulation in patients with a pre-dosing INR ≤ 4.5. [ABSTRACT FROM AUTHOR]

Abstract Background The weight-based dosing of ondansetron to reduce hypotension has never been investigated. The aim of this study is to determine the optimal dose of ondansetron required based on the patient’s weight to reduce hypotension following spinal anesthesia for cesarean section. Methods In this prospective, triple-blinded, parallel group, randomized controlled trial, a total of 228 pregnant women were randomized to receive either normal saline (group NS) or ondansetron 0.05 mg/kg (group O1) or ondansetron 0.1 mg/kg (group O2) intravenously 5 min before induction of spinal anesthesia. The incidence of hypotension, mean arterial pressure, heart rate, vasopressor requirements, and blood loss between the three groups were compared. Maternal and neonatal complications were also assessed. Changes in blood pressure and heart rate were compared using the generalized estimating equations method. Results Thirteen patients were excluded from the analysis because of no intervention (n = 12) and protocol violation (n = 1). Two hundred and fifteen patients remained for the intention-to-treat analysis. The incidence of hypotension in groups NS (n = 72), O1 (n = 71), and O2 (n = 72) were 81.9%, 84.5%, and 73.6%, respectively (P = 0.23). The episodes of hypotension before delivery (first 14 min after spinal anesthesia) were significantly higher in group O1 compared to NS (5 vs 2, P = 0.02). The overall heart rates throughout the operations were not different among the three groups. The ephedrine requirements and amount of blood loss were also similar among the three groups. The metoclopramide requirement was significantly lower in group O2 compared to group NS (2.8% vs 16.7%, P = 0.01). There were no serious adverse events in terms of maternal or neonatal complications. Conclusions Ondansetron 0.05 mg/kg or 0.1 mg/kg administered before spinal anesthesia did not reduce the incidence of hypotension in this study. Trial registration Thai Clinical Trials Registry, TCTR 20160323001, 22 March 2016.

Traditionally, there have been uniform antibiotic dosing guidelines for prophylaxis for clean-clean-contaminated surgery in both non-obese and obese adults. All other factors predisposing to surgical site infections (SSIs) being equal, over time, the preferred drug is cefazolin. The usual dose, given immediately pre-procedure, has been 1 g intravenously (IV) in non-penicillin-allergic patients, which has been highly effective, Recently, it has become common practice to use high-dose cefazolin; i.e., 3 g IV, in obese patients. This article reviews the literature on high-dose cefazolin prophylactic regimens in the obese from a pharmacokinetic (PK) point of view. There are no comparative studies to support this approach, which is based largely on the theory "more must be better." Weight-based dosing of cefazolin in the obese is flawed, because it does not take into account PK factors, which are critical in the obese. Cefazolin is a water-soluble (hydrophilic) antibiotic that does not penetrate adipose tissue regardless of IV dose. Importantly, adipose tissue is not a valid target tissue in clean-clean-contaminated SSI prophylaxis, as it does not become infected. Higher doses result in proportionately higher serum/non-adipose tissue concentrations, but adipose tissue concentrations are unaffected. Cefazolin displays time-dependent killing kinetics so that as long as serum/tissue concentrations are above the minimum inhibitory concentration (MIC) of SSI pathogens, there is no enhanced killing with higher concentrations relative to concentration-dependent antibiotics. Taking into account PK principles, a cefazolin 1 g IV bolus results in peak serum concentrations of ∼185 mcg/mL, provides at least six hours of intra-operative protection, aside from any post-antibiotic effects, and eliminates any rationale for intra-operative re-dosing for procedures lasting six hours or less. Some have argued that a cefazolin 3 g IV dose in the obese does not matter, as more must necessarily be better. However, from an antibiotic stewardship program (ASP) perspective, unneeded antibiotics are unnecessary. Moreover, the costs of cefazolin 1 g (IV push) at $0.75 versus 2 g (IV piggyback) at $ 6.83 can be significant in large centers using cefazolin prophylaxis for cardiothoracic, orthopedic, obstetric/gynecology, and bariatric surgery. Excessive antibiotics also expose the patient to potential adverse effects; i.e., Clostridium difficile. There is no dose-dependent or duration of exposure effect on resistance with one or two pre-operative or intra-operative doses. Well-done PK-based studies in obese patients clearly demonstrate the lack of benefit of using a 3-g dose or intra-operative re-dosing and show no incremental increase in adipose tissue concentrations with high doses. From an ASP point of view, antibiotic dosing recommendations should be reviewed and revised on the basis of PK principles that indicate that weight-based dosing has no basis for pre-operative prophylaxis in obese patients. [ABSTRACT FROM AUTHOR]

Background: Infections caused by Stenotrophomonas maltophilia  ( S. maltophilia )   and Pneumocystis jirovecii ( Pneumocystis jirovecii pneumonia (PJP)) require weight-based dosing for co-trimoxazole. The aim of this study is to assess the appropriateness of co-trimoxazole dosing in adult inpatients for the treatment of these infections., Methodology: This is a single-center, cross-sectional study that included adult inpatients treated with co-trimoxazole for a weight-based dose indication ( S. maltophilia and PJP). The primary outcome was the appropriateness of co-trimoxazole dosing for these infections., Results: Forty-three patients were included in the study. Of the 43 patients, 29 (67.4%) were using co-trimoxazole for PJP treatment, and 14 (32.6%) were using it for S. maltophilia treatment. The co-trimoxazole dose was appropriate in 22 (51.2%) patients, 21 (72.4%) in the PJP treatment group, and one (7.1%) in the S. maltophilia treatment group. Underdosing was observed in 21 (48.8%) patients, of whom eight (27.6%) were in the PJP treatment group and 13 (92.9%) were in the S. maltophilia treatment group., Conclusions: This study found a relatively high rate of underdosing of co-trimoxazole based on weight in hospitalized adults with PJP and S. maltophilia infections., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Alshehri et al.)

BACKGROUND: The study aimed to determine the frequency of enoxaparin dosing errors for patients who had a measured emergency department (ED) weight compared to those who did not have a measured ED weight, and to determine if demographic variables (e.g., weight, height, age, Englishspeaking, race) impact the likelihood of receiving an inappropriate dose. METHODS: This is a retrospective, electronic chart review of patients who received a dose of enoxaparin in the ED between January 1, 2008 and July 1, 2013. We identified all patients >18 years who received a dose of enoxaparin while in the ED, were admitted, and had at least one inpatient weight within the fi rst four days of hospitalization. Patients were excluded if they received enoxaparin for prophylaxis or a dose of more than 1.25 mg/kg. RESULTS: A total of 1,944 patients were included. Patients were more likely to experience an error if they did not have a measured ED weight. Over-doses of >10 mg were more likely to occur in patients without a measured ED weight. Patients with no documented ED weight or with a staffestimated ED weight were more likely to experience a dosing error than those with a patient-stated weight. Patients were more likely to experience an error if their fi rst inpatient weight was more than 96 kg, they were more than 175-cm tall, or were English speaking. CONCLUSION: Dosing errors are more likely to occur when patients are not weighed in the ED. Modifications to current workflows to incorporate weighing those patients who receive weightdosed medications may be warranted. [ABSTRACT FROM AUTHOR]

Background The current debate over the optimal Enoxaparin prophylactic dosing strategies in obese patients centre around whether it should be based on the actual weight of the patient (i.e. weight-based), or at an artificially fixed amount, as it is the case in Australia (40 mg daily). The vast majority of the evidence available today is laboratory-based, measuring serum Antifactor-X a activities as a marker for physiological response. Aim The aim of the parent study is to compare the clinical outcomes for obese patients who received fixed doses of enoxaparin compared to those who received weight-based doses within the licensed dosage recommendations. This review was conducted to examine whether a gap in knowledge exists in relation to dosing obese patients with enoxaparin as VTE prophylaxis after hospital admission to aid in development of the parent study concept. Method Databases such as Medline, EBSCOhost, ProQuest were interrogated using combinations of words such as “enoxaparin”, AND “dosing strategy”, AND “obese/obesity” AND “prophylaxis”. Only eleven out of 14 primary studies which were considered to be sufficiently similar in methodology and anticipated outcomes were reviewed and analysed. Results Pooled data from the eleven studies suggested that weight-based or higher-than-fixed dosing had a 36.2% higher success rate than fixed dosing, and was more likely to achieve the desired serum Anti-X a activity levels (52.2% and 16% respectively). The rate of failure to achieve this is significantly lower in the weight-based groups (13.3%) than in fixed-dose groups (18.5%). These eleven studies reviewed included 601 patients in total. Conclusion There is insufficient evidence to support or negate the current enoxaparin health outcomes in obese and very obese patients due to the lack of post-discharge follow-up from hospitals. Further research is required to compare long-term outcomes after fixed and weight-based dosing of enoxaparin. The optimal dose of enoxaparin per kilogram of body weight for prophylaxis remains to be determined. [ABSTRACT FROM AUTHOR]

Introduction Paroxysmal supraventricular tachycardia (PSVT) is an often-recurring tachyarrhythmia that frequently results in emergency department visits and is commonly treated using intravenous adenosine. Given the anecdotal variable success of adenosine, the question arose of which patient factors may affect its success. This retrospective cohort analysis seeks to test the hypothesis that adult patients who receive adenosine at doses of ≥0.1mg/kg will have greater rates of successful conversion upon receipt of the first dose of adenosine. Methods This retrospective cohort analysis examines the charts from patients with known paroxysmal supraventricular tachycardia from November 1, 2015, through March 31, 2020, who were treated with intravenous adenosine. The primary outcome was the first-dose success of adenosine when stratified by patient weight (greater than 0.1mg/kg or less than 0.1mg/kg). Baseline characteristics and adverse effects were also collected. Results Seventy-six patients were included in the analysis. Patients who received adenosine at doses greater than or equal to 0.1mg/kg were more likely to convert to sinus rhythm than those who received doses less than 0.1mg/kg (p=0.006). No difference in adverse effects was noted between the groups (p=0.75). Conclusion This retrospective cohort analysis found that patients who received adenosine at doses greater than or equal to 0.1mg/kg for the treatment of PSVT were more likely to convert to sinus rhythm than those who received lower doses, with no difference in adverse effects. This hypothesis-generating finding provides the basis for a subsequent randomized, controlled trial to investigate the effectiveness and safety of weight-based adenosine., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Deck et al.)

Antibody Drug Conjugates (ADCs) entered clinical trials in the mid 1990s to selectively deliver cytotoxic chemotherapy to cancer cells with the goal to increase the antitumor activity and decrease normal tissue toxicity. Over nearly 30 years of development the ADC platform has become established with now 11 approved agents and many more in the pipeline. This review is designed to highlight some of the problems and solutions encountered in clinical development as well as provide practical instruction to both clinical investigators on the efficient protocol design for ADCs and the lessons learned. [ABSTRACT FROM AUTHOR]

A fixed dose regimen for tyrosine kinase inhibitors (TKIs) is postulated to be responsible for variable safety outcomes in the treatment of chronic myelogenous leukemia (CML). The objective of this study was to explore an optimal dosing regimen for a TKI, radotinib, to improve its safety profile. Clinical data were obtained from a Phase 2 study of fixed-dose radotinib in 77 Asian patients with CML. The magnitude of radotinib dose adjusted for patient’s body weight (Dose/BW) and the probability of dose-limiting toxicity (DLT) demonstrated a positive association (Logit[P] = 0.86*[Dose/BW]-4.45,p = 0.001). There was a significant difference in the Kaplan-Meier curves for time to first DLT between the patient subgroups of Dose/BW <6 and ≥6 mg/kg (259versus83 days). Consequently, a two-tier weight-based dosing regimen may improve the safety of radotinib: 300 mg or 400 mg twice daily for patients weighing ≤65 or >65 kg, respectively. [ABSTRACT FROM AUTHOR]

Background In hematopoietic stem cell transplantation (HSCT), patients receive individualized treatment planning in conditioning regimens to prevent unwarranted toxicities while maximizing desired outcomes. The dose of a widely studied agent in this setting, busulfan, can be adjusted based on area under the curve (AUC); however, choice of actual body weight (ABW) versus adjusted body weight (DBW) weight to calculate the initial dose may be critical in attaining goal AUC. Objective To determine which weight best correlates with achievement of goal AUC for patients receiving busulfan conditioning for HSCT. Secondary objectives include evaluation of AUC results with clinical outcomes such as toxicity and survival. Methods An institutional review board-approved retrospective analysis was performed on 31 allogeneic HSCT recipients who received intravenous busulfan (Q6H with cyclophosphamide [Bu/Cy] or once daily with fludarabine [Flu/Bu]). Results Eighteen patients received Flu/Bu (50% ABW, 50% DBW) and 13 received Bu/Cy (23% ABW, 77% DBW). Overall, patients dosed by DBW were more likely to undershoot goal AUC (−12.8% vs. +19.5%, p = 0.018) and require dose increases (+20% vs. −19.9%, p = 0.012) versus those dosed by ABW. Subgroup analysis confirmed these results for Bu/Cy (−23.6% vs. +2.2%, p < 0.001 for goal AUC; +36.2% vs. −4.5%, p = 0.008 for busulfan dose increase), but not Flu/Bu (−0.8% vs. +25.3%, p = 0.123 for goal AUC; +3.4% vs. −25.1%, p = 0.174 for busulfan dose increase). Time to engraftment, progression-free survival, and overall survival were not different between dosing groups (p > 0.05). No patient experienced busulfan-related toxicity. Conclusions Further prospective studies are warranted to elucidate which weight is most likely to achieve goal AUC and subsequent optimal patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: In the United States, obesity affects approximately ⅖ adults and ⅕ children, leading to increased risk for comorbidities, like gastroesophageal reflux disease (GERD), treated increasingly with proton pump inhibitors (PPIs). Currently, there are no clinical guidelines to inform PPI dose selection for obesity, with sparse data regarding whether dose augmentation is necessary., Areas Covered: We provide a review of available literature regarding the pharmacokinetics (PK), pharmacodynamics (PD), and/or metabolism of PPIs in children and adults with obesity, as a step toward informing PPI dose selection., Expert Opinion: Published PK data in adults and children are limited to first-generation PPIs and point toward reduced apparent oral drug clearance in obesity, with equipoise regarding obesity impact on drug absorption. Available PD data are sparse, conflicting, and limited to adults. No studies are available to inform the PPI PK→PD relationship in obesity and if/how it differs compared to individuals without obesity. In the absence of data, best practice may be to dose PPIs based on CYP2C19 genotype and lean body weight, so as to avoid systemic overexposure and potential toxicities, while monitoring closely for efficacy.

1. The population pharmacokinetics of high-dose etoposide was studied in a group of young children and adolescents. 2. Twenty-six children and adolescent were administered high-dose etoposide as a continuous infusion over 24 h. Etoposide plasma concentration-time data was modelled using NONMEM® 7. The effect of age, weight, serum creatinine (SCr), and gender on pharmacokinetic parameters (CL and Vd) were determined by a nonlinear mixed effect model. 3. The pharmacokinetics of etoposide based on BSA dosing was best described with a 1-compartment structural model which was parameterised in terms of clearance (CL) and volume of distribution (Vd). An exponential error model was used to explain intersubject variability and a proportional error model was used to describe residual or intrapatient variability. The final model parameter estimates for the typical (normalised to 70 kg) values of CL and Vd were 2.31 L/hr and 17.5 L, respectively. The CL and Vd allometrically increased with weight with the power of 3/4 and 1, respectively. After accounting for weight dependence using the allometric scaling, age, serum creatinine, and gender did not have any influence on model parameters. 4. The results of this children and adolescent population pharmacokinetic study indicates that etoposide pharmacokinetics were influenced by body weight on an allometric basis. The pharmacokinetic parameters CL and Vd increased with increasing weight similar to BSA. [ABSTRACT FROM AUTHOR]

Background: Malaria is a potentially severe disease widely distributed in tropical and subtropical regions worldwide. Clinically, the progression of the disease can be life-threatening if it is not promptly diagnosed and properly treated. Through treatment, the radical cure of Plasmodium vivax infection can be achieved, thus preventing potential relapses and the emergence of new cases outside the Amazon region in Brazil. Surveillance for therapeutic failure in non-endemic areas is advantageous, as it is unlikely that recurrence of the disease can be attributed to a new malaria infection in these regions. Methods: An observational study of 53 cases of P. vivax and mixed (P. vivax and Plasmodium falciparum) malaria was conducted at a travel medicine centre between 2005 and 2011 in Rio de Janeiro and a descriptive analysis of the potential factors related to recurrence of P. vivax malaria was performed. Groups with different therapeutic responses were compared using survival analysis based on the length of time to recurrence and a set of independent variables thought to be associated with recurrence. Results: Twenty-one relapses (39.6%) of P. vivax malaria were observed. The overall median time to relapse, obtained by the Kaplan-Meier method, was 108 days, and the survival analysis demonstrated an association between non-weight-adjusted primaquine dosing and the occurrence of relapse (p<0.03). Primaquine total dose at 3.6 mg/kg gave improved results in preventing relapses. Conclusions: A known challenge to individual cure and environmental control of malaria is the possibility of an inappropriate, non-weight-based primaquine dosing, which should be considered a potential cause of P. vivax malaria relapse. Indeed, the total dose of primaquine associated with non-occurrence of relapses was higher than recommended by Brazilian guidelines. [ABSTRACT FROM AUTHOR]

Ribavirin is a synthetic guanosine analogue, which acts against hepatitis C virus (HCV) through several mechanisms that include 1) immune modulation; 2) inhibition of inosine monophosphate dehydrogenase 3) inhibition of RNA-dependent RNA polymerase; 4) induction of HCV mutagenesis; and 5) modulation of interferon-stimulated gene expression. Addition of ribavirin to peginterferon-α substantially improves sustained virologic response (SVR) and decreases relapse rates. Ribavirin can be associated with hemolytic anemia. However, recent data suggest that SVR is not negatively impacted by treatment-induce anemia. Notably, optimal dosing strategy and the proper management of anemia are crucial to achieve the best treatment outcome. Several advances have been made in the areas relevant to ribavirin, such as the discovery of inosine triphosphatase gene as a promising pharmacogenetic marker and a predictor of anemia, and the role for erythropoiesis-stimulating agent in the management of anemia related to ribavirin use. Recent observations indicate that ribavirin will remain as a critical component of HCV therapy, even in the context of direct acting antivirals. [ABSTRACT FROM AUTHOR]

Background & Aims: Pegylated interferon (peg-IFN) plus ribavirin (standard of care for chronic hepatitis C virus [HCV]), can cause dose-limiting anemia in up to 22% of patients. Viramidine is associated with a lower incidence of anemia because of its liver-targeting properties. Methods: The efficacy and safety of viramidine versus ribavirin plus peg-IFN alfa-2a was assessed in patients with HCV. Randomized patients received peg-IFN alfa-2a 180 mcg with viramidine 600mg twice daily or weight-based doses of ribavirin 1000 or 1200mg/day. Treatment duration was based on HCV ribonucleic acid (RNA) genotype: genotype 2/3 and non-2/3 patients were treated for 24 and 48weeks, respectively. The primary efficacy end point was the non-inferiority of viramidine versus ribavirin (proportion of patients achieving sustained virologic response at week 24). The primary safety end point was the proportion of patients experiencing a hemoglobin event. Results: In total, 962 patients received peg-IFN alfa-2a with viramidine (n =644) or ribavirin (n =318). Sustained virologic response was achieved in 40% of viramidine-treated patients and 55% of ribavirin-treated patients (difference of proportions 0.150 [95% CI, 0.09, 0.21]). Improved efficacy was seen with higher viramidine exposure on a mg/kg basis. Viramidine was significantly superior to ribavirin in hemoglobin event rates (54% vs. 80%; p <0.001). Adverse event rates were similar between groups except for diarrhea (viramidine 29.5%; ribavirin 15.7%; p <0.0001). Conclusions: Viramidine 600mg BID did not meet the primary efficacy non-inferiority end point but met the safety end point. Determination of a viramidine dosage that would yield superior efficacy over ribavirin is needed. [Copyright &y& Elsevier]

Objectives: To examine the safety and efficacy of omadacycline by body mass index (BMI) in adults with community-acquired bacterial pneumonia (CABP) from a Phase III trial., Methods: Patients hospitalized for suspected CABP were randomized 1:1 to receive intravenous omadacycline or moxifloxacin, with an optional transition to oral, for a total of 7-14 days. Early clinical response (ECR) was assessed 72-120 h after receipt of the first dose, and clinical success was assessed 5-10 days after the last dose (post-treatment evaluation [PTE]). ECR was defined as improvement in at least two CABP symptoms with no worsening of other symptoms or use of rescue antibacterial treatment; success at PTE was defined as resolution of signs and symptoms to the extent that further antibacterial therapy was unnecessary. Safety evaluations included treatment-emergent adverse events and laboratory measures. Between-treatment comparisons were made by World Health Organization BMI categories and by diabetes history., Results: Distribution of patients in the normal weight, overweight, and obese subgroups was fairly even. Clinical success for omadacycline-treated patients at ECR were similar across ascending BMI groups (OMC: 82.9%, 80.5%, 76.9%; MOX: 88.6%, 80.7%, 76.9%). Outcomes by diabetes status were generally similar in omadacycline- and moxifloxacin-treated patients. Patients who had clinical success or clinical stability at ECR generally showed continued clinical success at PTE. Safety profiles for omadacycline and moxifloxacin were largely similar across BMI subgroups and by diabetes history., Conclusion: The omadacycline fixed-dosing strategy showed consistent safety and efficacy in patients with CABP of different body sizes., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ceftriaxone is one of the most common antibiotics prescribed for hospitalized children in the United States. However, ceftriaxone is not dosed consistently. Sepsis/serious bacterial infection had high dosing variability. Dosing for central nervous system infection was frequently suboptimal. Future efforts should focus on optimizing and standardizing ceftriaxone dosing., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The digital PET/CT scanner with digital photon-counting technique promises a shorter scan time, improved small-lesion detectability, and reduced radiation dose for the PET and CT portions of the exam while improving image quality. Methods: In this single-institution retrospective review study, 84 participants who had undergone PET/CT on both analog and digital scanners were analyzed. The aim was to evaluate the impact of image field of view (FOV) and body mass index (BMI) on the digital compared with the analog PET/CT scanners. The participants were categorized into different groups based on their BMI. Total scan times, 18 F-FDG doses, and dose-length products (DLP) were collected and compared. Image quality was also assessed by certified nuclear medicine physicians and graded on a scale from 1 to 5. Results: In the skull-to-mid-thigh FOVs, the digital scanner had a scan time shorter by 37% ( P < 0.001), a 18 F-FDG dose lower by 16% ( P < 0.001), but only an 8% reduction in DLP ( P = 0.2). In the head-to-toe FOV cases, the digital scanner showed reductions in scan time (33%; P < 0.001), 18 F-FDG dose (13%; P < 0.001), and DLP (19%; P < 0.001). When BMI was accounted for, the digital scanner had a scan time shorter by 33% ( P < 0.001), as well as a reduced DLP ( P < 0.001) and 18 F-FDG dose ( P < 0.001), with the most prominent changes being in the overweight and obese participants. Image quality was also improved by the digital scanner, with a score of 4.5, versus 4.0 for the analog scanner. Conclusion: The digital scanner has a shorter scan time and lower DLP, requires a lower 18 F-FDG dose, and provides improved image quality when compared with the analog scanner. The most impactful difference in scan time, DLP, and 18 F-FDG dose were observed in obese and overweight participants., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata , C. albicans , and C. parapsilosis , respectively. The final 2-compartment model included weight as a covariate on volume of distribution ( V ). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant ( K e ) was 0.09 (SD, 0.04) h -1 , the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h -1 , and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h -1 A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients., (Copyright © 2020 Märtson et al.)

Introduction: The effect of body mass index (BMI) and chemotherapy dose reduction on pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for locoregional breast cancer remains unclear. Contemporary studies have reported largely on trial populations and used dose-capping., Patients and Methods: Patient registries at the University of Iowa were queried to identify patients with operable breast cancer who received NAC. Dose reductions were calculated for taxanes (T), anthracyclines (A) and non-A-T chemotherapy. Clinical-pathologic characteristics, chemotherapy dose reductions, and adverse events were compared between normal (BMI <25) and overweight/obese patients (BMI ≥25). Additionally, the synergistic effect of BMI and chemotherapy dose reduction on pCR was assessed., Results: Of 171 eligible patients, 112 were overweight/obese. Chemotherapy dosing was capped in 2 patients; all others initiated full weight-based treatment. Overweight/obese patients required more frequent taxane (44.6% vs. 25.4%; P = .01) and any chemotherapy dose reductions (50.9% vs. 33.9%; P = .03). pCR was attained in 29.2% of patients. In a multivariable model, the interaction term for BMI as a continuous variable and any chemotherapy dose reduction was significant independent of the clinical stage and tumor receptor status (P = .04). For obese patients, any chemotherapy dose reduction was significantly associated with increased odds of not attaining pCR., Conclusion: During NAC, overweight/obese patients more often have chemotherapy dose reductions. Chemotherapy dose reduction in obese patients was a powerful predictor of not attaining pCR. This was not seen for normal or overweight patients. Opportunities might exist to improve pCR rates in this higher-risk group., (Copyright © 2016 Elsevier Inc. All rights reserved.)