Different bioaugmentation regimes that mitigate ammonium/salt inhibition in repeated batch anaerobic digestion: Generic converging trend of microbial communities.

Bioaugmentation regimes (i.e., dosage, repetition, and timing) in AD must be optimized to ensure their effectiveness. Although previous studies have investigated these aspects, most have focused exclusively on short-term effects, with some reporting conflicting conclusions. Here, AD experiments of three consecutive repeated batches were conducted to determine the effect of bioaugmentation regimes under ammonium/salt inhibition conditions. A positive correlation between reactor performance and inoculum dosage was confirmed in the first batch, which diminished in subsequent batches for both inhibitors. Moreover, a diminishing marginal effect was observed with repeated inoculum introduction. While the bacterial community largely influenced the reactor performance, the archaeal community exhibited only a minor impact. Prediction of the key enzyme abundances suggested an overall decline in different AD steps. Overall, repeated batch experiments revealed that a homogeneous bacterial community deteriorated the AD process during long-term operation. Thus, a balanced bacterial community is key for efficient methane production.

A cost comparison of pembrolizumab: Fixed and weight-based dosing.

BACKGROUND: Pembrolizumab, an immune checkpoint inhibitor, indicated to treat multiple cancers, was initially approved in Australia as weight-based dosing at 2 mg/kg every 3 weeks (Q3W). Subsequent approvals used 'fixed' dosages of 200 mg Q3W or 400 mg every 6 weeks (Q6W). Pharmacokinetic equivalence was demonstrated between dosing strategies, with no significant differences in efficacy or toxicity. Fixed dosing regimens are routinely used in Australia. AIM: To model and compare the cost of weight-based dosing of pembrolizumab to standard fixed dosing regimens. METHOD: A single centre, retrospective review was conducted. Patients, identified from dispensing software, who commenced on pembrolizumab between January and December 2022 were included. Patient demographic and treatment data was extracted from electronic medical records. Costs of weight-based doses were calculated and compared to the cost of fixed dosing. Variables such as acquisition cost, funding mechanisms and 'vial sharing' were considered. RESULTS: Fifty-two patients were included (63% male, median age 68 years). Of the 211 doses of pembrolizumab administered (average 4.1 doses/patient), 161 were Q3W doses, and 50 were Q6W doses. The acquisition cost for a fixed 200 mg and 400 mg dose was $7646, and $15,292, respectively. The average patient weight was 77.6 kg (SD 19 kg), which equated to $5933 for a weight-based Q3W dose, and $11,867 for the Q6W dose; a potential cost avoidance of $1965 and $3930 per dose, respectively. This represented a possible 23.5% avoidance in medication acquisition cost. Over the study period of 1 year, using weight-based dosing for pembrolizumab had the potential to reduce medication expenditure by $467,996. DISCUSSION: Significant cost avoidance could be achieved via weight-based pembrolizumab dosing. Given the substantial total cost of pembrolizumab, the growing number of indications and the expected equivalent treatment outcomes with weight-based pembrolizumab, the potential cost reductions of weight-based pembrolizumab at both institution and government level should be further explored.

Impact of pegaspargase dose capping on incidence of pegaspargase-related adverse events in adults.

INTRODUCTION: Asparaginase derivatives are essential components of the treatment of acute lymphoblastic leukemia in adolescent and young adult patients. However, their associated toxicities limit wider use in older populations. This study seeks to determine if the practice of capping the pegaspargase dose at 3750 units reduces the risk of related adverse events in adults. METHODS: Adverse event data were retrospectively collected 28 days following each administration of pegaspargase in a single center. Doses were categorized as either capped (≤3750 units) (n = 57, 47.5%) or non-capped (>3750 units) (n = 63, 52.5%). The primary endpoint of this study was the composite incidence of serious pegaspargase-related adverse events, defined as grade 3 or higher. RESULTS: Of the 120 doses administered, 47 (39.2%) were administered to patients > 39 years. For the primary endpoint, 26 doses (45.6%) in the dose capped group versus 22 doses (34.9%) in the non-dose capped group were associated with serious pegaspargase-related adverse events (p = 0.23). Isolated laboratory abnormalities accounted for all hepatotoxicity and pancreatic toxicity events, while venous thromboembolism and bleeding occurred after 8.3% and 13.3% of doses, respectively. Multivariate analysis of the primary outcome to adjust for differences in baseline characteristics found no difference between groups (OR 2.56 (0.84, 7.77, p = 0.098)). CONCLUSIONS: The incidence of serious clinical toxicities was low in this study, particularly pegaspargase-related venous thromboembolism. This suggests that the practice of capping pegaspargase doses at 3750 units, coupled with vigilant monitoring and prophylaxis for pegaspargase-related adverse events, can allow for the inclusion of this drug in the treatment of older individuals.

Dynamics of a within-host drug resistance model with impulsive state feedback control.

Bacterial resistance poses a major hazard to human health, and is caused by the misuse and overuse of antibiotics. Thus, it is imperative to investigate the optimal dosing strategy to improve the treatment effect. In this study, a mathematical model of antibiotic-induced resistance is presented to improve the antibiotic effectiveness. First, conditions for the global asymptotical stability of the equilibrium without pulsed effect are given according to the Poincaré-Bendixson Theorem. Second, a mathematical model of the dosing strategy with impulsive state feedback control is also formulated to reduce drug resistance to an acceptable level. The existence and stability of the order-1 periodic solution of the system are discussed to obtain the optimal control of antibiotics. Finally, our conclusions are confirmed by means of numerical simulations.

An alternative dosing strategy for ropeginterferon alfa-2b may help improve outcomes in myeloproliferative neoplasms: An overview of previous and ongoing studies with perspectives on the future.

Ropeginterferon alfa-2b is a novel, long-acting mono-pegylated proline-IFN-alpha-2b approved for treatment of polycythemia vera in adults, regardless of thrombotic risk level or treatment history. Clinical trial data indicate the dose and titration of ropeginterferon alfa-2b is safe and effective. However, additional studies may provide rationale for an amended, higher initial dosage and rapid titration. This article is an overview of current and upcoming studies of ropeginterferon alfa-2b in myeloproliferative neoplasms that support the exploration of an amended dosing scheme in order to optimize patient tolerability and efficacy outcomes.

Validation and comparison between two warfarin dosing clinical algorithms and warfarin fixed dosing in specialized heart center: cross-sectional study

Background: Warfarin is well known as a narrow therapeutic index that has prodigious variability in response which challenges dosing adjustment for the maintenance of therapeutic international normalized ratio. However, an appreciated population not on new oral anticoagulants may still need to be stabilized with warfarin dosing. Objective: The current study’s main objective was to validate and compare two models of warfarin clinical algorithm models namely the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) with warfarin 5 mg fixed standard dosing strategy in a sample of Sudanese subjects. Method: We have conducted a cross-sectional study recruited from the out-patient clinic at a tertiary specialized heart center. We included subjects with unchanged warfarin dose (stabilized), and with therapeutic international normalized ratio. The predicted doses of warfarin in the two models were calculated by three different methods (accuracy, clinical practicality, and the clinical safety of the clinical algorithms). Main outcome measure: The primary outcomes were the measurements of the clinical (accuracy, practicality, and safety) in each of the two clinical algorithms models compared to warfarin 5 mg fixed standard dose strategy. (AU)

Population Pharmacokinetics of Colistin Sulfate in Critically Ill Patients: Exposure and Clinical Efficacy.

Background: Presently, colistin is commercially available in two different forms, namely, colistin sulfate and its sulphomethylated derivative, colistimethate sodium (CMS). However, in the currently reported studies, most of the clinical studies on colistin for parenteral use are referred to as CMS. Data on the pharmacokinetics (PK), clinical efficacy, and side effects of colistin sulfate in clinical use have not been reported. Methods: This retrospective study was performed on carbapenem-resistant organism (CRO)-infected patients treated with colistin sulfate for more than 72 h. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological eradication, and nephrotoxicity were assessed. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients with normal or decreased renal function. Results: A total of 42 patients were enrolled, of which 25 (59.52%) patients were considered clinical treatment success and 29 (69.06%) patients had successful bacteria elimination at the end of treatment. Remarkably, no patient developed colistin sulfate-related nephrotoxicity. A total of 112 colistin concentrations with a range of 0.28-6.20 mg/L were included for PK modeling. The PK characteristic of colistin was well illustrated by a one-compartment model with linear elimination, and creatinine clearance (CrCL) was identified as a covariate on the clearance of colistin sulfate that significantly explained inter-individual variability. Monte Carlo simulations showed that the recommended dose regimen of colistin sulfate, according to the label sheet, of a daily dose of 1-1.5 million IU/day, given in 2-3 doses, could attain PTA > 90% for MICs ≤ 0.5 µg/mL, and that a daily dose of 1 million IU/day could pose a risk of subtherapeutic exposure for MIC ≥1 µg/ml in renal healthy patients. Conclusion: Renal function significantly affects the clearance of colistin sulfate. A dose of 750,000 U every 12 h was recommended for pathogens with MIC ≤1 µg/ml. The dosage recommended by the label inserts had a risk of subtherapeutic exposure for pathogens with MIC ≥2 µg/ml. Despite higher exposure to colistin in patients with acute renal insufficiency, dose reduction was not recommended.

Daily and Not Every-Other-Day Intake of Anthocyanin-Rich New Zealand Blackcurrant Extract Alters Substrate Oxidation during Moderate-Intensity Walking in Adult Males.

Daily intake of anthocyanin-rich New Zealand blackcurrant (NZBC) extract can enhance exercise-induced fat oxidation. It is not known whether habitual dietary anthocyanin intake and body composition affects blackcurrant-induced fat oxidation or even if daily intake is required. We examined effects of daily and every-other-day intake of NZBC extract on metabolic and physiological responses during moderate-intensity walking. Sixteen physically active males (age: 24 ± 6 yr, body mass: 78 ± 16 kg, BMI: 24.7 ± 4.2 kg·m-2, body fat: 15.2 ± 5.0%) volunteered. A randomized, cross-over design with a control condition was used and habitual dietary anthocyanin intake quantified. For intake conditions, participants consumed two capsules of NZBC extract (i.e. 210 mg of anthocyanins, CurraNZ™) with breakfast daily or every-other-day for 14 days (14-D and 14-EOD) with 14-days washout. Final two capsules were taken 2-hr before the walk (speed: 5.7 ± 0.7 km·hr-1). There was a trend for lower respiratory exchange ratio and carbohydrate oxidation with changes only for 14-D. Fat oxidation was increased only for 14-D (p < 0.05) with 50% of the participants more than a 10% change. In 14-D, there was a positive correlation for BMI and body fat % with the absolute change in fat oxidation but not with habitual dietary anthocyanin intake. Daily intake of NZBC extract is required to enhance exercise-induced fat oxidation. Enhanced exercise-induced fat oxidation by daily intake of NZBC extract is related to body composition but not to habitual dietary anthocyanin intake in physically active males. Daily anthocyanin intake seems to be required to allow the gradual build-up and maintenance of anthocyanin-derived metabolites that are required to alter mechanisms for exercise-induced substrate oxidation.

Validation and comparison between two warfarin dosing clinical algorithms and warfarin fixed dosing in specialized heart center: cross-sectional study.

Background: Warfarin is well known as a narrow therapeutic index that has prodigious variability in response which challenges dosing adjustment for the maintenance of therapeutic international normalized ratio. However, an appreciated population not on new oral anticoagulants may still need to be stabilized with warfarin dosing. Objective: The current study's main objective was to validate and compare two models of warfarin clinical algorithm models namely the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) with warfarin 5 mg fixed standard dosing strategy in a sample of Sudanese subjects. Method: We have conducted a cross-sectional study recruited from the out-patient clinic at a tertiary specialized heart center. We included subjects with unchanged warfarin dose (stabilized), and with therapeutic international normalized ratio. The predicted doses of warfarin in the two models were calculated by three different methods (accuracy, clinical practicality, and the clinical safety of the clinical algorithms). Main outcome measure: The primary outcomes were the measurements of the clinical (accuracy, practicality, and safety) in each of the two clinical algorithms models compared to warfarin 5 mg fixed standard dose strategy. Results: We have enrolled 71 Sudanese subjects with mean age (51.7 ± 14 years), of which (49, 69.0%) were females. There was no significant difference between the warfarin 5 mg fixed standard dose strategy and the predicted doses of the two clinical algorithm models (MAE 1.44, 1.45, and 1.49 mg/day [P =0.4]) respectively. In the clinical practicality, all of the three models had a high percent of subjects (95.0%, 51.9%, and 66.7%) in the ideal dose range in middle dose group (3-7 mg/ day) for warfarin 5 mg fixed standard dosing strategy, Gage, and IWPC clinical algorithm models respectively. However, a small percent of subjects was exhibited in the warfarin low dose group ≤ 3 mg/day (0.0%, 15.0%, and 10.0%) and warfarin high dose group ≥ 7 mg/day (0.0%, 33.3%, and 33.3%) for warfarin 5 mg fixed standard dosing strategy, Gage, and IWPC clinical algorithms respectively. In terms of clinical safety, the percent of subjects with severely over-prediction were 28.2%, 22.5%, and 22.5% for warfarin 5 mg fixed standard dosing, Gage, and IWPC, respectively. While the percent of severely under-prediction was 12.7%, 7.0%, and 5.6% for the warfarin 5 mg fixed standard dosing, Gage, and IWPC, respectively. Conclusion: The Gage and IWPC clinical algorithm models were accurate, more clinically practical, and clinically safe than warfarin 5 mg standard dosing in the study population. The cardiologist can use either models (Gage and IWPC) to stratify subjects for accurate, practical, and clinically safe warfarin dosing..

A dual-targeted multifunctional nanoformulation for potential prevention and therapy of Alzheimer's disease.

Antioxidation and adjustable treatment strategies are critical for the effective treatment of Alzheimer's disease (AD). Here, we design a dual-targeted Prussian blue nanoformulation (PTCN) that can cross the blood-brain barrier and target amyloid beta aggregates further exert antioxidant effects. An adjustable gradient dosing strategy with PTCN is used for the first time to design the preventive and therapeutic trials based on the severity of oxidative stress at different AD stages. The results show that PTCN could effectively ameliorate AD-related pathological processes, improve the cognitive decline, and rescue hippocampal atrophy of APP/PS1 mice in both preventive and therapeutic trials. Altogether, PTCN provided here is a successful combination of three traditional biomaterials with good biosafety, which has broad prospects for the early prevention, mild remission, and late treatment of AD, and is expected to be developed into personalized therapeutic drugs and healthcare products for clinical AD in the future.

Removal of sulfamethoxazole by ferrous iron activation of persulfate: Optimization of dosing strategy and degradation mechanism.

In this paper, the degradation of sulfamethoxazole (SMX) was investigated using the ferrous iron (Fe2+) activation of persulfate (PS) (the Fe2+/PS process). The influence of the initial concentration of both PS and Fe2+ was investigated. It was found that increasing the PS concentration resulted in a higher SMX degradation efficiency. The influence of inhibiting reactions was found to increase with increasing Fe2+ concentration. In order to minimize these inhibiting reactions, different dosing strategies were applied. It was found that the SMX degradation efficiency could be enhanced significantly when changing from direct dosing (total amount of Fe2+ dosed at the start) to sequential dosing (dosing that same total amount but divided over specific time intervals) and even more when using continuous dosing (dosing the same total amount but continuously over 30 min reaction time). The contribution of different reactive species in this process was also investigated. It was found that hydroxyl radicals (•OH) were mainly responsible for the degradation of SMX during direct dosing, while using continuous dosing of Fe2+, the contribution of Fe(IV) and sulfate radicals (•SO4-) became more important (reduction of •OH contribution from 89 to 71%). Some degradation products formed during the SMX degradation process were identified and the difference in reaction mechanism between •OH on the one hand and Fe(IV) and •SO4- on the other hand was elucidated. At last, a comparison of different sulfate radical based advanced oxidation processes (SR-AOP) is performed by comparing the difference in SMX degradation efficiency, reactive species contribution and the formed degradation products. In most investigated processes, similar degradation products have been found, however, the large •OH contribution in the Fe2+/PS process resulted in distinct degradation products.

Effect of oral vancomycin dose on outcomes in patients with Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is a significant cause of morbidity and mortality. Oral vancomycin is a cornerstone of CDI treatment, but dosing strategies in clinical practice may differ from guideline recommendations. This study aimed to determine differences in outcomes between patients treated with standard (125 mg QID) and high-dose (≥250 mg QID) oral vancomycin. This dual-centre study evaluated adult patients admitted between January 2013 and July 2017. Patients were included in the study if they had a positive C. difficile toxin PCR, symptomatic infection and received ≥48 h of oral vancomycin. Disease severity was characterised using a variety of classifiers, including guideline definitions. The primary outcome was 90-day CDI recurrence; secondary outcomes included clinical failure, in-hospital mortality and 90-day re-admission. Inverse probability of treatment weighting (IPTW) was conducted to balance differences between groups. A total of 535 patients were included; 261 received standard and 274 received high-dose vancomycin. Baseline demographics were similar between groups, except that patients receiving high-dose vancomycin were more likely to have more severe disease and to be admitted to the ICU. Few patients had fulminant disease (14.4%). No significant differences in recurrence (OR, 1.52, 95% CI 0.82-2.84), clinical failure (OR, 0.64, 95% CI 0.328-1.26), mortality (OR, 1.44, 95% CI 0.78-2.66) or re-admission (OR, 1.03, 95% CI 0.70-1.51) were identified between patients receiving standard and high-dose vancomycin in the IPTW analyses. No differences in recurrence, mortality or re-admission were identified between standard and high-dose vancomycin for the treatment of CDI not requiring surgery.

Drug exposure of first-line anti-tuberculosis drugs in China: A prospective pharmacological cohort study.

AIM: Exploring the need for optimization of drug exposure to improve tuberculosis (TB) treatment outcome is of great importance. We aimed to describe drug exposure at steady state as well as the population pharmacokinetics (PK) of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) in Chinese TB patients. METHODS: A prospective multicentre PK study of RIF, INH and PZA was conducted in China between January 2015 and December 2017. Six blood samples were collected from each subject for drug concentration measurement. Nonlinear mixed effect analyses were used to develop population PK models. RESULTS: In total, 217 patients were included. Positive correlations between body weight, clearance and volume of distribution were identified for RIF and PZA, whereas body weight only influenced clearance for INH. In addition, males had higher RIF clearance and thus lower RIF exposure than women. Acetylator status was significantly associated with INH clearance as INH exposure in intermediate and fast acetylators was significantly lower than in slow acetylators, especially in low-weight bands. Simulations also showed significantly lower drug exposures in low-weight bands for all three drugs. Patients weighing <38 kg were respectively exposed to 30.4%, 45.9% and 18.0% lower area under the concentration-time curve of RIF, INH and PZA than those weighing ≥70 kg. Higher doses by addition of one fixed-dose combination tablet or 150 mg INH were simulated and found to be effective in improving INH drug exposures, especially in low-weight bands. CONCLUSION: PK variability of first-line anti-TB drugs is common in Chinese TB patients. The developed population PK models can be used to optimize drug exposures in Chinese patients. Moreover, standard dosing needs to be adjusted to increase target attainment.

An investigation into the variability of radiographers assessing body composition prior to CT contrast media administration.

INTRODUCTION: To evaluate and report the variability of radiographers in determining a patient's body type and using this to determine contrast media (CM) volumes for chest computed tomography (CT). METHODS: This prospective study recruited 50 patients undergoing chest CT examinations. Three radiographers independently used two methods to determine patient body type and consequently CM volume. In Method 1, subjective evaluation of body type together with patient weight determined CM volume. In Method 2, patient weight along with additional criteria applied by the radiographer determined CM volume. Both the determination of body type and CM volumes were compared in terms of agreement and variability between radiographers, and between methods. RESULTS: Fleiss' kappa was lower (0.583) for Method 1 when compared to Method 2 (0.926) indicating stronger agreement in the radiographer determination of body type for Method 2. Median (IQR) CM volume was 95.0 mL (85.0-110.0) for Method 1, compared to 92.5 mL (85.0-100.0) for method 2 (P < 0.001). CONCLUSION: Method 2 provided greater agreement in determination of body type, and reduction of CM volumes compared to Method 1. IMPLICATIONS FOR PRACTICE: Determining body type as part of a CT CM strategy can be subjective and enhanced methods are required to ensure that the most appropriate CM volumes are reliably used.

A Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD.

BACKGROUND: Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure-while reducing the need for red blood cell transfusions-is unknown. METHODS: In this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 µg/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician. RESULTS: There were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 µg) compared with the titration-dose group (53.6 µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) µg and 53.6 (31.1, 89.9) µg, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) µg. CONCLUSIONS: These findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.

Developing a restricted chlorine-dosing strategy for UV/chlorine and post-chlorination under different pH and UV irradiation wavelength conditions.

UV/chlorine and chlorination processes have drawn great interests of water treatment utilities for oxidation and disinfection purposes. This work proposed a restricted chlorine-dosing strategy for UV/chlorine and post-chlorination under different pH and UV irradiation conditions by comprehensively assessing the oxidation of natural organic matter (NOM), formation of 9 haloacetic acids (HAA9) and bromate, and alteration of toxicity. During UV/chlorine with restricted chlorine doses, the oxidation of NOM chromophores (i.e., ΔUVA254) showed an apparent dependence on cumulative exposures of free available chlorine (CTFAC); Meanwhile, HAA9 formation was determined by CTFAC values and could be linearly correlated with ΔUVA254 irrespective of pH and UV irradiation wavelength. Irradiated by 254 nm LP-Hg lamp, the faster chlorine photolysis produced relatively higher steady-state concentrations of Cl• and HO• species but resulted in lower CTFAC. Reducing CTFAC values by operation parameters (pH, UV wavelength and irradiation fluence) could mitigate HAA9 formation during UV/chlorine at a specific chlorine dose. Additionally, high bromide concentration and acidic pH promoted more bromo-HAAs formation, and the presence of NOM significantly suppressed bromate formation. Analogous to ozonation, the UV/chlorine pre-oxidation could reduce the HAA9 formation potentials during post-chlorination at mildly alkaline pH. The photobacterium bioassay further demonstrated that although the UV/chlorine treatment might have increased the acute toxicity, the post-chlorination treatment could polish the acute toxicity to the level of chlorination alone. These results suggest that with the restricted chlorine-dosing strategy, the trade-off between oxidation/disinfection efficiency and DBPs formation can be controlled by monitoring CTFAC and ΔUVA254 values during UV/chlorine treatment.

Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model.

Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19). To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens, a PBPK model, with parameterization of drug distribution extrapolated from animal data, was developed to predict human tissue distribution of CQ. The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism. Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships. The model was also validated by clinical data from Chinese patients with COVID-19. The novel PBPK model allows in-depth description of the pharmacokinetics of CQ in several key organs (lung, heart, liver, and kidney), and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID, Days 2-5: 500 mg BID, CQ phosphate), patients with moderate COVID-19 (Day 1: 750 mg and 500 mg, Days 2-3: 500 mg BID, Days 4-5: 250 mg BID, CQ phosphate), and other vulnerable populations (e.g., renal and hepatic impairment and elderly patients, Days 1-5: 250 mg BID, CQ phosphate). A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.

Dose Optimization of Gentamicin in Critically Ill Neonates.

BACKGROUND: Appropriate dosing of gentamicin in critically ill neonates is still debated. OBJECTIVE: To assess the peak concentration (Cmax) and area-under-the-time-concentration curve (AUC0-24) of gentamicin and to simulate the recommended doses using the Monte Carlo method. METHODS: This was a retrospective study on critically ill neonates carried over a one-year period. The demographic characteristics, dosage regimen and gentamicin concentrations were recorded for each neonate. Using Bayesian pharmacokinetic modeling, Cmax and AUC0-24 were predicted. Dose recommendations for the target Cmax (µg/ml) of 12 were obtained, and Monte Carlo simulation (100,000 iterations) was used for predicting the pharmacokinetic parameters and recommended doses for various birth weight categories. RESULTS: Eighty-two critically ill neonates (with an average gestational age of 33.7 weeks; and birth weight of 2.1 kg) were recruited. Higher Cmax and AUC0-24 values were predicted in premature neonates, with greater cumulative AUCs in extremely preterm neonates. The average administered dose was 4 mg/kg/day and 75% of the participants had Cmax greater than 12 µg/ml following a single dose, and 85% were found to be at steady state. On the contrary, only 25% of the study population had the recommended AUC0-24 (above 125 µg-hr/ml). Simulation tests indicate that 90% of the critically ill neonates would achieve recommended Cmax with doses ranging between 5 and 6 mg/kg/day. CONCLUSION: Currently used dose of 4 mg/kg/day is adequate to maintain Cmax in a large majority of the study population, with one-fourth population reporting the recommended AUC0-24. Increasing the dose to 5-6 mg/kg/day will more likely help to achieve both the recommended Cmax and AUC0-24 values.

Safety and effectiveness of apatinib in patients with previously treated metastatic gastric cancer: a sub-analysis from the real-world study of apatinib for gastric cancer treatment (AHEAD-G202).

Apatinib, a VEGFR2 receptor tyrosine kinase inhibitor, showed survival benefits in Asian patients with heavily pretreated advanced gastric cancer. However, the adverse event (AEs) profile of apatinib has limited its use. Dosing schedules are used to alleviate toxicities despite no supportive evidence. This study aimed to analyze the toxicity and effectiveness of apatinib alone, especially with different dosing strategies in advanced gastric cancer patients under a real-world setting. Data from the subpopulation of patients who failed ≥2 chemotherapy regimens enrolled in the AHEAD-G202 trial were analyzed. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Totally 120 patients were included into three groups by the initial daily doses: 43 (35.8%) patients in the low-dose (250 mg) group, 67 (55.8%) patients in the mid-dose (425 mg to 500 mg) group, and 10 (8.3%) patients in the high-dose (675 to 850 mg) group. Grade 3/4 treatment-emergent AEs were infrequent (<5%), with the most commonly reported grade 3/4 AEs being hand-foot syndrome (4.2%), hypertension (4.2%,), fatigue (4.2%), and difficulty in swallowing (4.2%) which gradually decreased among the high-, mid-, and low-dose groups. The median OS and PFS were 6.33 months (95% CI, 4.57-7.73) and 3.83 months (95% CI: 1.40-4.20), respectively and were comparable among the three doses groups. We found heavily pretreated advanced gastric cancer patients can tolerate and benefit from lower-doses of apatinib therapy. The lower initial daily dosing strategy represents an alternative approach for optimizing apatinib dosing in clinical practice.

Economics of alternative dosing strategies for pembrolizumab and nivolumab at a single academic cancer center.

BACKGROUND: The FDA initially approved pembrolizumab and nivolumab for doses based on patient weight, but subsequently amended approval to fixed doses. We estimated savings from novel dosing strategies based on real-world patient data from a single cancer center. METHODS: We analyzed all outpatient doses of pembrolizumab and nivolumab administered at three infusion centers affiliated with our academic hospital between July 1, 2018 and Oct 31, 2018. We estimated savings from several dosing strategies with and without vial sharing between patients. RESULTS: A total of 1029 doses of pembrolizumab or nivolumab were administered for multiple cancer types. For 77% of doses, the weight-based dose was less than the fixed dose. "Dose-minimization" (DM), defined as the lesser of weight-based and fixed dose decreased nivolumab spending by 9% without affecting pembrolizumab spending. DM plus vial sharing decreased pembrolizumab spending by 19% without affecting nivolumab. The differences in savings were due to availability of multiple vial sizes for nivolumab but not pembrolizumab. DM plus vial sharing for both drugs would have saved $1.5 million USD over the 4-month study period. CONCLUSION: New dosing strategies for pembrolizumab and nivolumab can generate large savings without anticipated decrease in efficacy. Barriers include FDA dosing labels, hospital policies against vial sharing, and inaccessibility of smaller vial sizes, which are currently available in other worldwide markets.