Population Pharmacokinetics and Individualized Medication of Azithromycin for Injection in Children Under 6 Years Old.

Pharmacokinetic data for injectable azithromycin in children remain limited. This study aims to develop and validate a population pharmacokinetic model of azithromycin for injection in children under 6 years old and optimize its dosage regimen in this population. We prospectively enrolled patients under 6 years old who received azithromycin for injection at Beijing Friendship Hospital, Capital Medical University. Demographic information, clinical characteristics, and venous blood samples were collected in accordance with the research protocol. Azithromycin concentrations were determined using a validated UPLC-MS/MS method. The population pharmacokinetic model was structured using Phoenix NLME. The adequacy and robustness of the model was evaluated using VPC and bootstrap. We optimized azithromycin's dosing regimen for injection through Monte Carlo simulations. We included 254 plasma concentration data from 148 patients to establish the model. The clearance and volume were 1.27 L/h/kg and 45.6 L/kg, respectively. The covariates included were weight and age. VPC plots and nonparametric bootstrap showed that the final PPK model was reliable and robust. Based on Monte Carlo simulation, we derived a simple and practical dosing scheme. The results provided reference for individualized dosing in this population. The individualized dosing scheme based on Monte Carlo simulation can optimize clinical decision-making and guide personalized therapy.

Course design, delivery, and assessment strategies for pharmaceutical calculations course in a doctor of pharmacy program: A review.

BACKGROUND: Pharmaceutical calculations is a fundamental course taken by doctor of pharmacy students in United States schools and colleges of pharmacy. To minimize medical errors and increase the accuracy with which future pharmacists perform calculations, a comprehensive training during the program is deemed. This review attempts to summarize research outcomes of interventions described thus far in the literature concerning the improvement of course design, delivery, and assessment strategies. METHODS: A detailed literature review of various educational resources was conducted using pharmaceutical calculations and related terms. RESULTS: The literature review outcomes were divided into three major categories: educational interventions in design, delivery, and assessment of pharmaceutical calculations courses. The research findings of course design describe a standalone course vs. an integrated course, a computer-aided course, use of compact disc read-only memory, and implementation of Gagne's Nine Events of Instructions. Findings in course delivery include the use of self-paced vs. integrated courses, flipped classroom vs. traditional lecture, Keller's Personalized System of Instruction, condensed videos, and podcasts. Finally, different types of assessments are presented such as those based on selected- vs. constructed-response questions, collaborative quizzes, the approach of repeated testing, and the use of technology. IMPLICATIONS: While the review intends to present educational interventions available to construct and/or modify an existing pharmaceutical calculations course, the choice of design, delivery, and assessment approaches depends upon various factors such as the purpose of course modification, resources available, and the number of students in class.

Population Pharmacokinetics and Dosing Optimization of Vancomycin in Pediatric Liver Transplant Recipients.

Methicillin-resistant Staphylococcus aureus infections are a significant cause of morbidity and mortality in pediatric liver transplant (LT) recipients. Physiological changes following LT may affect vancomycin pharmacokinetics; however, appropriate dosing to achieve sufficient drug exposure (i.e., 24-h area under the concentration-time curve [AUC24]/MIC ≥ 400) in pediatric LT recipients has not been reported. This retrospective pharmacokinetics study of LT recipients aged <18 years utilized data on patient characteristics with vancomycin concentrations and dosing information obtained from electronic medical records. Population pharmacokinetics analysis was conducted by nonlinear mixed-effects modeling with the Phoenix NLME software. Potential covariates were screened with univariate and multivariate analysis. Monte Carlo simulations were performed using the final model to explore appropriate dosing. The study included 270 pharmacokinetics profiles encompassing 1,158 concentrations measured in 161 patients. The median age was 13.3 (interquartile range, 7.6 to 53.5) months, serum creatinine (sCr) was 0.16 (0.12 to 0.23) mg/dl, and days from LT (DFLT) was 17 (6 to 31). Multivariate analysis demonstrated that lower sCr and shorter DFLT were associated with higher clearance. By post hoc estimation, the average clearance and volume of distribution were 0.18 liters/h/kg and 1.01 liters/kg, respectively. The Monte Carlo simulations revealed that only 16% of patients achieved an AUC24/MIC of ≥400 with the assumed vancomycin MIC of 1 µg/ml. DFLT and sCr were significant covariates for vancomycin clearance in pediatric LT recipients. Standard vancomycin dosing may be insufficient, and higher or more frequent dosing may be required to achieve an AUC24/MIC of ≥400 in pediatric LT recipients with normal renal function. IMPORTANCE We evaluated vancomycin pharmacokinetics in pediatric LT recipients and developed a population pharmacokinetics model by considering various factors that might account for alterations in vancomycin pharmacokinetics. Our analyses revealed that lower serum creatinine levels and a shorter duration from the day of LT were associated with higher vancomycin clearance and led to subtherapeutic drug exposure. We also performed Monte Carlo simulations to determine the appropriate dosing strategy in pediatric LT recipients, which revealed that a standard vancomycin dosing might be insufficient and that higher or more frequent dosing might be necessary to achieve an AUC24/MIC of ≥400 in pediatric LT recipients with normal renal function. To the best of our knowledge, this is the first study to assess vancomycin pharmacokinetics in pediatric LT recipients by population pharmacokinetics analysis.

A framework for economic evaluation of therapeutic drug monitoring-guided dosing in oncology.

The standard approach for dose individualization of chemotherapy in the oncology setting has long been based on body surface area (BSA) as a measure of body size. However, for many anticancer drugs, administration of dosages based on BSA may result in some patients receiving supratherapeutic or subtherapeutic concentrations due to substantial interindividual pharmacokinetic variability. Therapeutic drug monitoring (TDM)-guided dosing aims to ensure that the patient's serum drug concentration is in a target range which has been shown to produce optimal clinical outcomes. The management of several malignancies is now moving away from using traditional intravenous chemotherapy to longer-term treatment with targeted molecular therapies. These targeted anticancer drugs are currently dosed based on a fixed dose for all patients. The pharmacokinetic characteristics of most of these drugs (e.g., tyrosine-kinase inhibitors) support implementation of individualized dosing via TDM. However, prior to adopting TDM-guided dosing in oncology settings, the economic efficiency and value for money of introducing TDM interventions should be critically and systematically examined along with the impacts on patient care and outcomes. Yet, current evidence in this area is limited, and more generally, there is lack of methodological guidance on how to identify, estimate and value clinical and cost information necessary to conduct economic evaluations of TDM interventions. In this paper, we propose a coherent framework for conducting economic evaluation of TDM interventions in oncology settings and discuss some practical challenges of conducting economic evaluations of TDM.

Financial Burden of Discarded Weight-based Antineoplastic Drugs to Payers and Patients in the Private Insurance Market.

Background: Our study estimated insurance payments and patient out-of-pocket (OOP) expenses associated with discarded weight-based intravenous antineoplastic drugs for privately insured US adult patients with cancer. Methods: We identified patients who received weight-based antineoplastic drugs from a 2017 MarketScan health risk assessment (IBM Corp, Armonk, NY) linked to claims data. Using weight information in the health risk assessment, we derived the recommended dose and calculated the percentage of drugs discarded. We applied ß-regression to determine factors associated with the discarded percentages. To compare patients with and without high-deductible plans, we employed a generalized linear model and a 2-part model to examine insurance payment and OOP expense, respectively. All statistical tests were 2-sided. Results: Of 27 350 claims for 58 weight-based antineoplastic drugs from 1970 patients, the median discarded percentage was 9.8% (mean [SD] = 12.8% [10.5%]). Aside from drug and tumor type, statistically significantly higher discarded percentages were found for patients in the lowest weight group (5.5% [95% confidence interval = 4.7% to 6.4%]; P < .001; weight <150 lb [68.0 kg] vs ≥200 lb [90.7 kg]). Private payers spent $5090 per patient in 2017 on discarded weight-based antineoplastic drugs, and patients' mean OOP expense on discarded drugs was $63. In total, 39.7% of patients had high-deductible plans. The adjusted mean OOP expense for discarded drugs was statistically significantly higher for those in high-deductible plans ($95 vs $47; P < .001). Conclusions: Private insurers incurred substantial financial burden from discarded weight-based antineoplastic drugs. Although the OOP expenses of discarded drugs were modest for most privately insured patients with cancer, approximately 5% spent more than $400 on the discarded drugs. Policies designed to reduce drug waste from single-dose, weight-based antineoplastic drugs should evaluate their financial consequences for payers and patients.

Clinical Benefit of Therapeutic Drug Monitoring in Colorectal Cancer Patients Who Received Fluorouracil-Based Chemotherapy.

BACKGROUND The impact of therapeutic drug management (TDM) on reducing toxicity and improving efficacy in colorectal cancer (CRC) patients receiving fluorouracil-based chemotherapy is still unclear. MATERIAL AND METHODS A total of 207 patients (Study Group n=54, Historical Group n=153) with metastatic colorectal cancer were enrolled. All of them received 6 administrations of the 5-FU based regimens. Initial 5-FU dosing of all patients was calculated using body surface area (BSA). In the Study Group, individual exposure during each cycle was measured using a nanoparticle immunoassay, and the 5-FU blood concentration was calculated using the area under the curve (AUC). We adjusted the 5-FU infusion dose of the next cycle based on the AUC data of the previous cycle to achieve the target of 20-30 mg×h/L. RESULTS In the fourth cycle, patients in the target concentration range (AUC mean, 26.3 mg×h/L; Median, 28 mg×h/L; Range, 14-38 mg×h/L; CV, 22.4%) accounted for 46.8% of all patients, which were more than the ones in the first cycle (P<0.001). 5-FU TDM significantly reduced the toxicity of chemotherapy and improved its efficacy. The Study Group (30/289) showed a lower percentage of severe adverse events than that in the Historical Group (185/447) (P<0.001). The incidences of complete response and partial response in the Study Group were higher than those in the Historical Group (P=0.032). CONCLUSIONS TDM in colorectal cancer can reduce toxicity, improve efficacy and clinical outcome, and can be routinely used in 5-FU-based chemotherapy.

Personalized Variable vs Fixed-Dose Systemic Corticosteroid Therapy in Hospitalized Patients With Acute Exacerbations of COPD: A Prospective, Multicenter, Randomized, Open-Label Clinical Trial.

BACKGROUND: Systemic corticosteroids for the treatment of COPD exacerbations decrease treatment failure and shorten the length of hospitalization. However, the optimal dose is unclear. RESEARCH QUESTION: Is personalized-dose corticosteroid administered according to a dosing scale more effective than fixed-dose corticosteroid administration in hospitalized patients with COPD with exacerbations? STUDY DESIGN AND METHODS: This was a prospective, randomized, open-label trial. In-hospital patients with COPD with exacerbations were randomly assigned at a 1:1 ratio to either the fixed-dose group (receiving the equivalent of 40 mg of prednisolone) or the personalized-dose group for 5 days. The primary end point was a composite measure of treatment failure that included in-hospital treatment failure and medium-term (postdischarge) failure. Secondary end points were length of stay and cost. RESULTS: A total of 248 patients were randomly assigned to the fixed-dose group (n = 124) or personalized-dose group (n = 124). One patient in each group was not included in the intention-to-treat population because of incorrect initial COPD diagnosis. Failure of therapy occurred in 27.6% in the personalized-dose group, compared with 48.8% in the fixed-dose group (relative risk, 0.40; 95% CI, 0.24-0.68; P = .001). The in-hospital failure of therapy was significantly lower in the personalized-dose group (10.6% vs 24.4%; P = .005), whereas the medium-term failure rate, adverse event rate, hospital length of stay, and costs were similar between the two groups. After treatment failure, a lower additional dose of corticosteroids and a shorter duration of treatment were needed in the personalized-dose group to achieve control of the exacerbation. In the personalized-dose cohort, those receiving 40 mg or less had an average failure rate of 44.4%, compared with 22.9% among those receiving more than 40 mg (P = .027). INTERPRETATION: Personalized dosing of corticosteroids reduces the risk of failure because more patients were provided with a higher initial dose, especially > 60 mg, whereas 40 mg or less was too low in either group. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02147015; URL: www.clinicaltrials.gov.

Preoperative Management of Opioid and Nonopioid Analgesics: Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement.

There is a lack of guidelines for preoperative dosing of opioid and nonopioid pain medications for surgical patients, which can lead to suboptimal preoperative pain control. The Society for Perioperative Assessment and Quality Improvement identified preoperative dosing of opioid and nonopioid analgesics as an area in which consensus could improve patient care. The aim of this guideline is to provide consensus that will allow perioperative physicians to make optimal recommendations regarding preoperative pain medication dosing. Six categories of pain medications were identified: opioid agonists, opioid antagonists, opioid agonist-antagonists, acetaminophen, muscle relaxants, and triptans/headache medications. We then used a Delphi survey technique to develop consensus recommendations for preoperative dosing of individual medications in each of these groups.

Variation in Target Attainment of Beta-Lactam Antibiotic Dosing Between International Pediatric Formularies.

As antimicrobial susceptibility of common bacterial pathogens decreases, ensuring optimal dosing may preserve the use of older antibiotics in order to limit the spread of resistance to newer agents. Beta-lactams represent the most widely prescribed antibiotic class, yet most were licensed prior to legislation changes mandating their study in children. As a result, significant heterogeneity persists in the pediatric doses used globally, along with quality of evidence used to inform dosing. This review summarizes dosing recommendations from the major pediatric reference sources and tries to answer the questions: Does beta-lactam dose heterogeneity matter? Does it impact pharmacodynamic target attainment? For three important severe clinical infections-pneumonia, sepsis, and meningitis-pharmacokinetic models were identified for common for beta-lactam antibiotics. Real-world demographics were derived from three multicenter point prevalence surveys. Simulation results were compared with minimum inhibitory concentration distributions to inform appropriateness of recommended doses in targeted and empiric treatment. While cephalosporin dosing regimens are largely adequate for target attainment, they also pose the most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin, and meropenem doses as potentially requiring review/optimization in order to preserve the use of these agents in future.

Determination of vancomycin exposure target and individualised dosing recommendations for neonates: model-informed precision dosing.

INTRODUCTION: Few studies incorporating population pharmacokinetic/pharmacodynamic (Pop-PK/PD) modelling have been conducted to quantify the exposure target of vancomycin in neonates. A retrospective observational cohort study was undertaken in neonates to determine this target and dosing recommendations (chictr.org.cn, ChiCTR1900027919). METHODS: A Pop-PK model was developed to estimate PK parameters. Causalities between acute kidney injury (AKI) occurrence and vancomycin use were verified using Naranjo criteria. Thresholds of vancomycin exposure in predicting AKI or efficacy were identified via classification and regression tree analysis. Associations between exposure thresholds and clinical outcomes, including AKI and efficacy, were analysed by logistic regression. Dosing recommendations were designed using Monte Carlo simulations based on the optimised exposure target. RESULTS: Pop-PK modelling included 182 neonates with 411 observations. On covariate analysis, neonatal physiological maturation, renal function and concomitant use of vasoactive agents (VAS) significantly affected vancomycin PK. Seven cases of vancomycin-induced AKI were detected. Area under the concentration-time curve from 0-24 hours (AUC0-24) ≥ 485 mg•h/L was an independent risk factor for AKI after adjusting for VAS co-administration. The clinical efficacy of vancomycin was analysed in 42 patients with blood culture-proven staphylococcal sepsis. AUC0-24 to minimum inhibitory concentration (AUC0-24/MIC) ≥ 234 was the only significant predictor of clinical effectiveness. Monte Carlo simulations indicated that regimens in Neonatal Formulary 7 and Red Book (2018) were unsuitable for all neonates. CONCLUSION: An AUC0-24 of 240-480 (assuming MIC = 1 mg/L) is a recommended exposure target of vancomycin in neonates. Model-informed dosing regimens are valuable in clinical practice.

Population Pharmacokinetics of Intracellular 5-Fluorouridine 5'-Triphosphate and its Relationship with Hand-and-Foot Syndrome in Patients Treated with Capecitabine.

Capecitabine is an oral pro-drug of 5-fluorouracil. Patients with solid tumours who are treated with capecitabine may develop hand-and-foot syndrome (HFS) as side effect. This might be a result of accumulation of intracellular metabolites. We characterised the pharmacokinetics (PK) of 5-fluorouridine 5'-triphosphate (FUTP) in peripheral blood mononuclear cells (PBMCs) and assessed the relationship between exposure to capecitabine or its metabolites and the development of HFS. Plasma and intracellular capecitabine PK data and ordered categorical HFS data was available. A previously developed model describing the PK of capecitabine and metabolites was extended to describe the intracellular FUTP concentrations. Subsequently, a continuous-time Markov model was developed to describe the development of HFS during treatment with capecitabine. The influences of capecitabine and metabolite concentrations on the development of HFS were evaluated. The PK of intracellular FUTP was described by an one-compartment model with first-order elimination (ke,FUTP was 0.028 h-1 (95% confidence interval 0.022-0.039)) where the FUTP influx rate was proportional to the 5-FU plasma concentrations. The predicted individual intracellular FUTP concentration was identified as a significant predictor for the development and severity of HFS. Simulations demonstrated a clear exposure-response relationship. The intracellular FUTP concentrations were successfully described and a significant relationship between these intracellular concentrations and the development and severity of HFS was identified. This model can be used to simulate future dosing regimens and thereby optimise treatment with capecitabine.

Comparison of the Pharmacokinetic Properties of Extended Half-Life and Recombinant Factor VIII Concentrates by In Silico Simulations.

BACKGROUND: The pharmacokinetic (PK) properties of extended half-life (EHL) factor VIII (FVIII) concentrates differ, leading to variation in the optimal dosing regimen for the individual patient. The aim of this study was to establish these PK differences for various EHL FVIII concentrates by in silico simulations. METHODS: FVIII level over time profiles of rFVIII-SC, BAY 81-8973, rFVIII-Fc, BAX 855, BAY 94-9027, and standard half-life (SHL) rFVIII concentrates were simulated for 1,000 severe hemophilia A patients during steady-state dosing of 40 IU/kg every 72 hours or dosing as advised in the summary of product characteristics (SmPC). RESULTS: Although the elimination half-life values were comparable for rFVIII-FC, BAX 855, and BAY 94-9027, a higher area under the curve (AUC; 2,779 IU/h/dL) for BAY 94-9027 was obtained. During steady-state dosing of 40 IU/kg every 72 hours, 58.5% (rFVIII-SC), 69.3% (BAY 81-8972), 89.0% (rFVIII-Fc), 83.9% (BAX 855), and 93.7% (BAY 94-9027) of the patients maintained a trough level of 1 IU/dL, compared with 56.0% for SHL rFVIII. Following dosing schemes described in the SmPC, between 51.0 and 65.4% or 23.2 and 31.1% of the patients maintained a target trough level of 1 IU/dL or 3 IU/dL, respectively. CONCLUSION: BAY 94-9027 showed the largest increase of AUC and best target attainment compared with SHL rFVIII, followed closely by BAX 855 and rFVIII-Fc. BAY 81-8973 and rFVIII-SC showed smaller PK improvements. Although our analyses increase insight into the PK of these FVIII concentrates, more studies evaluating the relation between factor levels and bleeding risk are needed.

Population pharmacokinetics of unbound valproic acid in pediatric epilepsy patients in China: a protein binding model.

PURPOSE: The purpose of this study was to establish a protein binding model of unbound valproic acid (VPA) based on Chinese pediatric patients with epilepsy and provide a reference for clinical medication. METHODS: A total of 313 patients were included and both their total and unbound VPA concentrations (375 pairs of concentrations) were measured. NONMEM software was used for population pharmacokinetic modeling. The stepwise method was used to screen the potential covariates. Goodness-of-fit plot, bootstrap, and visual predictive check were used for model evaluation. In addition, dose recommendations for typical patients aged 0 to 16 years were proposed by Monte Carlo simulations. RESULTS: A one-compartment model of first-order absorption and first-order elimination was used to describe the pharmacokinetic characteristics of unbound VPA, and the linear non-saturable binding equation was introduced to describe the protein binding. Body weight, age-based maturation, and co-medicated with lamotrigine could affect the CL/F of unbound and bound VPA. Model evaluation showed satisfactory robustness of the final model. The dosing regimens for children aged 0 to 16 years were proposed based on the final established model. CONCLUSION: We developed a population pharmacokinetic model of unbound and bound VPA that took account of protein binding. The VPA dosing regimen in pediatric patients with epilepsy needs to be optimized by the body weight, age, and co-medications.

Model informed dosing of hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and gaps.

AIMS: In the absence of a commonly agreed dosing protocol based on pharmacokinetic (PK) considerations, the dose and treatment duration for hydroxychloroquine (HCQ) in COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. METHODS: We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. RESULTS: Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800 mg day on day 1 followed by 600 mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. CONCLUSION: Our results were clear, indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best benefit/risk balance.

Initial Dosage Optimization of Tacrolimus in Pediatric Patients With Thalassemia Major Undergoing Hematopoietic Stem Cell Transplantation Based on Population Pharmacokinetics.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an effective treatment for hematological disorders. Tacrolimus is widely used after HSCT, but it has highly interindividual variable pharmacokinetics. Population pharmacokinetics (PPK) researches of tacrolimus in children with ß-thalassemia major (ß-TM) undergoing HSCT are insufficient. OBJECTIVE: To establish a PPK model of tacrolimus in children with ß-TM and optimize initial dosing regimen for achieving target concentration of 5 to 15 ng/mL. METHODS: Data on patients aged <18 years were retrospectively collected from January 2017 to December 2018. PPK analysis and Monte Carlo simulations were performed using nonlinear mixed-effects modeling. RESULTS: A data set of 55 patients with 332 concentrations was included. A 2-compartment model could best describe the pharmacokinetics of tacrolimus. The body surface area and gender were significant covariates in the final model. The typical value of clearance, the distribution volume of the central room, the distribution volume of the peripheral room, and the intercompartmental clearance were 5.05L/h, 4.33L, 155L, and 6.22L/h, respectively. The optimal initial dosing regimen of 0.03, 0.04, 0.05, 0.06, and 0.10 mg/kg were appropriate for female children with a weight (WT) of 50 to 10 kg. The regimen of 0.04, 0.05, 0.06, 0.07, and 0.12 mg/kg is suitable for male children with a WT of 50 to 10 kg. The probability of target attainment (PTA) of each regimen reached 91%. CONCLUSION AND RELEVANCE: A stable PPK model of tacrolimus was established. The proposed dosage regimen reached a good PTA, which could provide a reference for tacrolimus therapy.

A Systematic Assessment of US Food and Drug Administration Dosing Recommendations For Drug Development Programs Amenable to Response-Guided Titration.

A key goal in drug development is optimized dosing for patients. Interactions between drug developers and regulatory scientists throughout development are important for the optimization of dosing and serve as a forum to discuss approaches for optimal dosing, such as precision or individualized dosing. To date, there has not been a systematic assessment of the advice provided by the US Food and Drug Administration (FDA) to drug developers from an individualized dosing perspective. Here, we reviewed FDA recommendations on dose selection for efficacy trials at end-of-phase meetings between the FDA and drug developers for 76 new molecular entities approved between 2013 and 2017 that are considered amenable for an individualized dosing method, response-guided titration. Forty FDA dosing recommendations were identified as specific to dose selection and design of the respective efficacy trials and subsequently: (i) characterized based on if they were supportive of individualized dosing and (ii) compared with dosing regimens used in efficacy trials and labeling at approval to evaluate if FDA recommendations were implemented. Of these 40 recommendations for efficacy trials, 35 (88%) were considered supportive of individualized dosing. Eighteen of these 40 recommendations (45%) were incorporated into efficacy trials and 11 (28%) were incorporated into labeling. This research suggests that early FDA-sponsor interactions can support the study of doses in efficacy trials that may lead to individualized dosing strategies in labeling.

Assessment of practices for suspended oral drugs by tablet crushing in pediatric units.

The aim of this study was to assess the impact of suspended drug by tablet crushing in our pediatric hospital in term of targeted dose and to identify parameters involved in the potential variability. Four usually crushed pediatric drug substances were selected: amiodarone, warfarin, hydrocortisone and captopril. Each tablet was crushed in a bag using a crusher device. Once crushed, a pre-determined volume of water was added using oral syringes before taking the necessary volume to obtain the targeted drug amount. For each drug, operators among pharmacy technicians and nurses investigated 2 targeted doses (high and low). Each suspension was assayed 3 times using the corresponding validated HPLC procedure. Statistical analysis was performed (GraphPad Prism®) to evaluate the impact of operators, the level of suction in bag, and actual drug doses. To investigate the impact of formulation change on syringe drug content, five generic drugs of amiodarone were selected. Syringes contents were compared using one-way ANOVA. Drug loss in syringe ranged from 8.1% to 54.1%. The drug loss represented 18.9% to 30.5% for amiodarone, 0.1% to 5.5% for captopril, 5.6% to 19.7% for warfarin and 5.0% to 30.7% for hydrocortisone. The comparison of level sampling of suspensions presented significant differences for amiodarone, hydrocortisone, and warfarin. Comparison of operators demonstrated significant difference between pharmacy technician and nurse (p = 0.0251). Finally, comparison of 5 generic drugs for amiodarone showed some statistical difference between the syringes content obtained when using the original medicine as compared to the generics. The physicochemical properties of each drug substance and the formulation of the drug product may both factor that should be considered. As a result, crushing tablets in water for oral administration needs a case by case assessment. Although appropriate pediatric formulations are lacking, suspend the crushed material in a given volume of water should be discouraged and not recommended because far from good practice.