Re-discover the value of protein binding assessments in hepatic and renal impairment studies and its contributions in drug labels and dose decisions.

One of the key pharmacokinetic properties of most small molecule drugs is their ability to bind to serum proteins. Unbound or free drug is responsible for pharmacological activity while the balance between free and bound drug can impact drug distribution, elimination, and other safety parameters. In the hepatic impairment (HI) and renal impairment (RI) clinical studies, unbound drug concentration is often assessed; however, the relevance and impact of the protein binding (PB) results is largely limited. We analyzed published clinical safety and pharmacokinetic studies in subjects with HI or RI with PB assessment up to October 2022 and summarized the contribution of PB results on their label dose recommendations. Among drugs with HI publication, 32% (17/53) associated product labels include PB results in HI section. Of these, the majority (9/17, 53%) recommend dose adjustments consistent with observed PB change. Among drugs with RI publication, 27% (12/44) of associated product labels include PB results in RI section with the majority (7/12, 58%) recommending no dose adjustment, consistent with the reported absence of PB change. PB results were found to be consistent with a tailored dose recommendation in 53% and 58% of the approved labels for HI and RI section, respectively. We further discussed the interpretation challenges of PB results, explored treatment decision factors including total drug concentration, exposure-response relationships, and safety considerations in these case examples. Collectively, comprehending the alterations in free drug levels in HI and RI informs treatment decision through a risk-based approach.

A Randomized Trial Comparing Standard of Care to Bayesian Warfarin Dose Individualization.

The quality of warfarin treatment may be improved if management is guided by the use of models based upon pharmacokinetic-pharmacodynamic theory. A prospective, two-armed, single-blind, randomized controlled trial compared management aided by a web-based dose calculator (NextDose) with standard clinical care. Participants were 240 adults receiving warfarin therapy following cardiac surgery, followed up until the first outpatient appointment at least 3 months after warfarin initiation. We compared the percentage of time spent in the international normalized ratio acceptable range (%TIR) during the first 28 days following warfarin initiation, and %TIR and count of bleeding events over the entire follow-up period. Two hundred thirty-four participants were followed up to day 28 (NextDose: 116 and standard of care: 118), and 228 participants (114 per arm) were followed up to the final study visit. Median %TIR tended to be higher for participants receiving NextDose guided warfarin management during the first 28 days (63 vs. 56%, P = 0.13) and over the entire follow-up period (74 vs. 71%, P = 0.04). The hazard of clinically relevant minor bleeding events was lower for participants in the NextDose arm (hazard ratio: 0.21, P = 0.041). In NextDose, there were 89.3% of proposed doses accepted by prescribers. NextDose guided dose management in cardiac surgery patients requiring warfarin was associated with an increase in %TIR across the full follow-up period and fewer hemorrhagic events. A theory-based, pharmacologically guided approach facilitates higher quality warfarin anticoagulation. An important practical benefit is a reduced requirement for clinical experience of warfarin management.

The development and evaluation of dose-prediction tools for allopurinol therapy (Easy-Allo tools).

AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.

The contributors to dosage calculation ability and its applicability to nursing education: An integrative review.

Medication errors are a major patient safety issue and account for 1-2 million hospitalizations and between 100,000 and 200,000 deaths annually. Approximately 41 % of all medication errors are due to improper dose calculations. Studies have shown mean scores on the medication dosage calculation test for nursing students range from 35 to 71 %. Despite new technology created to aid in dosage calculations, the issue is still prevalent among nurses. It is critical that the elements contributing to the nurses' ability to complete dosage calculations be determined so that calculation curriculum in nursing schools can be updated to better prepare students for practice. An integrative review was completed using the databases of PubMed, CINAHL, and Embase to answer the research question: What contributors impact nurses' and nursing students' ability to complete dosage calculations? Four articles met the specified inclusion criteria and were used for this review. The three most common contributing themes among the review sample included mathematical medication calculation ability, medication calculation frequencies, and dosage calculation education. Results from this review can inform the issue of dosage calculations and highlight the need for further research regarding the medication administration competencies taught in undergraduate nursing studies.

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.

Medication Errors in Pediatric Emergency Departments: A Systematic Review and Recommendations for Enhancing Medication Safety.

OBJECTIVE: This systematic review aims to investigate the prevalence, preventability, and severity of medication errors in pediatric emergency departments (P-EDs). It also aims to identify common types of medication errors, implicated medications, risk factors, and evaluate the effectiveness of interventions in preventing these errors. METHODS: A systematic review analyzed 6 primary studies with sample sizes ranging from 96 to 5000 pediatric patients in P-EDs. The review followed Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and included observational studies and randomized controlled trials involving patients aged 18 years and younger. Comprehensive searches in biomedical databases were conducted, and conflicts in record screening were resolved by a third reviewer using systematic review software. RESULTS: Medication errors in P-EDs are prevalent, ranging from 10% to 15%, with dosing errors being the most common, accounting for 39% to 49% of reported errors. These errors primarily stem from inaccurate weight estimations or dosage miscalculations. Inadequate dosing frequency and documentation also contribute significantly to medication errors. Commonly implicated medications include acetaminophen, analgesics, corticosteroids, antibiotics, bronchodilators, and intravenous fluids. Most errors are categorized as insignificant/mild (51.7% to 94.5%) or moderate (47.5%). Risk factors associated with medication errors in P-EDs include less experienced physicians, severely ill patients, and weekend/specific-hour ordering. Human factors such as noncompliance with procedures and communication failures further contribute to medication errors. Interventions such as health information technology solutions like ParentLink and electronic medical alert systems, as well as structured ordering systems, have shown promise in reducing these errors, although their effectiveness varies. CONCLUSIONS: Overall, this systematic review provides valuable insights into the complexity of medication errors in the P-ED, emphasizes the need for targeted interventions, and offers recommendations to enhance medication safety and reduce preventable errors in this critical health care setting.

The Importance of Assessing Drug Pharmacokinetics and Pharmacodynamics in the Obese Population During Drug Development.

Obesity remains a US national health crisis and a growing concern worldwide. Concerningly, individuals who are obese are at an increased risk for comorbid diseases that include, but are not limited to, hypertension, diabetes, cardiovascular disease, and cancer. Beyond the risk for developing these conditions, obesity may also impact the pharmacological activity of the therapies being used to treat them and other disease states. The pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of therapies, both currently marketed and under clinical development, may be directly impacted by the physiological alterations that occur secondary to the occurrence of chronic excess body weight. The increased prevalence of this disease should not be ignored. Both private and federal institutions involved in drug research and development should consider, as appropriate, a greater inclusion of individuals who are obese in clinical trials throughout the entirety of drug development, and leverage the available PK, PD, safety, and efficacy data to make more informed dosing recommendations.

'R' you ready to save time? Using R to facilitate question creation in a pharmaceutical calculations course.

BACKGROUND AND PURPOSE: Pharmacists are expected to perform quick and accurate calculations throughout their careers. To achieve a proficient skill level, student pharmacists need ample and varied opportunities to practice pharmaceutical calculations. However, the creation of practice modalities can be time-consuming and labor-intensive for instructors. EDUCATIONAL ACTIVITY AND SETTING: We used the statistical analysis programming language R to create an efficient method to generate multiple variations of existing calculation questions. The method was evaluated with a group of student pharmacists as part of an 11-week calculations course. FINDINGS: This process can be challenging to set up initially. The method was able to generate over 100 variations of each calculation question. The student pharmacists who participated in the pilot study found the method to be easy to use and helpful for practicing pharmaceutical calculations. SUMMARY: We have developed an efficient method to generate multiple variations of existing calculation questions. This method can be used to create practice modalities that are more varied and challenging, which can help student pharmacists develop the skills they need to perform accurate calculations in their future careers.

The effect of rocuronium priming dose based on actual versus corrected body weight in modified rapid sequence intubation.

Background: Rapid sequence intubation (RSI) is a technique that allows patients to be quickly intubated and have the airway secured. Aims: The purpose of this study was to investigate the effect of rocuronium priming and intubation dose calculated according to actual body weight (ABW) or corrected body weight (CBW) on the neuromuscular block and intubation quality in rapid sequence induction and intubation (RSII). Patients and Methods: This prospective randomized, double-blind study was conducted on a total of 60 patients randomized into two groups using the closed-envelope method between January 2021 and December 2021, with 30 individuals in each group. In group 1, CBW was used with the formula to calculate the neuromuscular blocking drug (NMBD) dose. The ABW of patients was used to calculate the NMBD dose in group 2. Results: The data of 50 female patients who underwent group 1 (CBW, n = 25) and group 2 (ABW, n = 25) were analyzed. Age, weight, height, body mass index (BMI), quality of laryngoscopy, post-priming side effects, mean arterial pressure (MAP), and heart rate (HR) values did not differ across the groups. When train-of-four (TOF) values, priming and intubation dose, and laryngoscopy time were compared, a statistically significant difference was found between the two groups of TOF count (TOF C) 1 (the duration of action). Conclusion: This study suggests that the application of rocuronium priming and intubation dose according to CBW in RSII, especially during the pandemic, provided similar intubation conditions as the application according to ABW, while its shorter duration of action shows that it can be preferred, especially in short-term surgical cases.

Equivalent doses for anticancer agents used in pediatric oncology: A literature review and evaluation of a novel approach for conversion factors.

BACKGROUND: Epidemiological research on late effects of therapy shows the necessity to aggregate chemotherapy agents to substance classes. This requires using conversion factors by substance classes. AIMS: The aim of this study was to identify previously used conversion factors from the literature, to present a novel approach for additional factors, and to compare these approaches. METHODS AND RESULTS: A literature review was performed, which identified two main principles of deriving conversion factors: effect-equivalence and equimolar. Thirty-five articles presenting effect equivalence-based factors in the widest sense were found in the literature. Ten articles presented the equimolar approach which can be applied to almost all chemotherapy substances. Based on a comprehensive list of treatment protocols used in German pediatric oncology, we derived alternative conversion factors from typical doses. We compared the conversion factors using Pearson correlation coefficients and linear regression. At least two types of conversion factor were available for each of the 49 substances included. The equivalent effect-based and the typical dose-based factors were highly correlated with a regression coefficient close to 1. The equimolar factors are independent. CONCLUSIONS: For substances for which no conversion factor based on some type of effect equivalence has been published so far, a factor based on a typical doses-approach may be used in epidemiological late effects research. Doses aggregated based on the equimolar approach may not be compatible with doses aggregated based on equivalent effects.

Development of Best Evidence Dosing Recommendations for Term and Preterm Neonates (NeoDose Project).

Many drugs are used off-label in neonates which leads to large variation in prescribed drugs and dosages in neonatal intensive care units (NICUs). The NeoDose project aimed to develop best evidence dosing recommendations (DRs) for term and preterm neonates using a three-step approach: 1) drug selection, 2) establishing consensus-based DRs, and 3) establishing best evidence DRs. METHODS: The selection of drugs was based on frequency of prescribing, availability of a neonatal DR in the Dutch Pediatric Formulary, and the labeling status. Clinical need, pharmacological diversity, and Working Group Neonatal Pharmacology (WGNP) preferences were also taken into account, using a consensus-based approach. For the second step, we requested local dosing protocols from all ten Dutch NICUs and established consensus-based DRs within the WGNP, consisting of neonatologists, clinical pharmacologists, hospital pharmacists, and researchers. In the third step, the consensus-based DRs were compared with the available literature, using standardized PubMed searches. RESULTS: Fourteen drugs were selected for which the local dosing protocols were collected. These protocols differed mostly in total daily dose, dosing frequency, and/or route of administration. Strikingly, almost none of the dosing protocols of these 14 drugs distinguished between preterm and term neonates. The working group established consensus-based DRs, which after literature review needed modification in 56%, mainly in terms of a dose increase. Finally, we established 37 best evidence DRs, 22 for preterm and 15 for term neonates, representing 19 indications. CONCLUSION: This project showed the successful three-step approach for the development of DRs for term and preterm neonates.

Triangle technique: An effective tool for improving nursing students' ability to calculate safe pediatric medication dosages.

Calculating the correct medication dosage for pediatric patients can be difficult for nurses to determine, as the pediatric dose is typically a small fraction of the adult dosage. This study aims to examine the impact of the Triangle Technique on the ability of nursing students to calculate low and high safe dosage ranges in children. To evaluate how this educational tool could improve a nurse's skill in this area, a quasi-experimental pre-/post-test research design was employed including one hundred fifty-eight third-year nursing students. The Pediatric Medication Administration Form and Pediatric Safe Dosage Calculations Quiz (PSDCQ) were used to measure the effectiveness of the Triangle Technique. While <50% (n < 79) of students gave correct answers to each question in PSDCQ before this intervention, all of the participants (N = 158, 100%) gave a correct answer to one question, and >89.2% (n > 141) of the students correctly answered the other four questions of PSDCQ. The change in scores (pre-PSDCQ median score = 0, IQR = 60; post-PSDCQ median score = 100, IQR = 0) post-intervention was statistically significant (z = 10.633, p ≤ .001), indicating that this teaching technique was effective for improving students' ability to calculate pediatric safe dose ranges. Nursing students (n = 144, 91.1%) were satisfied with using Triangle Technique. Using the Triangle Technique can increase nursing students' understanding of how they calculate safe pediatric medication dosages.

How to select the initial dose for a pediatric study?

In typical clinical development programs, a new drug is first developed for the adult use. Drugs are often approved for adult use or in the process of obtaining approval in adults in the target indication before pediatric development is initiated. In designing the first pediatric clinical trial, one of the challenges is to select the initial dose to be tested. The ICH E11 R1 guidance advises that chronologic age alone may not always be the most appropriate categorical determinant to define developmental subgroups in pediatric studies. In this manuscript, the approaches to utilize available data in adults related to those factors beyond age to inform the starting dose selection in pediatric drug development are discussed. Practical considerations and approaches are provided for informing pediatric starting dose. Additional considerations to use pre-clinical information are provided in the case when adult information is limited or not available.

Correlative and Comparative Study Assessing Use of a Mock Examination in a Pharmaceutical Calculations Course.

Objective. Faculty at Massachusetts College of Pharmacy and Health Sciences University's School of Pharmacy-Worcester/Manchester are engaged in continuous quality improvement of their teaching and assessment methods to prepare students for successful careers in pharmacy. This study evaluated the impact of a formative mock examination on student performance on a main summative examination (main examination) administered during the spring 2020 semester of a pharmaceutical calculations course.Methods. A retrospective analysis of student test scores in a summative assessment (main examination) was performed across two cohort years (2019 and 2020) during which students were not administered and administered a formative mock exam, respectively. Central tendency and comparative analysis measures were performed to assess differences in student performance.Results. Out of 237 students enrolled, 221 students participated in the optional mock exam, and all 237 students participated in the main examination, with average scores for the mock examination and the main examination being 67% and 94%, respectively. Ninety-two students who received a grade C or better on their mock examination had a main examination average score (98%) that was significantly higher than those who received a D or F (n=129, main average score of 92%). Further, the average score in the 2020 examination was significantly higher when compared to the 2019 examination when no mock examination was offered (94% vs 77%, respectively).Conclusion. This was a descriptive, cross-sectional study to understand the differences in student performance in a summative assessment across two cohort years with and without a formative mock assessment. The results demonstrate that the formative mock examination was correlated with better performance among students but did not establish a causal relationship.

Effects of Dimensional Analysis on Infusible Medication Calculation Skills Among Nursing Students in an Intensive Care Unit.

Medication errors are among the most common life-threatening mistakes made in health care. The ability to accurately calculate drug doses, especially in intensive care units (ICUs), where the majority of medications are infused, reduces medication errors. Researchers have proposed dimensional analysis to improve mathematical calculations of drugs. This study was conducted to determine the effects of dimensional analysis on the infusible medication calculation skills among nursing students in ICUs. In this quasi-experimental study, the research samples consisted of sixth-semester nursing students who were assigned to an intervention group (n = 34) and a control group (n = 32). For the intervention group, the calculations of common infusible drugs in the ICU were taught using the dimensional analysis method, whereas the control group received training without the dimensional analysis method. Data collection instruments included a demographic characteristics questionnaire and a 10-item questionnaire of drug calculations that were measured before and after the intervention in both groups. Data analysis was performed using SPSS 22. The mean pretest scores for infusible drug calculations of nursing students in the ICU were 5.15 ± 2.35 for the intervention group and 5.25 ± 2.56 for the control group (P = .86). The mean posttest scores of the intervention group and control group were 9.22 ± 0.79 and 6.27 ± 1.87, respectively (P = .0001). Dimensional analysis training significantly improved the infusible medication calculation skills of nursing students in the ICU. It is recommended to include this method in undergraduate, graduate, and continuing education nursing courses to increase skills in calculating infusible drugs and to reduce medication errors.

Evaluation of sources cited by an exotic animal formulary for supporting drug dosages and reference intervals in mammals.

OBJECTIVES: Formularies are intended to simplify clinical decision-making by collecting evidence-based information on drugs and their dosages. This study assessed the characteristics of sources used to support drug dosages and reference intervals for mammals in a specific exotic animal formulary, and how the sources had changed over five editions. METHODS: Each reference supporting drug dosages and reference intervals in the sections for ferrets, rabbits, rodents, hedgehogs and miniature pigs in all five editions of the formulary was evaluated and classified by two independent investigators in terms of the type of source cited. Univariable and multi-variable logistic regression models were built to evaluate changes between editions and sections. RESULTS: In total, 1338 references supporting drug dosages and 180 references supporting reference intervals were included from all editions of the formulary. Primary sources were cited by 525 (39.2%) and 39 (21.7%) of the drug and reference interval references, respectively. For drug dosages, the current edition of the formulary (2018) cited a higher proportion of primary rather than secondary sources compared with the first edition (odds ratios 3.4, 95% confidence interval 2.1 to 5.6), while for reference intervals there were no significant changes between editions. In the current edition of the formulary, the 168 secondary sources cited for drug dosages included 78 (46.4%) textbooks, 63 (37.5%) reviews, 14 (8.3%) personal communications and 7 (4.2%) other formularies. CLINICAL SIGNIFICANCE: A large proportion of references supporting drug dosages and reference intervals in the evaluated sections cited secondary sources. Although modest improvements have been observed over time, practitioners should be aware that the evidence supporting several drugs and dosages was limited, and assess the information within the formulary critically.

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.

Instruction strategies for drug calculation skills: A systematic review of the literature.

BACKGROUND: Medication errors and unsafe medication practices are a leading cause of injury and avoidable harm worldwide. OBJECTIVES: The aim of this review was to (i) explore and identify evidence-based strategies to teach medication calculation skills by determining the most common errors and assess the quality, level, and role of the evidence, and (ii) describe instruction strategies for drug calculation skills development or improvement based on seven research-based principles for smart teaching. DESIGN: Systematic review. DATA SOURCES: CINAHL, PubMed, and PsycINFO. REVIEW METHODS: The review followed Whittemore and Knafl's framework steps with an assessment of the studies reporting using PRISMA, STROBE, COREQ and categorizing their methods by evidence hierarchy and roles. Two authors independently assessed eligibility and extracted data. RESULTS: From the total 1793 articles, 51 studies met the eligibility criteria. The studies included 9210 nursing students/nurses and mainly used a quantitative approach (67.5%), followed by qualitative (22.5%) and mixed methods (10.0%), with the students/nurses doing arithmetic and conceptual mistakes. The findings presented were low levels of evidence III (23.5%) and V (41.2%), quality Level B (82.4%), and 47.1% focused on choosing the appropriate teaching and intervention approaches (role of the evidence). The teaching strategies addressed multiple smart teaching principles, but mainly prior knowledge (principle 1, 39.2%). The least used strategies were those addressing the levers that influence motivation and behaviors such as value, expectations, and environment climate (principle 3, 13.7%). Two studies addressed five principles simultaneously. CONCLUSIONS: Regarding teaching strategies, the most recurring strategies were early diagnostic assessments on knowledge, anxiety and/or self-confidence, considering knowledge organization with scaffolding complex tasks, being explicit about objectives and expectations, and usage of e-learning. However, e-learning was mainly used after 2018. Considering the low levels and quality of evidence, we recommend higher levels of research design for future research. Randomized Controlled Trials could be conducted when randomizing teaching methods per semester or questions embedded in software. Web-base software could be used to support teaching and research approaches.