Use of Real-World Data and Pharmacometric Modeling in Support of Lacosamide Dosing in Pediatric Patients Under 4 Years of Age.

The antiepileptic drug lacosamide (LCM) is approved in the United States and the European Union as monotherapy as well as adjunctive therapy for the treatment of focal seizures in children ≥4 years of age and adults. Using real-world therapeutic drug monitoring data, we performed a pharmacometric analysis for 315 pediatric patients (>1 month to <18 years of age) who received lacosamide as both monotherapy and adjunctive therapy. Population pharmacokinetic modeling was performed using nonlinear mixed-effects modeling with a 1-compartment structural model with linear elimination, where clearance and volume of distribution were allometrically scaled for body weight, with no further need for age-associated maturation functions. A covariate analysis for age, sex, race, and coadministration of other antiepileptic drugs identified phenobarbital and felbamate to significantly increase lacosamide clearance (1.71- and 1.46-fold, respectively). Based on the developed population pharmacokinetic model, simulations were performed in virtual pediatric patients to explore age-associated dose requirements to match lacosamide exposure in patient groups of different age with the exposure achieved in children ≥4 year of age with the weight-based dosing recommendations provided by the US Food and Drug Administration. Based on this approach, our analysis suggested that children ≥3 years of age needed the same dose as recommended by the US Food and Drug Administration for children ≥4 years of age (12 mg/kg/d), while children 1 to 3 years of age may need 13 to 14 mg/kg/d and infants between 1 month and 1 year of age may need 15 to 18 mg/kg/d (based on their actual age) to match the exposure seen in children ≥4 years of age.

Persistent Hypersomnolence Following Clobazam in a Child With Epilepsy and Undiagnosed CYP2C19 Polymorphism.

We describe an 11-year-old female who presented with severe hypersomnolence after receiving 1 week of modest doses of clobazam (CLB). In reviewing the above case, we considered that the hypersomnolence could be related to a pharmacodynamic, pharmacokinetic, or pharmacogenomic issue associated with CLB or to a combination of these factors. Although serum concentrations of CLB and its active metabolite are sensitive to factors that affect cytochrome-dependent metabolism, drug-drug interactions were omitted as a cause of the hypersomnolence. Subsequent DNA analysis of the cytochrome P450 2C19 gene revealed the patient as *2/*2 genotype with poor metabolizer enzyme activity. Because genetic testing of all patients treated with CLB is currently not practical, CLB dose/concentration ratios and pharmacokinetic drug-drug interaction impact models may be indicated. Genetic testing should be considered when an adverse effect suggests the possibility of a polymorphism important to drug metabolism.

Status Epilepticus: The Slow and Agonizing Death of Phenytoin.

Since its introduction in 1950, phenytoin (PHT) has been the premier parenteral anticonvulsant used in the management of generalized convulsive status epileptics (GCSE) that is refractory to benzodiazepines. Without question, its arrival was vital to the care of patients with acute seizures and was a welcomed alternative to paraldehyde and phenobarbital. However, after more than half a century of use, there continues to be insufficient evidence-based data to support its efficacy over other anticonvulsants as a first-line agent in pediatric or adult patients with GCSE. This coupled with its narrow mechanism of action, complex pharmacokinetics and pharmacogenomics, drug-drug interactions, unique adverse effects, and formulation issues that make administration difficult mandates that PHT be replaced by safer and superiorly effective anticonvulsants for the treatment of GCSE when benzodiazepines are ineffective. We believe that levetiracetam should become the preferred agent for seizures unresponsive to or recurring after treatment with a benzodiazepine as it is at least equally effective to PHT and has several important advantages. PHT has overstayed its welcome and it is simply time for it to exit the realm of acute seizure management as a first-line agent for benzodiazepine-refractory GCSE.

Implementation of an ACPE-Accredited PharmD Curriculum at a Saudi College of Pharmacy.

Objective. To establish an academic curricular collaboration between the newly established college of pharmacy at King Saud Bin Abdulaziz Saudi University for Health Sciences (KSAU-HS) and a US college of pharmacy accredited by the Accreditation Council for Pharmacy Education, and assess measures of success. Methods. Criteria for selecting a college for collaboration were established. A systematic approach was followed in negotiating legal, logistical, and financial issues with the selected collaborating institution. Course materials were transferred and implemented and minimal changes were made to the alignment and sequencing of lectures. The faculty at KSAU-HS developed and implemented research and seminar courses. Pharmacy practice experiences were designed and rubrics were developed. Results. All courses were implemented successfully. The PharmD students scored significantly higher in all academic levels in a benchmarked progress test than did students in other programs. Students' evaluation of 43 first-, second-, and third-year courses in 2017-2018 using a survey that assessed numerous aspects of each course showed significantly higher overall satisfaction than the institutional averages. Also, female students indicated significantly higher satisfaction with the PharmD program than did male students. Conclusion. The transfer and implementation of an accredited PharmD curriculum to the KSAU-HS College of Pharmacy went smoothly and the program was launched on time. Learning and teaching success was facilitated by the KSAU-HS faculty. Program outcomes were verified by students' high scores on a benchmarked examination and by their satisfaction with the courses.

Impact of Pharmacy School Characteristics on NAPLEX First-time Pass Rates.

Objective. To assess the impact of pharmacy school characteristics on the pass rates of students taking the North American Pharmacist Licensure Examination (NAPLEX) for the first time. Methods. A retrospective review of NAPLEX first-time pass rates, pharmacy school characteristics and percent of total graduating class who matched for a first postgraduate year (PGY1) residency was performed for 2014, 2015, and 2016. All US colleges of pharmacy accredited as of July 2017 were included. Independent samples t tests, paired samples t tests, correlational analysis, and multiple linear regression were conducted. Results. The first-time pass rates on the NAPLEX were significantly higher for the following: schools located within an academic health center; schools established before 2000, and public schools. The 2016 NAPLEX first-time pass rate was significantly higher for schools with a traditional four-year program structure versus an accelerated three-year structure. Also, a school's first-time pass rate on the NAPLEX was positively, significantly correlated with percentage of fourth-year students who matched for a PGY1 residency and being located within an academic health center. The NAPLEX first-time pass rate for the previous year and percent of the total graduating class that matched for a PGY1 residency were significant predictors in the final regression models for 2015 and 2016 NAPLEX first-time pass rates. Conclusion. While differences in certain program characteristics was coorelated with NAPLEX pass rate, many of these factors are not modifiable. Programs can proactively and critically evaluate their educational programs and the readiness of their students to sit for the NAPLEX.

Examination of Factors Relating to Student Performance on the Pharmacy Curriculum Outcomes Assessment.

Objective. To examine relationships between students' demographic and academic performance factors and their scores on the Pharmacy Curriculum Outcomes Assessment (PCOA). Methods. Students' PCOA scores and demographics (eg, age, race/ethnicity, sex), preadmission data [eg, cumulative and science grade point average (GPA), Pharmacy College Admissions Test (PCAT)], and academic performance variables (eg, pharmacy GPA, academic standing) were analyzed for one class of third-year pharmacy students (N=159). Independent t-tests and Analysis of Variance (ANOVA) were used to compare scores by demographic variables. Pearson's r correlations were used to assess relationships between PCOA scores and age, PCAT scores, and GPA. Stepwise linear regression was conducted to determine the predictive ability of variables with significant correlations to PCOA performance. Results. Significant correlations were found between sex and PCOA scores with males scoring higher than females. Significant correlations with PCOA scores were also found for PCAT scores, pre-pharmacy science GPA, and pharmacy didactic GPA. Significant differences were found by academic standing, where students in academic difficulty who were allowed to proceed without repeating curricular content scored significantly lower on the PCOA than those who did not experience academic difficulty. Conversely, there were no statistical differences between those who repeated courses and those who never experienced academic difficulty. PCOA performance predictors in the final regression model included PCAT composite score, pharmacy GPA and sex. Conclusion. New findings included differences in PCOA scores by sex and by academic standing, a variable not previously explored in published studies. Findings have implications for remediation decisions in pharmacy curricula.

A Clinician's Guide to Oral Extended-Release Drug Delivery Systems in Epilepsy.

Epilepsy is one of the most common chronic neurologic disorders that affects individuals of all ages. It is primarily managed with antiepileptic drugs (AEDs), with the goal of maintaining complete seizure control combined with minimal or no adverse effects. Oral administration is the mainstay of AED delivery for patients with chronic epilepsy and consists essentially of immediate-release (IR) and modified-release (delayed-release and extended-release [ER]) dosage formulations. Extended-release formulations (hydrophilic or hydrophobic matrix systems, reservoir systems, and osmotic-release systems) release a drug in a controlled manner during an extended period of time following administration. Extended-release formulations have many advantages compared with IR formulations, including simplification of dosing regimens, reduction in pill burden, and reduction in the peak-to-trough fluctuations in serum drug concentration that may be associated with a decreased risk of adverse effects and of seizures. These advantages have the potential to increase adherence to antiepileptic therapy, improve the quality of life of patients, and reduce health care costs. This article, which is intended as a practical guide for clinicians, reviews the properties of the different ER AED formulations currently available and discusses the advantages of ER over IR formulations. Subsequently, an explanation of the technologic basis of the different oral ER formulations, the critical attributes that differentiate ER products, and their individual strengths and weaknesses is provided. Specific recommendations to practitioners on treating patients with ER formulations are included.

Impact of Drug Interactions on Clobazam and N-Desmethylclobazam Concentrations in Pediatric Patients With Epilepsy.

BACKGROUND: Clobazam (CLB) is approved as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients aged 2 years and older. It is converted to an active metabolite N-desmethylclobazam (NCLB) by CYP3A4, which is then broken down to an inactive metabolite by CYP2C19. This study characterizes the impact of CYP3A4 and CYP2C19 drug interactions on CLB and NCLB serum concentrations (Cp) and concentration/dose (Cp/D) ratios in pediatric patients with epilepsy. METHODS: This was a retrospective chart review including patients older than 1 month, who received CLB between April 2012 and March 2017. Extracted data included patient demographics, CLB daily dose, CLB and NCLB Cp, calculated CLB and NCLB Cp/Cp and Cp/D ratios, and all concomitant drugs. RESULTS: The study included 995 CLB concentration sets from 302 patients (median age 7.6 years and range 0.2-40.1 years). Pharmacokinetic variability was extensive, as seen by widespread ranges of CLB and NCLB Cp, NCLB/CLB Cp ratio, and 3 Cp/D ratios (CLB, NCLB, and CLB + NCLB). Comedications, described as CYP3A4 inducers and/or CYP2C19 inhibitors (carbamazepine, eslicarbazepine, felbamate, (fos)phenytoin, oxcarbazepine, pentobarbital, phenobarbital, rufinamide, and topiramate), generally increased NCLB/CLB Cp ratio (267%-400%), NCLB Cp/D ratio (167%-202%), and CLB + NCLB Cp/D ratio (142%-185%) and decreased CLB Cp/D ratio (47%-76%) compared with a group of concentration sets in patients receiving only neutral comedications (P < 0.025 for all comparisons). Older age was associated with higher Cp/D ratios (mg/kg), indicative of decreased clearance. CONCLUSIONS: Pharmacokinetic variability of CLB in pediatric patients is extensive, and it is influenced by drug-drug interactions and age. Therapeutic drug monitoring of CLB and active metabolite NCLB with calculation of various Cp/Cp and Cp/D ratios can provide useful insight into CLB pharmacokinetics and help differentiate between causes of variability.

Examining the Association Between the NAPLEX, Pre-NAPLEX, and Pre- and Post-admission Factors.

Objective. To examine the relationship between the NAPLEX and Pre-NAPLEX among pharmacy graduates, as well as determine effects of pre-pharmacy, pharmacy school, and demographic variables on NAPLEX performance. Methods. A retrospective review of pharmacy graduates' NAPLEX scores, Pre-NAPLEX scores, demographics, pre-pharmacy academic performance factors, and pharmacy school academic performance factors was performed. Bivariate (eg, ANOVA, independent samples t-test) and correlational analyses were conducted, as was stepwise linear regression to examine the significance of Pre-NAPLEX score and other factors as related to NAPLEX score. Results. One hundred fifty graduates were included, with the majority being female (60.7%) and white (72%). Mean NAPLEX score was 104.7. Mean Pre-NAPLEX score was 68.6. White students had significantly higher NAPLEX scores compared to Black/African American students. NAPLEX score was correlated to Pre-NAPLEX score, race/ethnicity, PCAT composite and section scores, undergraduate overall and science GPAs, pharmacy GPA, and on-time graduation. The regression model included pharmacy GPA and Pre-NAPLEX score. Conclusion. The findings provide evidence that, although pharmacy GPA is the most critical determinant, the Pre-NAPLEX score is also a significant predictor of NAPLEX score.

Student Pharmacists' Perceptions of a Composite Examination in Their First Professional Year.

OBJECTIVE: To assess first-year (P1) pharmacy students' studying behaviors and perceptions after implementation of a new computerized "composite examination" (CE) testing procedure. METHODS: Student surveys were conducted to assess studying behavior and perceptions about the CE before and after its implementation. RESULTS: Surveys were completed by 149 P1 students (92% response rate). Significant changes between survey results before and after the CE included an increase in students' concerns about the limited number of questions per course on each examination and decreased concerns about the time allotted and the inability to write on the CEs. Significant changes in study habits included a decrease in cramming (studying shortly before the test) and an increase in priority studying (spending more time on one course than another). CONCLUSION: The CE positively changed assessment practice at the college. It helped overcome logistic challenges in computerized testing and drove positive changes in study habits.

Treatment of Generalized Convulsive Status Epilepticus in Pediatric Patients.

Generalized convulsive status epilepticus (GCSE) is one of the most common neurologic emergencies and can be associated with significant morbidity and mortality if not treated promptly and aggressively. Management of GCSE is staged and generally involves the use of life support measures, identification and management of underlying causes, and rapid initiation of anticonvulsants. The purpose of this article is to review and evaluate published reports regarding the treatment of impending, established, refractory, and super-refractory GCSE in pediatric patients.

A checklist for the development of faculty mentorship programs.

Mentoring of junior faculty members continues to be a widespread need in academic pharmacy in both new programs and established schools. The American Association of Colleges of Pharmacy (AACP) Joint Council Task Force on Mentoring was charged with gathering information from member colleges and schools and from the literature to determine best practices that could be shared with the academy. The task force summarized their findings regarding the needs and responsibilities for mentors and protégés at all faculty levels; what mentoring pieces are in existence, which need improvement, and which need to be created; and how effective mentoring is defined and could be measured. Based on these findings, the task force developed several recommendations as well as the PAIRS Faculty Mentorship Checklist. Academic institutions can benefit from the checklist whether they are planning to implement a faculty mentorship program or are interested in modifying existing programs.

Enteral topiramate in a pediatric patient with refractory status epilepticus: a case report and review of the literature.

We describe the use of topiramate in a healthy 12-year-old (88-kg) male who developed refractory generalized convulsive status epilepticus. Seizures persisted despite aggressive use of benzodiazepines (intravenous lorazepam; oral clorazepate), barbiturates (i.e., phenobarbital, pentobarbital), and hydantoins. The child's seizures were controlled with nasogastrically administered topiramate in doses up to 500 mg twice daily (11.4 mg/kg/day). The patient did not display any clinical or laboratory signs of metabolic acidosis while receiving topiramate. Topiramate should be considered as a treatment option in refractory status epilepticus.

Academic progression and retention policies of colleges and schools of pharmacy.

OBJECTIVE: To describe academic progression and retention policies used by US colleges and schools of pharmacy. METHODS: Student handbooks on the Web sites of 122 colleges and schools of pharmacy were reviewed between February 2012 and May 2012. RESULTS: Data were available and obtained from 98 (80%) programs. Most used grade point average (GPA) as a criterion for progression, with 66% requiring a minimum GPA of 2.0. Cumulative GPA was the most frequently used criteria for probation. Most handbooks did not address remediation, but 38% noted that a failed course could only be retaken once. The most common criteria for dismissal were the cumulative number of times a student was on probation. The graduation requirements of most programs were a cumulative GPA of 2.0 and completion of the program within 6 years of enrollment. CONCLUSIONS: Colleges and schools of pharmacy use various criteria for academic progression and retention and frequently provide incomplete or inadequate information related to probation, progression, and dismissal. Information regarding remediation and academic performance during experiential learning is lacking. A clearinghouse containing institutional data related to progression and retention would assist programs in developing academic policies. The study also highlights the need for ACPE to ensure this information is provided to students.

Clobazam: a newly approved but well-established drug for the treatment of intractable epilepsy syndromes.

Clobazam, a 1,5-benzodiazepine, was introduced in the 1970s as an anxiolytic and antiepileptic drug. Despite worldwide usage, it was only recently approved in the United States (seizures associated with Lennox-Gastaut syndrome). This article reviews historical and recent data to help practitioners better understand clobazam's clinical properties and usage. In many clinical trials, open-label studies, and retrospective reviews, clobazam was generally associated with ≥50% seizure reduction for more than half of Lennox-Gastaut syndrome patients, with approximately 10% achieving freedom from drop attacks. Efficacy is persistent, with little evidence for development of tolerance. Clobazam's safety profile appears to be similar to that of other benzodiazepines, but with substantially decreased sedation and increased psychomotor performance. Studies suggest clobazam acts through potentiation of gamma-aminobutyric acid type A receptors in a manner similar to other benzodiazepines. However, clobazam appears to display greater selectivity for receptors responsible for anticonvulsant activity than for those involved in sedation.

Evaluation of vancomycin dosing regimens in preterm and term neonates using Monte Carlo simulations.

STUDY OBJECTIVE: To compare four common dosing regimens for vancomycin in preterm and term neonates by assessing the probability that each regimen would achieve the widely used therapeutic target serum trough concentrations of 5-15 mg/L and the newly suggested target of 15-20 mg/L. DESIGN: Retrospective population pharmacokinetic analysis using therapeutic drug monitoring data obtained from 1990-2007, with a subsequent simulation study performed on the pharmacokinetic model. SETTING: Tertiary-care children's hospital. PATIENTS: One hundred thirty-four preterm (66%) and term (34%) neonates, with a postnatal age of 1-121 days and postmenstrual age of 24.6-44 weeks. MEASUREMENTS AND MAIN RESULTS: Therapeutic drug monitoring data for vancomycin were used to develop a population pharmacokinetic model in the target population. Parameter estimates for the derived pharmacostatistical model were used to perform Monte Carlo simulations for four recommended dosing regimens: a standard dose for all neonates, postmenstrual age-based dosing, postmenstrual and postnatal age-based dosing, and serum creatinine-based dosing. Multivariate age-weight distributions were established for term and preterm neonates using Centers for Disease Control and Prevention growth charts and intrauterine and postnatal growth charts from the literature, respectively. Each dosing regimen was treated as a separate scenario in which 200 replicates with 100 patients/replicate were simulated. The 5-15-mg/L target trough serum concentration was achieved in 34% (90% confidence interval [CI] 20-53%), 42% (90% CI 31-55%), 52% (90% CI 43-60%), and 63% (90% CI 54-72%) of patients receiving the standard dose, postmenstrual age-based dose, postmenstrual and postnatal age-based dose, and serum creatinine-based dose, respectively. Serum creatinine-based dosing produced trough concentrations predominantly in the 5-15-mg/L target range, with the smallest variability in both term and preterm neonates. As expected, when the target range was narrow and higher (15-20 mg/L), only 13-21% of patients were within the range across the four dosing regimens. CONCLUSION: Monte Carlo simulations based on our population pharmacokinetic model suggest that vancomycin dosing guidelines based on serum creatinine concentration have a greater likelihood of achieving trough concentrations in the 5-15-mg/L range compared with other evaluated dosing regimens. None of the four dosing regimens is suitable to produce target trough concentration of 15-20 mg/L in an acceptable number of patients.

Nebulized furosemide in the treatment of bronchopulmonary dysplasia in preterm infants.

Bronchopulmonary dysplasia (BPD) is a chronic pulmonary disease commonly seen in preterm infants who require supplemental oxygen and/or assisted mechanical ventilation. BPD, a major cause of morbidity and mortality among premature infants, occurs in 5,000 to 10,000 premature infants in the United States each year. Despite numerous medical advances, no single intervention will prevent or treat BPD; hence, premature infants have an increased risk for developing significant sequelae that affect both cognitive and motor function. This article provides a brief overview of BPD and reviews the available literature regarding the safe and effective use of nebulized furosemide in the treatment of this disorder.