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A systematic review and individual participant data (IPD) meta-analysis

This protocol outlines details for an IPD meta-analysis on the measurement properties and interpretability of a brain-based response biomarker of infant acute somatic nociceptive pain. This registration occurred prior to individual participant data collection and analysis.

Medicines and vaccines prescribed to pregnant women often have not had pregnant women or lactating women included in clinical trials and products are often not approved by regulatory agencies for use in pregnant women. As a result, practitioners may need to prescribe medicines and give vaccines to this special population with limited drug efficacy and safety information available. Multiple regulatory guidance documents regarding the development of medications for pregnant and lactating women have been developed to encourage drug development and the investigation of medicines and vaccines used in this population. However, clinical, regulatory, ethical, and drug development challenges are encountered when designing clinical trials that include pregnant women and their fetuses, in which innovative methods and trial designs are essential. This article provides an overview of an industry perspective on maternal-fetal drug development that includes a review of the regulatory landscape for developing medicines for pregnant women and their fetuses, trial designs that include pregnant women, identification of gaps and challenges, and strategies for potential maternal-fetal drug development considerations for the future development of medicines and vaccines for pregnant women. Early involvement and discussion of drug and vaccine products with multiple stakeholders, including therapeutic experts, patients, physicians, and regulators, is encouraged to optimize the development of safe and effective medicines and vaccines for pregnant women and their fetuses.

The conduct of clinical trials in small pediatric subspecialties such as pediatric nephrology is hampered by both clinical demands on the pediatric nephrologist and the small number of appropriate patients available for such studies. The American Society of Pediatric Nephrology Therapeutics Development Committee (TDC) was established to (1) identify the various stakeholders with interests and/or expertise related to clinical trials in children with kidney disease and (2) develop more effective partnerships among all parties regarding strategies for successful clinical trial development and execution. This article discusses the rationale, structure, and function of the TDC, the status of progress toward its goals, and the insights gained to date that may be useful for other subspecialties that face similar challenges.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition that affects children, adolescents, and adults worldwide. The purpose of this review was to inform pharmacists of the numerous options to treat ADHD, with a focus on one of the more recently approved formulations, methylphenidate extended-release oral suspension (MEROS). Symptoms of ADHD can negatively impact an individual's health and quality of life and impair function in multiple settings. Psychostimulants such as methylphenidate- and amphetamine-based agents are first-line pharmacologic treatments for ADHD. However, there are multiple formulations, including immediate release (administered two to three times/day), solid extended release (ER), or transdermal patch. MEROS is a once daily, long-acting liquid preparation that has demonstrated favorable safety and efficacy in patients with ADHD. MEROS may improve treatment adherence in patients who cannot tolerate or have difficulties administering pill or transdermal patch formulations.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Tolterodine and 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties of tolterodine; 5-HMT is the singular active moiety of fesoterodine. The formation of 5-HMT from tolterodine occurs via CYP2D6, and some subjects are poor metabolizers CYP2D6. On the other hand, the formation of 5-HMT from fesoterodine occurs via ubiquitous esterases. Cross-study comparisons of data from phase 1 studies suggest that active moiety exposures are considerably more variable following tolterodine extended release vs. fesoterodine. WHAT THIS STUDY ADDS • This head-to-head study confirmed the findings of reduced pharmacokinetic variability of fesoterodine and further delineates that tolterodine, and not 5-HMT, was the principal source of variability after administration of tolterodine extended release. The data suggest that fesoterodine delivers 5-HMT consistently, regardless of CYP2D6 status, with up to 40% higher bioavailability compared with tolterodine. AIMS Tolterodine and 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties of tolterodine; 5-HMT is the singular active moiety of fesoterodine. Formation of 5-HMT from fesoterodine and tolterodine occurs via esterases and CYP2D6 respectively. This randomized, crossover, open-label, multiple-dose study in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) compared the pharmacokinetics of fesoterodine vs. tolterodine extended release (ER). METHODS Subjects received fesoterodine and tolterodine ER with a ≥3-day washout period. Treatment comprised 4-mg once daily doses for 5 days escalated to 8-mg once daily for 5 days. Pharmacokinetics of active moieties were compared by drug, dose and genotype. RESULTS Active moiety exposures following fesoterodine and tolterodine ER increased proportional to dose in EMs and PMs. In EMs only, coefficients of variation for AUC and Cmax following fesoterodine (up to 46% and 48% respectively) were lower than those following tolterodine ER (up to 87% and 87% respectively). Following fesoterodine and tolterodine ER administration, active moiety exposures ranged up to sevenfold and 40-fold respectively. Mean urinary excretion of 5-HMT following fesoterodine 4 and 8 mg, respectively, was 0.44 and 0.89 mg in EMs and 0.60 and 1.32 mg in PMs. Following tolterodine ER 4 and 8 mg, it was 0.38 and 0.71 mg respectively (EMs only). Renal clearance was similar regardless of administered drug, dose or genotype. CONCLUSIONS Tolterodine, not 5-HMT, was the principal source of variability after tolterodine ER administration. Fesoterodine delivers 5-HMT with less variability than tolterodine, regardless of CYP2D6 status, with up to 40% higher bioavailability. The pharmacokinetics of fesoterodine were considerably less variable than TER.

OBJECTIVE To describe the results of an initiative to create awareness of coronary heart disease and provide education regarding cardiovascular (CV) risk and cholesterol (lipid) management in a community-based senior population. A multidisciplinary partnership composed of governmental agencies, a member of the pharmaceutical industry, a college of pharmacy, and several community-based health care practitioners collaborated in the program. DESIGN Prospective CV risk assessment, educational interventions, and follow-up. SETTING Community centers providing wellness and activity programs for ambulatory seniors. PATIENTS Ambulatory senior adults who were active participants in senior center programs were invited to participate in a series of health screenngs at a center-based health fair. Those who met specific evidence-based qualifying criteria were enrolled in the program. MAIN OUTCOME MEASURES Changes in CV risk profile, specifically, total cholesterol, low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), triglycerides (TG), blood glucose levels; and attainment of National Cholesterol Education Program (NCEP) lipid goals of the Adult Treatment Panel III. RESULTS Initial screening of 501 patients for eligibility allowed 273 patients to qualify and enroll in the program. A total of 112 (41.0%) participants returned for the year 2 follow-up, leaving a loss to follow-up of 161 patients. Compared with baseline, reductions occurred in total cholesterol (206.8 mg/dL vs.182.9 mg/dL), LDL-C (122.2 mg/dL vs. 105.5 mg/dL), HDL-C (51.5 mg/dL vs. 49.6 mg/dL), TG (164.8 mg/dL vs. 136.4 mg/dL), and blood glucose (115 mg/dL vs. 106.3 mg/dL); the number of patients with less than two risk factors decreased from 43 (38.4%) to 28 (25.0%) and those with two or more risk factors increased from 69 (61.6%) to 84 (75.0%); the number of patients at NCEP (lipid) goal increased from 57 (50.9%) to 80 (71.4%). CONCLUSION For senior adults participating in the program, improvements occurred in both the lipid profiles and the number of patients at their NCEP (lipid) goal, although the number of seniors with > or = two risk factors increased from 69 (61.6%) to 84 (75.0%). A multidisciplinary partnership for improving the CV health and awareness of an ambulatory senior population is a unique opportunity for pharmacists to provide wellness services for seniors.

OBJECTIVE To evaluate the efficacy of a standardized opiate-weaning protocol using methadone compared with methadone weaning before protocol development. DESIGN Time series, prospective study with comparison to historical controls. SETTING Twenty-bed medical-surgical intensive care unit in an academic children's hospital. PATIENTS Ten children, aged 6 months to 18 yrs, who received methadone for weaning from continuous opiate infusions for >or=7 days compared with ten patients undergoing weaning by standardized protocol. INTERVENTIONS Institution of standardized opiate-weaning protocol. MEASUREMENTS AND MAIN RESULTS Patient age, gender, and diagnosis were similar in both nonprotocol (NP) and protocol (P) groups (p = NS). Days of opiate use were also similar between groups. Nine of ten NP and seven of ten P patients were on continuous fentanyl infusions, and the remainder were on continuous morphine infusions. P patients were weaned significantly faster than NP patients (median, 9 days and 20 days, respectively; p