Model-Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy.

Ethosuximide was identified as the optimal option for new-onset childhood absence epilepsy (CAE) in a randomized, two-phase dose escalation comparative effectiveness trial of ethosuximide, lamotrigine, and valproic acid. However, 47% of ethosuximide initial monotherapy participants experienced short-term treatment failure. This study aimed to characterize the initial monotherapy ethosuximide exposure-response relationship and to propose model-informed precision dosing guidance. Dose titration occurred over a 16-20-week period until patients experienced seizure freedom or intolerable side effects. Subjects with initial monotherapy failure were randomized to one of the other two medications and dose escalation was repeated. A population pharmacokinetic model was created using plasma concentration data (n = 1,320), collected at 4-week intervals from 211 unique participants during both the initial and second monotherapy phases. A logistic regression analysis was performed on the initial monotherapy cohort (n = 103) with complete exposure-response data. Eighty-four participants achieved seizure freedom with a wide range of ethosuximide area under the curves (AUC) ranging from 420 to 2,420 µg·h/mL. AUC exposure estimates for achieving a 50% and 75% probability of seizure freedom were 1,027 and 1,489 µg·h/mL, respectively, whereas the corresponding cumulative frequency of intolerable adverse events was 11% and 16%. Monte Carlo Simulation indicated a daily dose of 40 and 55 mg/kg to achieve 50% and 75% probability of seizure freedom in the overall population, respectively. We identified the need for adjusted mg/kg dosing in different body weight cohorts. This ethosuximide proposed model-informed precision dosing guidance to achieve seizure freedom carries promise to optimize initial monotherapy success for patients with CAE.

Concomitant Ceftriaxone and Intravenous Calcium Therapy in Infants.

OBJECTIVE: To determine if increased mortality could be detected with the administration of ceftriaxone and IV calcium in infants through an analysis of a large repository of electronic health records. METHODS: Patients were split into 3 groups: 1) neonates, 2) infants, and 3) infants <1 year whose age was not specified. Deaths were classified into mutually exclusive categories based on the administration and timing of ceftriaxone and IV calcium. Crude death rates were calculated, and logistic regression modeling was used to calculate adjusted relative odds of death with associated covariates. RESULTS: A total of 259,149 infants were identified. Of 79,038 neonates, the proportion of patients that received ceftriaxone and IV calcium within 48 hours who died was 3.8%, compared with 1.95% (IV calcium), 0.3% (ceftriaxone), 1.54% (IV fluids), and 2.03% (parenteral nutrition). For 102,456 infants, the proportions of deaths were 5.47% (ceftriaxone and IV calcium within 48 hours), 0.45% (IV calcium), 0.15% (ceftriaxone), 0.39% (IV fluids), and 5.5% (parenteral nutrition). Multivariate analysis showed increased odds of death in infants who received ceftriaxone and IV calcium within 48 hours, regardless of age, and propensity score-matched analysis showed a more than 2-fold increased risk for death. CONCLUSIONS: The increased risk for death following ceftriaxone and IV calcium administration was noted not only in neonates, but among older infants as well.

How can we improve the safe use of herbal medicine and other natural products? A clinical pharmacologist mission.

INTRODUCTION: Three major classes of natural products (NPs) for medicinal purposes or improving wellbeing are generally available in the US: conventional drugs of herbal origin, botanical drugs, and dietary supplements (DSs). Consumer consumption of DSs is growing annually. The U.S. FDA regulates conventional and botanical drugs for safety and efficacy; however, DSs are minimally regulated. AREAS COVERED: This article will: i) highlight the importance of NP as a significant source of prescription drugs; ii) discuss differences in the regulation of conventional drugs of NP product, botanical drugs, and DSs; iii) discuss the safety and efficacy of DSs and iv) make recommendations for improvement of safety for minimally regulated NPs. EXPERT OPINION: Toxicities associated with the use of NPs, including vitamins and DSs, are mainly due to excessive use and interactions with conventional drug(s) and may represent challenges for clinicians. Conventional and botanical-based prescription drugs are rarely associated with unknown toxicities. However, DSs are minimally regulated and can produce severe adverse effects. We believe that clinical pharmacologists can have a role in developing criteria for DS safety analysis. There is also the potential for a standardized NP stewardship program(s) and the development of NP policies and practices nationally and globally.

Tolerability of Aerosolized Versus Intravenous Pentamidine for Pneumocystis jirovecii Pneumonia Prophylaxis in Immunosuppressed Pediatric, Adolescent, and Young Adult Patients.

OBJECTIVES: Pentamidine is an antifungal that is used alternatively to sulfamethoxazole-trimethoprim for the prophylaxis and treatment of Pneumocystis jirovecii pneumonia (PJP). The primary objective of this study was to assess the tolerability of aerosolized versus intravenous pentamidine for PJP prophylaxis in pediatric, adolescent, and young adult immunosuppressed patients. Secondary objectives included comparing pentamidine formulation reaction to dosing frequency and diagnosis. METHODS: This retrospective chart review used electronic medical record (EMR) data from patients at a tertiary care pediatric teaching institution from January 1, 2014, to January 1, 2017. Information used from the EMR included pentamidine dosing, ordering, and laboratory values. Inclusion criteria consisted of patients with a cancer diagnosis, hematopoietic stem cell transplant (HSCT) recipients, and renal transplant recipients who received pentamidine for PJP prophylaxis. RESULTS: Ninety-six patients met inclusion criteria, of which 31 received aerosolized pentamidine. Ten of the 96 patients experienced a drug-related reaction to either aerosolized or intravenous pentamidine (p = 0.134). Nine of 10 patients who experienced a reaction received intravenous pentamidine versus 1 patient who received aerosolized pentamidine (p = 0.132). In those patients who reacted to pentamidine there was a higher incidence of reactions after subsequent administration (p = 0.039) and in patients with a blood cancer diagnosis (p = 0.042). CONCLUSIONS: Data suggest that patients who receive aerosolized pentamidine may tolerate therapy better compared to intravenous administration. Additional studies involving larger numbers of pediatric, adolescent, and young adult patients are needed for stronger statistically significant clinical differences in tolerability of aerosolized versus intravenous pentamidine.

Developmental Changes in Pharmacokinetics and Pharmacodynamics.

Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug-response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics.

Pharmacokinetics of Clindamycin in Obese and Nonobese Children.

Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size. The final model included TBW and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (liters/hour) = 13.8 × (TBW/70)0.75 × [PMA2.83/(39.52.83+PMA2.83)]; volume of distribution (V) was associated with TBW, albumin (ALB), and alpha-1 acid glycoprotein (AAG): V (liters) = 63.6 × (TBW/70) × (ALB/3.3)-0.83 × (AAG/2.4)-0.25 After accounting for differences in TBW, obesity status did not explain additional interindividual variability in model parameters. Our findings support TBW-based dosing for obese and nonobese children.

Dosage Adjustments Related to Young or Old Age and Organ Impairment.

Differences in physiology related to young or old age and/or organ system impairment alter the absorption, distribution, metabolism, and excretion of many medications and consequently their effectiveness and toxicity. This module discusses common alterations in medication use and dosage that are required in the pediatric age group, in the elderly, and in patients with renal or hepatic disease.

Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms.

The Clinical and Laboratory Standards Institute (CLSI) revised cefepime (CFP) breakpoints forEnterobacteriaceaein 2014, and MICs of 4 and 8 µg/ml were reclassified as susceptible-dose dependent (SDD). Pediatric dosing to provide therapeutic concentrations against SDD organisms has not been defined. CFP pharmacokinetics (PK) data from published pediatric studies were analyzed. Population PK parameters were determined using NONMEM, and Monte Carlo simulation was performed to determine an appropriate CFP dosage regimen for SDD organisms in children. A total of 664 CFP plasma concentrations from 91 neonates, infants, and children were included in this analysis. The median patient age was 1.0 month (interquartile range [IQR], 0.2 to 11.2 months). Serum creatinine (SCR) and postmenstrual age (PMA) were covariates in the final PK model. Simulations indicated that CFP dosing at 50 mg/kg every 8 h (q8h) (as 0.5-h intravenous [i.v.] infusions) will maintain free-CFP concentrations in serum of >4 and 8 µg/ml for >60% of the dose interval in 87.1% and 68.6% of pediatric patients (age, ≥30 days), respectively, and extending the i.v. infusion duration to 3 h results in 92.3% of patients with free-CFP levels above 8 µg/ml for >60% of the dose interval. CFP clearance (CL) is significantly correlated with PMA and SCR. A dose of 50 mg/kg of CFP every 8 to 12 h does not achieve adequate serum exposure for older children with serious infections caused by Gram-negative bacilli with a MIC of 8 µg/ml. Prolonged i.v. infusions may be useful for this population.

Serum adipocytokines and adipose weight gain: a pilot study in adolescent females initiating depot medroxyprogesterone acetate.

OBJECTIVE: To evaluate whether serum adipocytokine concentrations, controlling for baseline adiposity, are predictive of adipose weight gain in adolescents initiating depot medroxyprogesterone acetate (DMPA). METHODS: Percent body fat was measured at baseline and 6 months. Baseline serum adipocytokine concentrations were quantified. RESULTS: Mean percent body fat was 31.6% (±7.6) at baseline and 33.5% (±7.6) at 6 months. In multivariable linear regression modeling (adjusted for baseline percent body fat), Hispanic ethnicity and baseline serum adiponectin concentration were inversely associated (p≤.05) with absolute change in percent body fat at 6 months. CONCLUSIONS: Serum adiponectin concentration may be useful for assessing risk of DMPA-associated adipose gains.

Assessing contributions of nucleus accumbens shell subregions to reward-seeking behavior.

BACKGROUND: The nucleus accumbens (NAc) plays a key role in brain reward processes including drug seeking and reinstatement. Several anatomical, behavioral, and neurochemical studies discriminate between the limbic-associated shell and the motor-associated core regions. Less studied is the fact that the shell can be further subdivided into a dorsomedial shell (NAcDMS) and an intermediate zone (NAcINT) based on differential expression of transient c-Fos and long-acting immediate-early gene ΔFosB upon cocaine sensitization. These disparate expression patterns suggest that NAc shell subregions may play distinct roles in reward-seeking behavior. In this study, we examined potential differences in the contributions of the NAcDMS and the NAcINT to reinstatement of reward-seeking behavior after extinction. METHODS: Rats were trained to intravenously self-administer cocaine, extinguished, and subjected to a reinstatement test session consisting of an intracranial microinfusion of either amphetamine or vehicle targeted to the NAcDMS or the NAcINT. RESULTS: Small amphetamine microinfusions targeted to the NAcDMS resulted in statistically significant reinstatement of lever pressing, whereas no significant difference was observed for microinfusions targeted to the NAcINT. No significant difference was found for vehicle microinfusions in either case. CONCLUSION: These results suggest heterogeneity in the behavioral relevance of NAc shell subregions, a possibility that can be tested in specific neuronal populations in the future with recently developed techniques including optogenetics.

Longitudinal assessment of bone growth and development in a facility-based population of young adults with cerebral palsy.

AIM: Osteoporosis is a significant clinical problem in persons with moderate to severe cerebral palsy (CP), causing fractures with minimal trauma. Over the past decade, most studies examining osteoporosis and CP have been cross-sectional in nature, focused exclusively on children and adolescents and only involving one evaluation of bone mineral density (BMD). The purpose of this study was to assess BMD in a group including adults with CP, and changes in each individual's BMD over a 5- to 6-year period. METHOD: The study group included 40 residents of a long-term care facility aged 6 to 26 years at the time of their initial evaluation. Twenty-one patients (52.5%) were male, 35 (88%) were white, and 38 (95%) were in Gross Motor Function Classification System level V. BMD was assessed by dual-energy X-ray absorptiometry on the right and left distal femurs for three distinct regions of interest. RESULTS: Five residents had a fracture that occurred during the study period; this represented a fracture rate of 2.1% per year in the study group. Longitudinally, annualized change in the median BMD was 0.7% to 1.0% per year in the different regions of the distal femur, but ranged widely among the study group, with both increases and decreases in BMD. Increase in BMD over time was negatively correlated with age and positively correlated with change in weight. INTERPRETATION: Changes in BMD over time in profoundly involved persons with CP can range widely, which is important to recognize when evaluating potential interventions to improve BMD. Age and changes in body weight appear the most relevant factors.

Pediatric drug development programs for type 2 diabetes: A review.

Considerable progress has been made in pediatric drug development. Despite these gains there remain certain therapeutic areas where a high percentage of drugs approved for use in adults do not gain approval for use in children. Lack of sufficient US Food and Drug Administration (FDA)-approved labeling correlates with diminished therapeutic efficacy and increased risk for adverse drug reactions. Despite the increasing prevalence and important clinical challenge with pediatric type 2 diabetes mellitus (T2DM), only 1 drug (metformin) of the first 4 T2DM drugs to complete testing in children gained FDA approval. This analysis reviews 4 pediatric drug development programs for orally administered antidiabetic agents that have undergone FDA review and discusses factors influencing failure to meet specified end points for approval. Recommendations to guide future study are also provided.

A pilot study of depot medroxyprogesterone acetate pharmacokinetics and weight gain in adolescent females.

OBJECTIVE: To explore the relationship between medroxyprogesterone acetate (MPA) pharmacokinetic (PK) parameter estimates and weight gain. STUDY DESIGN: Prospective study of adolescents (N=40; age 12-21 years) initiating DMPA. PK parameters were calculated: maximum MPA concentration (Cmax, ng/mL), time to Cmax (Tmax, days) and elimination rate constant (ng/mL/day). Optimal PK cut points were determined for predicting body mass index (BMI) increase ≥10%. RESULTS: Cmax <2.88 ng/mL and elimination rate constant <0.021 ng/mL/day were associated (p<.05) with BMI increase ≥10%. Elimination rate constant was most predictive of weight gain. CONCLUSIONS: PK evaluation may help identify adolescents at risk of excessive DMPA-associated weight gain.

Targeted liquid chromatography-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children.

AIM: Long-chain acylcarnitines have been postulated to be sensitive biomarkers of acetaminophen (APAP)-induced hepatotoxicity in mouse models. In the following study, the relationship of acylcarnitines with other known indicators of APAP toxicity was examined in children receiving low-dose (therapeutic) and high-dose ('overdose' or toxic ingestion) exposure to APAP. MATERIALS & METHODS: The study included three subject groups: group A (therapeutic dose, n = 187); group B (healthy controls, n = 23); and group C (overdose, n = 62). Demographic, clinical and laboratory data were collected for each subject. Serum samples were used for measurement of APAP protein adducts, a biomarker of the oxidative metabolism of APAP and for targeted metabolomics analysis of serum acylcarnitines using ultra performance liquid chromatography-triple-quadrupole mass spectrometry. RESULTS: Significant increases in oleoyl- and palmitoyl-carnitines were observed with APAP exposure (low dose and overdose) compared with controls. Significant increases in serum ALT, APAP protein adducts and acylcarnitines were observed in overdose children that received delayed treatment (time to treatment from overdose >24 h) with the antidote N-acetylcysteine. Time to peak APAP protein adducts in serum was shorter than that of the acylcarnitines and serum ALT. CONCLUSION: Perturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the ß-oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity.