Safety of Enalapril in Infants Admitted to the Neonatal Intensive Care Unit.

Enalapril is used to treat hypertension and congestive heart failure in infants. However, enalapril is not labeled for neonates, and safety data in infants are sparse. To evaluate the safety of enalapril in young infants, we conducted a retrospective cohort study of infants who were exposed to enalapril in the first 120 days of life and were cared for in 348 neonatal intensive care units from 1997 to 2012. We determined the proportion of exposed infants who developed adverse events, including death, hypotension requiring pressors, hyperkalemia, and elevated serum creatinine. Using multivariable logistic regression, we examined risk factors for adverse events, including postnatal age at first exposure, exposure duration, gestational age group, small for gestational age status, race, sex, 5-min Apgar score, and inborn status. Of a cohort of 887,910 infants, 662 infants (0.07%) were exposed to enalapril. Among exposed infants, 142 infants (21%) suffered an adverse event. The most common adverse event was hyperkalemia (13%), followed by elevated serum creatinine (5%), hypotension (4%), and death (0.5%). Significant risk factors for adverse events included postnatal age <30 days at first exposure and longer exposure duration. This study is the largest to date examining the safety of enalapril in young term and preterm infants without significant structural cardiac disease.

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine.

BACKGROUND: Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. METHODS: Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. RESULTS: For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 mcg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7-1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. CONCLUSIONS: This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration-response relationships.

Dosing in neonates: special considerations in physiology and trial design.

Determining the right dose for drugs used to treat neonates is critically important. Neonates have significant differences in physiology affecting drug absorption, distribution, metabolism, and elimination that make extrapolating dosages from adults and older children inappropriate. In spite of recent legislative efforts requiring drug studies in this population, most drugs given to neonates remain insufficiently studied. Many ethical and logistical concerns make designing studies in this age group difficult. Fortunately, specialized analytical techniques, such as the use of dried blood spots, scavenged sampling, population pharmacokinetics analyses, and sparse sampling, have helped investigators better define doses that maximize efficacy and safety. Through the use of these methods, successful clinical trials have resulted in recent changes to drug dosing in this population.

Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus.

Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice. The model was developed using prospective data from a pediatric clinical trial comparing diazepam to lorazepam for treatment of SE. Altogether, 87 patients aged ≥ 3 months to < 18 years contributed 162 diazepam concentrations. Diazepam PKs were well characterized by a two-compartment model scaled by body size. No significant or clinically important relationships were observed between diazepam PKs and safety or efficacy. Simulations demonstrated that, compared with label dosing, the study dose (0.2 mg/kg i.v., maximum 8 mg) resulted in greater frequency in rapidly achieving the target therapeutic range of 200-600 ng/mL.

Prolonged furosemide exposure and risk of abnormal newborn hearing screen in premature infants.

BACKGROUND: At very high doses, furosemide is linked to ototoxicity in adults, but little is known about the risk of hearing loss in premature infants exposed to furosemide. AIMS: Evaluate the association between prolonged furosemide exposure and abnormal hearing screening in premature infants. STUDY DESIGN: Using propensity scoring, infants with prolonged (≥28 days) exposure to furosemide were matched to infants never exposed. The matched sample was used to estimate the impact of prolonged furosemide exposure on the probability of an abnormal hearing screen prior to hospital discharge. SUBJECTS: A cohort of infants 501-1250 g birth weight and 23-29 weeks gestational age discharged home from 210 neonatal intensive care units in the United States (2004-2013). OUTCOME MEASURES: We defined abnormal hearing screen as a result of either "fail" or "refer" for either ear. RESULTS: Altogether, 1020 infants exposed to furosemide for ≥28 days were matched to 790 unique infants never exposed, yielding a total of 1042 matches due to sampling with replacement and propensity score ties. Matching resulted in a population similar in baseline characteristics. After adjusting for covariates, the proportion of infants with an abnormal hearing screen in the furosemide-exposed group was not significantly higher than the never-exposed group (absolute difference 3.0% [95% CI -0.2-6.2%], P = 0.07). CONCLUSIONS: Prolonged furosemide exposure was associated with a positive, but not statistically significant, difference in abnormal hearing screening in premature infants. Additional studies with post-hospital discharge audiology follow-up are needed to further evaluate the safety of furosemide in this population.

Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin-Tazobactam Safety in Infants.

BACKGROUND: Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking. METHODS: To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. Using a previously published population pharmacokinetic model in the target population, we simulated piperacillin steady state area under the concentration versus time curve from zero to τ (AUCss,0-τ) and steady state maximal drug concentration (Cmaxss). Next, we used multivariable logistic regression to evaluate the association between simulated AUCss,0-τ and Cmaxss with clinical AEs (seizure and rash) and laboratory AEs controlling for gestational age. The odds ratios (95% confidence intervals) comparing the third versus the first tertiles for AUCss,0-τ and Cmaxss were reported. RESULTS: We identified 746 infants with a median (interquartile range) gestational age of 30 weeks (26-33) and postnatal age of 11 days (6-25). The median (interquartile range) piperacillin dose was 225 mg/kg/d (176-300). No significant associations were found between simulated piperacillin exposure (AUCss,0-τ and Cmaxss) and clinical and laboratory AEs. CONCLUSIONS: We found no associations between predicted piperacillin exposures and the occurrence of AEs. This study confirms the feasibility of using population pharmacokinetics and EHR to relate drug exposure with safety.

Bacterial meningitis in infants.

Neonatal bacterial meningitis is uncommon but devastating. Morbidity among survivors remains high. The types and distribution of pathogens are related to gestational age, postnatal age, and geographic region. Confirming the diagnosis is difficult. Clinical signs are often subtle, lumbar punctures are frequently deferred, and cerebrospinal fluid (CSF) cultures can be compromised by prior antibiotic exposure. Infants with bacterial meningitis can have negative blood cultures and normal CSF parameters. Promising tests such as the polymerase chain reaction require further study. Prompt treatment with antibiotics is essential. Clinical trials investigating a vaccine for preventing neonatal Group B Streptococcus infections are ongoing.