Population Pharmacokinetic and Pharmacodynamic Analysis of Buprenorphine for the Treatment of Neonatal Abstinence Syndrome

Neonatal abstinence syndrome (NAS) is a condition affecting newborns exposed to an opioid in utero. Symptoms of NAS include excessive crying, poor feeding, and disordered autonomic control. Up to 2/3 of infants will require pharmacologic therapies to reach symptom control. Opioids including morphine and methadone are the current first-line treatments. Buprenorphine is being investigated as a treatment of NAS. The purpose of this analysis was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of BUP in infants with NAS. Poster presented at American Society for Clinical Pharmacology and Therapeutics (ASCPT) 2017 Annual Meeting, March 15-18, 2017 in Washington DC.https://jdc.jefferson.edu/petposters/1004/thumbnail.jp

Ethanol Pharmacokinetics in Neonates Secondary to Medication Administration

Purpose: Ethanol serves as a solvent and microbial preservative in oral liquid medications and is the second most commonly used solvent in liquid medications following water. Despite widespread use of ethanol in liquid medications for neonates, the pharmacokinetics and toxicity of ethanol in young children are not well described. The aim of the current study is to quantify blood ethanol levels in neonates secondary to oral ethanol containing medications. Methods: Neonates who received either oral phenobarbital (15% ethanol) and/or oral dexamethasone (30% ethanol) per standard of care were eligible for enrollment. A maximum of 6 blood samples per patient (4.5 mL total) were taken over the study period. Blood samples were collected via heel stick at the time of clinical laboratory collections or following a specific collection for study purposes. In addition, blood samples were collected from neonates receiving sublingual buprenorphine (30% ethanol) for neonatal abstinence syndrome from a separate clinical study. Blood ethanol levels were measured using a validated headspace gas chromatography-mass spectrometry method utilizing micro-volume ( ̴100uL) plasma samples. The limit of detection and lower limit of quantification for the assay were 0.1 mg/L and 0.5 mg/L respectively. Results: A total of 39 plasma samples from 15 neonates who were on ethanol containing medications were collected over the study period. Four neonates were exposed to phenobarbital and/or dexamethasone, while eleven neonates were exposed to buprenorphine alone or in combination with phenobarbital. Patients were exposed to an average of 71.6 mg/kg (range 13.1 to 215 mg/kg) of ethanol after a single dose of an ethanol containing medication. Blood ethanol levels were detectable in 98% (38/39) of samples, quantifiable in 67% (26/39) of samples, and ranged from below detection to 85.4 mg/L. Ethanol was rapidly cleared and did not accumulate with current dosing regimens. Conclusion: Ethanol intake secondary to medication administration varied widely. Blood ethanol levels in neonates were low and ethanol was eliminated rapidly after a single dose of oral medications that contained a sizable fraction of ethanol.https://jdc.jefferson.edu/petposters/1000/thumbnail.jp

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BackgroundEstimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period.Methods22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution.FindingsGlobal all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations.InterpretationGlobal adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic