Methadone dosing strategies in preterm neonates can be simplified

Aims: A dramatic increase in newborn infants with neonatal abstinence syndrome has been observed and these neonates are frequently treated with complex methadone dosing schemes to control their withdrawal symptoms. Despite its abundant use, hardly any data on the pharmacokinetics (PK) of methadone is available in preterm neonates. Therefore we investigated developmental PK of methadone and evaluated current dosing strategies and possible simplification in this vulnerable population. Methods: A single-centre open-label prospective study was performed to collect PK data after a single oral dose of methadone in preterm neonates. A population PK model was built to characterize developmental PK of (R)- and (S)-methadone. Model-based simulations were performed to identify a simplified dosing strategy to reach and maintain target methadone exposure. Results: A total of 121 methadone concentrations were collected from 31 preterm neonates. A one-compartment model with first order absorption and elimination kinetics best described PK data for (R)- and (S)-methadone. Clearance increases with advancing gestational age and differs between R- and S-enantiomer, being slightly higher for the former (0.244 vs 0.167 L/h). Preterm neonates reached target exposure after 48 hours with currently used dosing schedules. Output from simulations revealed that target exposures can be achieved with a simplified dosing strategy during the first 4 days of treatment. Conclusion: Methadone clearance in preterm neonates increases with advancing gestational age and its disposition is influenced by its chirality. Simulations that account for developmental PK changes indicate a shorter methadone dosing strategy can maintain target exposure to control withdrawal symptoms. © 2019 The British Pharmacological Societ

Oral ibuprofen is more effective than intravenous ibuprofen for closure of a patent ductus arteriosus: can pharmacokinetic modeling help us to understand why?

Introduction: Oral ibuprofen is more effective than intravenous (IV) ibuprofen for closure of a patent ductus arteriosus (PDA). This study explored whether higher concentrations of the biologically active S-enantiomer or increased R- to S-conversion following oral dosing could explain this finding. Methods: Two datasets containing 370 S- and R-ibuprofen concentrations from 95 neonates with PDA treated with oral (n = 27, 28%) or IV ibuprofen were analyzed using nonlinear mixed effects modeling. Concentration-time profiles in typical neonates were explored and compared in different dosing or R- to S-conversion scenarios. Results: Postnatal age (PNA), gestational age (GA), and being small for GA impacted S- and R-ibuprofen clearance. Upon oral dosing, S-ibuprofen concentrations were lower compared to IV ibuprofen for a large part of the dosing interval. We could show that R- to Sconversion will not exceed 45%. Exploration of a 30% presystemic R- to S-conversion resulted in a 25-32% increase in S-ibuprofen exposure following oral administration with AUC(72h) values varying between 700-2,213 mg*h/L (oral) and 531-1,762 (IV) for the standard or 1,704-2,893 (oral) and 1,295-2,271 mg*h/L (IV) for PNA-based dosing. Discussion: The absence of higher S-ibuprofen concentrations does not support a beneficial concentration-time profile after oral dosing. While a fraction of up to 45% presystemic R- to S-conversion could not be ruled out, the impact of such a low conversion might be only relevant for the standard but not high dosing regimens, considering reported exposure-response targets. Perhaps, the lack of high peak concentrations observed following IV dosing may play a role in the observed effects upon oral dosing. 1.% 2022 The Author(s).Pharmacolog

Safety of Sildenafil in Infants

Objectives: To describe the prevalence of neurologic injury in a recent cohort of patients 18 years old or younger cannulated for venoarterial extracorporeal membrane oxygenation. To evaluate the association of carotid artery cannulation with neurologic injury when compared with other cannulation sites. To determine if age impacts the association of carotid artery cannulation with neurologic injury. Design: Retrospective analysis of data from the Extracorporeal Life Support Organization registry. Setting: Neonatal and pediatric medical/surgical and cardiac ICUs of 118 international tertiary care centers worldwide. Patients: Pediatric patients 18 years old or younger cannulated for venoarterial extracorporeal membrane oxygenation and reported to the Extracorporeal Life Support Organization registry during 2007 and 2008. Interventions: None. Measurements and Main Results: Two thousand nine hundred seventy-seven patients underwent venoarterial extracorporeal membrane oxygenation during the study period. Indications for extracorporeal membrane oxygenation included pulmonary (n = 1,390, 47%), cardiac (n = 1,168, 39%), extracorporeal membrane oxygenation during cardiopulmonary resuscitation (n = 418, 14%), and unknown (n = 1). Arterial cannulation sites were aorta (n = 938, 32%), femoral artery (n = 118, 4%), and carotid artery (n = 1,921, 64%). Overall, 611 patients (21%) had evidence of neurologic injury defined as seizures, infarction, and/or hemorrhage. The occurrence of neurologic injury varied significantly by cannulation site: femoral artery (n = 18, 15%), aorta (n = 160, 17%), and carotid artery (n = 433, 23%); p equals 0.001. Neonates represented the largest group of patients cannulated for venoarterial extracorporeal membrane oxygenation (n = 1,807, 61%), the majority of patients cannulated via the carotid artery (n = 1,276, 66%), and had the highest burden of neurologic injury (n = 398, 22%). Age, preextracorporeal membrane oxygenation high-frequency oscillatory ventilation use, preextracorporeal membrane oxygenation arterial pH and serum bicarbonate level, and preextracorporeal membrane oxygenation cardiac arrest were independently associated with neurologic injury in a covariate model. Carotid artery cannulation site was added to this adjusted model and found to independently increase odds of neurologic injury (odds ratio, 1.4 [95% CI, 1.01-1.69]). An interaction term containing age and cannulation site was not associated with neurologic injury (odds ratio, 1.06 [95% CI, 0.84-1.34]). Conclusions: Carotid artery cannulation for venoarterial extracorporeal membrane oxygenation in patients 18 years old or younger is associated with statistically significant increased odds of neurologic injury. These increased odds are present across all age groups

Trends in pregnancy labeling and data quality for US-approved pharmaceuticals

OBJECTIVE: Over the past decades, there have been significant efforts in the United States to improve pharmaceutical labeling pertaining to pregnancy. The goal of this study was to describe trends in pregnancy labeling at the time of drug approval and over time. STUDY DESIGN: The labeling data of 213 new pharmaceutical approvals between January 2003 and December 2012 were systematically reviewed. Initial approval data and subsequent labeling revisions were evaluated for pregnancy category, source of pregnancy and breast-feeding data, data in labor and delivery, presence of a registry, black-box warnings, and utilization of the new labeling format. RESULTS: The most commonly approved pregnancy category was C (51.6%). Most pharmaceuticals (92.9%) had pregnancy data based on animal studies and 5.2% had human pregnancy data. For breast-feeding, there were no data in 47.9% of labels, animal data in 42.7%, and human data in 4.7%. There were no labor and delivery data in 85.9% of labels. Only 2.8% of medications had human data, with the remainder having animal data. The majority of medications (85%) did not have a pregnancy registry. Of those that had a registry, 68.7% were by therapeutic category, not agent specific. Seven medications had black-box warnings related to teratogenicity. Since the new labeling recommendations, 4.7% of medications incorporated the new format into the labeling, primarily approvals that occurred in 2012. CONCLUSION: Despite significant efforts to improve drug labeling for pregnancy and lactation, there remains a paucity of human data in this understudied population

Oral ibuprofen is more effective than intravenous ibuprofen for closure of a patent ductus arteriosus: can pharmacokinetic modeling help us to understand why?

Introduction: Oral ibuprofen is more effective than intravenous (IV) ibuprofen for closure of a patent ductus arteriosus (PDA). This study explored whether higher concentrations of the biologically active S-enantiomer or increased R- to S-conversion following oral dosing could explain this finding. Methods: Two datasets containing 370 S- and R-ibuprofen concentrations from 95 neonates with PDA treated with oral (n = 27, 28%) or IV ibuprofen were analyzed using nonlinear mixed effects modeling. Concentration-time profiles in typical neonates were explored and compared in different dosing or R- to S-conversion scenarios. Results: Postnatal age (PNA), gestational age (GA), and being small for GA impacted S- and R-ibuprofen clearance. Upon oral dosing, S-ibuprofen concentrations were lower compared to IV ibuprofen for a large part of the dosing interval. We could show that R- to Sconversion will not exceed 45%. Exploration of a 30% presystemic R- to S-conversion resulted in a 25-32% increase in S-ibuprofen exposure following oral administration with AUC(72h) values varying between 700-2,213 mg*h/L (oral) and 531-1,762 (IV) for the standard or 1,704-2,893 (oral) and 1,295-2,271 mg*h/L (IV) for PNA-based dosing. Discussion: The absence of higher S-ibuprofen concentrations does not support a beneficial concentration-time profile after oral dosing. While a fraction of up to 45% presystemic R- to S-conversion could not be ruled out, the impact of such a low conversion might be only relevant for the standard but not high dosing regimens, considering reported exposure-response targets. Perhaps, the lack of high peak concentrations observed following IV dosing may play a role in the observed effects upon oral dosing. 1.% 2022 The Author(s)

Safety of milrinone use in neonatal intensive care units

Background: Milrinone use in the neonatal intensive care unit has increased over the last 10. years despite a paucity of published safety data in infants. We sought to determine the safety of milrinone therapy among infants in the neonatal intensive care unit. Methods: We conducted a retrospective data analysis, identifying all infants who were exposed to milrinone and discharged from 322 neonatal intensive care units managed by the Pediatrix Medical Group from 1997-2010. We identified adverse events (AEs) during milrinone exposure. The unit of observation for clinical AEs was the first course of milrinone and for laboratory AEs it was an infant-day of exposure to milrinone. Results: Overall, 1446 of 716,821 (0.2%) infants received milrinone for a total of 6894 infant-days. The proportion of infants exposed to milrinone increased from 0 in 1997 to 4/1000 infant cases in 2010. Persistent pulmonary hypertension (40%) was the most commonly reported diagnosis at the start of milrinone administration. Overall, 606/1446 (42%) of infants had at least 1 clinical AE recorded during milrinone therapy. Hypotension requiring pressors and thrombocytopenia (<100,000/mm3) were the most commonly reported clinical and laboratory AEs, respectively. Death was reported in 8% of infants during the first course of milrinone therapy. Conclusion: Among infants hospitalized in the neonatal intensi

Supplementary Material for: Oral Ibuprofen Is More Effective than Intravenous Ibuprofen for Closure of a Patent Ductus Arteriosus: Can Pharmacokinetic Modeling Help Us to Understand Why?

Introduction: Oral ibuprofen is more effective than intravenous (IV) ibuprofen for closure of a patent ductus arteriosus (PDA). This study explored whether higher concentrations of the biologically active S-enantiomer or increased R- to S-conversion following oral dosing could explain this finding. Methods: Two datasets containing 370 S- and R-ibuprofen concentrations from 95 neonates with PDA treated with oral (n = 27, 28%) or IV ibuprofen were analyzed using nonlinear mixed effects modeling. Concentration-time profiles in typical neonates were explored and compared in different dosing or R- to S-conversion scenarios. Results: Postnatal age (PNA), gestational age (GA), and being small for GA impacted S- and R-ibuprofen clearance. Upon oral dosing, S-ibuprofen concentrations were lower compared to IV ibuprofen for a large part of the dosing interval. We could show that R- to S-conversion will not exceed 45%. Exploration of a 30% presystemic R- to S-conversion resulted in a 25–32% increase in S-ibuprofen exposure following oral administration with AUC72h values varying between 700–2,213 mg*h/L (oral) and 531–1,762 (IV) for the standard or 1,704–2,893 (oral) and 1,295–2,271 mg*h/L (IV) for PNA-based dosing. Discussion: The absence of higher S-ibuprofen concentrations does not support a beneficial concentration-time profile after oral dosing. While a fraction of up to 45% presystemic R- to S-conversion could not be ruled out, the impact of such a low conversion might be only relevant for the standard but not high dosing regimens, considering reported exposure-response targets. Perhaps, the lack of high peak concentrations observed following IV dosing may play a role in the observed effects upon oral dosing

Sildenafil and retinopathy of prematurity risk in very low birth weight infants

Objective: To examine the effect of sildenafil therapy on development of severe retinopathy of prematurity (ROP) requiring surgical intervention in premature infants. Study Design: We identified premature infants who were discharged from Pediatrix Medical Group neonatal intensive care units from 2003 to 2012 and who received an ophthalmologic exam. We matched each infant exposed to sildenafil before first eye exam to three nonexposed infants using propensity scoring to control for differences in baseline infant characteristics. We evaluated the association between sildenafil exposure and development of severe ROP using conditional logistic regression. Result: Of the 57 815 infants meeting inclusion criteria, 88 were exposed to sildenafil. We matched 81/88 (92%) sildenafil-exposed with 243 nonexposed infants. There was no difference in the proportion of infants who developed severe ROP in the sildenafil-exposed vs nonexposed groups (17/81 (21%) vs 38/243 (16%), P=0.27). On adjusted analysis, there was no difference in severe ROP in the sildenafil-exposed vs nonexposed infants (odds ratio=1.46, 95% confidence interval=0.76 to 2.82, P=0.26). Conclusion: We did not observe an association between risk of severe ROP and sildenafil exposure before first eye exam in this cohort of premature infants