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

P76 The effect of the pregnancy and lactation labeling rule on prescribing information of FDA-approved drugs

BackgroundThe U.S. Food and Drug Administration implemented the new Pregnancy and Lactation Labeling Rule (PLLR) in June 2015. Under PLLR, all new drug applications were to present a narrative risk assessment (as opposed to letter category), while drug approvals after June 2001, were required to phase in by June 2020. The purpose of this study was to assess the quality of presented pregnancy and lactation data in the drug labeling and degree of adherence to the PLLR.Design/MethodsWe reviewed the labeling data of all new molecular entities (NMEs) approved from 1999–2017. The pregnancy and lactation information was classified as: 1. Harmful to use 2. Safe to use 3. Consideration of safety and efficacy. For drugs approvals after June 2001, presence of pregnancy letter category system was noted.ResultsOf the 456 NMEs, 131 (29%) were classified as harmful to use in pregnancy and 207 (45%) as harmful to use during lactation. This number did not follow any specific pattern over the course of 19 years. Less than 1% of drugs were deemed to be safe during pregnancy or lactation. Human data was the source of pregnancy or lactation information for only 2% of drugs. Up to 70% of drugs belonged to each implementation schedule has yet to meet the PLLR compliance requirement.Conclusion(s)Pregnant and lactating women are mostly advised against use of medications that might be needed for their health and health of their infants based on very limited data. Pharmaceutical companies lagged behind the required adherence rule for labeling updates on pregnancy and lactation information.Disclosure(s)Nothing to disclose</jats:sec

O06 Methadone dosing strategies in preterm neonates can be simplified

AimsA 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 of methadone is available in preterm neonates. Therefore we investigated developmental pharmacokinetics of methadone and evaluated current dosing strategies and possible simplification in this vulnerable population.MethodsA single center open-label prospective study was performed to collect pharmacokinetic data after a single oral dose of methadone in preterm neonates. A population pharmacokinetic model was built to characterize developmental pharmacokinetics of methadone and to assess the effects of weight and age on clearance and volume of distribution. In addition, simulation techniques were applied to evaluate reported dosing scenarios, investigate methadone exposure levels and examine the feasibility of simplified dosing recommendations.ResultsIn total, 121 methadone concentrations were collected from 31 preterm neonates. The median weight and gestational age amounted 1.6 kg and 32 weeks, respectively. A one-compartment model with first order absorption and elimination kinetics best described the data for (R)- and (S)-methadone. Clearance was observed to be higher for the (R)-enantiomer as compared to the (S)-enantiomer (0.244 versus 0.167 L/h). Target exposures, based on simulations, can be maintained with a simplified dosing strategy during the first four days of treatment. It is therefore questionable if there is a need for the currently used more extended dosing regimen of methadone in neonates.conclusionsThis clinical investigation demonstrates that the clearance of methadone increases with advancing gestational age and higher clearance values and volumes of distribution can be observed for (R)-methadone as compared to (S)-methadone in preterm neonates. Simulations that account for developmental pharmacokinetics indicate that a simplified methadone dosing strategy can maintain target exposure to control withdrawal symptoms in preterm neonates.Disclosure(s)Nothing to disclose</jats:sec