Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations.

Optimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (Cmax/MIC ≥ 10) and safe trough concentrations (Cmin ≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations

Amoxicillin Dosing Regimens for the Treatment of Neonatal Sepsis: Balancing Efficacy and Neurotoxicity.

INTRODUCTION: Large variability in neonatal amoxicillin dosing recommendations may reflect uncertainty about appropriate efficacy and toxicity targets. OBJECTIVE: The aim of this study was to model efficacious and safe exposure for current neonatal amoxicillin dosing regimens, given a range of assumptions for minimal inhibitory concentration (MIC), targeted %fT > MIC, and potential for aminopenicillin-related neurotoxicity. METHODS: Individual intravenous amoxicillin exposures based on 6 international and 9 Swiss neonatal dosing recommendations, reflecting the range of current dosing approaches, were assessed by a previously developed population pharmacokinetic model informed by neonatal data from an international cohort. Exposure was simulated by attributing each dosing regimen to each patient cohort. End points of interest were %fT > MIC and potential neurotoxicity using Cmax > 140 mg/L as threshold. RESULTS: None of the dosing regimens achieved targets of ≥100%fT > MIC at any of the relevant MICs for a desired probability of target attainment (PTA) of ≥90%. All regimens achieved a PTA ≥90% for Streptococcus agalactiae (MIC 0.25 mg/L) and Listeria monocytogenes (MIC 1 mg/L) when targeting ≤70%fT > MIC. In contrast, none of the regimens resulted in a PTA ≥90% targeting ≥70%fT > MIC for enterococci (MIC 4 mg/L). The maximum amoxicillin concentration associated with potential neurotoxicity was exceeded using 4 dosing regimens (100 mg/kg q12, 60/30 mg/kg q12/8, 50 mg/kg q12/8/6, and 50 mg/kg q12/8/4) for ≥10% of neonates. CONCLUSIONS: The acceptability of regimens is highly influenced by efficacy and toxicity targets, the selection of which is challenging. Novel randomized trial designs combined with pharmacometric modeling and simulation could assist in selecting optimal dosing regimens in this understudied population

Amikacin or vancomycin exposure alters the postnatal serum creatinine dynamics in extreme low birth weight neonates

Background: Disentangling renal adverse drug reactions from confounders remains a major challenge to assess causality and severity in neonates, with additional limitations related to the available tools (modified Kidney Disease Improving Global Outcome, or Division of Microbiology and Infectious Diseases pediat

Creatinine Trends to Detect Ibuprofen-Related Maturational Adverse Drug Events in Neonatal Life: A Simulation Study for the ELBW Newborn

Background: Recognizing a change in serum creatinine concentrations is useful to detect a renal adverse drug reaction signal. Assessing and characterizing the nephrotoxic side-effects of drugs in extremely low birth weight (ELBW, ≤1000 g) neonates remain challenging due to the high variability in creatinine in this population. This study aims to investigate and quantify the impact of ibuprofen treatment on kidney function, reflected by serum creatinine. Method: A recently developed dynamical model for serum creatinine was used to simulate creatinine profiles for typical, reference ELBW neonates with varying gestational and postnatal ages whilst being exposed to ibuprofen treatment. Results: The increase of serum creatinine concentrations due to ibuprofen treatment is most apparent during the first week of life. The difference in serum creatinine values between ibuprofen-exposed vs. non-exposed neonates decreases with increasing postnatal age, independent of gestational age. Conclusion: The difference in serum creatinine concentrations between ibuprofen-exposed vs. non-exposed neonates decreases with postnatal age, indicating an increased clearing capacity and resulting in a weak ibuprofen-related adverse drug reaction signal beyond early neonatal life

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

Two 'transitions': the political economy of Joyce Banda's rise to power and the related role of civil society organisations in Malawi

This is an Accepted Manuscript of an article published by Taylor & Francis in Review of African Political Economy on 21/07/2014, available online: http://www.tandfonline.com/doi/abs/10.1080/03056244.2014.90194

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