Once-Daily Dosing Algorithm for Neonates
Once-Daily Dosing Algorithm for Neonates
Study Objective: To develop a gentamicin pharmacokinetic population model and once-daily dosing algorithm for neonates younger than 10 days.
Design: Prospective, open-label study.
Setting: Neonatal intensive care unit.
Patients: One hundred thirty-nine neonates prescribed gentamicin.
Measurements and Main Results: Gentamicin peak and trough serum concentrations were collected from 139 neonates divided into three groups who were receiving one of the following intravenous 24-hour gentamicin regimens during the first 10 days of life, based on gestational age and birth weight (group 1, < 28 wks, 2.5 mg/kg; group 2, 28-34 wks, 3 mg/kg; and group 3, > 34 wks, 4 mg/kg). A structural model was developed in ADAPT II software using a MAP Bayesian approach. Final population parameter estimates were calculated using iterative two-stage analysis. The median (range) gestational age and birth weight, respectively, were 32 weeks (23-42 wks) and 1.92 kg (0.47-5.00 kg). The final one-compartmental linear model had a median (range) gentamicin total clearance, half-life, and volume of distribution of 0.0709 L/hour (0.0151-0.246 L/hr), 8.59 hours (4.88-16.9 hrs), and 0.262 L (0.0903-0.929 L), respectively. Total clearance increased as gestational age increased (p<0.001). Group 1 (10.2 hrs) had a significantly longer half-life than either group 2 (8.89 hrs, p<0.01) or group 3 (6.98 hrs, p<0.01). Total clearance was associated with gestational age and birth weight: clearance (L/hr) = (0.00504 + [0.00108
gestational age])
birth weight (coefficient of determination [r ] = 0.897), and volume of distribution was associated with birth weight (r = 0.700). The following dosing algorithm was designed to reach a therapeutic 24-hour area under the curve (87.5 mg/L
hr) in neonates during the first 10 days after birth: 24-hour gentamicin dose (mg) = (0.441 + [0.0945
gestational age])
birth weight.
Conclusion: This dosing algorithm provides a new approach for determining initial gentamicin dosing regimens in neonates; however, clinical validation is required.
Gentamicin is one of the most commonly prescribed antibiotics in neonates for culture-proved or suspected sepsis. Over the last several years, interest has increased in refining dosing regimens for neonates in order to improve efficacy and decrease toxicity. Traditional gentamicin dosing regimens were 2.5 mg/kg infused at intervals based on birth weight, with target peak concentrations of 5-10 mg/L to maximize efficacy and trough concentrations below 2 mg/L to minimize toxicity. Studies in children and neonates have demonstrated that this dosing protocol often resulted in subtherapeutic peak and unacceptably high trough concentrations.
To achieve target peak and trough concentrations more consistently, gentamicin dosing in neonates has evolved to once-daily dosing (ODD) regimens. Investigators have published results that support the use of ODD regimens in clinical practice. Additional reasons for the evolution of ODD in clinical practice are ease of administration, less chance of order error, and a more consistent way to monitor blood concentrations. In many published retrospective descriptive analyses of ODD regimens, authors reported only the indexes of exposure, such as the percentage of patients who achieved a predetermined target peak and trough concentration, but not the pharmacokinetic parameters of gentamicin in the observed population. Furthermore, information gained from these descriptive analyses often is not used to improve the current dosing algorithm. In our analysis, a population pharmacokinetic model was developed for neonates with a gestational age of 24-40 weeks in their first 10 postnatal days and results of the model were used to improve the existing ODD algorithm.
Study Objective: To develop a gentamicin pharmacokinetic population model and once-daily dosing algorithm for neonates younger than 10 days.
Design: Prospective, open-label study.
Setting: Neonatal intensive care unit.
Patients: One hundred thirty-nine neonates prescribed gentamicin.
Measurements and Main Results: Gentamicin peak and trough serum concentrations were collected from 139 neonates divided into three groups who were receiving one of the following intravenous 24-hour gentamicin regimens during the first 10 days of life, based on gestational age and birth weight (group 1, < 28 wks, 2.5 mg/kg; group 2, 28-34 wks, 3 mg/kg; and group 3, > 34 wks, 4 mg/kg). A structural model was developed in ADAPT II software using a MAP Bayesian approach. Final population parameter estimates were calculated using iterative two-stage analysis. The median (range) gestational age and birth weight, respectively, were 32 weeks (23-42 wks) and 1.92 kg (0.47-5.00 kg). The final one-compartmental linear model had a median (range) gentamicin total clearance, half-life, and volume of distribution of 0.0709 L/hour (0.0151-0.246 L/hr), 8.59 hours (4.88-16.9 hrs), and 0.262 L (0.0903-0.929 L), respectively. Total clearance increased as gestational age increased (p<0.001). Group 1 (10.2 hrs) had a significantly longer half-life than either group 2 (8.89 hrs, p<0.01) or group 3 (6.98 hrs, p<0.01). Total clearance was associated with gestational age and birth weight: clearance (L/hr) = (0.00504 + [0.00108
gestational age])
birth weight (coefficient of determination [r ] = 0.897), and volume of distribution was associated with birth weight (r = 0.700). The following dosing algorithm was designed to reach a therapeutic 24-hour area under the curve (87.5 mg/L
hr) in neonates during the first 10 days after birth: 24-hour gentamicin dose (mg) = (0.441 + [0.0945
gestational age])
birth weight.
Conclusion: This dosing algorithm provides a new approach for determining initial gentamicin dosing regimens in neonates; however, clinical validation is required.
Gentamicin is one of the most commonly prescribed antibiotics in neonates for culture-proved or suspected sepsis. Over the last several years, interest has increased in refining dosing regimens for neonates in order to improve efficacy and decrease toxicity. Traditional gentamicin dosing regimens were 2.5 mg/kg infused at intervals based on birth weight, with target peak concentrations of 5-10 mg/L to maximize efficacy and trough concentrations below 2 mg/L to minimize toxicity. Studies in children and neonates have demonstrated that this dosing protocol often resulted in subtherapeutic peak and unacceptably high trough concentrations.
To achieve target peak and trough concentrations more consistently, gentamicin dosing in neonates has evolved to once-daily dosing (ODD) regimens. Investigators have published results that support the use of ODD regimens in clinical practice. Additional reasons for the evolution of ODD in clinical practice are ease of administration, less chance of order error, and a more consistent way to monitor blood concentrations. In many published retrospective descriptive analyses of ODD regimens, authors reported only the indexes of exposure, such as the percentage of patients who achieved a predetermined target peak and trough concentration, but not the pharmacokinetic parameters of gentamicin in the observed population. Furthermore, information gained from these descriptive analyses often is not used to improve the current dosing algorithm. In our analysis, a population pharmacokinetic model was developed for neonates with a gestational age of 24-40 weeks in their first 10 postnatal days and results of the model were used to improve the existing ODD algorithm.
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