Simulation and Development of a Netilmicin Extended Dosing Regimen for Extremely Premature Neonates

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Objectives: To develop an optimal extended dosing regimen for netilmicin in neonates.

Methods: A retrospective chart review was performed for all neonates admitted to the neonatal unit at Dunedin Hospital between 1 February 1999 to 27 July 2003 who were treated with netilmicin. The study included 97 neonates aged from two days up to an age of 28 days, corrected for gestational age (GA) at birth. Neonates with suspected sepsis who were > 48 h of age were treated with netilmicin. Netilmicin was discontinued after 48 h unless neonates were confirmed septic or remained clinically unwell. Patients received a loading dose of 4 mg/kg netilmicin by intravenous (IV) infusion over 30 min. Loading doses ≥ 5 mg in total, were followed with a 1 mL saline flush. Maintenance doses were given by IV bolus over 3-5 min at 2.5 mg/kg/dose according to the patient's current weight (CWT). The dosing interval was determined by postmenstrual age (PMA) and postnatal age (PNA). Netilmicin plasma concentrations (peak and trough) were determined at the third dose after initiation of treatment or after a change in dose or dosing interval. Trough samples were taken immediately prior to the next dose and were considered to indicate a lesser risk of toxicity if they were less than 2 mg/L. Peak concentrations were taken 60 min after commencement of the IV bolus. A total of 361 netilmicin therapeutic concentrations were collected, an average of three samples per patient. All data analyses were performed using NONMEM (version.5). A mixed effects one-compartment, first order elimination model was developed to fit the dataset. The pharmacokinetic (PK) model was used to simulate various dosing regimens using a nonparametric dataset that comprised of covariate distribution values for CWT and PMA from 719 individual neonates. PMA ranged from 24.7-44.1 (weeks) and CWT 0.45-4.43 (kg) within the dataset. MATLAB (student version 7.1) was used to perform simulations for each proposed dosing regimen. Consistent with other neonatal dosing regimens PMA was split into groups based on renal maturation. The model simulated the administration of two doses via IV infusion at duration of 0.5 h. For this simulation, the criteria were achievement of maximum peak plasma concentration (Cmax) and area under the curve over 24 h (AUC24) on day one and day two, 5-12 mg/L and 50-300 mg/L h respectively.

Results: The principle factors influencing netilmicin clearance (CL) were PMA and CWT, and the principal determinant of volume of distribution (V) was CWT. The final covariate model was CL = 0.192 · (CWT/2)1.35 · (PMA/40)1.03, V=1.5 · (CWT/2)0.3. Simulation was assessed by determining the percentage of success against specific criteria. The primary evaluation of treatment success was based on achieving Cmax within the stated boundaries. The independent variables used in the simulation included number of patients (n = 1000), dose interval (24-48 h) and dose given (3-8 mg). Currently recommended dosing regimens indicate a dose of 4 mg/kg in neonates > 34 weeks. The dosing regimen in the present study based on overall achievement of treatment success (Cmax and AUC24 for days 1 and 2), proposed a higher dose (7 mg/kg) for neonates PMA ≥ 34 weeks. The optimal dosing was 5 mg/kg 36 hourly, 5 mg/kg 24 hourly, 6 mg/kg 24 hourly and 7 mg/kg 24 hourly for neonates ≤27, 28 to 30, 31 to 33, and ≥34 weeks PMA respectively.

Conclusions: Individualisation of netilmicin dosing in neonates requires adjustment of dose by body weight, and dosing interval by both postmenstrual age and current weight. Overall, the simulated netilmicin dosing regimen suggested realistic recommendations. However, the simulated dosing regimen appears to be very well suited for extremely premature neonates.