Population Pharmacokinetics of Teicoplanin in Preterm and Term Neonates: Is It Time for a New Dosing Regimen?

Abstract

Our objective was to develop a population pharmacokinetic (PK) model in order to evaluate the currently recommended dosing regimen in term and preterm neonates. By using an optimal design approach, a prospective PK study was designed and implemented in 60 neonates with postmenstrual ages (PMA) of 26 to 43 weeks. A loading dose of 16 mg/kg was administered at day 1, followed by a maintenance dose of 8 mg/kg daily. Plasma concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population PK (popPK) analysis was performed using NONMEM software. Monte-Carlo (MC) simulations were performed to evaluate currently recommended dosing based on a pharmacodynamic index of area under the concentration-time curve (AUC)/MIC ratio of ≥400. A two-compartment model with linear elimination best described the data by the following equations: clearance (CL) = 0.0227 × (weight [wt]/1,765)0.75 × (estimated creatinine clearance [eCRCL]/22)0.672, central compartment volume of distribution (V1) = 0.283 (wt/1,765), intercompartmental clearance (Q) = 0.151 (wt/1,765)0.75, and peripheral compartment volume (V2) = 0.541 (wt/1,765). The interindividual variability estimates for CL, V1, and V2 were 36.5%, 45.7%, and 51.4%, respectively. Current weight (wt) and estimated creatinine clearance (eCRCL) significantly explained the observed variability. MC simulation demonstrated that, with the current dosing regimen, an AUC/MIC ratio of ≥400 was reached by only 68.5% of neonates with wt of <1 kg when the MIC was equal to 1 mg/kg, versus 82.2%, 89.7%, and 92.7% of neonates with wt of 1 to <2, 2 to <3, or ≥3 kg, respectively. Augmentation of a maintenance dose up to 10 or 11 mg/kg for preterm neonates with wt of 1 to <2 or <1 kg, respectively, increases the probability of reaching the therapeutic target; the recommended doses seem to be adequate for neonates with wt of ≥2 kg. Teicoplanin PK are variable in neonates, with wt and eCRCL having the most significant impact. Neonates with wt of <2 kg need higher doses, especially for Staphylococcus spp. with an MIC value of ≥1 mg/liter.

Population Pharmacokinetics of Unbound and Total Teicoplanin in Critically Ill Pediatric Patients

“…However, changes in serum concentrations of renal function biomarkers are often delayed [33], limiting their use in critically ill patients to assess GFR. A recently published study did however find eGFR using the Swartz S cr -based formula to be predictive of teicoplanin clearance in a neonatal patient population [18]. This predictive ability of eGFR was also found in a study conducted in a pediatric population with hematological malignancies [16].…”

“…The pharmacokinetics of total teicoplanin concentrations in pediatric populations has previously been described using two-compartment population-PK models [15][16][17][18]. Unbound teicoplanin pharmacokinetics has been described for an adult patient population with hematological malignancies [19].…”

Optimal Teicoplanin Dosing Regimen in Neonates and Children Developed by Leveraging Real-World Clinical Information

“…This value was within the previously reported teicoplanin CL range of 0.46-1.51 L/h/70 kg with an eGFR of 90 mL/min/1.73 m 2 . 10,12,37 The observed variability of CL might be explained in part by disease characteristics of the tested populations and other underlying diseases in addition to innate variability. For instance, hemodynamic alterations could increase renal CLs in critically ill children.…”

“…To date, body weight (WT) and creatinine clearance have been identified as significant fundamental covariates in teicoplanin clearance (CL) through population PK modeling approaches. [10][11][12] Further scrutiny of clinical and physiological patient characteristics in neonates and infants would be beneficial to establish a precise dosing strategy. As a supplemental modeling approach, the physiologically based PK (PBPK) model is known to provide mechanistic insights into factors contributing to variability in PK of drugs among patients with different diagnoses and disease states.…”

Use of Antibiotics in Preterm Newborns

“…In order to assess the optimal dosing regimen, especially in preterm newborns, a popPK model was developed by Kontou A and colleagues (2020) [ 211 ]. In particular, the authors analyzed plasma teicoplanin concentrations from 60 neonates with PMAs of 26 to 43 weeks using a nonlinear mixed-effects modeling approach to develop a popPK model with NONMEM software.…”