Population pharmacokinetics of teicoplanin in preterm and term neonates with late-onset sepsis
A. Kontou, K. Sarafidis, O. Begou, E. Gika, A. Tsiligiannis, K. Ogungbenro, A. Dokoumetzidis, V. Drossou, E. Roilides
1st Department of Neonatology, Aristotle University School of Health Sciences, Thessaloniki, Greece; Infectious Diseases Unit, 3rd Department of Pediatrics, Aristotle University School of Health Sciences, Thessaloniki, Greece; Laboratory of Analytical Chemistry, School of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece; Laboratory of Forensic Medicine and Toxicology, Aristotle University School of Health Sciences, Thessaloniki, Greece; Department of Pharmacy, University of Athens, Athens, Greece; Manchester Pharmacy School, The University of Manchester, Manchester, UK
Objectives: Although glycopeptides are among the most commonly used antimicrobials in neonates with suspected late-onset sepsis, little is known about the pharmacokinetics (PK) of teicoplanin in term and preterm neonates. We aimed to develop a population pharmacokinetic model in order to evaluate currently recommended dosing regimen. The sparse PK clinical study was desgned prospectively by use of D-Optimal design.
Methods: By using D-Optimal design approach with the OptDes MATLAB code and literature priors from a children study [1], a sparse PK study was designed and implemented in 60 neonates with post-menstrual age (PMA) of 26-43wks. Dosing regimen: loading dose 16mg/kg, maintenance dose 8mg/kg once daily (i.v. 30min infusion). Four blood samples per neonate were collected. Concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population PK analysis was performed using NONMEM software while covariates were tested based on clinical and statistical significance, with an allometric rationale while alternative options were also tested. Final PK model was validated by nonparametric bootstrapping and visual predictive check. Monte-Carlo (MC) simulations were carried out for various doses, to assess probability of target attainment (PTA) using 2 different targets, Ctrough(120h)>15mg/L and AUC/MIC>400, the latter for a range of MIC values.
Results: D-Optimal design methodology determined 3 sampling groups of patients with 2 sampling times on each of the 1st and the 5th day, respectively, which was implemented in the hospital closely. The final model was a 2-compartment model with the following relationships for the PK parameters: clearance, CL=0.0227*(WT/1765)^0.75*(CRCL/22)^0.672 L/h, central volume, V1= 0.283*(WT/1765) L, intercompartmental clearance, Q=0.151*(WT/1765)^0.75 L/h and peripheral volume, V2= 0.541*(WT/1765) L. Inter-individual variability on clearance (CL), central volume (V1) and peripheral volume (V2) was 37%, 46%, 51.4%, respectively. For the MC simulations a model without the CRCL on CL was used which has similar parameter estimates, in order to avoid assumptions on the distribution of CRCL. Simulations demonstrated that with a dose of 8 mg/kg: 81.6% of neonates with weight (WT)<1kg versus 89.6%, 95.1% and 97% of neonates with WT 1-2kgr, 2-3kg, ≥4kg, respectively, reach the target of Ctrough(120h)>15mg/L. Increase in dose at 11mg/kg results in 91.9% of neonates with WT<1kg achieving Ctrough(120h)>15mg/L. Also using as a target AUC/MIC>400 the smaller WT band needed a higher dose of 11 mg/kg to achieve 90% at MIC=1 mc/ml, 1- 2 kg band achieved 93% with 10 mg/kg while higher WT bands achieved 89.7% and 92.7% PTA with 8 mg/kg, respectively.
Conclusions: We present a very informative PopPK model for pre-term and term neonates with late onset sepsis, utilizing a well implemented D-optimal design sampling scheme. The results indicate that teicoplanin PK is variable in neonates, with body WT having the most significant impact on the parameters, while CRCL is also an important covariate on clearance. Based on MC simulations ELBW and VLBW neonates below 2 kg may need higher doses than the 8 mg/kg currently recommended in the SPC, especially for Staphylococcus spp. with MIC≥1 mc/ml, while for neonates of WT>2 kg, the recommended doses seem to be adequate. According to these findings, there seems to be no need for TDM contrary to what was suggested recently by other authors [2].
References:
[1] Lukas JC, Karikas G, Gazouli M, Kalabalikis P, Hatzis T, Macheras P. Pharmacokinetics of teicoplanin in an ICU population of children and infants. Pharm Res. 2004 Nov;21(11):2064-71.
[2] Ramos-Martín V, Neely MN, Padmore K, Peak M, Beresford MW, Turner MA, Paulus S, López-Herce J, Hope WW. Tools for the Individualized Therapy of Teicoplanin for Neonates and Children. Antimicrob Agents Chemother. 2017 Sep 22;61(10). pii: e00707-17. doi: 10.1128/AAC.00707-17.