Mueller, F. (1, 2), Hermans E. (3, 4, 5) Bindellini, D. (1,2), Aulin, L.B.S. (1), Michelet, R. (1), De Paepe, P. (3, 6), De Cock, P (3, 7, 8), Devreese, M. (4), Kloft, C. (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) and Graduate Research Training program PharMetrX, Germany, (3) Department of Basic and Applied Medical Sciences, Ghent University, Belgium, (4) Department of Pathobiology, Pharmacology and Zoological Medicine, Ghent University, Belgium, (5) Department of Pediatrics, Ghent University Hospital, Belgium, (6) Department of Emergency Medicine, Ghent University Hospital, Belgium, (7) Department of Pharmacy, Ghent University Hospital, Belgium, (8) Department of Pediatric Intensive Care, Ghent University Hospital, Belgium
Objectives: Case fatality rates of septic children are reported at 20% [1]. Inadequate target tissue exposure is hypothesised to lead to treatment failure [2] and the effect of sepsis on this exposure in children for piperacillin (PIP) and tazobactam (TAZ) has not been not investigated. Insights into this process can be gained by using animal models, such as lipopolysaccharide (LPS) induced septic juvenile pigs. Microdialysis (µD) is the gold standard method to obtain drug interstitial space fluid concentrations (CISF), i.e. target tissue exposure [3,4]. In µD, molecules diffuse across a semipermeable membrane into the µD-catheter dialysate. A constant flow through the catheter does not allow an equilibrium between perfusate and CISF, prompting the need for catheter calibration. Catheter-specific calibration is conducted by retrodialysis or calibration by internal standard (IS). Both methods use the delivered drug fraction of a highly concentrated perfusate into the tissue to calculate the relative delivery, assumed to equal the relative recovery (RR). Retrodialysis is conducted with the analyte of interest while calibration by IS uses a drug with similar physicochemical properties to the analyte: For PIP and TAZ, penicillin (PEN) has been used [5]. The use of NLME methods is the most adequate to handle the analysis of µD-based data [6] but has to date not been applied to calibration by IS. By using both calibration techniques in a porcine animal study, the feasibility of a combined calibration approach in NLME models should be investigated.
Methods: Data of 22 piglets (4 weeks old) in a prospective, randomised controlled study were used to build separate NLME models for PIP and TAZ administration (study design details: [7]). The 4-day study was divided into two phases separated by 24 h: a control (2 days) and an LPS septic phase (2 days), in which 10 pigs received an LPS infusion. The µD catheters were implanted in the paraspinal musculature and calibrated using retrodialysis before and calibration by PEN (IS) during µD sampling intervals. 7 plasma and 10 µD samples were collected for each of the 4 dosing intervals. Separate NLME models using the integral-based method for µD and retrodialysis [8], and a combined approach of both calibration methods to characterise differences in pharmacokinetics (PK) were developed using NONMEM 7.4.3. Structural models were developed using plasma data only, after which µD data were added. Additive, proportional and combined error models were tested and IIV and IOV were evaluated on all PK- and µD-related parameters. Model evaluation was done using parameter plausibility, GOF plots and VPCs.
Results: PIP and TAZ plasma and µD concentrations were best described by 2-CMT models with linear elimination. The µD data was allocated to the peripheral CMT and a tissue scaling factor was introduced to translate peripheral estimated concentrations to CISF. IIV was included for both drugs on CL, V1 and RR; IOV on CL and RR. Furthermore, an observed increase in RR over time in the healthy control pigs was described using a power function. The increase in RR was not observed in the LPS group. By implementing the IS-RR as a covariate on retrodialysis-RR (fractional change), IIV on RR decreased by 47% and 43% for TAZ and PIP, respectively, IOV and RUV decreased marginally. An improvement for predictions for µD concentrations in the control group was observed, however predictions during LPS infusion did not improve. Model evaluation demonstrated overall plausible parameters and good predictive performance.
Conclusion: Improvements in the predictive performance for the control group in µD VPC concentrations and reduction of IIV on retrodialysis-RR suggested feasibility of the combined calibration approach. However, PEN RR did not account for an LPS effect, as the change over the study day and LPS effect were similar compared to retrodialysis-RR. The decrease of RR during LPS infusion may be related to blood flow in the muscles [9,10] being related to the pig’s activity. Control piglets became more comfortable, thus, more active over time and higher perfusion might have led to higher RR. A decreased blood flow due to sickness and less movement may alter the tissue permeability for a substance, thus reducing RR. This and further LPS effects on all parameters need further investigation.
References:
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Reference: PAGE 32 (2024) Abstr 11019 [www.page-meeting.org/?abstract=11019]
Poster: Drug/Disease Modelling - Infection