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Background

The emergence of β-lactamase-producing bacteria limits the effectiveness of β-lactam (BL) antibiotics, and the combination with a β-lactamase inhibitor (BLI) aims to counteract this resistance. However, existing guidelines primarily focus on optimizing the dosing of BLs and do not adequately address the interaction between BLs and BLIs, leading to uncertain pharmacokinetic/pharmacodynamic (PK/PD) targets and potentially suboptimal dosing strategies.

Objectives

To investigate optimal PK/PD targets and dosing strategies for avibactam (BLI) combined with ceftazidime (BL) using mechanism-based PKPD models.

Methods

PK models for ceftazidime and avibactam were integrated with mechanism-based PKPD models for Gram-negative bacteria. Simulations explored dose regimens in mice and humans, evaluating PK/PD indices and computing the PTA for diverse dosing strategies and infusion modes.

Results

fAUC/MIC_CAZ/AVI was the most predictive index for avibactam against Enterobacteriaceae in both mice and humans, regardless of infusion mode. Against Pseudomonas aeruginosa, fT > C_T predicted efficacy in mice, while fAUC/MIC_CAZ/AVI and fCmax/MIC_CAZ/AVI were more predictive in humans, particularly for continuous infusion regimens. Higher PTAs were achieved with increased avibactam doses relative to ceftazidime, particularly with 1:1 and 2:1 ceftazidime:avibactam ratios. Continuous infusion improved PTA against P. aeruginosa but had limited impact on Enterobacteriaceae.

Conclusion

The PK/PD indices predictive of avibactam efficacy varied by species (mice and humans), bacterial strains, and mode of infusion. Dosing simulations suggest that increasing avibactam relative to ceftazidime and using continuous infusion regimens may enhance bacterial killing. These findings highlight the importance of refining dosing strategies for both components of the combination therapy.

Purpose: To investigate the pharmacokinetics (PK) of ceftazidime-avibactam (CAZ-AVI) in critically ill patients undergoing continuous venovenous hemodiafiltration (CVVHDF), and compare with a general phase III trial population.

Methods: A prospective PK study was conducted in critically ill patients who received CVVHDF for acute kidney injury, treated with CAZ-AVI (1000/250 mg or 2000/500 mg q8h). Plasma and CVVHDF-circuit samples were collected to determine CAZ-AVI concentrations. Individual PK parameters at steady-state were estimated using non-compartmental analysis. For visual comparison, plasma concentrations from CVVHDF patients were overlaid with simulated data from patients not receiving CVVHDF based on previously developed population PK models.

Results: A total of 35 plasma samples and 16 CVVHDF-circuit samples were obtained from four patients, with two patients sampled on two separate occasions. Median total clearance and volume of distribution were 4.54 L/h and 73.2 L for CAZ and 10.5 L/h and 102 L for AVI, respectively. Median contribution of CVVHDF to total clearance was 19.8% for CAZ and 5.3% for AVI. Observed CAZ-AVI PK profiles were generally within the 90% confidence interval of model predictions, but the observed concentrations were notably lower early (0-2 h) and higher later (4-8 h) in the dosing interval, suggesting a higher volume of distribution.

Conclusions: These results suggest that the CAZ-AVI dose regimens used in this study can be applicable in critically ill patients undergoing CVVHDF, despite the different shape of the PK profiles observed in this population. Further research with a larger patient cohort is warranted to validate and refine these findings.

β-lactam/β-lactamase inhibitor (BL/BLI) combinations are essential for treating infections caused by multidrug-resistant Gram-negative bacteria, particularly in critically ill patients. However, pharmacokinetic (PK) and pharmacodynamic (PD) variability complicates dosing, potentially leading to suboptimal exposure, reduced bacterial eradication, and treatment failure. Despite widespread use, BL/BLI therapy relies largely on standard dosing approaches, with limited individualisation. This thesis explores pharmacometric strategies to better understand the complexities of BL/BLI therapy in critically ill patients by evaluating drug exposure, efficacy target attainment, and dosing strategies through real-world patient data, PKPD modelling, and simulation-based approaches.

Both simulated and patient-derived data were analysed. Population PK analysis was applied to characterise ceftazidime-avibactam (CAZ-AVI) disposition in critically ill patients with pneumonia and those undergoing continuous venovenous hemodiafiltration (CVVHDF). PK/PD indices and targets for avibactam were investigated in preclinical and clinical settings. In simulations, target attainment was evaluated for multiple BL/BLI regimens across different infection sites and renal function groups. Additionally, host response biomarkers were assessed for their potential role in treatment monitoring and individualisation.

Significant interindividual variability in CAZ-AVI PK was observed, even after accounting for renal function, suggesting additional unexplained sources of variability. Standard dosing in CVVHDF patients resulted in lower early (0-2 h) and higher later (4-8 h) concentrations compared to non-CVVHDF patients, indicating a larger volume of distribution and the need for tailored regimens. Both fT>C_T and fAUC/MIC were identified as the best PK/PD indices for avibactam, depending on bacterial strain and mode of infusion, challenging the assumption of universal PK/PD indices. Simulations revealed that insufficient BLI exposure frequently limited target attainment, underscoring the need to consider both BL and BLI concentrations in dose optimisation. Analysis of immune response biomarkers revealed dynamic changes over the course of treatment, with one identified relationship between drug exposure and host response, though further clinical validation is needed.

This work demonstrates how model-based approaches can enhance BL/BLI therapy evaluation and individualisation by characterising PK variability, refining efficacy targets, and assessing dosing strategies in critically ill patients. Future research should focus on linking target attainment to clinical outcomes and integrating therapeutic drug monitoring and biomarker-guided approaches where relevant to optimise therapy.

Glofitamab is a novel T cell bispecific antibody developed for treatment of relapsed-refractory diffuse large B cell lymphoma and other non-Hodgkin's lymphoma indications. By simultaneously binding human CD20-expressing tumor cells and CD3 on T cells, glofitamab induces tumor cell lysis, in addition to T-cell activation, proliferation, and cytokine release. Here, we describe physiologically-based pharmacokinetic (PBPK) modeling performed to assess the impact of glofitamab-associated transient increases in interleukin 6 (IL-6) on the pharmacokinetics of several cytochrome P450 (CYP) substrates. By refinement of a previously described IL-6 model and inclusion of in vitro CYP suppression data for CYP3A4, CYP1A2, and 2C9, a PBPK model was established in Simcyp to capture the induced IL-6 levels seen when glofitamab is administered at the intended dose and dosing regimen. Following model qualification, the PBPK model was used to predict the potential impact of CYP suppression on exposures of various CYP probe substrates. PBPK analysis predicted that, in the worst-case, the transient elevation of IL-6 would increase exposures of CYP3A4, CYP2C9, and CYP1A2 substrates by less than or equal to twofold. Increases for CYP3A4, CYP2C9, and CYP1A2 substrates were projected to be 1.75, 1.19, and 1.09-fold following the first administration and 2.08, 1.28, and 1.49-fold following repeated administrations. It is recommended that there are no restrictions on concomitant treatment with any other drugs. Consideration may be given for potential drug-drug interaction during the first cycle in patients who are receiving concomitant CYP substrates with a narrow therapeutic index via monitoring for toxicity or for drug concentrations.

Background: The emergence of β-lactamase-producing bacteria has led to the use of β-lactam (BL) antibiotic and β-lactamase inhibitor (BLI) drug combinations. Despite therapeutic drug monitoring (TDM) being endorsed for BLs, the impact of TDM on BLIs remains unclear.

Objectives: Evaluate whether BLIs are available in effective exposures at the site of infection and assess if TDM of BLIs could be of interest.

Methods: Population pharmacokinetic models for 9 BL and BLI compounds were used to simulate drug concentrations at infection sites following EMA-approved dose regimens, considering plasma protein binding and tissue penetration. Predicted target site concentrations were used for probability of target attainment (PTA) analysis.

Results: Using EUCAST targets, satisfactory (≥90%) PTA was observed for BLs in patients with typical renal clearance (CrCL of 80 mL/min) across various sites of infection. However, results varied for BLIs. Avibactam achieved satisfactory PTA only in plasma, with reduced PTAs in abdomen (78%), lung (73%) and prostate (23%). Similarly, tazobactam resulted in unsatisfactory PTAs in intra-abdominal infections (79%), urinary tract infections (64%) and prostatitis (34%). Imipenem-relebactam and meropenem-vaborbactam achieved overall satisfactory PTAs, except in prostatitis and high-MIC infections for the latter combination.

Conclusions: This study highlights the risk of solely relying on TDM of BLs, as this can indicate acceptable exposures of the BL while the BLI concentration, and consequently the combination, can result in suboptimal performance in terms of bacterial killing. Thus, dose adjustments also based on plasma concentration measurements of BLIs, in particular for avibactam and tazobactam, can be valuable in clinical practice to obtain effective exposures at the target site.