Editor's Note: Antimicrobial drugs play a crucial role in clinical treatment, essential for controlling infectious diseases caused by various pathogens, including bacteria, mycoplasma, and chlamydia. However, inappropriate use of these drugs can lead to increased resistance and treatment failures. Therapeutic Drug Monitoring (TDM) is especially important in the clinical application of antimicrobial drugs. At the 10th Academic Conference of the Chinese Medical Education Association's Infectious Diseases Professional Committee (IDSC 2024), held recently in Nanjing, Dr. Libo Zhao from Peking University Third Hospital provided a comprehensive overview of the progress in TDM practices for anti-infective drugs, both domestically and internationally. His presentation covered model-informed precision dosing (MIPD), the development of new antimicrobial agents, and the exploration and application of novel monitoring technologies.
1. Model-Informed Precision Dosing (MIPD)
MIPD and Its Decision Support Systems
MIPD utilizes modeling and simulation technologies based on mathematical and statistical principles, integrating drug development and clinical application data to achieve quantitative assessments of therapeutic outcomes. Core models in this field include PopPK (Population Pharmacokinetics), PK/PD (Pharmacokinetics/Pharmacodynamics), PBPK (Physiologically Based Pharmacokinetics), Artificial Intelligence, QSP (Quantitative Systems Pharmacology), MBMA (Model-Based Meta-Analysis), Virtual Twins, and Pharmacoeconomic Models. These models collectively advance the development of MIPD.
In the area of Clinical Decision Support Systems (CDSS), population PK/PD models have become mainstream due to their maturity and widespread application. However, despite the robust modeling and computational capabilities of existing software such as NONMEM, Phoenix NLME, Lixoft, and MATLAB, their complexity and specialization limit their use among clinicians and pharmacists. To address this challenge, scholars and institutions globally have actively developed various CDSS platforms, including computer-based, web-based, and mobile app platforms, aiming to enhance accessibility and ease of use.
Dr. Libo Zhao highlighted the latest advancements in CDSS by discussing the TDM and individualized dosing platform for vancomycin. Vancomycin is primarily used to treat Gram-positive cocci infections, especially methicillin-resistant Staphylococcus aureus (MRSA) infections, and is considered the first-choice treatment for such resistant strains. Due to significant interpatient variability in vancomycin pharmacokinetics, some patients may experience nephrotoxicity or ototoxicity, making precise dose adjustments based on TDM results crucial. Dr. He Na and her research team at the Department of Pharmacy, Peking University Third Hospital, conducted a comprehensive comparison of different individualized dosing software/web platforms for vancomycin. The study concluded that while clinical applicability varies significantly among platforms, tools like Bestdose, PharmVAN, Doseme, Nextdose, and PrecisePK showed broader clinical utility and better prediction accuracy, especially when TDM was used after the first blood concentration point. Overall, the PharmVAN platform, launched by Peking University Third Hospital, demonstrated wide clinical applicability and strong predictive accuracy, based on its foundation in public welfare.
2. Development of New Antimicrobial Drugs
In response to the emergence of new pathogens and the growing issue of antimicrobial resistance, countries worldwide are accelerating the development of new antimicrobial agents. TDM-related efforts provide indispensable technical support for the rational clinical use of these new drugs. Dr. Libo Zhao emphasized the significance of TDM in this context by using PAXLOVID (containing nirmatrelvir and ritonavir) as an example.
The clinical trial results of PAXLOVID, announced on November 5, 2021, showed that this oral COVID-19 treatment significantly reduced hospitalization or death rates among non-hospitalized COVID-19 patients by up to 89%. This breakthrough finding propelled further exploration of nirmatrelvir in clinical practice. However, for patients with impaired liver or kidney function, especially those with severe hepatic impairment or severe renal impairment (eGFR <30 mL/min), existing data do not yet support its safety and efficacy, warranting cautious use. Against this backdrop, Dr. Rongsheng Zhao ‘s team at Peking University Third Hospital developed an HPLC-MS/MS-based precise detection method for Chinese COVID-19 inpatients and conducted a PopPK study to understand the pharmacokinetic characteristics of nirmatrelvir in Chinese patients, particularly the impact of renal function differences. The study involved recruiting 40 eligible patients from 18 departments at Peking University Third Hospital, starting in January 2023.
The clinical pharmacy team worked closely with doctors to ensure informed consent and the collection and transport of clinical samples. The laboratory team built a model using Phoenix NLME 8.0 software, ultimately establishing a PopPK model for nirmatrelvir suitable for Chinese patients. The model indicated that nirmatrelvir follows a one-compartment model with first-order elimination kinetics, with creatinine clearance (Ccr) as a significant covariate affecting pharmacokinetic parameters. The study found that Chinese patients’ Cmax was higher, while CL and Vd were lower compared to previous reports.
Based on these findings, the research team proposed dose adjustment strategies for nirmatrelvir in patients with varying renal functions: for patients with normal renal function, the recommended dose is 300 mg twice daily; for those with Ccr of 30-50 mL/min, the dose should be reduced to 150 mg twice daily; and for those with Ccr of 50-79 mL/min, the original dose may be maintained or slightly reduced, depending on the patient’s actual renal function.
3. Emergence of New Monitoring Technologies
The continuous emergence of new sensor technologies, sampling methods, and monitoring techniques has brought unprecedented technological innovation to the field of TDM and precision medicine. Among these, biosensors, as core analytical tools, convert biological responses into quantifiable electrical signals through unique molecular recognition mechanisms, greatly enhancing the real-time accuracy of TDM.
Biosensors encompass enzyme sensors, microbial sensors, immunosensors, and tissue-based sensors, each with unique advantages and applications. Enzyme sensors are known for their high sensitivity and selectivity, despite challenges in complexity, cost, and stability. Microbial sensors, while offering lower cost and greater stability, have longer response times and less selectivity, but have found success in environmental monitoring and medical diagnostics. Tissue-based sensors, noted for their simplicity and long working life, are potential alternatives to enzyme sensors, though they face challenges in selectivity and material preservation during practical applications.
The rise of semiconductor biosensors marks a deep integration of biotechnology and semiconductor technology, paving the way for the miniaturization, micro-sizing, and multifunctionalization of biosensors. The real-time TDM tri-level model, based on biosensors, effectively overcomes the limitations of traditional TDM in terms of laboratory dependence, invasiveness, and real-time capabilities, injecting new vitality into the field of drug monitoring.
Biosensors are now widely used to monitor blood concentrations of various drugs, including β-lactams (e.g., ampicillin, piperacillin-tazobactam, penicillin), glycopeptides (e.g., vancomycin), aminoglycosides (e.g., tobramycin, gentamicin), tetracyclines (e.g., tetracycline), and quinolones (e.g., ciprofloxacin). This technology provides strong support for individualized treatment and precise dosing.
4. Conclusion
PK/PD theory serves as the cornerstone of TDM, providing a solid theoretical foundation for the development of precision dosing strategies. As medical technology continues to advance, the application of model-based individualized dosing techniques is becoming more widespread and in-depth, predicting pharmacokinetic characteristics and pharmacodynamic responses in individuals, thereby enhancing the safety and effectiveness of drug therapy. The ongoing development of new drugs continues to drive innovation and diversification in antimicrobial agents, and the emergence of new monitoring technologies offers unprecedented opportunities for the clinical application of TDM. This progress will further promote the development of precision medicine, enabling patients to receive more personalized and effective treatment plans.
