BACKGROUND
Pharmacometrics is an emerging science that pursues a model-based study on the data of pharmacokinetics (PK), pharmacodynamics (PD), body functions, disease processes, and trial project progression using modeling and simulation methods. This emerging discipline usually describes and reflects the relationships between drug dosage, exposure, response, and patient characteristics in terms of concentration-effect, dose-response, and PK-PD correlations. Adoption of pharmacometric approaches at an early stage and in the full course of new drug research and development (R&D) is helpful for building a model-guided drug R&D strategy, which is more time- and cost-efficient to shorten drug development course. Therefore, pharmacometrics plays an extremely important role in drug R&D, treatment guidance, and regulatory decisions [1-3].
The goal of antimicrobial treatment is to cure patients by inhibiting or killing the invading pathogens and minimize the emergence of bacterial resistance by formulating an effective, safe, and rational dosing regimen. Pharmacometric modeling and simulation are apparently practical tools for the development of antimicrobial agents to achieve such a goal. Pharmacometrics is particularly instrumental in efficacy evaluation, dose selection, regimen optimization, and endpoint analysis when combining the in vitro susceptibility results with the findings of bacterial resistance surveillance. For example, pharmacometric methods can be used to define the PK-PD indices and breakpoints indicating antimicrobial activity/susceptibility in clinical patient population by combining PK with the preclinical in vitro susceptibility results; develop the optimal effective and safe dosing regimens for general and special patient populations (e.g., pediatric/geriatric patients, patients with hepatic or renal impairment); and further optimize the dosing regimen in clinical development and post-marketing evaluation [4, 5].
Unlike other drug classes, antimicrobial treatment is based on the key mechanism of action of each antimicrobial agent against pathogens. Appropriate PK-PD targets can be determined by associating the microbiological and clinical efficacy with PK-PD indices, such as the percentage of time the free concentration of antibiotic is above the MIC (fT%>MIC), the ratio between the area under the plasma drug concentration-time curve (AUC) and MIC (fAUC/MIC), and the maximum plasma concentration (Cmax) to MIC ratio (fCmax/MIC). Furthermore, Monte Carlo simulation can be applied to calculate the probability of target attainment (PTA) of different dosing regimens for the selection of optimal dosage and regimen [6, 7]. Pharmacometric researches based on the understanding of tissue penetration can reveal the relationship between the concentration of antimicrobial agent at the site of infection and treatment efficacy, which is more precise than plasma concentration in predicting the antimicrobial efficacy [8].
As members of International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), China National Medical Products Administration (NMPA), US Food and Drug Administration (FDA), and European Medicines Agency (EMA) all adopt the important ICH guidelines regarding pharmacometrics, including ICH E1: The Extent of Population Exposure to Assess Clinical Safety; ICH E4: Dose-Response Information to Support Drug Registration; and ICH E5: Ethnic Factors in the Acceptability of Foreign Clinical Data [9]. In addition, regulatory agencies also issued a series of guidelines concerning pharmacometrics according to national or regional reality. These efforts not only reflect the concerns of regulatory authorities but also provide specifications and guidance for the development of antimicrobial agents.
FDA emphasizes the role of pharmacometrics in drug R&D and review and has rich experience in this respect. It has issued several important guidelines regarding pharmacometrics, e.g., Guidance for Industry: Population Pharmacokinetics (1999), Guidance for Industry: Exposure-Response Relationship - Study Design, Data Analysis, and Regulatory Applications (2003) [10, 11]. The updated version of Guidance for Industry: Population Pharmacokinetics was recently posted online in July 2019 [12]. This document aims to guide the population PK modeling analysis in drug development and new drug application (NDA). The EMA also published a series of pharmacometrics-related guidelines, including Guideline on Reporting the Results of Population Pharmacokinetic Analyses (2007) [13], Guideline on the Use of Pharmacokinetics and Pharmacodynamics in the Development of Antimicrobial Medicinal Products (2016) [14], Guideline on the Evaluation of Medicinal Products Indicated for Treatment of Bacterial Infections (2018) [15], Guideline on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Hepatic Function (CPMP/EWP/2339/02) (2005) [16], and Note for Guidance on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Renal Function (CHMP/EWP/225/02) (2004) [17].
Most of the pharmaceutical products made in China were generic drugs in the past decades. Pharmacometrics is introduced into drug R&D in China lately. However, in recent years, Chinese regulatory authority has made strong moves to encourage the development of innovative drugs, and facilitate the application of pharmacometrics in new drug development [18]. NMPA has released several guidelines relevant to pharmacometrics, including Technical Guidance on the Pharmacokinetic and Pharmacodynamic Study of Antimicrobial Agents (2017), Technical Guidance on Studying the Breakpoints of Antimicrobial Agents (2018), Technical Guidance on Pharmacokinetic Study in Patients with Impaired Renal Function (2012), Technical Guidance on Pharmacokinetic Study in Patients with Impaired Hepatic Function (2012), and Technical Guidance on Pharmacokinetic Study in Pediatric Patients (2014) [3]. These guidelines provide important specifications and guidance to pharmaceutical companies regarding drug development and evaluation in China. In 1979, the Society of Pharmacometrics under Chinese Pharmacological Society was founded, led by Sun Ruiyuan and Jin Zhengjun. Sun Ruiyuan published the first textbook of Pharmacometrics in China in 1987 [19]. Xie Haitang et al compiled an anthology titled Pharmacometrics and New Drug Evaluation [20] in October 2011 on the basis of the proceedings of the first International Conference of Pharmacometrics and New Drug Evaluation which was held in October 2007. This publication summarizes and elaborates on the basic principles of pharmacometrics and its applications in new drug development. Pharmacometrics meetings of Chinese Pharmacological Society and the “International Conference of Pharmacometrics and New Drug Evaluation” have promoted academic communication in the field. The Society of Infectious Diseases under China Medical Education Association published the Expert Consensus on Clinical Application of Antimicrobial Pharmacokinetic/Pharmacodynamic Theory in 2018 [21], which emphasizes the importance of PK-PD in guiding antimicrobial therapy in clinical practice and summarizes the antibacterial and antifungal agents in terms of PK-PD profile. This Consensus document also proposes recommendations and common understanding for optimizing the dosing regimen for common infectious diseases in the patients complicated with chronic organ dysfunction, hypoproteinemia, or infected with resistant microorganism. Liu D., et al published The value and general consideration of pharmacometric study in new drug development in September 2018 [3], which expounds the value, characteristics, application, and technical specifications of pharmacometric study in new drug development and provides insights for new drug R&D in China.
The drug review reports of China NMPA are not open to the public. So, we here summarize the focus of regulatory concerns in the perspective of pharmacometrics by analyzing the review reports of the antimicrobial agents approved by FDA and EMA from January 2001 to May 2019. We also compared the role of pharmacometric content in FDA-approved and EMA-approved drug labeling and package leaflet for our colleagues’ consideration and reference to accelerate and standardize the development of new antimicrobial agents for benefits of patients.
THE ANTIMICROBIAL AGENTS APPROVED BY FDA AND EMA
The Drugs@FDA database and EMA official website were searched to retrieve the review reports of the antimicrobial agents approved during the period from January 2001 to May 2019. FDA approved 31 antimicrobial agents (Supplementary Table S1), including antibacterial agents (21, 68%), antifungal agents (9, 29%), and antituberculosis drug (1, 3%) (Table 1, Figure 1). The antibacterial agents (18 single-component and 3 combination products) are licensed to treat community- or hospital-acquired pneumonia, urinary tract infections, skin and skin structure infections. All the approved antifungal agents (n = 9) and antituberculosis drug (n = 1) are single-component products. EMA approved 26 antimicrobial agents (Supplementary Table S1), including 18 (69%) antibacterial agents, 5 (19%) antifungal agents and 3 (12%) antituberculosis drugs (Table 1, Figure 1). The antibacterial agents (16 single-component and 2 combination products) are approved to treat pneumonia, urinary tract infections, skin, and other infections. All the approved antifungal agents (n = 5) and antituberculosis drugs (n = 3) are single-component products. Overall, 13 antimicrobial agents (9 antibacterial, 3 antifungal, and 1 antituberculous drugs) were approved by both FDA and EMA.
TABLE 1 & FIGURE 1 PLACEHOLDER