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