Racial /Ethnical sensitivity is an important factor that affects the effectiveness and safety of drugs in different ethnic groups. Among them, pharmacokinetics (PK) is the most important source of drug racial sensitivity. one.
According to the definition of racial factors in ICHE5 [1], factors that cause racial differences include internal factors such as genetics and physiology (such as genetic polymorphism, receptor sensitivity, weight, liver and kidney function, etc.), as well as social culture and Living environment and other external factors (such as climate, sunshine, medical measures, eating habits, social economy, educational status, etc.).
From 2008 to 2013, among the 167 innovative drugs approved by the U.S. Food and Drug Administration (FDA), 35 (21%) reported the presence of PK, safety, effectiveness and/or pharmacogenetics in the drug label In terms of ethnic differences, 19 species reported racial differences in PK (the exposure difference of patients of different races> 20%), of which 3 reported safety and effectiveness concerns due to exposure differences [2] .
The clinically significant PK ethnic differences may directly lead to differences in the usage and dosage of drugs in different ethnic groups. For example, the exposure of the same dose of rosuvastatin calcium in Asian patients is twice that of Caucasians. The FDA-approved instructions recommend Asian patients Give a lower dose; the exposure of tacrolimus in blacks is lower than that of Caucasians. In order to maintain the same steady-state concentration, the instructions recommend blacks to give a higher dose [3].
In addition, an earlier article in the Office of New Drugs of the Pharmaceuticals and Medical Devices Agency (PMDA) of the Ministry of Native Labor and Labor reported that about one-third (13/41) of innovative drugs approved in Japan from 2003 to 2005 The standard recommended doses are different from those approved in Europe and the United States. The reasons for the differences in the doses of these drugs are partly based on the differences in the sponsor’s drug development strategies and regulatory policies, and the other part is based on ethnic differences [4].
In July 2018, the National Medical Products Administration (NMPA) of my country issued the “Technical Guidelines for Accepting Data from Overseas Clinical Trials of Drugs” [5]. For clinical trials conducted overseas, applicants need to apply for registration in China when applying for registration in China. Fully analyze the ethnic sensitivity of the Chinese population and the non-Chinese population to support the bridging of overseas research data to the Chinese population.
In recent years, the clinical pharmacology major of the Drug Evaluation Center has found in the evaluation of new drugs that there are differences in the evaluation methods of PK racial differences between various companies, and the evaluation methods are unreasonable or the analysis results are unreliable and other reasons. occur. This article aims to combine the author’s work experience to summarize the acceptable PK racial differences assessment methods used in the past review of varieties, and to discuss the consideration of adjusting drug usage and dosage based on PK racial differences for discussion by new drug development companies and researchers.
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1 Common methods for assessing PK racial differences
1.1 Traditional PK comparison method
The traditional PK comparison method is to directly compare the complete PK curves obtained by the drug in two different ethnic groups, and usually compare the PK parameters calculated by the non-compartmental model analysis, and analyze the PK of the drug by evaluating the amount of exposure, etc. difference.
The advantage of this method is that it can visually and clearly see the differences in drug exposure among different populations. However, the premise of this comparison method usually requires the use of similar PK test designs in two ethnic groups, collecting intensive blood drug concentration data, and obtaining a complete PK curve, so that reliable conclusions can be obtained after the comparison. If the PK test protocol of the drug in the two ethnic groups is quite different, such as using different doses or sampling points, or only collecting sparse blood drug concentration data, it is difficult to use this method for comparison.
1.2 Population pharmacokinetics (PopPK) analysis method
Quantitative pharmacology has been widely used in various fields of new drug research and development [6-7], and it also has important applications in the evaluation of ethnic differences in PK [8-10]. PopPK is a comprehensive discipline that combines the traditional PK compartment model with statistical principles. It can quantitatively analyze the PK process and influencing factors of drugs in the human body. PopPK analysis is used to evaluate PK ethnic differences, mainly by establishing a PopPK model to quantitatively analyze the impact of ethnic factors on important drug PK parameters (such as clearance rate, apparent distribution volume).
The advantage of this method is that the PopPK model can analyze PK data from unbalanced designs at home and abroad, and unlike the traditional PK comparison method, PopPK can analyze both densely sampled data and sparsely sampled data. In addition, the analysis of covariates can be combined The effects of race factors and other factors on PK are quantitatively distinguished. The common practice of using PopPK analysis to assess PK ethnic differences can usually be divided into two situations, which are summarized as follows.
Judging from past reviews, the most commonly used method is covariate analysis. By collecting blood drug concentration data in different ethnic groups, a PopPK model was established, and factors such as race were used as covariates to analyze its impact on PK parameters. If the results of the covariate analysis of the PopPK model show that race is a significant covariate that affects the PK parameters of the drug, it indicates that the PK race difference is statistically significant, and vice versa, it indicates that the PK race difference is not statistically significant.
This method is the classic method of the PopPK model to analyze PK racial differences. For example, when the first programmed death receptor 1 (PD-1) drug nivolumab was imported into China, it was obtained from 2 Chinese studies and 5 global studies. PK data establishes a PopPK model, taking ethnicity (Chinese, non-Chinese Asian, non-Asian) as a covariate to examine its impact on drug clearance [8]. But it should be noted that sometimes when statistical results show significant differences, comprehensive evaluation should be combined with clinical significance, see below for details.
For some imported varieties that have been marketed abroad, the corresponding PopPK model has usually been established using global research data when they are registered and marketed in the United States or Europe. The establishment of this model may not include the latest Chinese population PK for registration in China. research data.
In this case, the researcher may use the empirical Bayesian estimation method to estimate the PK data of the Chinese subjects using the PopPK model established abroad, and then compare the exposure estimation results with the actual measurement results of the Chinese subjects, and analyze the previous stage Applicability of the PopPK model based on global research data to the Chinese population.
If the external verification results show that there is no significant difference between the model estimate and the actual measured value of the Chinese subjects, it is considered that the risk of significant PK racial differences is small, otherwise, there may be PK racial differences. In the preliminary review of imported drugs, the Center for Drug Evaluation found that individual varieties used this method to assess PK racial differences.
The author believes that, compared to the covariate analysis method, this method may have certain limitations in some cases. When the model estimation results and the subjects’ blood drug concentration measured results show differences, it may be difficult to intuitively measure the differences. Statistical significance is quantified.
1.3 Thoughts on assessment methods
The evaluation of PK racial differences has important reference value for judging whether or not to accept the data of overseas clinical trials of drugs, or whether it is necessary to adjust the usage and dosage based on race. It is generally believed that the traditional PK comparison method and the PopPK analysis method have their own advantages in evaluating PK ethnic differences. It is usually recommended to use the above two methods to evaluate separately, and to combine the evaluation results of the two methods to comprehensively evaluate the drug PK ethnic differences.
Under special circumstances, if it is not possible to collect data on intensive sampling of the Chinese population, consider only using the PopPK method to evaluate PK racial differences. In the previously reported cases, multiple breeds used both the PK comparison method and the PopPK analysis method to assess PK racial differences.
When the anti-tumor drug Axitinib tablets were imported into Japan and China, two independent PK studies were carried out in Japanese and Chinese healthy subjects respectively, and the PK study results were respectively compared head-to-head with the PK data of Caucasians. Comparison, direct comparison of PK ethnic differences, and at the same time summarize the PK data of all populations to establish a PopPK model, use covariate analysis to examine factors such as race, and evaluate the impact of race on the PK characteristics of axitinib [9].
In addition, the antibody-drug conjugate used to treat breast cancer, enmetrastuzumab for injection, also used the above two methods to analyze the difference in PK between Asian patients and patients of other races [ 10].
2 General considerations for adjusting drug usage and dosage based on PK ethnic differences
Generally, if the result of ethnic sensitivity analysis shows a certain PK difference, should the usage and dosage be adjusted based on race? The core question to be evaluated is whether this PK difference has clinical significance, that is, whether this PK difference will affect the safety and effectiveness of clinical application Have a significant impact.
In some cases, although drugs show statistically significant differences in PK ethnicity, this difference does not necessarily lead to significant differences in the safety and effectiveness of clinical applications. Among the 167 innovative drugs approved by the U.S. FDA mentioned above, a total of 19 varieties reported racial differences in PK in the labeling, but only 3 reported safety and efficacy concerns due to differences in exposure. The final instructions clearly suggest that only one species can be adjusted based on race [2].
The author believes that whether PK ethnic differences are of clinical significance should be comprehensively judged based on the dose-effect relationship of specific species in terms of clinical effectiveness and safety, that is, the therapeutic window of the drug. For example, for drugs in the plateau phase of clinical effectiveness and dose-effect relationship, small PK differences usually do not significantly affect the efficacy, while for drugs in the steep part of the dose-effect relationship, small PK differences may lead to significant changes in efficacy. At this time, full attention is needed.
Previous reviews have found that the exposure of most drugs in Asian patients is higher than that in Caucasians. At this time, researchers should pay full attention to the impact of PK racial differences on safety based on the dose-effect relationship in safety, and then comprehensively judge whether it is necessary to be based on Race to adjust usage and dosage. Sometimes a comprehensive consideration is required in combination with the indication population. For example, for drugs used for cancer patients, sometimes in order to obtain greater efficacy, the regulatory authority will choose to accept a dose that may cause manageable safety issues, even though the dose is close to the human body’s maximum tolerance. Received dose (MTD).
3 discuss
Ethnic sensitivity is an important factor affecting the differences in the safety and effectiveness of drugs in different ethnic groups. This article briefly introduces the assessment methods of ethnic differences in PK, and initially discusses the general considerations of adjusting drug usage and dosage based on ethnic differences in PK.
In the study of racial sensitivity of new drugs, in addition to the racial differences in PK, it is usually necessary to pay attention to the racial differences in the safety and effectiveness of the final clinical drug due to differences in the pathogenesis of different populations, differences in target sensitivity, and differences in clinical medication habits.
For most drugs, patient weight is one of the most important factors affecting exposure. The average weight of the Chinese population is usually lower than that of the European and American population. Without considering other factors, the Chinese population and the Caucasian population may show differences in exposure based on the difference in weight.
The author believes that for fixed-dose drugs, PK differences between different ethnic groups due to weight differences are also part of ethnic differences in a broad sense. Researchers also need to pay full attention to the clinical significance of this difference and the possible drug safety. Changes in effectiveness.
The clinical pharmacology major of the Center for Drug Evaluation found in previous reviews that individual applicants only paid attention to the differences between Asian and non-Asian populations when analyzing PK racial differences. However, as mentioned above, the factors that cause ethnic differences include not only internal factors such as genetics and physiology, but also external factors such as social culture and living environment.
Chinese people and Asian people such as Japanese, Koreans, Indians, and Southeast Asians have large differences in living environment and eating habits, sometimes in terms of background treatment. Therefore, racial sensitivity analysis generally recommends paying attention to the differences between the Chinese and non-Chinese people. Non-Chinese people can be Asians, Caucasians, and blacks other than Chinese.
Judging from the evaluation methods described in this article, the necessary clinical studies in the Chinese population are the basis for the evaluation of PK ethnic differences. For drugs that have never conducted any clinical studies in the Chinese population, in view of the unknown ethnic sensitivity that may exist, based on risk considerations, it is generally recommended that applicants first evaluate their tolerability and safety in the Chinese population and PK ethnic differences. After ensuring that the Chinese population can tolerate and assessing ethnic differences, follow-up clinical research content should be designed accordingly.
Ethnic sensitivity is an important factor that affects the safety and effectiveness of drugs. For drugs registered with overseas clinical trial data, the evaluation of PK racial differences is an important research content of the clinical pharmacology of new drugs. Based on the author’s work experience, this article briefly introduces the acceptable PK racial differences assessment methods used in the past review of varieties, and initially discusses the general considerations of adjusting the dosage of drugs based on PK racial differences.
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