Pharmacokinetic Model Based Pediatric Extrapolation

Background and ObjectivePediatric new drug clinical trials with large sample are difficult to carry out for ethical reasons.The method of extrapolation from adult data to children’s,as known as the pediatric extrapolation,can effectively reduce the difficulty of conducting pediatric clinical trials,and thus it can help improve the success rate of clinical trials and deal with the situation of no drug or label available for pediatric patients.However,this method has only a short history and is still in the exploration stage.Relevant documents and case reports are fragmentary especially at home.Except for a system integration of the existing guidelines and pediatric extrapolation method,this paper also made a comprehensive evaluation of pediatric extrapolation,and studied the problems of bridge model between adults and children,data analysis method,evaluation system and clinical trial design in the process of extrapolation.We tried to provide useful references for the pediatric extrapolation in traditional Chinese medicine research and development strategy.MethodsFirst of all,the published guidance documents of pediatric extrapolation at home and abroad were systematically evaluated,and the extrapolation conditions,extrapolation decision-making methods and other information of each document were summarized.Then,the general process and research framework of pediatric extrapolation were formulated.Secondly,according to the framework of pediatric extrapolation established above,azithromycin iv.was used as a research tool to investigate the bridging factors between adults and children,such as age,weight,gender,race and other possible covariates,and finally establish the population pharmacokinetic model of azithromycin iv.for wide range of people.Then the accuracy and reliability of this model are evaluated by internal validation,external validation and other methods.In the end,through the simulation of clinical trials,the optimal dosage of azithromycin iv.drops in children was obtained whose exposure is similar to the expected human therapeutic exposure for adults,so as to determine the pediatric drug regimen.The data analysis and model validation methods of pediatric extrapolation involved in this part can provide technical reference for the corresponding research.Finally,this study takes andrographolide as an example,which is a chemical marker reflecting the efficacy of andrographis,to make a methodological exploration of the design of extrapolation validation experiments in Chinese traditional medicine.We evaluate the accuracy of estimation of pharmacokinetic parameters under different sample number（2-4 points）and different sample size（10-80 cases）,in order to provide methodological basis for clinical trial design in pediatric extrapolation studies.ResultsAt present,a basic consensus reached at home and abroad is that pediatric extrapolation can be divided into three types:complete extrapolation,partial extrapolation and non-extrapolation.The three hypotheses to judge whether extrapolation can be carried out and the degree of extrapolation are:whether the disease progression,treatment response and exposure-effect relationship between adults and children are similar.The three hypotheses of the tool drug azithromycin intravenous preparation are roughly same in adults and children,so its data can be completely extrapolated.When extrapolating from adults to children,we used allometric scaling model to bridge their PK parameters.The scaling of clearance was fixed as 0.75,and of distribution volume was fixed as 1.The results of simulation in this part have shown that for children aged2-11 years with standard weight,10 mg/kg is a suitable dosage of azithromycin iv.while for children aged 12-16 years of age,350 mg fixed dosage could be considered whose AUC can be ensured within the range of 80%-125%of adult exposure,and children above 60 kg can be used as the same dose 500 mg as adults.The above administration regimen can be considered as the recommended dose of intravenous azithromycin for pediatric patients with community-acquired pneumonia.The pharmacokinetic characteristics of andrographolide tablet are in line with the two-compartment oral model,which has a fast absorption,wide distribution but low bioavailability.The simulations in this study part showed that under the condition of sparse sampling,the sample size of 80 people at 3 sampling points or 40 people at 4sampling points is required if the residual prediction error of all PK parameters of 50%subjects need to be controlled within 40%.The 60 sample sizes at 4 sampling points are required to achieve the power of test of all PK parameters limited to within the range of 60%～140%of the original value reaching 0.8.If AUC,C_max and other exposure parameters are required to be accurately estimated,40 samples at 4 sampling points or 60 samples at 3 sampling points can be considered.The results of this study can provide important information for the population pharmacokinetic（PPK）design of andrographolide tablets and an effective reference for the PPK design of pediatric extrapolated clinical trials of traditional Chinese medicine.ConclusionThe similarity of disease progression,treatment response and exposure-effect relationship between adults and children is the premise of pediatric extrapolation.Allometric scaling model is always used in the pediatric extrapolation.The establishment of population pharmacokinetic model of traditional Chinese medicine is the basis of pediatric extrapolation.The accurate estimate of pharmacokinetic parameters in clinical trials requires a reasonable sparse sampling design,and the sampling number and sample size need to be estimated in advance.