| Premature infant is far different from adults in drug's absorption,distribution,metabolism and excretion,because their body organ is not yet mature.Meanwhile,due to the restriction of ethical factors and related guidance,the traditional pharmacokinetics in the premature infants is difficult to carry out,and the relevant clinical data is deficient.Given all that,it's an important issue in the treatment of premature infants that how to ensure the safe and effective use of medications in premature infants.In recent years,population pharmacokinetics?PPK?,which was developed on the basis of traditional pharmacokinetics,can be used for statistical analysis of sparse sample data.Different from traditional pharmacokinetics,the number and density of the blood samples is lower.Until now,PPK has been widely used to provide scientific and effective data for individualized administration in foreign clinical research in neonatal research.Apnea is one of the common complications of premature infant,with the high incidence in which who has small gestational age and light weight.Apnea of prematurity can lead to cerebral hypoxia damage,even death.Xanthine drugs are commonly used to treat premature with apnea.Caffeine citrate is the first-line drug for apnea of premature,which was exempted from clinical trials into China in 2013.Currently,no study has focused on pharmacokinetic and population pharmacokinetic of caffeine in Chinese neonate.Therefore,the purposes of this study is to investigate PPK of caffeine in the prevention and treatment of premature infant in China,as to predict caffeine plasma concentration and provide a scientific basis to clinical application of caffeine.PART ? Determination of caffeine and theophylline in serum by HPLCObjective To establish a new method to determinate caffeine and theophylline concentration in PPK of premature infants.Methods Caffeine and theophylline serum concentration was determinated by HPLC.0.2ml serum was extracted with ethyl acetate-dichloromethane?4:1?,then the extract supernatants was subjected to HPLC analysis.Diprophylline was used as the internal standard.Chromatographic separation was performed on a ZORBAX SB-C18 column?150 mm×4.6 mm,5 ?m?.The mobile phase consisted of methanol–water?containing 0.2% acetic acid??25:75?,pumped at a flow rate of 1 m L·min-1.The wavelength for detection was 273 nm.And the column temperature was 40?.Results The retention time of caffeine,theophylline and diprophylline was 5.2min,3.5min and 3.1min,respectively.The standard curve for the concentration of caffeine and theophylline is 0.5 to 50.0?g·m L-1.The relative recoveries for caffeine and theophylline of the method?n=5?was 99.4%-107.7% and 100.2%114.0%,while the extraction recoveries was 69.2%-73.0% and 50.5%54.4%,respectively.The RSD of within-batch and between-batch was 2.2%-4.9% and 2.5%6.7% for caffeine,1.7%4.7% and 1.9%5.3% for theophylline.Conclusion The method is proved by methodology validation that it is suitable for pharmacokinetic study of caffeine in premature.PART ? Population Pharmacokinetic Study of Caffeine in the Prevention and Treatment of Premature InfantObjective To establish PPK model of caffeine in the prevention and treatment of premature infant with apnea,to predict the prophylactic effective plasma concentration of caffeine,and to provide basis on the rational medication therapy.Methods This study was divided into two stages.The first stage was to establish PPK model of caffeine.From July 2015 to March 2016,99 neonates whose birth gestational age less than 34 weeks stayed at neonatal department were enrolled according to the inclusion and exclusion criteria.The premature infants were given intravenous infusion of caffeine citrate 20 mg·kg-1 for 30 min after 24 hours of birth.5 mg·kg-1·d-1 caffeine citrate was administrated intravenously for 10 min after 24 h following first dose.10 mg·kg-1·d-1 dose was given when apnea happened.The clinical and demographic characteristics with each serum sample,caffeine citrate administration time and blood collecting time were recorded in detail.And adverse event and serious adverse events have been recorded if happened.The pharmacokinetic model of caffeine was established by NONMEM software.The physiological characteristics,such as gender,gestational age,birth weight,body length,body surface area,hepatic function?ALT value?,renal function?CLcr,Scr value?,combined with pathological factors and medication information have been analyzed in the process of building PPK model of caffeine.The model was evaluated by model of goodness of fit and Bootstrap.In the second stage of this study,29 neonates were collected to authenticate the model.The predicted values of the pharmacokinetic model of caffeine citrate were compared with the measured values,and the accuracy of the model was further verified.Results 99 neonates were included in this study whose gestational age was 30.69±1.89 weeks and birth weight was 1.41±0.30 kg.The mean serum concentration of caffeine was 14.29±6.89?g·m L-1,and the t1/2 was 71 hour.The pharmacokinetic parameters of caffeine were as follows: the clearance rate CL was?0.0124 ± 0.00066?L·h-1and the apparent volume V was?1.25 ± 0.12?L,expressed by group value and standard error.The final PPK model of caffeine was: CL = ?1???2?1.36?3 ? 0??1??V = 2? 0)?2?.?CL: Clearance;V: Apparent volume of distribution;1: group typical value in CL;2: group typical value in V;1:intra-individual variance in CL;2: intra-individual variance in V?.The model of robustness showed that the model-predicted concentration was close to the detected caffeine concentration.The Bootstrap result showed that the model was stable and predictive.Using the established PPK model of caffeine,the serum concentration of 29 neonates was predicted and compared with the actual measured serum concentration.The mean prediction error and the mean absolute error was 2.8?g·m L-1and 3.62?g·m L-1,respectively.The final model was further validated by the fact that detected caffeine concentrations of these neonates fit well with model-predicted values.The final model of PPK has a good stability and predictive efficacy.Conclusion The PPK model of caffeine established by NONMEM software has a good stability and predictive accuracy.It can be used for the prediction of clinical caffeine serum concentration in premature infants,and is suitable to provide basis on the rational medication therapy. |
PDF Full Text Request