Clinical Pharmacokinetic Studies Of Pegylated Recombinant Human Granulocyte Colony Stimulating Factor

The classification of drug registration include traditional Chinese medicine,chemical medicine and biological products.The research of pharmacokinetic study aims at illuminating the absorption,distribution,metabolism and excretion properties of drugs in human,and it's an essential part for comprehensive understanding of the interaction between the human and drug.Also it has been playing an important role in guiding clinical rational administration.Most biological samples come from serum,plasma,urine and so on.All these clinical biological samples have a common feature in less sample,low concentration,various interferents and individual differences.Therefore,it is of great importance to develop and evaluate a sensitive,accurate,reliable quantitative method for detecting the drug concentration of biological samples.In this study,we aim to assess the clinical pharmacokinetic profiles of pegylated recombinant human granulocyte colony-stimulating factor(PEG-rhG-CSF)and sabarubicin in patients with advanced cancer respectively.We haved developed and evaluated a rapid and sensitive method to determine the concentration of PEG-rhG-CSF and rhG-CSF in human serum using enzyme-linked immune sorbent assay(ELISA),and a method for determination the concentration of sabarubicin and its alchol metabolism M3 in human urine using ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS).Both the methods can supply information for their pharmacokinetic studies and monitoring the drugs concentration,so as to explore the pharmacokinetic characteristics,and provide reference for clinical applications.Section 1.The comparative pharmacokinetic studies of PEG-rhG-CSF and recombinant human granulocyte colony-stimulating factor(rhG-CSF)Polyethylene glycol is a flexible,water-soluble and low toxic polymer.The mechanism of PEG-rhG-CSF is the same as rhG-CSF with longer half-life in serum,thus we can avoid frequent intakes of medicines,poor compliance,longer treatment cycles,and so on.The aim of this comparative pharmacokinetic studies between PEG-rhG-CSF and rhG-CSF is to further investigate the efficacy and safety of PEG-rhG-CSF while widely used.Chapter 1:Established an ELISA method for determination of PEG-rhG-CSF and rhG-CSF.The assay was validated over the concentration range of 39?2500 pg/mL for both PEG-rhG-CSF and rhG-CSF.The range of intra-day accuracy of the quality control samples is-9.3%?-4.6%and-6.0%?-11.7%for PEG-rhG-CSF and rhG-CSF respectively.The range of inter-day precision of the quality control samples is 0.1%?12.8%and 0.9%?11.8%respectively.The method was successfully applied to perform serum pharmacokinetic studies of PEG-rhG-CSF and rhG-CSF in cancer patients.Chapter 2:Clinical pharmacokinetic studies of PEG-rhG-CSF and rhG-CSF in advanced cancer patients.This study was designed as a single-center,open label and comparative study.Now we have finished the concentration detection of 13 patients for the treatment group and 6 patients for the control group.The serum concentration-time curve shows single apex profiles.The half-time of PEG-rhG-CSF was significantly longer than rhG-CSF(22.82±6.17h and 2.76±1.36h,respectively).The drug exposure of PEG-rhG-CSF was 8982.9±4775.8 ng·h/mL,and 121.1±57.9 ng·h/mL for rhG-CSF.And the results also showed significant differences between the two groups in t1/2,Cmax,AUC0-t and CL.Chapter 3:Development and validation of an ELISA method for determination the immunogenicity of G-CSF.The assay was validated over the concentration range of 12.5?400 ng/mL.The range of intra-day accuracy and inter-day precision of the quality control samples is-4.8%?-0.4%and 0.5%?11.5%.This method was proved to be stable at several conditions,and able to meet the requirement of clinical immunogenicity accessment.Section 2.Phase I clinical pharmacokinetic studies of sabarubicin in patients with extensive small cell lung cancerSabarubicin is a relative novel anthracyclines with disaccharide,and it has similar anti-tumor effect and mechanism with anthracyclines,but with stronger efficacy and more slightly cardiotoxicity.In this study,we aim to investigate the pharmacokinetics of sabarubicin in extensive stage small cell lung cancer patiens,and then can provide a basis for phase II dosage.Chapter 1:Development and validation of a UPLC-MS/MS method for determination of sabarubicin and its metabolism M3 in human urine.A seven-point calibration curve exhibited excellent linearity over the range 2?200 ng/ml for both sabarubicin and M3.The intra-and inter-day precision and accuracy of the quality control samples at low,medium and high concentration levels showed 2.6%?8.2%for sabarubicin and 7.0%?11.2%for M3 relative standard deviation(RSD),and-5.6%?3.2%and-1.2%?10.7%for sabarubicin and M3 relative errors(RE),respectively.The method was successfully applied to perform urine pharmacokinetic studies of sabarubicin in extensive stage SCLC after intravenous infusion.Chapter 2:Clinical pharmacokinetic studies of sabarubicin in refractory or recurrent SCLC patients.This study was designed as an open-label,non-randomized and dose-escalation study.A total of 15 patients were enrolled and given intravenous infusion sabarubicin,and we have finished analyzing the pharmacokinetic characteristics in this study.