| Transtuzumab-maytansinoid is an antibody cytotoxic agents conjugate (antibody drug conjugate ADC) in clinical development for the treatment of human epidermal growth factor receptor 2(HER2)-positive cancer. Inhere, a series of studies about pharmacokinetics, drug absorption, distribution metabolism and excretion (ADME) as well as pharmacokinetic parameters were integrated into research on two catabolites of T-DM1 including DM1-MCC and DM1.In the first chapter, we briefly introduced the overview of preclinical and clinical studies of T-DM1 for HER2-positive breast cancer treatment. Then, the concept of pharmacokinetic and drug-like property were discussed deeply about the research design in drug development stage. In addition, sulfhydryl compound was widely used in drug delivery system(DDS), which get seriously attention for targeting cell tumor. Finally, the thesis contrapose the characteristic of thiol containing compound DM1 and DM1-MCC, put forward the countermeasure and evaluation of pharmacokinetics.In the second chapter:the experimental design was divided into 4 parts:(1) DM1-MCC and free DM1 were conducted in four species of plasma including Balb/c nude mouse, SD rat, beagle dog and human to access plasma stability data. (2) Permeability of DM1-MCC was described by MDR1-MDCK cell line model. (3) The pharmacokinetic studies of DM1-MCC were conducted in Balb/c nude mice and beagle dog to measure the plasma concentration of DM1-MCC, free state of DM1, total DM1 by LC-MS/MS. In addition, the routes of administration were Ⅳ, IP, PO(10% captisol) and PO(corn oil) in nude mouse as well as Ⅳ, SC, PO in beagle dog. The results shows:(1) The data of plasma stability indicate that the half-life of DM1-MCC is very short in Balb/c nude mouse(t1/2<1min) and SD rat(t1/2=1.5min), which is stable in beagle dog and human plasma. Free DM1 behaves similarly with clarence to Balb/c nude mouse, SD rat and human plasma stability assay, of which terminal half life (t1/2) were 13.2min, 11.7min,29min, respectively; half-life of free DM1 in beagle dog plasma was 108.5min.(2) The data of MDR1-MDCK model shows the permeability of DM1-MCC is poor and the efflux ratio is high(RE>15 in all conditional). (3) The pharmacokinetic parameters of DM1-MCC in Balb/c nude mouse represent a high Clarence, of which the concentration is not detected in all route of administration (LLOQ=lng/ml). The parameters of free DM1 in IP dose were listed below:Tmax=0.25hr, Cmax=24.4ng/ml, t1/2=2hr, AUClast=18.1 hr·ng/ml. After IV dose, the CL, Vss and MRTinf of total DM1 were 16.5L/hr/kg,11.2L/kg and 0.681 hr, respectively. The bioavailability(F) of total DM1 after IP, PO(10% captisol formulation), PO(corn oil) dose were 133%,5.43% and 19.8%. DM1-MCC were observed in beagle dogs after IV and SC dose, while higher plasma concentration of free DM1 and total DM1 were detected in all administration. The parameters of free DM1 and total DM1 in IV dose were listed below:Cl=1.05L/hr/kg and 0.436L/hr/kg; Vss=0.466 and 1.35; t1/2=0.576hr and 5.67hr; AUClast=104.2hr·ng/ml and 213hr· ng/ml; MRTINF=0.531hr and 2.77hr. The bioavailability(F) of total DM1 after SC, PO were 133%,89.1% and 45.8% in beagle dog.In the third chapter, DM1-MCC (thiol-ester) is easily hydrolyzed in plasma, which leads to maintain a low plasma concentration level in Balb/c nude mouse and beagle dog. It is probably that DM1-MCC is a substrate of p-gp due to high efflux ration and poor solubility results in poor permeability. When comparing bioavailability, corn oil formulation is significantly higher than 10% captisol formulation after PO dose in nude mouse. The concentration of free DM1 in beagle dog is generally higher than nude mouse, which indicate a greater risk of toxicity. |
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