Study Of Plasma Concentrations And Adverse Reactions Of High-dose Methotrexate Therapy Applied In Hemotological Malignant Disease

Objectives:①To study the correlation between plasma Methotrexate concentration of high-dose Methotrexate(HD-MTX)with factors of physiological or pathological status and drug delivery,discovering influcing factors of internal drug elimination,and providing evidences for population pharmacokinetics study of HD-MTX in the treatment of hematological malignancy diseases.② To study the correlation between plasma concentration of high-dose Methotrexate with interaction drugs,exploring the potential and incentive of Methotrexate toxicity caused by interaction drugs.③To summarize the adverse reactions of HD-MTX combined chemotherapy regimens,and explore the correlation between each adverse reaction with factors of physiological and pathological status,drug delivery and plasma Methotrexate concentration,in order to find out the risk factors of MTX related adverse reactions.④To report cases of severe centrul nervous system adverse cases in detail,and investigate the features,pathogenic mechanism and treatment methods of the Methotrexate related severe neurotoxicity.Providing the clinic with evidence of significative statistcs and suggestions for safe application of HD-MTX.Methods:Research material:A total of 1050 cases of HD-MTX chemotherapy applied in hematological malignancy diseases from January 2014 to February 2016 were collected,and review all cases to record ①patients information including age,sex,height,weight,diagnosis,regimen,dosage,infusion lasting time;② laboratory indicators including alanine transaminase(ALT),total bilirubin(Tbil),creatinine,albumin(ALB)level within 24h before administration and within 48h after drug withdrawal,and also urine volume and urine PH on the day of administration;③Methotrexate plasma comcentration of 20h,44h,68h after withdrawal;④all the combination drugs during administration and the following 24h,and also all the adverse reactions severer than II degree(CTCAE4.03).Data statistics:① Analysis of influcing factors of plasma Methotrexate concentration:Data were analysed in single factor and multiple factor linear regression analysis separately with Matlab and SPSS,take above research data as independent variables,take 20h or 68h plasma comcentration as dependent variables,the P value<0.05 was thought to be statistical significant,and the regression coefficient(B)indicated the direction of the correlation.②Analysis of influcing significance of conbination drugs with HD-MTX:Compare diffidence between drug combination groups of proton pump inhibitors(PPIs),compound sulfomethoxazole(TMP Co),and non-steroidal anti-imflammortory drugs(NSAIDs)separately with no drug combination group;③Analysis of influcing factors of related adverse reactions:Data were analysed in single factor and multiple factor binary logistic regression,take the events of adverse reactions as dependent variables,above research data(including plasma Methotrexate concention of 20h after withdrawal)as independent varialbes,the P value<0.05 was thought to be statistical significant,of which P<0.05 and OR>1 as significant risk factors,P<0.05 and OR>1as significant protective factors.Case record and literature review:①Record typical cases of plasma Methotrexate concentration increased siginificantly(≥5.0μmol·L-1)due to interaction drug factors,and analysis in detailed and in depth with literature review.②Record cases of Methotrexate related severe neurotoxicity,collected and analysis cases of Methotrexate related neurotoxicity treated with Dextromethorphan through literature review.Results:Multiple factor linear regression analysis of plasma Methotrexate concentrations showed that,body mass index(BMI),infusion lasting,dosage,basal Tbil and ALB have significant effect on the 20h after drug withdrawal(P<0.05),while effects of basal ALT levels,urine pH have no statistically significance(P>0.05).Single factor analysis showed that,age≥60,BMI>25 kg/m2,infusion lasting 4h and dosage>2.0g/m2,may lead to plasma Methotrexate concentration increasing.There was no significant difference between plasma Methotrexate concentration at 20h after withdrawal between PPIs combination group with no combination drug group(P>0.05),while TMP Co or NSAIDs combination group have significant difference with no combination drug group(P<0.05).Multiple factor binary logistic regression analysis of adverse reactions showed that:①The most incidence of HD-MTX related adverse reactions was ALT increasing,suggesting the HD-MTX related hepatic dysfunction is mainly hepatocellular type.While only significant influcing factor of Tbil increasing is basal Tbil level,and the correlation is positive.②Infusion lasting time has positive correlation between creatinine increasing and ALT increasing,suggesting that extending MTX exposure time may lead to aggravate MTX related hepatic or renal dysfunction.③ HD-MTX related nerve system adverse reaction have significant positive correlation with dosage and GDP/ML regimen,while have significant negative correlation with infusion lasting time.The incidence of severe MTX-related nerve system reactions was 3.These 3 cases were all nasal type extranodal NK/T cell lymphoma patients,developed paralysis after administration of GDP/ML combination chemotherapy regimen(Gemcitabine,Cisplatin,Methotrexate,Dexamethasone,and Pegaspargase).They developed severe neurotoxicity symptoms featuring as paralysis,dysarthria,confusion etc.within 48h after intravenous injection of Methotrexate,without obvious improvement after common treatment.Through literature review,26 patients developed similar neurotoxicity symptoms after intravenous or intracranial injection of Methotrexate.Most patients relived with oral Dextromethorphan without sequelae.The average onset time was 10.1h,and the average remission time was 10.8d.Conclusions:①Before administration of HD-MTX,patients should be routinely tested for creatinine levels,ALB and Tbil levels to ensure that CrCl is above 60 ml/min,and administration of HD-MTX should be delayed if ALB and Tbil are abnormal;②Unnecessary combinations should be avoided during HD-MTX administration and elimination.Prophylactic administration of TMP Co is recommended to suspend.When it is necessary to combination with TMP Co,it is recommended to strictly pre-hydration and pre-alkalization before administration,testing urine pH to ensure the alkalization effect.When it is necessary to combination with PPIs,it is recommended to monitor blood potassium levels and ensure that they reach at least the normal range;③Patients with basal hepatic disfunction are more prone to HD-MTX-associated hepatorenal impairment,and overweight patients are more prone to HD-MTX-associated renal impairment.The incidence of hepatic and renal impairment also increased with large doses of HD-MTX and continuous infusion of 24 hours.It is recommended that intensive care should be given to specific patients and specific chemotherapy regimens;④Dextromethorphan is a potential therapeutic drug for HD-MTX-associated neurotoxicity,and early administration after onset of symptoms can shorten onset and remission time.