Study On Pharmacokinetics And Pharmacodynamics Of Efavirenz In Chinese HIV-Infected Patients

ObjectivesTo develop a high performance liquid chromatography method coupled with UV detection for quantitative determination of efavirenz in human plasma and investigate the influence of HBV and HCV co-infection on plasma efavirenz concentrations,efficacy and hepatotoxicity in HIV/AIDS patients.To investigate the steady-state pharmacokinetie features of efavirenz in Chinese HIV-infected patients who take efavirenz 400 mg once daily,also explore the safety and efficacy in long-term treatment by analyzing the relationship among plasma efavirenz concentrations,viralogical efficancy and adverse reactions of central nervous system based on the data of laboratory tests.Methods10 ?L internal standard diazepam and 500 ?L plasma sample were extracted with methyl-tert-butyl ether(MTBE),followed by evaporating to dryness under nitrogen stream and re-dissolving with 100 ?L mobile phase.The separation was carried out on a Shimadzu Shim-pack CLC-ODS column(6mmID×15cm,5?m)at 35?.The mobile phase consisted of phosphate buffer-acetonitrile(50:50,v/v).The flow rate was 1.2 mL/min and the injection volume was 20-80?L.Ultraviolet detection was performed at 240 nm.This was a prospective,multicenter cohort study with 494 HIV-infected patients receiving efavirenz 600 mg as a part of their initial antiretroviral therapy between July 2012 and July 2014.During the treatment period,subjects were supervised at baseline,week 4,24 and 48 for clinical features,plasma efavirenz concentrations and laboratory values including hepatic function,CD4 cell counts and plasma viral load.Efavirenz plasma concentrations,efficiency and hepatic function were compared among the three groups.A total of 8 patients receiving efavirenz 400 mg once daily as a part of antiretroviral regimen were enrolled into the pharmacokinetic study.Whole blood samples were collected just before administration of the study drug and at 1,2,3,4,5,6,8,10,12 and 24 hours after dosing.Plasma samples were analyzed for efavirenz concentrations by using the developed HPLC assay.WinNonlin software was applied to calculate PK parameters.Twenty-four patients administrated with 2NRTIs+efavirenz 400 mg were followed up at baseline,week 4,12,24 and 48.Plasma efavirenz concentrations were measured at each visit and the relationships between efavirenz concentration and virological efficacy and adverse reactions were analyzed.ResultsThe calibration curve of efavirenz was linear with the range of 0.1-10?g/mL(r=0.9996).The intra-run and inter-run relative standard deviations were 1.90%-2.41%(n=10)and 2.88%-3.99%(n=5)for the three check samples(0.2,2,9?g/mL),respectively.The accuracy was 98.22%-105.00%(n=3).The extraction recoveries were 53.81%-67.42%(n=3).The median(IQR)efavirenz concentrations at week 48 of HIV-monoinfected patients,HBV-and HCV-coinfected patients were 3.781(3.012-4.980)mg/L,3.057(2.040-5.144)mg/L,2.557(2.212-4.334)mg/L,respectively(p<0.05),while the proportions of virus partial and complete inhibition were 78.59%,76.36%,100.00%,respectively.The mean±SD CD4 cell counts steadily increased over time from 290±118,273±120,282±134 cells/mm3 to 442±184,457±221,391±151 cells/mm3 from baseline to week 48,respectively(p<0.05)and the indexes of liver functions were all basically within normal limits.The pharmacokinetics of EFV 400mg in Chinese HIV-infected patients complied with two-compartment model,and the steady-state PK parameters(n=7)were as follows:Tmax 2.938±1.483 h,Cmax2.532±0.652 mg/L,AUC 53.197±13.468 mg·h/L,t1/2 51.255±19.942 h,CL/F 8.067±2.567 L/h.The non-compartment model PK parameters(n=8)were as follows:Tmax3.875±2.748 h,Cmax3.883±0.967 mg/L,Ctrough 1.484±0.422 mg/L,AUC 50.754±11.140 mg·h/L,t1/2 30.581±15.589 h,CL/F 4.145±2.285 L/h.The mean±SD efavirenz concentrations at week 4,12,24 and 48 of HIV-infected patients who taken EFV 400 mg once daily were 1.989±0.706,1.729±0.429,2.054±0.690,1.963±0.576 mg/L,respectively(p>0.05),94.12%(64/68)of the plasma EFV concentrations in all patients were within 1-4 mg/L range.For the vast majority of patients received virus partial and complete inhibition at 12 weeks.The mean±SD CD4 cell counts steadily increased over time from baseline to week 48(p>0.05)and the indexes of blood routine examination,hepatic and renal function were all basically within normal limits.Dizziness was the main central nervous system-related adverse event.ConclusionsThe established HPLC method is simple,sensitive and accurate,and it can be used for the measurement of efavirenz concentration in human plasma.No accumulation of efavirenz 600mg was observed in HIV-infected patients with viral hepatitis.Efavirenz 600mg coadministered with TDF and 3TC were safe and effective for HBV and HCV co-infection treatment-naive patients.The pharmacokinetics of EFV 400mg demonstrated longer half-life,increased Cmax and lower C1/F in Chinese patients compared with those reported in foreign literatures,while the other PK parameters were similar.The immune reconstruction was smooth in those long-term treatment patients who used EFV 400mg once daily and they also had favorable prognosis with less adverse reactions.In addition,the plasma EFV concentrations at 8-20 hours after the drug administration were within the recommended therapeutic range,1-4 mg/L,in most of the patients.The 400 mg once daily regimen of EFV may be safe and effective in Chinese HIV/AIDS patients and is worthy of promotion.