Pharmacological Characteristics Of Valganciclovir In Chinese Renal Allograft Recipients

Objective:A method for the determination of valganciclovir and its metabolite ganciclovir by liquid chromatography-tandem mass spectrometry(LC-MS/MS)was established.Valganciclovir(VGCV)treatment is recommended for the prevention of cytomegalovirus(CMV)infection in renal allograft recipients.To investigate the pharmacokinetic characteristics of ganciclovir(GCV)after administration of VGCV in Chinese renal allograft recipients,establish a population pharmacokinetic model in the early stage of renal transplantation and estimate the exposure to GCV using limited sample strategy(LSS).Methods:Electrospray ionization(ESI)was selected as the source of ionization,acyclovir was used as the internal standard,2 mmol/L ammonium formate aqueous solution and 2 mmol/L methanol as the mobile phase,and plasma valganciclovir and ganciclovir concentrations were determined by multiple reaction monitoring(MRM)mode.40 Chinese renal allograft recipients were given 450 mg or 900 mg VGCV daily.Blood samples were drawn before treatment and 0.5,1,1.5,2,3,4,6,8,12 and 24 h after 5 days of VGCV therapy,and the plasma concentrations of VGCV and GCV were determined using a liquid chromatography-mass spectrometry assay.The major pharmacokinetic parameters for GCV and VGCV were determined using a noncompartment assay.Totally 440 blood samples were collected from their GCV PK profiles with corresponding physiological,pathological and laboratory data.A population pharmacokinetic model of GCV was established by Nonlinear mixed effect modeling;Multiple stepwise linear regression analysis was conducted to establish a model equation for the estimation of the GCV AUC0-24 h in Chinese patients using LSS.Results:The plasma concentrations of VGCV and GCV were determined by LC-MS/MS.The electrospray ionization source was in positive ion mode,the M/Z of GCV was 256.2?135.1amu,VGCV was 355.3amu?151.9amu,and acyclovir was226.2?151.9amu.When the concentrations of GCV and VGCV were 0.048-9.6mg/L(r~2>0.999)and 0.0048-0.95 mg/l(r~2>0.999),respectively,a linear relationship was observed.The recovery rates of VGCV and GCV were 83.0-93.6%and 86.2-98.9%,respectively.Matrix effects were 107.7-125.3%and 107.0-124.7%respectively.The within-day and between-day variation were 5.52-7.12%and 8.66-10.4%for VGCV and 3.28-14.8%and 6.33-12.3%for GCV.The stability of both is acceptable.The intra-day and inter-day RSD values were less than 15%.In the 450 and900 mg groups,the Cmax for VGCV was 0.20±0.10 and 0.35±0.16 mg/L,respectively;the Cmax for GCV was 4.24±1.07 and 8.64±1.65 mg/L,respectively;the AUC0-24 h for GCV was 28.40±8.35 and 60.67±17.50 mg.h/L,respectively.A two-compartment model with first-order absorption appropriately described the data.With CLcr as a covariate of CL/F,the variation among individuals of CL/F decreased from 26.3%to21.4%.Based on either 3(C0,C2 and C8)or 2 sampling time points(C0 and C4),the model equations used for the calculation of AUC0-24 h for GCV,AUC0-24 h=0.64+9.51×C0+2.05×C2+13.7×C8(r~2=0.984)and AUC0-24 h=9.43+24.4×C0+5.59×C4(r~2=0.922),respectively,were established.The MPE and MAPE values for the two model equations were 2.18±13.8%and 0.79±6.79%,and 10.8±8.72%and 4.55±5.04%,respectively.The accuracy and stability of the models were verified using a bootstrap procedure.Conclusion:The established LC-MS/MS method was proved to be applicable to the pharmacokinetic study of ganciclovir and valganciclovir.For the first time,the pharmacokinetic characteristics of VGCV were calculated in Chinese renal allograft recipients.After oral administration of 900mg VGCV,the GCV AUC for the Chinese renal allograft recipients appeared to be slightly greater than that of Caucasian patients.There is under-exposure and over-exposure in 450 mg group and 900 mg group,respectively.Systemic clearance was markedly influenced by the glomerular filtration rate(GFR),no significant drug interaction was detected.The LSS models that included C0,C2,and C8 or C0 and C4 in the estimation of AUC for GCV had favorable performance and can be used for therapeutic drug monitoring in the prevention of CMV infection using VGCV in Chinese renal allograft recipients.