Pharmacokinetics And Influencing Factors Of Ganciclovir In Chinese Adult Renal Transplant Recipients Administered Valganciclovir

Ganciclovir（GCV）is a nucleoside analog,which is the most commonly used drug for the prophylaxis and treatment of cytomegalovirus（CMV）infection after solid organ transplant（SOT）.Valganciclovir（VGCV）is a prodrug of GCV which improves the oral bioavailability of GCV significantly.VGCV is absorbed from gastrointestinal tract and rapidly transformed to GCV in epithelium of intestinal and liver.Different physiological and pathological factors may affect the process of GCV in vivo.We studied the pharmacokinetics and individual variation after various dosage regimen of VGCV in renal transplant patients,which may be valueable for the optimization of the individualized therapy regimen.The blood samples of 70 renal transplant patients after VGCV administration were collected and clinical data were recorded.The plasma concentrations of VGCV and GCV were determined by high performance liquid chromatography-mass spectrometry（LC-MS/MS）after oral administration of 450 mg qd or 900 mg qd of VGCV in renal transplant patients,and the factors influencing the pharmacokinetic parameters of VGCV/GCV were further investigated.We used Win Nonlin software to calculate the pharmacokinetic parameters of GCV and VGCV by non-compartment method.The pearson assay was used to analyze the correlation between different physiological and pathological factors and pharmacokinetic parameters.The results showed AUC_0-24h and C_max of patients received 450 mg of VGCV was 28.63±7.97 mg·L·h^-1 and 4.21±1.06 mg·L^-1,respectively.For patients received 900 mg of VGCV the value was 52.72±14.22 mg·L·h^-1 and7.81±1.84 mg·L^-1,respectively.The exposure of VGCV and GCV showed a good multiple ratio relationship among different dose groups.Serum creatinine,urea nitrogen,albumin and hemoglobin,especially creatinine clearance rate,were significantly correlated with GCV clearance（P<0.05）.Population pharmacokinetics（PPK）model of GCV was established by NONMEM method.The PK of GCV was best described by a two-compartment model with a first-order absorption process.The CL/F,V₂/F,Q/F,V₃/F,K_a and absorbtion lag time of GCV were 15.8±0.71 L?h^-1,10.9±2.38 L?h^-1,3.98±0.40 L?h^-1,167±44.0 L,0.23±0.0078 h^-1,and 0.93±0.017 h,respectively.Clearance of creatinine was found to have a significant impact on the CL/F of GCV（P<0.01）.Sampling strategies consisted of plasma concentrations at 0-2 h and 0-2-4 h after VGCV administration were shown to be suitable for the estimation of the GCV AUC_0-24h.Combination of the final PPK model and the Bayesian feedback method,Monte Carlo method was used to simulate the relationship between the various dosage regimen and AUC_0-24h under different renal function.Dosing regimens that were associated with a probabilities of target attainment（PTA）of 75-80%of AUC_0-24h in the range of 40-50 mg?h?L^-1 were defined as optimal.The results showed for patients with normal renal function(CLcr>90m L?min^-1),900 mg VGCV daily may have over90%probability of producing an AUC_0-24h>40mg?h?L^-1 and approximately 50%probability of producing an AUC_0-24h>50mg?h?L^-1.On the other hand,we found for patients with mild and moderate renal function(60<CLcr<90 and 30<CLcr<60m L?min^-1),675 mg VGCV daily may be preferable.In conclusion,our study found the renal function is the most important factor influence the CL/F of GCV.PPK model established can describe the PK of GCV in Chinese renal transplant patients administered VGCV.The AUC_0-24h of GCV in Chinese renal transplant patients can be estimated through a limited sampling strategy method,based on which individualized administration of VGCV can be conducted.