Limited sampling strategy for the estimation of the area under the concentration-time curve for ganciclovir in Chinese adult renal allograft recipients

• Published in: European journal of clinical pharmacology Vol. 75; no. 5; pp. 677 - 686
• Main Authors: Rui, Wen-Bin, An, Hui-Min, Shao, Kun, Zhai, Xiao-Hui, Lu, Jia-Qian, Hu, Shan-Shan, Chen, Bing, Zhou, Pei-Jun
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2019; Springer Nature B.V
• Subjects: Adolescent; Adult; Antiviral Agents - blood; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Antiviral drugs; Area Under Curve; Asian Continental Ancestry Group; Assaying; Biomedical and Life Sciences; Biomedicine; Blood Specimen Collection - methods; Cytomegalovirus; Cytomegalovirus Infections - metabolism; Cytomegalovirus Infections - prevention & control; Drug Monitoring - methods; Female; Ganciclovir; Ganciclovir - blood; Ganciclovir - pharmacokinetics; Ganciclovir - therapeutic use; Humans; Immunosuppressive Agents - adverse effects; Infections; Kidney Transplantation; Liquid chromatography; Male; Mass spectrometry; Mass spectroscopy; Middle Aged; Patients; Pharmacokinetics and Disposition; Pharmacology/Toxicology; Regression analysis; Sampling; Tempering; Therapeutic drug monitoring; Transplantation, Homologous; Valganciclovir - blood; Valganciclovir - pharmacokinetics; Valganciclovir - therapeutic use; Therapeutic drug monitoring; Renal transplantation; Valganciclovir (VGCV); Pharmacokinetics; Ganciclovir (GCV); Limited sampling strategy
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-018-02613-w

Objectives Valganciclovir (VGCV) treatment is recommended for the prevention of cytomegalovirus (CMV) infection in renal allograft recipients. The aim of the present study is to investigate the pharmacokinetic characteristics of ganciclovir (GCV) after administration of VGCV in Chinese adult renal allograft recipients and estimate the exposure to GCV using limited sampling strategy (LSS). Methods Forty 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 noncompartmental assay. Multiple stepwise linear regression analysis was conducted to establish a model equation for the estimation of the GCV AUC 0–24 h in Chinese patients using LSS. Results In the 450 and 900 mg groups, the C max for VGCV was 0.2 ± 0.10 and 0.4 ± 0.16 mg/L, respectively; the C max for GCV was 4.2 ± 1.1 and 8.6 ± 1.6 mg/L, respectively; and the AUC 0–24 h for GCV was 28.4 ± 8.4 and 60.7 ± 17.5 mg·h/L, respectively. For the establishment of LSS models, 40 patients were divided into the training group ( n = 24) and validation group ( n = 16). The model equations used for the calculation of AUC 0–24 h for GCV were established in the training group by using multiple linear regression assay. Equations including AUC = 8.1 + 29.7 × C 0 + 5.7 × C 4 ( r 2 = 0.91) and AUC = − 0.4 + 11.0 × C 0 + 2.1 × C 2 + 13.7 × C 8 ( r 2 = 0.98) were acceptable. The %MPE and %MAPE values obtained from the validation group for the two model equations were 5.89 ± 14.5% and 12.1 ± 9.53%, and − 1.30 ± 4.40% and 3.28 ± 3.11%, respectively. Conclusions The LSS models that included C 0 and C 4 or C 0 , C 2 , and C 8 in the estimation of AUC 0–24 h 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.