(T-119) Development of a Population Pharmacokinetic Model for Ganciclovir to Assess the Renal Impairment Impact in Chinese Patients

Zhiteng Tian, B.Sc., Current M.Sc. Candidate – Master's Student, Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; Zhenzhen Yang, Ph.D., Associate Researcher, Master's Supervisor – Associate Researcher, Master's Supervisor, Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; Dongyang Liu, Ph.D., Senior Researcher, Ph.D. Supervisor – Deputy Director, Drug Clinical Trial Center; Ph.D. Supervisor; Senior Researcher, Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China

Objectives:
The ganciclovir (GCV) by intravenous administration is the gold standard treatment of cytomegalovirus infection or prevention in solid organ transplantation, which dose should be adjusted according to the renal function[1]. There are high interindividual pharmacokinetic variability in ganciclovir, mainly due to wide variability in renal function and body weight[2]. This study aimed to develop and verify a population pharmacokinetic model for GCV in Chinese patients, to explain the high variability between individuals and quantitatively explore the impact of renal impairment (RI) on the pharmacokinetics (PK) of GCV.

Methods: Clinical data and serum GCV levels were collected from Chinese patients that received intravenous GCV therapy. Ganciclovir concentration-time data were analyzed using nonlinear mixed-effect modeling (NONMEM v.21.11.1). The preferred estimation algorithm was the first-order conditional estimation with interaction (FOCE-I). PK modeling and covariate analyses were performed. Bootstrap and visual predictive checks were used to determine model adequacy.

Results: In total, 131 GCV serum concentration measurements were obtained from routine therapeutic drug monitoring in 73 patients after intravenous administration. The PK profile of GCV was conformed to an one-compartment model with first-order elimination. After multivariate analyses, only the categorical covariate RI (renal impairment degrees including normal, mild, moderate and severe were classified based on eGFR) (P < 0.001) were included as covariates on clearance (CL). In the final model, the estimated CL and volume of distribution (V) were 22.3 L/h and 178 L, respectively. The inclusion of RI contributed to a decrease of interindividual variability (IIV) of CL by 47.6%. The final model demonstrated that CL was 0.451, 0.156, 0.096 times of the normal population for mild, moderate, and severe renal impairment population, respectively. The covariate RI revealed that the deterioration of renal impairment was closely associated with the reduction in CL.

Conclusions:
A large interindividual variability was quantitatively explored from the PK profile of GCV among Chinese patients, and RI could partially explain the interindividual variability. The developed model results could lead to refine recommendation for dose adjustment according to the various degrees of renal impairment.

Citations: Citations:
[1] Humar A, Snydman D; AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009, 9 Suppl 4: S78-86.
[2] Franck B, Woillard JB, Théorêt Y, Bittencourt H, Demers E, Briand A, Marquet P, Lapeyraque AL, Ovetchkine P, Autmizguine J. Population pharmacokinetics of ganciclovir and valganciclovir in paediatric solid organ and stem cell transplant recipients. Br J Clin Pharmacol. 2021, 87(8): 3105-3114.