Population pharmacokinetics of aciclovir and its major metabolite 9-carboxymethoxymethylguanine and safety profile of valaciclovir in early liver transplant recipients

Valaciclovir is frequently prescribed for cytomegalovirus infection prophylaxis. Its major metabolite 9-carboxymethoxymethylguanine (9-CMMG), when accumulated in renally impaired patients, is neurotoxic. Its synthesis involves enzymes that could be impacted in liver transplant recipients. This retrospective study aimed to describe the pharmacokinetic (PK) and safety profile of aciclovir and 9-CMMG early after liver transplantation in patients receiving valaciclovir prophylaxis. Consecutive (ideally five) blood samples were drawn. Plasma concentrations of aciclovir/9-CMMG were quantified by UPLC-MS/MS. Medical data were collected from digital records. A joint population PK model for aciclovir/9-CMMG was developed (Monolix 2023R1). Monte Carlo simulations were used to estimate Cmin and AUC0-24. Fifty patients (21 women) in the postoperative phase of liver transplantation were enrolled, with median age of 56.0 years and median weight of 69.5 kg; 255 samples were collected 19.0 days after transplantation. No drug-drug interaction was reported. A one-compartment model with first-order absorption best described the pharmacokinetics (PK). Covariate analysis showed that aciclovir and 9-CMMG clearances correlated with estimated glomerular filtration rate (eGFR). In normorenal patients, receiving valaciclovir 2000 mg q8h, estimated AUC0-24 values were 44.8 and 13.3 mg·h/L for aciclovir and 9-CMMG, respectively. The median estimated metabolic ratio of AUC0-24 (9-CMMG/aciclovir) was 30.4% and 129.9% for patients with >90 and <30 mL/min/1.73 m2 eGFR, respectively. There were no valaciclovir-related adverse events during hospitalization. This model allowed the PK and basal metabolic ratio of aciclovir and 9-CMMG in early liver transplantation to be defined. The correlation with renal function suggests important implications for therapeutic drug monitoring of these compounds, which will need confirmation in different cohorts.