Population Pharmacokinetics of Ganciclovir in Allogeneic Hematopoietic Stem Cell Transplant Patients

Selby, P.; Heffernan, Aaron; Yeung, David T.; Warner, Morgyn S.; Peake, Sandra; Hahn, Uwe; Wallis, Steven C.; McWhinney, Brett; Ungerer, Jacobus; Shakib, Sepehr; Roberts, Jason A.

doi:10.1128/aac.01550-22

Cited by 2 publications

(2 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Numerous pharmacokinetic studies have been conducted in transplantation in adult and pediatric populations [19,41 ▪ ,42,43]. The most common structural population pharmacokinetic (PK) model utilized was a two-compartment model with lagged first-order absorption (for oral ValGCV) and elimination from central compartment [19,34,42,44–46].…”

Section: Population Pharmacokinetic Modelsmentioning

confidence: 99%

“…One study identified the type of SOT as a significant covariate for GCV clearance with kidney transplant recipients having higher clearance compared to lung, liver, or heart transplant recipients [44]. In comparison, covariates identified in hematopoietic stem cell transplant (HCT) recipients included creatinine clearance as estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the presence of continuous renal replacement therapy [41 ▪ ]. Studies comparing ValGCV in HCT recipients with and without Grade I–II gastrointestinal graft-versus-host-disease (GVHD) did not find a significant difference in exposures achieved [23,47].…”

Section: Population Pharmacokinetic Modelsmentioning

confidence: 99%

See 1 more Smart Citation

Evidence supporting the use of therapeutic drug monitoring of ganciclovir in transplantation

Wong,

Ho,

Domazetovska

et al. 2023

Current Opinion in Infectious Diseases

View full text Add to dashboard Cite

Purpose of review This review describes current knowledge of ganciclovir (GCV) and valganciclovir (ValGCV) pharmacokinetic/pharmacodynamic characteristics, highlighting the likely contribution from host genetic factors to interpatient variability. The evidence and challenges surrounding optimization of drug dosing through therapeutic drug monitoring (TDM) are examined, with recommendations made. Recent findings Pharmacokinetic studies of current dosing guidelines have shown high interindividual and intraindividual variability of GCV concentrations. This is sometimes associated with a slow decline in cytomegalovirus (CMV) viral load in some transplant recipients. A high incidence of GCV-associated myelosuppression has limited the use of this drug in the transplant setting. Patient groups identified to benefit from GCV TDM include pediatric patients, cystic fibrosis with lung transplantation, obese with kidney transplantation, and patients with fluctuating renal function or on hemodialysis. The emergence of refractory resistant CMV, particularly in immune compromised patients, highlights the importance of appropriate dosing of these antivirals. Host genetic factors need to be considered where recently, two host genes were shown to account for interpatient variation during ganciclovir therapy. Therapeutic Drug Monitoring has been shown to improve target antiviral-level attainment. The use of TDM may guide concentration-based dose adjustment, potentially improving virological and clinical outcomes. However, evidence supporting the use of TDM in clinical practice remains limited and further study is needed in the transplant cohort. Summary Further studies examining novel biomarkers are needed to guide target concentrations in prophylaxis and treatment. The use of TDM in transplant recipients is likely to improve the clinical efficacy of current antivirals and optimize outcomes in transplant recipients.

show abstract

Section: Population Pharmacokinetic Modelsmentioning

confidence: 99%

Section: Population Pharmacokinetic Modelsmentioning

confidence: 99%

Evidence supporting the use of therapeutic drug monitoring of ganciclovir in transplantation

Wong,

Ho,

Domazetovska

et al. 2023

Current Opinion in Infectious Diseases

View full text Add to dashboard Cite

show abstract

Serum ganciclovir drug exposure in children receiving standard ganciclovir dosing

Yang,

Irwin,

Weerdenburg

et al. 2024

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Intravenous ganciclovir (GCV) is used for the treatment of cytomegalovirus (CMV) infection in immunocompromised children. Although the therapeutic target for treatment is unclear, studies have shown a serum area under the concentration–time curve (AUC 24h ) ≥40 mg/L·h correlates with effective CMV prevention. This study aimed to externally validate existing GCV population pharmacokinetic (PopPK) models and develop a model if needed and evaluate the serum AUC 24h achieved with standard GCV dosing and propose an optimized dosing strategy for immunocompromised children. Ganciclovir drug monitoring data from two pediatric hospitals were retrospectively collected, and published pediatric PopPK models were externally validated. The population AUC 24h with standard GCV dosing (5 mg/kg twice daily) was calculated, and an optimized dosing strategy was determined using Monte Carlo simulations to achieve an AUC 24h between 40 and 100 mg/L·h. Overall, 161 samples from 23 children with a median (range) age of 9.0 years (0.4–17.0) and weight of 28.2 kg (5.6–73.3) were analyzed. Transferability of published pediatric PopPK models was limited. Thus, a one-compartment model with first-order absorption and elimination with weight and serum creatinine as covariates was developed. The median (5th–95th percentiles) steady state AUC 24h with standard dosing was 38.3 mg/L·h (24.8–329.2) with 13 children having an AUC 24h <40 mg/L·h, particularly those aged <4 years (8/13). An optimized simulated GCV dosing regimen, ranging from 2 to 13 mg/kg twice daily for children with normal renal function, achieved 61%–78% probability of target attainment. Standard GCV dosing likely results in inadequate drug exposure in more than half of the children, particularly those aged <4 years. An optimized dosing regimen has been proposed for clinical validation.

show abstract

Population Pharmacokinetics of Ganciclovir in Allogeneic Hematopoietic Stem Cell Transplant Patients

Cited by 2 publications

References 47 publications

Evidence supporting the use of therapeutic drug monitoring of ganciclovir in transplantation

Evidence supporting the use of therapeutic drug monitoring of ganciclovir in transplantation

Serum ganciclovir drug exposure in children receiving standard ganciclovir dosing

Contact Info

Product

Resources

About