Contribution of Population Pharmacokinetics to Dose Optimization of Ganciclovir-Valganciclovir in Solid-Organ Transplant Patients

• Published in: Antimicrobial agents and chemotherapy Vol. 60; no. 4; pp. 1992 - 2002
• Main Authors: Padullés, A, Colom, H, Bestard, O, Melilli, E, Sabé, N, Rigo, R, Niubó, J, Torras, J, Lladó, L, Manito, N, Caldés, A, Cruzado, J M, Grinyó, J M, Lloberas, N
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.04.2016
• Subjects: Adult; Aged; Anemia - chemically induced; Anemia - diagnosis; Anemia - physiopathology; Antiviral Agents; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Area Under Curve; Bayes Theorem; Cytomegalovirus - drug effects; Cytomegalovirus - growth & development; Cytomegalovirus - pathogenicity; Cytomegalovirus Infections; Cytomegalovirus Infections - prevention & control; Cytomegalovirus Infections - virology; Drug Combinations; Drug Dosage Calculations; Female; Ganciclovir; Ganciclovir - administration & dosage; Ganciclovir - adverse effects; Ganciclovir - analogs & derivatives; Ganciclovir - pharmacokinetics; Heart Transplantation; Humans; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Neutropenia - chemically induced; Neutropenia - diagnosis; Neutropenia - physiopathology; Pharmacology; Recurrence; Viral Load - drug effects
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02130-15

Treatment of solid-organ transplant (SOT) patients with ganciclovir (GCV)-valganciclovir (VGCV) according to the manufacturer's recommendations may result in over- or underexposure. Bayesian prediction based on a population pharmacokinetics model may optimize GCV-VGCV dosing, achieving the area under the curve (AUC) therapeutic target. We conducted a two-arm, randomized, open-label, 40% superiority trial in adult SOT patients receiving GCV-VGCV as prophylaxis or treatment of cytomegalovirus infection. Group A was treated according to the manufacturer's recommendations. For group B, the dosing was adjusted based on target exposures using a Bayesian prediction model (NONMEM). Fifty-three patients were recruited (27 in group A and 26 in group B). About 88.6% of patients in group B and 22.2% in group A reached target AUC, achieving the 40% superiority margin (P< 0.001; 95% confidence interval [CI] difference, 47 to 86%). The time to reach target AUC was significantly longer in group A than in group B (55.9 ± 8.2 versus 15.8 ± 2.3 days,P< 0.001). A shorter time to viral clearance was observed in group B than in group A (12.5 versus 17.6 days;P= 0.125). The incidences of relapse (group A, 66.67%, and group B, 9.01%) and late-onset infection (group A, 36.7%, and group B, 7.7%) were higher in group A. Neutropenia and anemia were related to GCV overexposure. GCV-VCGV dose adjustment based on a population pharmacokinetics Bayesian prediction model optimizes GCV-VGCV exposure. (This study has been registered at ClinicalTrials.gov under registration no. NCT01446445.).