title: Contribution of Population Pharmacokinetics to Dose Optimization of Ganciclovir-Valganciclovir in Solid-Organ Transplant Patients.
abstract: 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.).
authors.affiliation: Pharmacy Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Padullés
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, Biopharmaceutics and Pharmacokinetics Unit, School of Pharmacy, University of Barcelona, Barcelona, Spain.
authors.forename: H
authors.initials: H
authors.lastname: Colom
authors.affiliation: Nephrology Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Bestard
authors.affiliation: Nephrology Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Melilli
authors.affiliation: Infectious Diseases Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Sabé
authors.affiliation: Biochemistry Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Rigo
authors.affiliation: Microbiology Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Niubó
authors.affiliation: Nephrology Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Torras
authors.affiliation: Digestive Surgery Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Lladó
authors.affiliation: Cardiology Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Manito
authors.affiliation: Nephrology Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Caldés
authors.affiliation: Nephrology Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Cruzado
authors.affiliation: Nephrology Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Grinyó
authors.affiliation: Nephrology Department, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain nlloberas@ub.edu.
authors.forename: N
authors.initials: N
authors.lastname: Lloberas
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001499:Bayes Theorem; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000517:prevention & control* / Q000821:virology; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D016027:Heart Transplantation; D006801:Humans; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology; D012008:Recurrence; D000077562:Valganciclovir; D019562:Viral Load / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004338:Drug Combinations; D000077562:Valganciclovir; D015774:Ganciclovir
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