title: A Physiologically Based Pharmacokinetic Model for Ganciclovir and Its Prodrug Valganciclovir in Adults and Children.
abstract: A physiologically based pharmacokinetic (PBPK) model has been developed for ganciclovir and its prodrug valganciclovir. Initial bottom-up modeling based on physicochemical drug properties and measured in vitro inputs was verified in preclinical animal species, and then, a clinical model was verified in a stepwise fashion with pharmacokinetic data in adult, children, and neonatal patients. The final model incorporated conversion of valganciclovir to ganciclovir through esterases and permeability-limited tissue distribution of both drugs with active transport processes added in gut, liver, and kidney. A PBPK model which accounted for known age-related tissue volumes, composition and blood flows, and renal filtration clearance was able to simulate well the measured plasma exposures in adults and pediatric patients. Overall, this work illustrates the stepwise development of PBPK models which could be used to predict pharmacokinetics in infants and neonates, thereby assisting drug development in a vulnerable patient population where clinical data are challenging to obtain.
authors.affiliation: Simulations Plus, Inc., 42505 10th Street West, Lancaster, California, 93534, USA.
authors.forename: V
authors.initials: V
authors.lastname: Lukacova
authors.affiliation: Teva Pharmaceuticals, West Chester, Pennsylvania, 19380, USA.
authors.forename: P
authors.initials: P
authors.lastname: Goelzer
authors.affiliation: Array BioPharma, Boulder, Colorado, 80301, USA.
authors.forename: M
authors.initials: M
authors.lastname: Reddy
authors.affiliation: Clinical Pharmacology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Greig
authors.affiliation: Clinical Pharmacology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Reigner
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. neil_john.parrott@roche.com.
authors.forename: N
authors.initials: N
authors.lastname: Parrott
mesh_terms: D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D002648:Child; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008954:Models, Biological; D011355:Prodrugs / Q000493:pharmacokinetics*; D000077562:Valganciclovir
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D000077562:Valganciclovir; D015774:Ganciclovir
keywords: esterases; pediatrics; permeability limited distribution; physiologically based pharmacokinetic models