Aim: To develop a PBPK model for acyclovir incorporating processes affecting the drug’s absorption and distribution after i.v. administration of acyclovir (ACV) as well as its in vivo formation after p.o. administration of the prodrug valacyclovir (VACV) pharmacokinetics in children.
Methods: A mechanistic absorption/PBPK model for VACV and ACV were developed using GastroPlus™ 8.5 (Simulations Plus, Inc.). The program’s Advanced Compartmental Absorption and Transit (ACAT™) model described the absorption of both drugs, while PK for both was simulated with its PBPKPlus™ module. All physiologies were generated by the program’s Population Estimates for Age-Related (PEAR™) Physiology™ module. Intestinal absorption and tissue distribution accounted for passive diffusion and carrier-mediated transport of both drugs. Total ACV clearance consisted of renal secretion (passive and carrier-mediated), biliary secretion, and metabolic clearance (Figure 1). VCAV clearance consisted of metabolic conversion to ACV and passive renal filtration (Figure 1). A pH-dependent model accounted for the degradation rate of VACV in the guy lumen . Passive diffusion through cell membranes in the tissues was calculated from specific permeability-surface area product (SpecPStc) for each drug along with tissue cell volumes .
SpecPstc and carrier-mediated Vmax in gut, liver, and kidneys for ACV were fitted against in vivo data (Cp-time profiles and urine data) after 1- and 6-hr i.v. infusions of ACV in adults . Reported in vitro Km values were used for MATE1, MATE2K, OCT and OAT [2,3]. The model was validated by predicting ACV PK after 1-hr i.v. infusions of ACV doses raning from 2.5 to 15 mg/kg .
SpecPstc, carrier-mediated uptake to gut, liver, and kidneys of VACV and metabolic conversion of VACV to ACV were fitted against Cp-time profiles of ACV after 100, 500, 1000mg p.o. administration of VACV. Reported in vitro Km values were used for Valacyclovirase and PepT1 [1,4]. The model was validated by predicting ACV PK after 250 and 750mg p.o. administration of VACV .
ACV PK in different pediatric groups was predicted using drug-dependent parameters obtained from the adult model and known age-dependent physiological changes.
American Association of Pharmaceutical Scientists (AAPS), November 2-6, 2014, San Diego, CA
By Viera Lukacova, Michael B. Bolger, Walter S. Woltosz