title: Prediction of nanoparticle prodrug metabolism by pharmacokinetic modeling of biliary excretion.
abstract: Pharmacokinetic modeling and simulation is a powerful tool for the prediction of drug concentrations in the absence of analytical techniques that allow for direct quantification. The present study applied this modeling approach to determine active drug release from a nanoparticle prodrug formulation. A comparative pharmacokinetic study of a nanoscale micellar docetaxel (DTX) prodrug, Procet 8, and commercial DTX formulation, Taxotere, was conducted in bile duct cannulated rats. The nanoscale (~40nm) size of the Procet 8 formulation resulted in confinement within the plasma space and high prodrug plasma concentrations. Ex vivo prodrug hydrolysis during plasma sample preparation resulted in unacceptable error that precluded direct measurement of DTX concentrations. Pharmacokinetic modeling of Taxotere and Procet 8 plasma concentrations, and their associated biliary metabolites, allowed for prediction of the DTX concentration profile and DTX bioavailability, and thereby evaluation of Procet 8 metabolism. Procet 8 plasma decay and in vitro plasma hydrolytic rates were identical, suggesting that systemic clearance of the prodrug was primarily metabolic. The Procet 8 and Taxotere plasma profiles, and associated docetaxel hydroxy-tert-butyl carbamate (HDTX) metabolite biliary excretion, were best fit by a two compartment model, with both linear and non-linear DTX clearance, and first order Procet 8 hydrolysis. The model estimated HDTX clearance rate agreed with in vitro literature values, supporting the predictability of the proposed model. Model simulation at the 10mg DTX equivalent/kg dose level predicted DTX formation rate-limited kinetics and a peak plasma DTX concentration of 39ng/mL at 4h for Procet 8, in comparison to 2826ng/mL for Taxotere. As a result of nonlinear DTX clearance, the DTX AUCinf for the Procet 8 formulation was predicted to be 2.6 times lower than Taxotere (775 vs. 2017h×ng/mL, respectively), resulting in an absolute bioavailability estimate of 38%. As DTX clearance in man is considered linear, this low bioavailability is likely species-dependent. These data support the use of pharmacokinetic modeling and simulation in cases of complex formulations, where analytical methods for direct measurement of free (released) drug concentrations are unavailable. Uses of such models may include interpretation of preclinical toxicology studies, selection of first in man dosing regimens, and PK/PD model development.
authors.affiliation: Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick Inc., Frederick National Lab for Cancer Research, Frederick, 21702, USA. Electronic address: sternstephan@mail.nih.gov.
authors.forename: Stephan T
authors.initials: ST
authors.lastname: Stern
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.forename: Sarah
authors.initials: S
authors.lastname: Skoczen
authors.forename: Sherwin
authors.initials: S
authors.lastname: Xie
authors.forename: Barry
authors.initials: B
authors.lastname: Liboiron
authors.forename: Troy
authors.initials: T
authors.lastname: Harasym
authors.forename: Paul
authors.initials: P
authors.lastname: Tardi
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Mayer
authors.forename: Scott E
authors.initials: SE
authors.lastname: McNeil
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001646:Bile / Q000378:metabolism*; D003198:Computer Simulation; D000077143:Docetaxel; D005260:Female; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D008823:Micelles; D008954:Models, Biological; D053758:Nanoparticles / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D011355:Prodrugs; D043823:Taxoids; D000077143:Docetaxel
keywords: Biliary clearance; Nanomicellar prodrug; Pharmacokinetic modeling and simulation