title: Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects.
abstract: Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven-compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent.
authors: Mayo Clinic, Rochester, MN 55905, USA.
authors: Alexander K
authors: AK
authors: Berg
authors: Sumithra J
authors: SJ
authors: Mandrekar
authors: Katie L Allen
authors: KL
authors: Ziegler
authors: Elsa C
authors: EC
authors: Carlson
authors: Eva
authors: E
authors: Szabo
authors: Mathew M
authors: MM
authors: Ames
authors: Daniel
authors: D
authors: Boring
authors: Paul J
authors: PJ
authors: Limburg
authors: Joel M
authors: JM
authors: Reid
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002214:Capsules; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000517:prevention & control; D013467:Sulindac / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002214:Capsules; D013607:Tablets; D013467:Sulindac; C025462:sulindac sulfide; C025463:sulindac sulfone