Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects

Alexander K. Berg, Sumithra J Mandrekar, Katie L Allen Ziegler, Elsa C. Carlson, Eva Szabo, Mathew M. Ames, Daniel Boring, Paul John Limburg, Joel M Reid

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)403-412
Number of pages10
JournalJournal of Clinical Pharmacology
Volume53
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Sulindac
Chemoprevention
Healthy Volunteers
Pharmacokinetics
Population
Neoplasms
Therapeutic Equivalency
Biological Availability
Prescriptions
Creatinine
Anti-Inflammatory Agents
Body Weight

Keywords

  • Chemoprevention
  • Exisulind
  • NONMEM
  • Population pharmacokinetics
  • Sulindac

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects. / Berg, Alexander K.; Mandrekar, Sumithra J; Ziegler, Katie L Allen; Carlson, Elsa C.; Szabo, Eva; Ames, Mathew M.; Boring, Daniel; Limburg, Paul John; Reid, Joel M.

In: Journal of Clinical Pharmacology, Vol. 53, No. 4, 04.2013, p. 403-412.

Research output: Contribution to journalArticle

Berg, Alexander K. ; Mandrekar, Sumithra J ; Ziegler, Katie L Allen ; Carlson, Elsa C. ; Szabo, Eva ; Ames, Mathew M. ; Boring, Daniel ; Limburg, Paul John ; Reid, Joel M. / Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects. In: Journal of Clinical Pharmacology. 2013 ; Vol. 53, No. 4. pp. 403-412.
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