Pharmacokinetics and pharmacodynamics of intraperitoneal cancer chemotherapeutics

Peritoneal carcinomatosis remains a significant cause of morbidity and is a marker of poor prognosis in a range of malignancies, including those of the gastrointestinal and gynaecological tracts. In these cases, regional therapy has been explored as a treatment strategy to take advantage of the prolonged confinement of such tumours within the peritoneal cavity and the steep dose-response relationship for most cytotoxic agents. The pharmacokinetic rationale is based on exploiting the peritoneal-plasma barrier, which slows the rate of drug clearance from the peritoneal to systemic compartments and creates a concentration differential in favour of the peritoneal cavity. This allows higher drug concentrations, and thus increased cytotoxicity, to be achieved at the site of a tumour within the peritoneal cavity. There is pharmacodynamic evidence from a number of clinical trials to support the translation of these pharmacokinetic advantages of intraperitoneal chemotherapy into clinical benefit. However, its clinical application remains controversial because of concerns regarding intraperitoneal drug distribution, technical challenges and toxicity associated with regional drug delivery and the clinical relevance of the studies undertaken. The purpose of this review is to summarize the pharmacokinetic rationale of intraperitoneal drug delivery, review the pharmacodynamic studies performed in ovarian, colorectal and gastric cancers, and outline the future directions and challenges in the clinical application of this mode of treatment.