Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences. Genetic variants in the DNA of these enzymes and transporters could predict a part of the drug-related toxicity and efficacy of treatment, which has been shown in retrospective and prospective trials and meta-analyses. Patient characteristics, lifestyle and comedication also influence irinotecan pharmacokinetics. Other factors, including dietary restriction, are currently being studied. Meanwhile, a more tailored approach to prevent excessive toxicity and optimize efficacy is warranted. This review provides an updated overview on today’s literature on irinotecan pharmacokinetics, pharmacodynamics, and pharmacogenetics.

Drug–drug interactions (DDIs) are of major concern in oncology, since cancer patients typically take many concomitant medications. Retrospective studies have been conducted to determine the prevalence of DDIs. However, prospective studies on DDIs needing interventions in cancer patients have not yet been carried out. Therefore, a prospective study was designed to identify DDIs leading to interventions among ambulatory cancer patients receiving anticancer treatment. Patients starting with a new treatment regimen with i.v. or oral anticancer medication were asked to participate. The patients’ medication was checked for DDIs by using drug interaction software. An expert team of clinical pharmacologists evaluated the relevance of these identified DDIs. If a DDI was qualified as potentially clinically relevant, an intervention was proposed to the treating (hemato)oncologist. Several variables were studied as determinants for performing an intervention. Descriptive statistics and uni- and multivariate logistic regression analyses were carried out. In this study, 302 patients were included. A total of 603 DDIs were identified by the drug interaction software and judged by the expert team. Of all 603 DDIs, 120 DDIs were considered potentially clinically relevant. These 120 DDIs, present in a total of 81 patients, resulted in a clinical intervention already executed by the (hemato)oncologist in 39 patients (13%), while an additional intervention was proposed by a clinical pharmacologist in 42 patients (14%). The number of comorbidities and the number of ‘over-the-counter’ drugs were identified as determinants. Clinical interventions on DDIs are frequently required among patients starting with anticancer therapy. Structured screening for these potentially clinically relevant DDIs, by (hemato)oncologists in close collaborations with clinical pharmacologists, should take place before the start and during anticancer treatment. This study was registered at the Dutch Trial Registry under number NTR3760.

Regorafenib exposure could potentially be influenced by an interaction with acid‐reducing drugs. In this crossover trial, patients were randomized into two sequence groups consisting of three phases: regorafenib intake alone, regorafenib with concomitant esomeprazole, and regorafenib with esomeprazole 3 hours prior. The primary end point was the relative difference (RD) in geometric means for regorafenib 0–24‐hour area under the concentration‐time curve (AUC_0–24h) and was analyzed by a linear mixed model in 14 patients. AUC_0–24h for regorafenib alone was 55.9 μg·hour/mL (coefficient of variance (CV): 40%), and for regorafenib with concomitant esomeprazole or with esomeprazole 3 hours prior AUC_0–24h was 53.7 μg·hour/mL (CV: 34%) and 53.6 μg·hour/mL (CV: 43%), respectively. No significant differences were identified when regorafenib alone was compared with regorafenib with concomitant esomeprazole (RD: −3.9%; 95% confidence interval (CI): −20.5 to 16.1%; P = 1.0) or regorafenib with esomeprazole 3 hours prior (RD: −4.1%; 95% CI: −22.8 to 19.2%; P = 1.0). These findings indicate that regorafenib and esomeprazole can be safely combined in clinical practice.