Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

Clin Pharmacokinet https://doi.org/10.1007/s40262-018-0644-7 REVIEW ARTICLE Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics Femke M. de Man1 • Andrew K. L. Goey2 • Ron H. N. van Schaik3 • Ron H. J. Mathijssen1 • Sander Bins1  The Author(s) 2018. This article is an open access publication Abstract 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 & Sander Bins 1 Department of Medical Oncology, Erasmus MC Cancer Institute, ‘s-Gravendijkwal 230, 3015 Rotterdam, The Netherlands 2 Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands 3 Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands overview on today’s literature on irinotecan pharmacokinetics, pharmacodynamics, and pharmacogenetics. Key Points Irinotecan metabolism is complex due to the involvement of many enzymes and transporters, and is therefore prone to drug–drug interactions. Prior to starting with irinotecan chemotherapy, patients should be evaluated for possible interactions with comedication. Single nucleotide polymorphisms in several drug metabolizing enzymes (e.g. uridine diphosphate glucuronosyltransferase [UGT] 1A1, UGT1A7, UGT1A9) and drug transporters (e.g. ATP-binding cassette [ABC] B1, ABCC1) have been reported to be significantly associated with irinotecan toxicity. Caucasian patients should be screened for UGT1A1*28 and Asian patients for UGT1A1*6 in advance of irinotecan treatment as these polymorphisms are common in those populations and dosing can be personalized if UGT1A1 functioning is constitutionally altered. Despite existing genotype-based dosing guidelines, upfront UGT1A1 genotyping is not yet routinely performed in patients starting with irinotecan chemotherapy. F. M. de Man et al. 1 Introduction Irinotecan (CPT-11) is a camptothecin derivative that demonstrates anticancer activity in many solid tumors. Currently, it is widely used in the treatment of colorectal, pancreatic, and lung cancer. Irinotecan is the prodrug for SN-38, which inhibits topoisomerase-I, an enzyme involved in DNA replication [1, 2]. SN-38 is 100- to 1000-fold more cytotoxic than irinotecan, and its exposure is highly variable [3]. SN-38 is inactivated by further enzymatic conversion into SN-38 glucuronide (SN-38G). 2 Pharmacokinetics 2.1 Distribution Irinotecan is a hydrophilic compound with a large volume of distribution estimated at almost 400 L/m2 at steady state [4]. At physiological pH, the lactone-ring of irinotecan and SN-38 can be hydrolyzed to a carboxylate isoform (Fig. 1). Consequently, a pH-dependent equilibrium between these forms exists [5]. As only the lactone form has antitumor activity, a small change in pH could alter the pharmacokinetics and efficacy of irinotecan [6]. However in plasma the carboxylate form of irinotecan and the lactone form of SN-38 dominate [7, 8]. This could be explained by a higher tissue distribution of irinotecan lactone and the preferential binding of SN-38 lactone to plasma proteins Fig. 1 pH-dependent equilibrium of irinotecan and SN-38 isoforms [4, 9]. Conversion of irinotecan lactone to carboxylate within the circulation is rapid, with an initial half-life of between 9 and 14 min, which results in a 50% reduction in irinotecan lactone concentration after 2.5 h, compared with end of infusion (66 vs. 35%) [4, 7, 8]. After the end of drug infusion, a rapid decrease in irinotecan plasma concentrations is seen. Peak concentrations of SN-38 are reached within 2 h after infusion [8]. Irinotecan is assumed to exhibit linear pharmacokinetics because of the correlation between dose and systemic exposure, which is highly variable between patients [8]. In plasma, the majority of irinotecan and SN-38 is bound to albumin, which has a stronger binding capacity for the more hydrophobic active metabolite, and albumin also stabilizes the lactone forms of irinotecan and SN-38 [10]. In blood, SN-38 is almost completely bound, with twothirds located in platelets and, predominantly, red blood cells [11]. The binding constant of SN-38 with erythrocytes is almost 15-fold higher than that of irinotecan [11]. Thus far, several population pharmacokinetic models of irinotecan have been developed. All models confirmed the large interindividual variability in pharmacokinetic parameters of approximately 30%. In general, a threecompartmental model for irinotecan and a two-compartmental model for SN-38 is assumed [4, 12–16]. A mean SN-38 distribution half-life was estimated to be very short (approximately 8 min) [13]. Several models showed a second peak in the SN-38 plasma area under the curve (AUC), which was explained by an enterohepatic re- Irinotecan Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics circulation of SN-38. SN-38 is reabsorbed after intestinal deconjugation of SN-38G by (bacterial) b-glucuronidases [15]. Alternatively, release of SN-38 from erythrocytes has also been proposed to cause this second plasma peak [17]. 2.2 Metabolism 2.2.1 Metabolism by Carboxylesterases and Butyrylcholinesterase The prodrug irinotecan is hydrolyzed into the active metabolite SN-38 by two isoforms of carboxylesterases (CES1 and 2) and butyrylcholinesterase in the human body (Fig. 2) [18, 19]. CES1 and CES2 are localized in liver, colon, kidney, and blood cells, while butyrylcholinesterase is mainly found in plasma [20]. Conversion by these esterases mainly occurs intrahepatically and is a relatively slow and inefficient process as only 2–5% of irinotecan is converted into SN-38 [12, 18]. CES2 has a 12.5-fold higher affinity for irinotecan than CES1 and is therefore the predominant enzyme in this conversion [21–23]. In addition, this process also o (...truncated)