Irinotecan (CPT-11, Camptosar) is a semisynthetic, water-soluble camptothecin derivative approved for the treatment of patients with colorectal cancer. Irinotecan(Drug information on irinotecan) is also undergoing phase I/II clinical testing and has shown promising activity against a wide variety of tumor types, including recurrent malignant gliomas. A phase II trial conducted at Duke University in patients with recurrent high-grade glioma receiving weekly irinotecan doses of 125 mg/m² reported a 15% objective response rate. Of note, the toxicity and plasma exposure to irinotecan and its potent metabolite SN-38 appeared to be lower than that of a historical database comprising colorectal cancer patients.
Intravenously administered irinotecan (molecular weight [MW]: 587) is metabolized in the liver by cytochrome P450 3A4/5 (CYP 3A4/5) enzymes to the less active oxidative metabolites APC7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperi-dino]-carbonyloxycamptothecin (MW: 619)and NPC7-ethyl-10[4-(piperidino)-1 amino]carbonyl-oxycamptothecin (MW: 519).[2,3] Irinotecan is also bioactivated in the liver by carboxylesterases (predominantly hCE2) to the potent topoisomerase I inhibitor SN-38 (MW: 393)[4-6] (Figure 1).
SN-38 is eliminated mainly through conjugation by hepatic uridine-diphosphoglucuronosyl transferase (UGT-1A1) to SN-38 glucuronide (SN-38G) (Figure 2). SN-38G has only 1/100 the antitumor activity of SN-38. UGT-1A1 is the same isoenzyme responsible for glucuronidation of bilirubin. Grade 4 toxicity (neutropenia/diarrhea) has been reported in patients with deficient UGT-1A1 activity (Gilbert’s syndrome) after receiving irinotecan. The relationship of genetic polymorphism of UGT-1A1 and irinotecan toxicity was recently reported. Patients who are either homozygous or heterozygous for the UGT-1A1*28 genotype are at risk for severe irinotecan-associated toxicity.
The canalicular multispecific organic anion transporter (MRP-2) reportedly is responsible for the biliary transport of the carboxylate forms of irinotecan and SN-38, as well as the lactone and carboxylate forms of SN-38G. MRP-2 is present in apical membranes of the liver, kidney, and intestine, and is expressed in human lung, gastric, and colorectal cancer cells. MRP-2 functions as a conjugate export pump mediating the unidirectional transport of bilirubin glucuronides, reduced folate and amphiphilic anions, particularly lipophilic substances conjugated with glutathione, glucuronide or sulfide. In the rat, a single nucleotide deletion results in a frame shift, reduced mRNA levels, and absence of the protein. The phenotype found in humans with the deletion is termed Dubin-Johnson syndrome, an autosomal recessive disorder characterized by chronic hyperbilirubinemia. Reports also suggest that SN-38 may be a substrate for the mitoxantrone(Drug information on mitoxantrone) (Novantrone)-resistance half-transporter (MXR) protein.[16,17] The effect of MXR on hepatic disposition of SN-38 has yet to be determined.
Pretreatment of rats with phenobarbital(Drug information on phenobarbital), an inducer of UGT-1A1 and CYP 3A4, was shown to enhance formation of SN-38G and diminish the area under the concentration-time curve (AUC) for both SN-38 and irinotecan. However, valproic acid increased the AUC of SN-38. Additionally, phenobarbital combined with irinotecan successfully treated a patient with Gilbert’s syndrome. Recent studies have demonstrated that patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) obtain lower plasma concentrations of chemotherapeutic agents when administered at conventional doses.[20,21] Failure to achieve adequate plasma drug levels may account in part for lack of chemotherapy efficacy demonstrated in previous brain tumor trials.
The trial reported herein (NABTC-9801) is being conducted to determine the dose-limiting toxicities, maximum tolerated dose, and antitumor activity of irinotecan administered every 3 weeks to patients with progressive or recurrent malignant glioma receiving EIAEDs (phase I portion). In the phase II portion of the study, the antitumor activity of irinotecan including response rate, time to tumor progression, and 6-month progression-free survival (primary end point) will be determined. The influence of anticonvulsants on the metabolism and elimination of irinotecan and its metabolites is also to be characterized, and this is the main focus of this report.