Bol, J.M. van der

Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: A prospective cross-over drug-drug interaction study (Article)

2011-04-01T00:00:00Z

Background: Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan. Methods: Fourteen patients were treated with single agent irinotecan (600 mg i.v., 90 min) followed 3 weeks later by a second cycle with concurrent use of omeprazole 40 mg once daily, which was started 2 weeks prior to the second cycle. Plasma samples were obtained up to 55 h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10- hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1- piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5- aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS. Results: The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole. Conclusion: Omeprazole 40 mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.

Therapeutic drug monitoring for the individualization of docetaxel dosing: A randomized pharmacokinetic study (Article)

2011-01-15T00:00:00Z

Purpose: Docetaxel pharmacokinetic (PK) parameters, notably clearance and exposure (AUC), are characterized by large interindividual variability. The purpose of this study was to evaluate the effect of PKguided [area under the plasma concentration versus time curve (AUC) targeted], individualized docetaxel dosing on interindividual variability in exposure. Experimental Design: A limited sampling strategy in combination with a validated population PK model, Bayesian analysis, and a predefined target AUC was used. Fifteen patients were treated for at least 2 courses with body surface area-based docetaxel and 15 with at least 1 course of PK-guided docetaxel dosing. Results: Interindividual variability (SD of ln AUC) was decreased by 35% (N = 15) after 1 PK-guided course; when all courses were evaluated, variability was decreased by 39% (P = 0.055). PK-guided dosing also decreased the interindividual variability of percentage decrease in white blood cell and absolute neutrophil counts by approximately 50%. Conclusions: Further research is required to determine whether the decrease in PK variability can contribute to a reduction in interindividual variability in efficacy and toxicity.

Effects of methimazole on the elimination of irinotecan (Article)

2011-01-01T00:00:00Z

Purpose: To study the possible pharmacokinetic and pharmacodynamic interactions between irinotecan and methimazole. Methods: A patient treated for colorectal cancer with single agent irinotecan received methimazole co-medication for Graves' disease. Irinotecan pharmacokinetics and side effects were followed during a total of four courses (two courses with and two courses without methimazole). Results: Plasma concentrations of the active irinotecan metabolite SN-38 and its inactive metabolite SN-38-Glucuronide were both higher (a mean increase of 14 and 67%, respectively) with methimazole co-medication, compared to irinotecan monotherapy. As a result, the mean SN-38 glucuronidation rate increased with 47% during concurrent treatment. Other possible confounding factors did not change over time. Specific adverse events due to methimazole co-treatment were not seen. Conclusions: Additional in vitro experiments suggest that these results can be explained by induction of UGT1A1 by methimazole, leading to higher SN-38G concentrations. The prescribed combination of these drugs may lead to highly toxic intestinal SN-38 levels. We therefore advise physicians to be very careful in combining methimazole with regular irinotecan doses, especially in patients who are prone to irinotecan toxicity.

Effects of mannose-binding lectin polymorphisms on irinotecan-induced febrile neutropenia (Article)

2010-10-01T00:00:00Z

Objective. Mannose-binding lectin (MBL) is important in the innate immune response. MBL2 gene polymorphisms affect MBL expression, and genotypes yielding low MBL levels have been associated with an elevated risk for infections in hematological cancer patients undergoing chemotherapy. However, these reported associations are inconsistent, and data on patients with solid tumors are lacking. Here, we investigated the effects of MBL2 genotypes on irinotecan-induced febrile neutropenia in patients with solid tumors. Patients and Methods. Irinotecan-treated patients were genotyped for the MBL2 gene. Two promoter (550 H/L and 221 X/Y) and three exon polymorphisms (52 A/D, 54 A/B, and 57 A/C) were determined, together with known risk factors for irinotecan-induced toxicity. Neutropenia and febrile neutropenia were recorded during the first course. Results. Of the 133 patients, 28% experienced severe neutropenia and 10% experienced febrile neutropenia. No associations were found between exon polymorphisms and febrile neutropenia. However, patients with the H/H promoter genotype, associated with high MBL levels, experienced significantly more febrile neutropenia than patients with the H/L and L/L genotypes (20% versus 13% versus 5%). Moreover, patients with the HYA haplotype encountered significantly more febrile neutropenia than patients without this high MBL-producing haplotype (16% versus 4%). In the subgroup with wild-type exon polymorphisms (A/A), patients with the high MBL promoter phenotype had the highest incidence of febrile neutropenia, regardless of known risk factors. Conclusion. Patients with high MBL2 promoter genotypes and haplotypes seem more at risk for developing febrile neutropenia. If confirmed, these preliminary findings may contribute to more individualized approaches of irinotecan treatment.

A CYP3A4 phenotype-based dosing algorithm for individualized treatment of irinotecan (Article)

2010-01-15T00:00:00Z

Purpose: Irinotecan, the prodrug of SN-38, is extensively metabolized by cytochrome P450-3A4 (CYP3A4). A randomized trial was done to assess the utility of an algorithm for individualized irinotecan dose calculation based on a priori CYP3A4 activity measurements by the midazolam clearance test. Experimental Design: Patients were randomized to receive irinotecan at a conventional dose level of 350 mg/m2(group A) or doses based on an equation consisting of midazolam clearance, γ-glutamyltransferase, and height (group B). Pharmacokinetics and toxicities were obtained during the first treatment course. Results: Demographics of 40 evaluable cancer patients were balanced between both groups, including UGT1A1*28 genotype and smoking status. The absolute dose of irinotecan ranged from 480 to 800 mg in group A and 380 to 1,060 mg in group B. The mean absolute dose and area under the curve of irinotecan and SN-38 were not significantly different in either group (P > 0.18). In group B, the interindividual variability in the area under the curve of irinotecan and SN-38 was reduced by 19% and 25%, respectively (P > 0.22). Compared with group A, the incidence of grades 3 to 4 neutropenia was >4-fold lower in group B (45 versus 10%; P = 0.013). The incidence of grades 3 to 4 diarrhea was equal in both groups (10%). Conclusions: Incorporation of CYP3A4 phenotyping in dose calculation resulted in an improved predictability of the pharmacokinetic and toxicity profile of irinotecan, thereby lowering the incidence of severe neutropenia. In combination with UGT1A1*28 genotyping, CYP3A4 phenotype determination should be explored further as a strategy for the individualization of irinotecan treatment.

Renal function as a predictor of irinotecan-induced neutropenia (Article)

2008-08-01T00:00:00Z

Although approximately half of the administered dose of irinotecan is recovered in urine, scarce data are available on the association of renal function with irinotecan pharmacokinetics and toxicity. Here, these relationships are investigated in 187 patients treated with irinotecan in a three-weekly schedule. No significant effects on irinotecan pharmacokinetics were found in these patients. However, in 131 patients treated with the registered dose, categorized renal function was related to hematological toxicity. The incidence of grade 3-4 neutropenia decreased as function of creatinine clearance, particularly in nonsmoking patients (P < 0.01). Patients with slower creatinine clearance (35-66 ml/min) had a four-times higher risk of grade 3-4 neutropenia (58% vs. 14%; P < 0.001). This study suggests that pretreatment renal function values are associated with irinotecan-induced neutropenia. A confirmatory analysis is warranted to determine whether measures of renal function should be incorporated in future attempts toward individualized treatment with irinotecan.

Flat-fixed dosing versus body surface area-based dosing of anticancer drugs in adults: Does it make a difference? (Article)

2007-08-01T00:00:00Z

The current practice of using body-surface area (BSA) in dosing anticancer agents was implemented in clinical oncology half a century ago. By correcting for BSA, it was generally assumed that cancer patients would receive a dose of a particular cytotoxic drug associated with an acceptable degree of toxicities without reducing the agent's therapeutic effect. More recently, doubt has arisen to this hypothesis, and for many drugs, the effects of BSA on the pharmacokinetics of these agents have therefore been studied retrospectively. In (by far) most cases, use of BSA does not reduce the interindividual variation in the pharmacokinetics of adults, and thus, a logical rationale for further use of this tool in dosing adults is lacking. As a result, alternative dosing strategies have been proposed in order to replace BSA-based dosing. Flat-fixed dosing regimens have been suggested, thereby avoiding potential dose calculation mistakes. As flat-fixed dosing does not typically lead to greater pharmacokinetic variability, it does not seem worse than using BSA-based dosing. While it provides a simplification, it can, however, be questioned whether to call this an improvement or not. The implementation of socalled genotyping and phenotyping strategies, and therapeutic drug monitoring, may probably be of more clinical value. In the end, the nonscientifically based BSA-based dosing strategy should be replaced by alternative strategies. Despite the lack of basic fundamentals, BSA-based dosing still seems "untouchable" in clinical oncology. Even when alternatives will be shown to be indisputably better, many hurdles will probably have to be overcome before physicians will be willing to ban BSA-based dosing.

Cigarette smoking and irinotecan treatment: Pharmacokinetic interaction and effects on neutropenia (Article)

2007-07-01T00:00:00Z

Purpose: Several constituents of cigarette smoke are known to interact with drug metabolizing enzymes and potentially affect treatment outcome with substrate drugs. The purpose of this study was to determine the effects of cigarette smoking on the pharmacokinetics and adverse effects of irinotecan. Patients and Methods: A total of 190 patients (49 smokers, 141 nonsmokers) treated with irinotecan (90-minute intravenous administration on a 3-week schedule) were evaluated for pharmacokinetics. Complete toxicity data were available in a subset of 134 patients receiving 350 mg/m2or 600 mg flat-fixed dose irinotecan. Results: In smokers, the dose-normalized area under the plasma concentration-time curve of irinotecan was significantly lower (median, 28.7 v 33.9 ng·h/mL/mg; P = .001) compared with nonsmokers. In addition, smokers showed an almost 40% lower exposure to SN-38 (median, 0.54 v 0.87 ng·h/mL/mg; P < .001) and a higher relative extent of glucuronidation of SN-38 into SN-38G (median, 6.6 v 4.5; P = .006). Smokers experienced considerably less hematologic toxicity. In particular, the incidence of grade 3 to 4 neutropenia was 6% in smokers versus 38% in nonsmokers (odds ratio [OR], 0.10; 95% CI, 0.02 to 0.43; P < .001). There was no significant difference in incidence of delayed-onset diarrhea (6% v 15%; OR, 0.34; 95% CI, 0.07 to 1.57; P = .149). Conclusion: This study indicates that smoking significantly lowers both the exposure to irinotecan and treatment-induced neutropenia, indicating a potential risk of treatment failure. Although the underlying mechanism is not entirely clear, modulation of CYP3A and uridine diphosphate glucuronosyltransferase isoform 1A1 may be part of the explanation. The data suggest that additional investigation is warranted to determine whether smokers are at increased risk for treatment failure.