Coadministration Of Erlotinib Research Articles

Pharmacokinetic drug-drug interaction between erlotinib and paracetamol: A potential risk for clinical practice

BackgroundErlotinib is a tyrosine kinase inhibitor available for the treatment of non-small cell lung cancer. Paracetamol is an analgesic agent, commonly used in cancer patients. Because these drugs are often co-administered, there is an increasing issue of interaction between them. ObjectiveThe aim of the study was to investigate the effect of paracetamol on the pharmacokinetic parameters of erlotinib, as well as the influence of erlotinib on the pharmacokinetics of paracetamol. MethodsThe rabbits were divided into three groups: the rabbits receiving erlotinib (IER), the group receiving paracetamol (IIPR), and the rabbits receiving erlotinib+paracetamol (IIIER+PR). A single dose of erlotinib was administered orally (25mg) and was administered intravenously (35mg/kg). Plasma concentrations of erlotinib, its metabolite (OSI420), paracetamol and its metabolites – glucuronide and sulphate were measured with the validated method. ResultsDuring paracetamol co-administration we observed increased erlotinib maximum concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) by 87.7% and 31.1%, respectively. In turn, erlotinib lead to decreased paracetamol AUC0-∞ by 35.5% and Cmax by 18.9%. The mean values of paracetamol glucuronide/paracetamol ratios for Cmax were 32.2% higher, whereas paracetamol sulphate/paracetamol ratios for Cmax and AUC0-∞ were 37.1% and 57.1% lower in the IIPR group, when compared to the IIIER+PR group. ConclusionsParacetamol had significant effect on the enhanced plasma exposure of erlotinib. Additionally, erlotinib contributed to the lower concentrations of paracetamol. Decreased glucuronidation and increased sulphation of paracetamol after co-administration of erlotinib were also observed.

Effect of erlotinib on CYP3A activity, evaluated in vitro and by dual probes in patients with cancer

In vitro, erlotinib (0-30 µmol/l) and C-labelled midazolam (MDZ) (5 µmol/l) were incubated with human liver microsomes; separately, microsomes were preincubated with erlotinib (10 µmol/l) before the addition of MDZ. Results showed a time-dependent inhibition of MDZ metabolism by erlotinib, with a Ki of 7.5 µmol/l and an inactivation rate constant of 0.009/min. Patients with cancer (n=24) received a single oral dose of 7.5 mg MDZ and a single intravenous dose of 3 µCi [C-N-methyl] erythromycin on days 1, 8, 14 and 21. Patients also received 150 mg oral erlotinib daily from day 8 to day 14. Plasma concentrations of erlotinib and OSI-420 were determined on days 8 and 14; MDZ and 1'-hydroxymidazolam were determined on days 1, 8, 14 and 21. Coadministration of erlotinib resulted in a 4 and a 16% increase in CO2 on days 8 and 14, respectively, after the administration of erythromycin. The mean AUC0-last of MDZ decreased 17 and 34% after erlotinib treatment on day 8 and day 14, respectively. The half-life of MDZ and the AUC ratio of 1'-hydroxymidazolam to MDZ were not significantly changed. Although erlotinib may be a weak mechanism-based irreversible inhibitor of CYP3A4 in vitro, in vivo, erlotinib did not inhibit CYP3A-mediated metabolism, as determined by the erythromycin breath test and the MDZ pharmacokinetics. The mechanism for reduced exposure of MDZ is unclear, but may be because of an increase in intestinal metabolism or decreased absorption. These findings suggest that coadministration of erlotinib may not result in clinically relevant increases in exposure of CYP3A substrates.

Coadministration of Erlotinib and Curcumin Augmentatively Reduces Cell Viability in Lung Cancer Cells

Resistance to erlotinib in lung cancer cases includes T790M mutant epidermal growth factor receptor and c-Met gene amplification, but other unknown mechanisms account for about 30% of the resistance. Activation of the nuclear factor kappa B (NFkappaB)-related pathways in association with the reduction in ikappaB level may be one of such potential mechanisms. It is known that curcumin inhibits the inducible activation of NFkappaB at least in part by sustaining ikappaB expression level. Therefore, we evaluated the effects of coadministration of erlotinib and curcumin on lung cancer cells. We found that erlotinib and curcumin augmentatively reduced cell viability. Studies in PC9 cells showed that induction of apoptosis was involved. Expression of ikappaB was elevated in PC9 cells by curcumin administration, and pretreatment with siRNAs for ikappaB significantly attenuated the reduction in cell viability after coadministration of erlotinib and curcumin. Furthermore, coadministration of erlotinib and/or curcumin augmentatively attenuated the growth of PC9 tumors in mice. These results suggested the existence of an augmentative tumor growth inhibitory effect between erlotinib and curcumin, and this effect was at least in part mediated by the increase in the expression of ikappaB induced by curcumin.

Abstract 3353: Effect of erlotinib on the pharmacokinetics of irinotecan and its metabolites: A drug-drug interaction study.

Abstract Purpose: Since irinotecan and erlotinib are used in treatment for non-small cell lung cancer (NSCLC), co-administration of these drugs might be an effective treatment for NSCLC. However, drug-drug interaction should be concerned because these drugs are metabolized by CYP3A4 and excreted into bile by ABC transporters. To clarify the drug-drug interaction when these drugs are co-administered, we examined the effect of this co-administration on the pharmacokinetics of irinotecan, its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide (SN-38G) in animal model. Methods: Cytotoxicity of irinotecan and SN-38 with erlotinib against NSCLC cell line (A549) was assessed. To elucidate the effect of drug-drug interaction between irinotecan and erlotinib, male Sprague-Dawley rats were treated with 10 mg/kg irinotecan and 25 mg/kg erlotinib. The concentrations of irinotecan, SN-38, SN-38G and erlotinib in plasma, bile, and tissues were analyzed by high-performance liquid chromatography. Pharmacokinetic parameters were calculated by non-compartmental model methods. Results: Co-exposured erlotinib enhanced the cytotoxicity of SN-38 in a dose-dependent manner, however it did not significantly affect the cytotoxicity of irinotecan against A549 that is resistant to erlotinib. Additionally, co-administration of erlotinib resulted in a significant increase of plasma concentration of irinotecan, SN-38 and SN-38G compared to irinotecan alone, but decrease in the biliary excretion. Erlotinib significantly increased the concentration of irinotecan and SN-38G in kidney and that of SN-38 in lung and jejunum. On the other hand, co-administration of irinotecan intended to decrease the plasma concentration of erlotinib but significant differences of pharmacokinetic parameters were not observed. Also, levels of erlotinib in tissues were not affected by co-administration of irinotecan. Conclusions: We proposed the possibility of combination therapy of irinotecan with erlotinib because the plasma concentration of irinotecan and its active metabolite SN-38 significantly increased in vivo and the cytotoxicity of SN-38 against NSCLC cell line enhanced. New effective salvage chemotherapy regimens are needed in patients with NSCLC. We conducted a phase I/II clinical study of combination chemotherapy with irinotecan and erlotinib for recurrent NSCLC because our data have shown synergistic/additive effects between irinotecan and epidermal growth factor receptor-tyrosine kinase inhibitor. Citation Format: Emiko Sanematsu, Issei Toyooka, Yuki Takashima, Tamio Okimoto, Yukari Tsubata, Hideyuki Saito, Takeshi Isobe, Akinobu Hamada. Effect of erlotinib on the pharmacokinetics of irinotecan and its metabolites: A drug-drug interaction study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3353. doi:10.1158/1538-7445.AM2013-3353

The UGT1A1∗28 polymorphism correlates with erlotinib’s effect on SN-38 glucuronidation

The combination of irinotecan and erlotinib has been evaluated in clinical trials, although toxicity has been significant. We aimed to investigate the effect of erlotinib on SN-38 glucuronidation and the association between UGT1A polymorphisms and SN-38 glucuronidation activity in the presence of erlotinib. The inhibitory effect of erlotinib on SN-38 glucuronidation was determined by measuring the formation rates for SN-38 glucuronide, using recombinant human UGT1A1, pooled human liver microsomes (HLMs) and 52 Caucasian liver microsomes in the absence or presence of erlotinib. Inhibition kinetic studies were conducted. AUC ratios were used to predict the risk of potential drug–drug interactions (DDI) in vivo. Our data showed that erlotinib exhibited potent non-competitive inhibition against SN-38 glucuronidation in pooled HLMs and UGT1A1. Using the physiological and pharmacokinetic parameters obtained from the literature, we estimated the in vivo concentrations of unbound erlotinib available for UGT1A1 active site and thus the AUC ratios of SN-38 were also quantitatively predicted. It is estimated that erlotinib administered at 50 mg/day or higher doses may result in at least a 24% increase in SN-38 AUC. Significant correlations were observed between SN-38 glucuronidation activity in the presence of erlotinib and UGT1A1∗28 in 52 Caucasian liver microsomes. Our results suggest that erlotinib is a potent inhibitor of SN-38 glucuronidation via UGT1A1 inhibition. The coadministration of erlotinib with irinotecan may result in clinically significant DDI. UGT1A1∗28 polymorphism correlates with erlotinib’s effect on SN-38 glucuronidation. The present findings shed light on the development and optimisation of combinations involving irinotecan and erlotinib.

Abstract LB-305: Why two are better than one: Suppression of carcinoma cell growth in vitro and in human HGF/SF transgenic SCID by inhibitors of MET (SGX523) and EGFR (erlotinib)

Abstract The signaling cascade originating from hepatocyte growth factor/scatter factor (HGF/SF)-MET ligand-receptor pair is frequently observed in a broad spectrum of human cancers. Inappropriate activation of this pathway has been shown to occur via: paracrine/autocrine activation; by amplification or mutation in the MET gene; or through ligand independent mechanisms (www.vai.org/met). Various MET drugs targeting this pathway are under development and in need of relevant in vivo tumor models to allow assessment of drug efficacy alone or in combination against human MET expressing tumors. Conventional mouse models post a significant limitation on fulfilling such demand as mouse HGF/SF has low affinity/activity on the human MET. Such limitations are abrogated in human HGF/SF transgenic SCIDs (designated hHGFtg-SCID), which, unlike its non-transgenic littermates, produce human HGF/SF to allow human MET signaling on cells of human cancer xenografts. Here, we show that the hHGFtg-SCID mouse significantly enhances tumor xenograft growth of many MET-expressing human carcinoma cell lines including lung, breast, kidney, colon, gastric and pancreatic cancers. Using the hHGFtg-SCID mouse model systems, we demonstrated that SGX523, a MET small molecule kinase inhibitor which suppressed MET phosphorylation and downstream signaling activation in vitro, partially inhibits the growth of xenografts derived from NCI-H596 lung cancer cells, HCC1954 breast cancer cells and HPAF II pancreatic cancer cells. Furthermore, we found that the partial tumor growth inhibition by SGX523 was significantly enhanced by co-administration of erlotinib, the EGFR small molecule kinase inhibitor. In vitro, erlotinib also enhanced SGX523 inhibitory activity in cell proliferation and G1/S cell cycle progression assays. Our data suggest that the hHGFtg-SCID mouse is a valuable system for evaluating MET drugs, and simultaneously targeting MET and EGFR pathways may provide a better treatment for cancers harboring inappropriate activation of both pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-305.

Comparison of the Drug-Drug Interactions Potential of Erlotinib and Gefitinib via Inhibition of UDP-Glucuronosyltransferases

We aimed to investigate and compare the effects of erlotinib and gefitinib on UDP-glucuronosyltransferase (UGT) activities and to quantitatively evaluate their drug-drug interaction (DDI) potential due to UGT inhibition. The inhibitory effects of erlotinib and gefitinib on UGTs were determined using high-performance liquid chromatography by measuring the formation rates for 4-methylumbelliferone (4-MU) glucuronide, imipramine N-glucuronide, and bilirubin glucuronides using recombinant human UGT isoforms and human liver microsomes (HLMs) in the absence or presence of erlotinib and gefitinib. Inhibition kinetic studies were conducted. Area under the curve (AUC) ratios were used to predict the risk of potential DDI in vivo. Erlotinib exhibited selective potent competitive inhibition against 4-MU glucuronidation by UGT1A1, and gefitinib demonstrated a wide range of inhibition against UGT-mediated 4-MU glucuronidation, particularly against UGT1A1, UGT1A7, UGT1A9, and UGT2B7. Erlotinib also exerted potent mixed inhibition against bilirubin glucuronidation in HLMs. We estimated that coadministration of erlotinib at 100 mg/day or higher doses may result in at least a 30% increase in the AUC of drugs predominantly cleared by UGT1A1. Thus, the coadministration of erlotinib with drugs primarily cleared by UGT1A1 may result in potential DDI. In contrast, gefitinib is unlikely to cause a clinically significant DDI through inhibition of glucuronidation.

Interaction between sorafenib and erlotinib

2500 Background: The combination of sorafenib plus erlotinib was evaluated in patients with recurrent glioblastoma (GBM). In addition to defining the maximum tolerated dose (MTD), pharmacokinetics (PKs) for single agent and combination were determined. Methods: Adults with recurrent GBM with the usual phase I inclusion/exclusion criteria were eligible. No enzyme inducing anti-epileptic agents were allowed. Starting doses for erlotinib and sorafenib were 100mg PO QD and 200 mg PO BID, respectively, for 28 days (a cycle). For cycle 1 PKs, erlotinib was started on day 1 followed on day 2 by sorafenib. Eight plasma samples were collected over 24hrs on days 1, 15 and 28. Sorafenib and its metabolite (N-oxide) were analyzed by HPLC and erlotinib and OSI-420 by LC/MS. PK parameters were characterized by standard non-compartmental methods. Results: The MTD was sorafenib 200 mg PO BID and erlotinib 100 mg PO QD. The PKs for erlotinib (OSI) are displayed below. Conclusions: The PKs for sorafenib are in agreement with previous reports and not affected by the co-administration of erlotinib. However, there is an apparent affect of sorafenib on the PKs of erlotinib. The expected accumulation of erlotinib's Cmax and AUC at steady-state was not observed. This interaction results in at least a 2+ fold decrease in exposure to erlotinib and its active metabolite. The interaction does not appear to be the classical enzyme induction due to the rapidity of the onset/offset. This same phenomenon has been reported with the co-administration of sorafenib with gefitinib (Clin Cancer Res 13:2684,2007). Increasing the maximal velocity (Vmax) of CYP3A4, not the quantity of enzyme, is suggested as a testable hypothesis (J Pharmacol Exp Ther 290:1.1998). The clinical relevance of this interaction with regard to toxicity and efficacy warrants further evaluation. [Table: see text] No significant financial relationships to disclose.