Plasma Concentrations Of Erlotinib Research Articles

Ritonavir-Boosted Exposure of Kinase Inhibitors: an Open Label, Cross-over Pharmacokinetic Proof-of-Concept Trial with Erlotinib.

BackgroundAlthough kinase inhibitors (KIs) are generally effective, their use has a large impact on the current health care budget. Dosing strategies to reduce treatment costs are warranted. Boosting pharmacokinetic exposure of KIs metabolized by cytochrome P450 (CYP)3A4 with ritonavir might result in lower doses needed and subsequently reduces treatment costs. This study is a proof-of-concept study to evaluate if the dose of erlotinib can be reduced by co-administration with ritonavir.MethodsIn this open-label, cross-over study, we compared the pharmacokinetics of monotherapy erlotinib 150 mg once daily (QD) (control arm) with erlotinib 75 mg QD plus ritonavir 200 mg QD (intervention arm). Complete pharmacokinetic profiles at steady-state were taken up to 24 h after erlotinib intake for both dosing strategies.ResultsNine patients were evaluable in this study. For the control arm, the systemic exposure over 24 h, maximum plasma concentration and minimal plasma concentration of erlotinib were 29.3 μg*h/mL (coefficient of variation (CV):58%), 1.84 μg/mL (CV:60%) and 1.00 μg/mL (CV:62%), respectively, compared with 28.9 μg*h/mL (CV:116%, p = 0.545), 1.68 μg/mL (CV:68%, p = 0.500) and 1.06 μg/mL (CV:165%, p = 0.150) for the intervention arm. Exposure to the metabolites of erlotinib (OSI-413 and OSI-420) was statistically significant lower following erlotinib plus ritonavir dosing. Similar results regarding safety in both dosing strategies were observed, no grade 3 or higher adverse event was reported.ConclusionsPharmacokinetic exposure at a dose of 75 mg erlotinib when combined with the strong CYP3A4 inhibitor ritonavir is similar to 150 mg erlotinib. Ritonavir-boosting is a promising strategy to reduce erlotinib treatment costs and provides a rationale for other expensive therapies metabolized by CYP3A4.

The Effect of Single-Dose Ougan Juice Application on the Pharmacokinetics of Erlotinib.

The aim of our study was to investigate the effects of single-dose Ougan (Citrus reticulata cv. Suavissima) juice application on the pharmacokinetics of erlotinib in vivo. Twelve Sprague-Dawley rats were randomly divided into the Ougan juice and control groups (n = 6 each). The rats were given a single dose of 1 mL/100 g Ougan juice or 1 mL/100 g normal saline (NS) by intragastric administration, followed by a single oral administration of 20 mg/kg erlotinib. The plasma concentration of erlotinib in rats was determined using ultra performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Erlotinib-d6 was used as the internal standard for chromatographic analysis on the UPLC BEH C18 analysis column (2.1 mm × 50 mm, 1.7 μm). The mobile phase was composed of acetonitrile and 0.1% formic acid eluting by gradient. Different pharmacokinetic (PK) parameters of erlotinib were calculated. The Ougan juice promoted the absorption of erlotinib and reduced the clearance of the drug. The area under the curve of erlotinib in the single-dose Ougan juice pretreatment group was approximately 1.87 times higher, and the maximum blood concentration (Cmax) was approximately 1.34 times higher than that in the control group. The mean residence time of erlotinib in the Ougan juice group was larger, and the clearance rate was smaller than those in the control group; the difference was statistically significant (P < 0.05). Ougan juice affected the PK spectrum of erlotinib in rats by improving the bioavailability of the drug and significantly increasing its plasma concentration.

Population Pharmacokinetics of Erlotinib in Patients With Non–small Cell Lung Cancer: Its Application for Individualized Dosing Regimens in Older Patients

PurposeErlotinib is an oral first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for non–small cell lung cancers (NSCLC) with EGFR-activating mutations. Older patients experience more toxicities compared with younger patients at the standard recommended dose of 150 mg once daily. The aims of this study were to describe the pharmacokinetic profile of erlotinib in unselected patients with NSCLC, to quantify and explain its variability, to challenge the standard recommended dose in older patients, and to propose clinical recommendations for the therapeutic management of patients taking erlotinib. Methods: A population pharmacokinetic model was developed using erlotinib plasma concentrations collected from patients with NSCLC participating in a routine therapeutic drug monitoring program (with the nonlinear mixed effect modeling program NONMEM). Relevant demographic characteristics, clinical factors, and co-medications were tested as potential covariates. An independent dataset was used for model validation. Simulations based on the final model allowed comparison of expected erlotinib concentrations under standard and alternative dosing regimens for smokers and for several age groups. FindingsA total of 481 erlotinib plasma concentrations from 91 patients with NSCLC were used for model building and 239 plasma drug concentrations from 107 patients for model validation. A one-compartment model with first-order absorption and elimination provided the best fit. Average erlotinib CL/F with interindividual variability (%CV) was 3.8 L/h (41.5%), and V/F was 166 L (53.8%). The absorption rate constant was 1.48 h−1. The external validation showed a negligible bias of −4% (95% CI, −7 to −1) in the individual predictions, with a precision of 23%. Current smoking and use of proton pump inhibitors were associated with higher CL/F, whereas age was associated with lower CL/F. Simulations suggest that a lower dose in older patients would decrease the risk of overexposure. ImplicationsThis large cohort study confirms the substantial interindividual variability in erlotinib plasma exposure and the impact of smoking and proton pump inhibitor intake. This large variability in erlotinib pharmacokinetics indicates that the standard recommended dose of 150 mg once daily is likely not appropriate to reach the expected concentrations in each patient. Concentration monitoring should be performed to individually adjust the erlotinib dosing regimen. The observed decrease in erlotinib CL/F with age suggests that a lower starting daily dose of 100 mg with concentration-guided dose adjustment would prevent overexposure and potential toxicity in older frail patients with co-morbidities.

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation–Positive Non–Small Cell Lung Cancer

Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients. To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer. Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study. Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks. The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms. Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome. Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option. UMIN-CTR Identifier: UMIN000015949.

Monitoring of erlotinib in pancreatic cancer patients during long-time administration and comparison to a physiologically based pharmacokinetic model

PurposeIn this study, a therapeutic drug monitoring (TDM) of erlotinib in pancreatic cancer patients was performed over 50 weeks to reveal possible alterations in erlotinib plasma concentrations. Additionally, a physiologically based pharmacokinetic (PBPK) model was created to assess such variations in silico.MethodsPatients with advanced pancreatic cancer received a chemotherapeutic combination of 100 mg erlotinib q.d., 500–900 mg capecitabine b.d. and 5 mg/kg bevacizumab q.2wks. Samples were analyzed by HPLC and the results were compared to a PBPK model, built with the software GastroPlus™ and based on calculated and literature data.ResultsThe erlotinib plasma concentrations did not show any accumulation, but displayed a high inter-patient variability over the whole investigated period. Trough plasma concentrations ranged from 0.04 to 1.22 µg/ml after day 1 and from 0.01 to 2.4 µg/ml in the long-term assessment. 7% of the patients showed concentrations below the necessary activity threshold of 0.5 µg/ml during the first week. The impact of some co-variates on the pharmacokinetic parameters Cmax and AUC0–24 were shown in a PBPK model, including food effects, changes in body weight, protein binding or liver function and the concomitant intake of gastric acid reducing agents (ARAs).ConclusionThis study presents the approach of combining TDM and PBPK modeling for erlotinib, a drug with a high interaction potential. TDM is an important method to monitor drugs with increased inter-patient variability, additionally, the PBPK model contributed valuable insights to the interaction mechanisms involved, resulting in an effective combination from a PK perspective to ensure a safe treatment.

Abstract 2872: Quantitative mass spectrometry imaging of erlotinib in skin rashes of cancer patients receiving erlotinib

Abstract Background The development of rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR-TKI) such as erlotinib. A significant relationship exists between the severity of a rash and survival in various cancers. However, whether erlotinib becomes distributed to the skin and whether its concentration is higher in a rash than in normal skin of treated cancer patients remains unknown. Here, using quantitative mass spectrometry imaging (qMSI), we successfully visualized the distribution of erlotinib in rashes and normal skin of patients with advanced pancreatic cancer receiving this drug. Methods We studied five patients with advanced pancreatic cancer who developed rashes after treatment with gemcitabine (1000 mg/m² by intravenous infusion for 30 minutes on days 1, 8, and 15 every 4 weeks) and erlotinib (given orally at 100 mg/day). We biopsied both rashes and normal skin, and compared the distribution of erlotinib using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). The plasma concentration of erlotinib was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results Erlotinib concentrations in five patients were 2.55 ± 1.46 ng/mm3 in normal skin and 3.18 ± 1.53 ng/mm3 (mean ± SD) in rashes (p=0.123). In four out of five patients, the erlotinib concentration in rashes was higher than that in normal skin. The epidermis showed the strongest expression of EGFR in skin as judged by immunohistological staining. Erlotinib showed a greater tendency for distribution to the epidermis than subcutaneous tissue. There was no correlation between erlotinib plasma concentrations vs. concentrations in rashes or normal skin. Conclusions Using qMSI, we, for the first time, visualized the distribution of erlotinib in skin tissue of pancreatic cancer patients receiving erlotinib. We found a tendency for a higher concentration of erlotinib in rashes than in normal skin. A greater distribution of erlotinib to the epidermis than subcutaneous tissue suggests erlotinib may directly bind EGFR expressed in the epidermis. Citation Format: Meiko Nishimura, Hiroaki Aikawa, Mitsuhiro Hayashi, Yu Mizutani, Kei Takenaka, Yoshinori Imamura, Naoko Chayahara, Masanori Toyoda, Naomi Kiyota, Toru Mukohara, Akinobu Hamada, Hironobu Minami. Quantitative mass spectrometry imaging of erlotinib in skin rashes of cancer patients receiving erlotinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2872. doi:10.1158/1538-7445.AM2017-2872

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.

P-139 Monitoring of erlotinib plasma concentrations after long time administration of 100 mg in advanced pancreatic cancer patients

P-139 Monitoring of erlotinib plasma concentrations after long time administration of 100 mg in advanced pancreatic cancer patients

The alteration of pharmacokinetics of erlotinib and OSI420 in type 1 diabetic rabbits.

Alterations in blood glucose levels observed in diabetes, may change the pharmacokinetics of co-administered drugs and in consequence, the efficacy and safety of therapy. Many oncological patients are diabetics and it is important to determine the interaction of anticancer drugs with this chronic disease. Erlotinib is a tyrosine kinase inhibitor (TKI), approved for the treatment of patients with non-small-cell lung cancer and pancreatic cancer in combination with gemcitabine. The aim of the study was to investigate the influence of the diabetes on the pharmacokinetics of erlotinib in rabbits. Additionally, the effect of erlotinib on glucose levels was examined. The pharmacokinetics of erlotinib was studied in healthy rabbits (n=6, control group) and type 1 diabetic rabbits (n=6, diabetic group). Erlotinib was administered in a single oral dose of 25mg. Plasma concentrations of erlotinib and its metabolite (OSI420) were measured with the validated method. The plasma concentrations of erlotinib and OSI420 were markedly increased in diabetic rabbits. Statistically significant differences between the groups were revealed for almost all analysed pharmacokinetic parameters for erlotinib and OSI420. The maximum glycaemia drop of 7.7-33.5% was observed in the diabetic animals, but no significant changes in glucose concentration were observed in the control group. The research proved the significant influence of diabetes on the pharmacokinetics of erlotinib and OSI420. Due to higher exposure to erlotinib, there may be an increased risk of adverse drug reactions in diabetic patients. Therefore, in some cases lower doses of the drug should be considered.

Chronopharmacokinetics of Erlotinib and Circadian Rhythms of Related Metabolic Enzymes in Lewis Tumor-Bearing Mice.

The purpose of the current study was to investigate the effect of the dosing time on the pharmacokinetics of erlotinib and the circadian rhythms of the metabolism enzymes in tumor-bearing mice. Female C57BL mice were randomly assigned to six groups. Erlotinib was orally administrated to the mice in each group at six different times of day. The plasma concentration of erlotinib was determined through a high-performance liquid-chromatographic assay, and the total mRNA was extracted from liver tissues to determine the expression of the mRNA of the related drug metabolism enzymes by qRT-PCR. The results indicated that AUC0-24h and MRT0-24h were the lowest in the 20:00 group (P<0.01). T max of the 13 HALO (hour after light onset), 17 HALO and 21 HALO groups was higher than that of the 1 HALO and 5 HALO groups (P<0.01). CL of the light-phase groups was lower than that of the dark-phase groups (P<0.01). The peak value of C max appeared in the 5 HALO group (P<0.01). The mRNA levels of Cyp3a11, Cyp3a13 and Cyp1a2 were generally higher during the afternoon and the dark phase. Circadian rhythm plays a critical role in the pharmacokinetics of erlotinib in mice, and the mechanisms may be attributed to gene expression rhythms of drug-metabolizing enzymes in liver tissues.

Is standard dose appropriate in elderly non-small cell lung carcinoma (NSCLC) patients treated with erlotinib?

9537 Background: Given the median age of 70 years in patients (pts) presenting NSCLC, the impact of age on outcomes including efficacy and toxicity of erlotinib remains unclear. In the BR21 study, analysis of subgroup based on age have reported similar survival benefits of erlotinib compared with placebo; however, elderly pts (³ 70 years) had significantly more toxicity, and were more likely to discontinue treatment (Paul Wheatley-Price et al., J Clin Oncol 2008). Thus we hypothesized that elderly were more exposed than younger pts. Methods: All consecutive pts with advanced or metastatic NSCLC treated with erlotinib between 2010 and 2014 were eligible in this prospective cohort. Erlotinib concentrations in plasma were determined using high-performance liquid chromatography at Day 15 after treatment initiation. We compared dose-normalized concentrations between pts < or ³ 75 years old using the Mann-Whitney U test and the occurrence of acute grade ³ 2 adverse events (AE) or treatment modifications by Fisher’s test. AE reports were graded using the National Cancer Institute Common Terminology Criteria V4. Lean body mass was estimated using Janmahasatian’s equation. Results: Out of 55 pts, erlotinib plasma concentration was analyzed in 45 pts. Median age was 65.6 (range 25-83), and 14 pts were over 75 years old. Among these 45 pts, 58% were female, 93% had an adenocarcinoma subtype; 44% were never smoker. Eighty-six percent of the pts had a performans status at baseline ≤ 2. Elderly pts had significantly lower estimated lean body mass (36.6 kg vs 47.7 kg; p = 0.00038). Within 2 weeks, grade ³ 2 AE occurred in 20% of pts, and 28 % in elderly. In the subgroup of pts over 75 years old, there was a trend for higher dose-normalized concentration at day 15 (1923.3 mg/L vs 1380.9 mg/L; p = 0.07), and the difference was significant in pts older than 80 (7 pts; 2484.6 mg/L vs 1377.4 mg/L; p = 0.0074). Four pts > 75 years old had dose reduction or discontinuation versus 0 in younger pts (p = 0.014, CI95% [1.2532; infinite]). Conclusions: Elderly patients are susceptible to be overexposed to erlotinib at 150mg/day, resulting in increased acute toxicity and treatment discontinuation.

Erlotinib: another candidate for the therapeutic drug monitoring of targeted therapy of cancer? A pharmacokinetic and pharmacodynamic systematic review of literature.

Erlotinib is currently marketed at fixed standard dosage against pancreatic cancer and non-small-cell lung carcinoma. However, erlotinib pharmacokinetics (PK) is characterized by significant variability that may affect efficacy and tolerability. The aim of this review is to assess evidence that would justify therapeutic drug monitoring (TDM) and provide key information for the interpretation of erlotinib plasma concentrations. Literature was systematically reviewed to evaluate the standard criteria defining the potential clinical usefulness of TDM. Assessment was focused on the existence of unpredictable and wide PK variability and of consistent PK-pharmacodynamic relationships. PK parameters actually show marked variability (apparent clearance estimated to 4.85 ± 4.71 L/h, elimination half-life to 21.86 ± 28.35 hours, and apparent volume of distribution to 208 ± 133 L). Many covariates influence these parameters (CYP3A4 inducers or inhibitors, food, age, liver impairment), but most sources of variability still have to be identified. Some studies have demonstrated a relationship between exposure to erlotinib and clinical outcomes or skin toxicity. Erlotinib activity and target concentrations furthermore depend on tumor characteristics (eg, mutations on epidermal growth factor receptor and on K-ras). These results are in favor of TDM in addition to treatment adjustment for tumor biomarkers, but prospective clinical trials validating its clinical benefits are lacking. This review provides all the relevant information available to assist clinical interpretation of erlotinib plasma measurements. PK percentile curves and consideration to covariates yield information on whether a concentration measured is expected, whereas half maximal inhibitory concentration values determined in vitro provide preliminary insights on target concentration values to reach. Eventually, dosage adaptation might be considered in patients with intolerable toxicity because of excessive plasma levels or conversely nonresponse imputable to insufficient exposure.

Pharmacokinetic properties of two erlotinib 150 mg formulations with a genetic effect evaluation in healthy Korean subjects.

Erlotinib is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor that acts on the epidermal growth factor receptor and inhibits cell proliferation, growth, migration, invasion and survival. This study was performed for the subsequent marketing of a test erlotinib formulation in Korea. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy adult volunteers. A total of 46 healthy male subjects were enrolled in a single-dose, randomized, open-label, two-period, two-sequence, crossover, bioequivalence study. During each treatment period, subjects received 150 mg of erlotinib in either the test or reference formulation. There was a 2-week washout period between each period. Blood samples were obtained 15 times during each period, before dosing and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72 and 96 h after oral administration. Plasma concentrations of erlotinib were determined using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (C(max)), area under the plasma concentration-time curve to the last sampling time (AUC(t)), AUC from time zero to infinity (AUC(∞)), and time to reach C(max) (t(max)), were measured, and all treatment-emergent adverse events and their relationships with the study medications were recorded throughout the study. An additional analysis was performed to characterize the association between the cytochrome P450 (CYP) 1A1, CYP1A2 and CYP3A4 genotypes and the erlotinib pharmacokinetic parameters. A total of 41 subjects completed the study. There were no significant differences in the prevalence of adverse events between the two formulations, and there were no serious or unexpected adverse events during the study. Both formulations had very similar C(max), AUC, terminal half-life (t ½) and t(max) values. The 90% confidence intervals of the geometric least-squares mean ratios of the test to reference formulation were 1.09 (0.98-1.22) for C(max) and 1.10 (1.01-1.21) for AUCt. Statistical significance was observed between the CYP1A2*1M genotype and the erlotinib pharmacokinetic parameter, particularly C(max) (p = 0.015). This study suggests that the test and reference formulations of 150 mg erlotinib have similar pharmacokinetic characteristics. Both had no major safety issues and were well-tolerated. The test formulation met the regulatory criteria for assuming bioequivalence to the reference formulation for both AUCt and C max. The additional genetic analysis demonstrated that the major metabolic enzymes of erlotinib did not significantly affect erlotinib metabolism, with the exception of CYP1A2*1M.

Association of Pharmacokinetics or Pharmacogenomics with Toxicity of Erlotinib in Patients with Recurrent Advanced Non-Small Cell Lung Cancer

ABSTRACT Aim: Erlotinib is a potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is a key drug for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutation. The orally administered erlotinib showed large interindividual variability in its pharmacokinetics. The aim of this study was to evaluate the association of pharmacokinetics or pharmacogenomics with toxicity of erlotinib in patients with advanced NSCLC. Methods: The evaluation of pharmacokinetics was performed using samples obtained on day 1 at 0, 1, 2, 4, 6, 8, 24 hour and day 8 and day 15 after starting of erlotinib 150 mg administration. Plasma concentrations of erlotinib were analyzed by high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, ABCC2, CYP3A4, CYP3A5, CYP1A1, and CYP1A2 were analyzed by direct sequencing. Results: From January 2010 through June 2012, 25 patients with advanced NSCLC (18 men and 7 women; median age, 68 years; range, 31 to 80 years) were enrolled. 17 patients had adenocarcinoma, 8 had squamous cell carcinoma, and 1 was other. Four patients were EGFR mutation positive, 14 were negative, and 8 were unknown. There were no statistically significant associations of pharmacokinetics or pharmacogenomics with toxicity, such as skin toxicity, diarrehea, stomatitis, liver injury, and interstitial lung disease (ILD) of erlotinib. However, one patient who died of drug induced ILD was homozygous for ABCG2 C > A and showed the highest AUC. Additionally, Cmax was trending towards a higher value in 4 patients with liver injury than in those without (p = 0.054). Conclusions: The homozygote of ABCG2 C > A could be associated with elevated erlotinib exposure and drug induced ILD. Further studies of the association of pharmacokinetics or pharmacogenomics with toxicity of EGFR tyrosine kinase inhibitor are needed. Disclosure: All authors have declared no conflicts of interest.

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.

Pilot Study Of Erlotinib In Patients With Acute Myeloid Leukemia

BackgoundPreclinical data suggest “off-target” efficacy of EGFR tyrosine kinase inhibitor erlotinib in MDS and AML by inducing apoptosis and promoting differentiation in myeloblasts (Boehrer et al., Blood, 2008). The cytotoxic effect of erlotinib on leukemic myeloblasts ex vivo occurs at concentrations below the plasma levels achievable with regular dosing of this drug. Two case reports, in literature, of patients with concomitant AML and lung cancer, treated with erlotinib and demonstrated AML response, corroborate these findings. The exact targets of erlotinib in MDS/AML are unknown but inhibition of SRC family kinases, Syk, mTOR, and drug efflux system has been suggested. Since normal CD34+ bone marrow cells are not affected by this agent, and no myelosuppression is seen in patients taking erlotinib, clinical application of this drug for the treatment of MDS/AML seems attractive. Clinical studies testing efficacy of erlotinib in MDS are undergoing. We report a pilot study of administration of erlotinib in AML. MethodsThis was a single-institution pilot study. The study was approved by scientific review committee and IRB. All patients signed informed consent. Eligibility included a confirmed diagnosis of AML per WHO classification (>20% blasts), no pre-existing history of MDS, newly diagnosed disease in patients older than 70 or relapsed disease in younger patients unfit for chemotherapy or refractory disease at any age. All cytogenetics and molecular profile categories were eligible. An ECOG performance status of 0-3 was acceptable. WBC count had to be less than 20,000/cumm, and hydroxyurea or other therapies to be discontinued at least 14 days prior to treatment; therefore, patients with high proliferative rate disease were excluded. Smokers were excluded due to potential diminished erlotinib plasma concentration with cigarette smoking. Drugs with potential interaction with erlotinib metabolism were not allowed. Erlotinib was given orally at 150 mg per day continuously in 28-day cycles. Bone marrow at baseline was evaluated for morphology, cytogenetics, flow-cytometry, and molecular profile (FLT3, NPM1, CEBPA mutations). CD34+ cells were separated from bone marrow aspirates taken at baseline, day 3-4, and day 8+1 of treatment, and frozen/banked for future correlative studies. Response was evaluated by bone marrow examination after each cycle. A flow-cytometry was performed on the bone marrow aspirate after the first cycle to be compared with baseline, specifically for evidence of differentiation. Given possibility of “slow/delayed response” with erlotinib, patients were planned to continue at least 3 cycles of treatment in the absence of disease progression or toxicity. Assessment of overall response was the primary endpoint of the study. ResultsBetween August 2010 and August 2012, a total of 11 patients were treated on this study at Indiana University Simon Cancer Center. One patient had relapsed AML, and 1 had relapsed/refractory disease; 9 patients were older than 70 with newly diagnosed AML. Two patients with newly diagnosed AML demonstrated modest response with the first cycle of treatment, with reduction of bone marrow blasts from 89% and 88% to 71% and 73%, respectively, but both experienced disease progression subsequently. Nine other patients had progression of the disease without any response. Of these, 6 completed at least one cycle of treatment, and 3 were taken off study earlier due to disease progression (per peripheral blood blast count) and clinical deterioration. None of the patients with circulating blasts showed meaningful response by total WBC or absolute peripheral blood blast count. Flow-cytometry of bone marrow aspirate following the first cycle compared to pre-treatment sample did not show evidence of differentiation in any of the 8 patients who completed at least one cycle of therapy. None of the patients experienced drug-related toxicity. ConclusionThis pilot study, which enrolled mostly older AML patients with newly diagnosed disease, did not demonstrate clinical response to erlotinib monotherapy when administered continuously at 150 mg per day. No evidence of differentiation was observed in AML blasts after 4 weeks of therapy. The treatment was well tolerated without drug-related adverse events. Disclosures:No relevant conflicts of interest to declare.

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

Erlotinib is used to treat non-small-cell lung cancer (NSCLC), which targets epidermal growth factor receptor (EGFR) tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR (pEGFR) levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model. Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib (4, 12.5, or 50 mg/kg). Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration. The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays. The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC50 value of 1.80 μg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a Kbio value of 0.507 cm(3)/week, which described the impact of pEGFR degradation on tumor growth. The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.

Tumor, skin, and plasma concentrations of protein kinase inhibitors (PKIs) in patients with advanced cancer.

11087 Background: PKIs are selective for target receptors at low concentrations, but they act promiscuously at higher concentrations (PMID 18183025). This lack of selectivity may be relevant for their antitumor activity and for the development of PKI treatment selection tools. To obtain more insight in their clinical mechanism of action, we designed a pilot study to determine PKI tumor, skin and plasma concentrations in patients (pts) after 2 weeks of treatment. Results are related to cell line sensitivity data. Methods: Prior to standard palliative systemic treatment, pts were allocated to standard-dose PKI treatment (N=5 per PKI) for 10-14 days. Plasma, tumor and skin biopsies were collected within 24 hours of last dose. Sample PKI concentrations were determined by liquid chromatography – tandem mass spectrometry (LC-MS/MS); tissue concentrations in pg/mg were converted to molarity for comparison with preclinical sensitivity data (PMID 21980135). Concentrations of sunitinib (SUN), sorafenib (SOR), erlotinib (ERL), dasatinib (DAS) and everolimus (EVE) that inhibit 50% of cell proliferation (IC50) were determined by MTT assay in 1 RCC (786-O) and 8 CRC cell lines (HCT 116, HT-29, RKO, SW480, SW1398, DLD-1, COLO 205, CaCo-2). Results: Since August 2011 samples were obtained from 27 pts; 5 received SUN, 4 SOR, 4 ERL, 5 DAS and 5 EVE. After 12 ± 1 days of treatment, median tumor concentration (TC) was 9.0 µM (2.3-50.0) (range) for SUN, 8.5 µM (3.7-22.0) for SOR, 5.3 µM (0.9-10.8) for ERL and 2.1 µM (0.2-64.0) for DAS. EVE was measurable in 2 of 5 tumors: 3.5 µM (3.4-3.6). On average, PKI skin concentrations were 2.4-fold lower than TCs. SOR and ERL plasma concentrations (PCs) were in the range of TCs while SUN and DAS PCs were at least 14-fold lower than in tumors. Mean IC50 of the cell line panel was 1.3 µM (0.8-1.4) for SUN, 2.2 µM (1.4-3) for SOR, 8.2 µM (4-11.5) for ERL, 0.06 µM (0.02-1.8) for DAS and 1.2 µM (0.05-11) for EVE. Conclusions: PKI tumor concentrations may vary considerably from plasma concentrations, but are in the IC50 range of cancer cells in vitro. These results are indicative for the inhibitory concentrations of PKIs in patient tumors and should be considered for the development of individualized treatment strategies. Clinical trial information: NCT01636908.

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

Ophthalmic acid in plasma: A possible predictor for elevated risk of erlotinib-induced hepatotoxicity.

e13072 Background: Erlotinib is metabolized by cytochrome P450 enzymes to form a para-hydroxyaniline metabolite that is further metabolized to quinone-imine. Erlotinib is detoxified when it conjugates with sulfate or glucuronide. We recently demonstrated that patients who experienced severe erlotinib-induced hepatotoxicity had higher metabolic ratios of glucuronides than those who developed moderate toxicity; this finding indicates that glucuronidation could be saturated and high levels of reactive metabolites might be trigger of glutathione (GSH) depletion. Ophthalmic acid (OA), which is an analog of GSH, may be a useful biomarker for hepatotoxicity because it is a sensitive indicator of GSH depletion in animal model. GSH acts as an enzyme-catalyzed antioxidant when cells and organisms experience electrophilic stress that arises from metabolic processes. Here, we examined the association between plasma concentration of OA and hepatotoxicity in patients who were treated with erlotinib in Japanese patients. Methods: We assessed data from 26 patients with NSCLC who each received a 150 mg dose of erlotinib. Plasma concentrations of OA and erlotinib were measured at before treatment using the liquid chromatography-quadrupole mass spectrometer system. Results: All 26 patients experienced one or more erlotinib-induced adverse events. The most frequent erlotinib-induced adverse events were mild to moderate skin rashes and diarrhea. There seemed to be a relationship between the plasma concentration of erlotinib and the grades of skin rashes and diarrhea. Interestingly, OA was detected only in one patient who developed grade 4 hepatotoxicity, indicating that this patient, who had a higher level of OA (36.9 ng/mL) in plasma. In contrast, the other 25 patients, who did not develop hepatotoxicity, had no detectable OA in plasma. Thus, the plasma concentration of OA was not related to the plasma concentration of erlotinib nor to the grade of skin rash. Conclusions: OA might be useful as a predictive biomarker of hepatotoxicity if measured before starting erlotinib treatment. Larger studies are needed to investigate the association between OA levels and the development of severe hepatotoxicity.