Plasma Concentrations Of Gefitinib Research Articles

Pilot phase II study of preoperative gefitinib in early stage non-small cell lung cancer with assessment of intratumor gefitinib levels and tumor target modulation

7603 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) can provide clinical benefit in advanced non-small cell lung cancer patients. Here we examined the effect of single agent gefitinib in patients with early stage NSCLC with additional assessment of plasma and tumor concentrations of gefitinib. Previous studies have suggested considerably higher tumor concentrations of gefitinib compared to levels identified in blood, yet the results in human lung cancers is unknown. Methods: We conducted a pilot phase II study of a 28 day preoperative course of gefitinib 250 mg PO daily followed by surgical resection for patients with stage IA to selected IIIA non-small cell lung cancer. Response was assessed by RECIST using CT and changes in FDG metabolism were assessed using PET. Tumor penetration of gefitinib was assessed in surgically resected tumor samples along with plasma assessment on day 28. Results: Sixteen patients (7 men, 9 women) completed therapy on protocol and all who started on gefitinib were able to undergo a complete surgical resection. There were 0/16 objective responses (CR/PR), 14/16 SD, and 2/16 PD. Three of the 6 patients had more than 20% reductions in FDG SUVmax assessed by PET scanning. Day 28 plasma concentrations of gefitinib averaged 531 ± 344 nM (range 65 to 1,211 nM) while tumor concentrations of gefitinib averaged 33,108 ± 44,312 nM (range 474 to 134,669 nM). Conclusions: Our results demonstrate that NSCLC tumor penetration of gefitinib is much higher than concentrations found in plasma. Assessment of pharmacodynamic markers including tumor EGFR and downstream signaling pathways is ongoing. PET scanning may be an early marker of clinical benefit of EGFR TKI. No significant financial relationships to disclose.

CYP3A Phenotyping Approach to Predict Systemic Exposure to EGFR Tyrosine Kinase Inhibitors

Gefitinib is an orally active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) with activity in non-small-cell lung cancer. The response to gefitinib is variable, possibly because of interindividual variation in the activity of cytochrome P450 3A (CYP3A), the principal enzyme that metabolizes gefitinib. We prospectively assessed the influence of CYP3A activity on gefitinib disposition and toxicity. Twenty-seven patients with advanced cancer were treated with daily oral gefitinib at 250 mg (n = 13) or 500 mg (n = 14) for 28 days. Concentration-time profiles of midazolam and geftinib were constructed based on measurement of their concentration in serial blood samples using high-performance liquid chromatography and mass spectroscopy. CYP3A activity was determined at baseline by assessment of midazolam apparent oral clearance. Pharmacokinetic studies were performed for a period of 28 days, and population modeling was performed using NONMEM software. A structural pharmacokinetic model was developed to describe the concentration-time profiles of unbound and total gefitinib plasma concentrations, and patient-specific covariates were added to the model to account for unexplained interindividual variability in pharmacokinetic parameters. Statistical tests were two-sided. Gefitinib pharmacokinetics exhibited wide interindividual variability (interindividual variability on total and unbound gefitinib apparent oral clearance was 79% and 74%, respectively). Midazolam clearance (mean = 40 L/h, range = 10-111) was highly correlated with that of total and unbound gefitinib (R2 = .60 and R2 = .68, respectively) and with steady-state plasma trough concentrations of gefitinib (R2 = .58 and R2 = .60, respectively), and it accounted for approximately 40% of interindividual variability in gefitinib clearance in the pharmacokinetic model. Both total and unbound gefitinib steady-state plasma trough concentrations were associated with the development of diarrhea (P<.05), but not skin rash. At a dose of 250 mg gefitinib, 11 of 13 patients achieved steady-state plasma trough concentrations above the IC50 for inhibition of mutant EGFR in vitro (0.015 microM), but only one achieved a steady-state plasma trough concentration above the IC50 for inhibition of wild-type EGFR (0.1 microM). As an in vivo phenotypic probe of CYP3A, midazolam oral clearance may have utility for prediction of gefitinib exposure and dose selection. A pharmacokinetic model incorporating this indicator of CYP3A activity has potential for optimization of treatment with gefitinib and other TK inhibitors that are metabolized in a similar manner.

Pharmacokinetic study of paclitaxel and gefitinib in combination

13123 Background: Both gefitinib and paclitaxel are metabolized by CYP3A4, thus co-administration may result in a pharmacokinetic interaction (Miller V.A. et al. JCO 2003, 21:2094–2100). Paclitaxel is formulated in Cremophor EL (crEL), which also has the potential for pharmacokinetic interactions by either altering protein binding or inhibition of P-glycoprotein transporter systems (Gelderblom H. et al. EJC 2001, 37:1590–1598). Gefitinib is a high extraction ratio drug so changes in protein binding are not a concern, but inhibition of P-glycoprotein transporter systems could change gefitinib’s absorption profile. Methods: In a Phase II study, 17 patients (pts) with metastatic breast cancer received paclitaxel (100 mg/m2 on days 8, 15 q21) with gefitinib (250 mg daily, from day 1 to day 15). Blood samples were collected to measure plasma concentrations of gefitinib on days 7, 8, and 15 from six pts at pre-dose and at 3, 7 and 25 hours after gefitinib administration. The AUC at steady-state (AUCss) was calculated by the linear trapezoidal rule using WinNonlin and the minimum concentration at steady-state (Css, min) was taken directly from the data. Results: The effect of paclitaxel or crEL on the exposure to gefitinib was assessed by comparing the AUCss and Css,min on days 8 and 15 in the presence of paclitaxel to those on day 7 when gefitinib was alone. The geometric mean AUCss increased by 30 to 42% and Css,min by 28 to 58% in the presence of paclitaxel. Individual ratios of days 8 and 15 to day 7 also showed a trend to be greater than 1.0, further indicating an increase in exposure to gefitinib in the presence of paclitaxel. Conclusions: Steady state exposure to gefitinib increased by about 30 to 40% in the presence of paclitaxel. As the increase on day 15 was similar to that on day 8, the effect of paclitaxel appears to be transient, and would be unlikely to affect the safety profile of 250 mg gefitinib when in combination with paclitaxel compared to gefitinib monotherapy. [Table: see text]

Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: in vitro and in cancer patients

Gefitinib exhibits wide inter-subject pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug. Thus it is desirable to determine gefitinib binding in plasma and factors affecting this process. An equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (fu) gefitinib in human plasma. Gefitinib binding in plasma from four different species and isolated protein solutions as well as drug partitioning in human blood cells were investigated. Unbound gefitinib plasma concentrations were measured in 21 cancer patients receiving daily oral gefitinib 250 mg or 500 mg. It was found that gefitinib was extensively bound in human rat mouse and dog plasma with mean fu values of 3.4%, 3.8%, 5.1% and 6.0% respectively. In isolated protein solutions approximately 90% and 78% of gefitinib was bound to human serum albumin (HSA) (40 mg/dL) and alpha1-acid glycoprotein (AAG) (1.4 mg/dL) with binding constants of 1.85 x 10(4) M(-1) and 1.13 x 10(5) M(-1) respectively. In whole blood 2.8% of gefitinib existed as the free drug while 79.4% and 17.8% was bound to plasma proteins and blood cells respectively. In plasma from cancer patients fu at pre-treatment varied 2.4-fold (mean 3.4 +/- 0.6%; range 2.2-5.4%) and fu was constant over the 28-days of treatment (P > 0.05). Pre-treatment AAG concentration was negatively correlated with pre-treatment fu (R2 = 0.28, P = 0.01). In conclusion gefitinib is highly protein bound (approximately 97%) in human plasma. Variable AAG concentrations observed in cancer patients may affect gefitinib fu with implications for inter-subject variation in drug toxicity and response.

Exploring the Relationship Between Expression of Cytochrome P450??Enzymes and Gefitinib Pharmacokinetics

Exposure to gefitinib (IRESSA, ZD1839), an epidermal growth factor receptor-tyrosine kinase inhibitor, is highly variable between subjects. In an attempt to explain this variability, three pharmacokinetic studies were carried out in healthy volunteers to investigate the relationship between exposure to gefitinib and cytochrome P450 (CYP) 3A phenotype (study 1), CYP3A5 genotype (study 2) and CYP2D6 genotype (study 3). In study 1 all 15 healthy volunteers received single oral doses of midazolam (7.5 mg), as a CYP3A probe, and gefitinib (500 mg), separated by an appropriate washout period. Plasma concentrations of midazolam and gefitinib were measured. In study 2, 73 healthy volunteers with previously defined single-dose gefitinib pharmacokinetic profiles were genotyped for CYP3A5. In study 3 a single oral dose of gefitinib (250 mg) was administered to poor and extensive CYP2D6 metabolisers (n = 15 in each group). Plasma concentrations of gefitinib and its major metabolite, M523595, were measured. Plasma concentrations of gefitinib, M523595 and midazolam were measured using high-performance liquid chromatography with tandem mass spectrometric detection, and appropriate pharmacokinetic parameters were determined by non-compartmental methods. Genetic analysis of CYP3A5 (study 2) and CYP2D6 (study 3) alleles was carried out using standard methodology. In study 1 there was some indication of a correlation between the area under the plasma concentration-time curve from time zero to infinity (AUCinfinity) values of midazolam and gefitinib, although this did not reach statistical significance (p = 0.062, regression analysis). In study 2 eight of 73 volunteers (11%) were identified as CYP3A5 expressers. No apparent relationship was observed between the occurrence of the CYP3A5 expresser genotype and gefitinib plasma clearance or terminal elimination halflife. In study 3 M523595 was not detected in any plasma samples collected from poor CYP2D6 metabolisers. Gefitinib geometric mean AUCinfinity and peak plasma drug concentration were higher in poor CYP2D6 metabolisers compared with extensive metabolisers (AUCinfinity 3060 vs 1430 ng . h/mL, p < 0.05, ANOVA), although the range of values was wide with considerable overlap between the groups. Gefitinib was well tolerated in both groups. Individual differences in CYP3A expression do not explain all the interindividual variability in gefitinib exposure. There is no apparent relationship between CYP3A5 genotype and gefitinib clearance. The lack of measurable levels of M523595 in poor CYP2D6 metabolisers confirms that production of this metabolite is mediated by CYP2D6. Although higher exposure to gefitinib occurs in individuals who are poor CYP2D6 metabolisers, genotyping prior to initiation of therapy and dosage adjustment are not warranted.

Minimal contribution of desmethyl-gefitinib, the major human plasma metabolite of gefitinib, to epidermal growth factor receptor (EGFR)-mediated tumour growth inhibition

Desmethyl-gefitinib is a major metabolite of gefitinib observed in human plasma at concentrations similar to those of gefitinib. The epidermal growth factor receptor (EGFR)-related inhibitory effects of gefitinib and desmethyl-gefitinib have been compared both in vitro, using enzyme kinase assays and tumour cell growth inhibition, and in vivo by assessment of tumour xenografts growth inhibition in the mouse. Both gefitinib (IC50 = 0.022 µM) and its desmethyl metabolite (0.036 µM) inhibited subcellular EGFR tyrosine kinase activity with a similar potency and selectivity. However, desmethyl-gefitinib (IC50 = 0.76 µM) was 15 times less active than gefitinib (0.049 µM) against EGF-stimulated KB cell growth in a whole cell assay. Following a preliminary pharmacokinetic study to compare apparent oral bioavailability, gefitinib (75 mg kg−1) and desmethyl-gefitinib (150 mg kg−1) were administered orally for 15 days to female nude mice bearing LoVo tumour xenografts. Tumour concentrations of gefitinib (AUC = 300 µg h g−1) were much higher than those of desmethyl-gefitinib (44.3 µg h g−1), although plasma concentrations of gefitinib (48.4 µg h ml−1) and desmethyl-gefitinib (39.0 µg h ml−1) were quite similar at these dose levels. Gefitinib produced significant tumour growth inhibition throughout the course of the study ultimately resulting in a 50% decrease (compared with controls) by day 15. In contrast, although present at comparable plasma levels, desmethyl-gefitinib had little effect on tumour growth and is, therefore, considered unlikely to contribute significantly to the therapeutic activity of gefitinib in the clinical situation.

Single-Dose Clinical Pharmacokinetic Studies of Gefitinib

The objective of the five clinical studies presented in this article was to investigate the single-dose pharmacokinetics of gefitinib (IRESSA, ZD1839), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in healthy volunteers and patients with advanced cancer. Studies 1 and 3-5 recruited healthy male volunteers aged 18-65 years; study 2 recruited male or female patients aged>or=18 years with any solid malignant tumour expressing EGFR and refractory to standard therapy. Gefitinib administration was as follows: study 1 (bioavailability in healthy volunteers; n=12)--intravenous infusion of 50 or 100 mg followed by a single oral dose of 250 mg; study 2 (bioavailability in cancer patients; n=19)--intravenous infusion of 50 mg followed by a single oral dose of 250 mg; study 3 (intrasubject variability; n=24)--two single oral doses of 250 mg; study 4 (dose-proportionality; n=15)--three single oral doses of 50-500 mg; study 5 (effect of food; n=26)--two single doses of 250 mg under either fed or fasted conditions. In all studies, venous blood samples for determination of gefitinib plasma concentrations were collected at predetermined intervals. Plasma concentrations of gefitinib were measured using liquid-liquid extraction after basification followed by high-performance liquid chromatography with tandem mass spectrometric detection. Appropriate pharmacokinetic parameters were determined by noncompartmental methods. Study 1: Oral bioavailability of a gefitinib 250 mg dose was 57% in healthy volunteers. Absorption was moderately slow, with geometric mean (gmean) peak plasma concentration (Cmax) of 85 ng/mL (range 43.5-110 ng/mL) reached 5 hours following an oral dose of 250 mg. Study 2: Oral bioavailability of a gefitinib 250 mg dose was 59% in patients. Absorption was again moderately slow, with gmean Cmax of 159 ng/mL (range 48.7-324 ng/mL) typically reached 3 hours (range 1-8 hours) following an oral dose of 250 mg. Study 3: Area under the plasma concentration-time curve from time zero to infinity (AUCinfinity) and Cmax were variable--up to 15-fold between subjects and 2-fold within an individual. Study 4: AUCinfinity and Cmax increased with dose across the range of 50-500 mg, and increased dose-proportionally up to 250 mg. Study 5: Small, clinically insignificant increases in AUCinfinity and Cmax were seen in the presence of food (32% and 37%, respectively). The gefitinib 250 mg tablet is orally bioavailable in both healthy volunteers and cancer patients; bioavailability is independent of dose and unaffected by food to any clinically significant extent. Gefitinib undergoes rapid plasma clearance and has an extensive volume of distribution, resulting in a pharmacokinetic profile supportive of a once-daily dosage regimen.

Intratumoral and plasma concentrations of gefitinib in breast cancer patients: Preliminary results from a presurgical investigatory study (BCIRG 103)

581 Background: Gefitinib (‘Iressa’, ZD1839) has a high volume of distribution in animals and humans, with a volume of 1400 L in cancer patients. Consistent with these pharmacokinetic data, gefitinib is extensively distributed into the tissues of rats and mice, with tissue:blood ratios of >10 in a number of organs. Concentrations of gefitinib in mouse subcutaneous tumour xenografts (LoVo: colorectal; A549: non-small-cell lung cancer) are considerably higher (10–15-fold) than plasma. Concentrations of gefitinib have been determined in plasma and breast cancer tissue as a secondary endpoint in a study designed primarily to identify molecular alterations in human breast cancer tissue after short-term exposure of patients to gefitinib. Preliminary concentration data are reported here. Methods: BCIRG 103 is a multicentre, open-label, noncomparative, presurgical study in women with invasive adenocarcinoma of the breast. Patients receive gefitinib (250 mg) once daily for at least 14 days and up to a maximum of 45 days prior to definitive surgery. Blood samples are taken immediately before and 24 h after the final dose of gefitinib. A sample of tumour tissue (100 mg) is taken and immediately snap-frozen during definitive surgery. Plasma and tumour samples were assayed for gefitinib and its major metabolites by high-performance liquid chromatography (HPLC) with mass spectrometric detection. Results: So far, 16 out of 40 patients have been enrolled and samples from 9 patients have been examined. Concentrations of gefitinib in tumour (2.3–25.8 μg/g) were much higher than plasma (0.10–0.42 μg/ml). There was no apparent correlation between tumour and plasma concentrations. Conclusions: The pronounced tumour:plasma ratio (mean 54-fold) was much higher than that from the mouse xenograft model. Gefitinib tumour concentrations will also be compared with the biomarker data as they become available. Data on a larger sample size will be presented. ‘Iressa’ is a trademark of the AstraZeneca group of companies Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca

Intratumoral and plasma concentrations of gefitinib in breast cancer patients: Preliminary results from a presurgical investigatory study (BCIRG 103)

Intratumoral and plasma concentrations of gefitinib in breast cancer patients: Preliminary results from a presurgical investigatory study (BCIRG 103)

Gastric mucosa protection in patients treated with iressa and COX-2 inhibitors in malignancies

Background: Gefitinib (ZD1893, Iressa) is an orally active, selective EGFR tyrosine-kinase inhibitor recently approved for the treatment of non-small cell lung cancer (NSCLC) by the FDA. At present, this drug represents one of the most attractive perspectives for the therapy of advanced stage patients especially with brain metastases, who are not eligible for conventional chemotherapy. Also COX-2 inhibitors have been shown to have inhibitory effect on different types of neoplastic conditions including NSCLC. Drugs that cause significant sustained elevation in gastric pH (>5), may reduce plasma concentrations of gefitinib resulting in reduced efficacy. Therefore, no form of antacids including H2-blockers or PPIs can be recommended.