Plasma Concentrations Of Gefitinib Research Articles

P8‐58: Association between proton‐pump inhibitors and the ABCG2 C421A polymorphism and plasma concentration of gefitinib

P8‐58: Association between proton‐pump inhibitors and the ABCG2 C421A polymorphism and plasma concentration of gefitinib

Effect of Single-Dose and Short-Term Administration of Si Jun Zi Tang on the Pharmacokinetics of Gefitinib in Rats.

Background Si Jun Zi Tang (SJZ), a four-herb Chinese medicine formula that has been described for approximately one thousand years, is often prescribed for cancer patients as a complementary therapy in China. However, the mechanism by which Si Jun Zi Tang enhances the efficacy of gefitinib is unclear. Methods We investigated how Si Jun Zi Tang affected the pharmacokinetics of gefitinib in rats. A rapid, specific, and reliable ultra-performance liquid chromatography method with mass spectrometry was established to determine the plasma concentration of gefitinib. Results The results showed that a single intragastrically administered dose of Si Jun Zi Tang increased the pharmacokinetic parameters of gefitinib (Cmax, 3156.13 μg/L; A UC, 46281.5 μg/L/h) by 3 folds in rats compared with the administration of gefitinib alone (Cmax, 1352.07 μg/L; AUC, 11823.7 μg/L/h). Si Jun Zi Tang could also alter the pharmacokinetics of gefitinib by prolonging the time to reach Cmax. Conclusions Potential pharmacokinetic interactions between gefitinib and SJZ were evaluated, and SJZ extended Tmax and T1/2 and increased the Cmax and AUC of gefitinib. Long-term administration of gefitinib in combination with Si Jun Zi Tang would improve the efficacy of gefitinib.

ABCG2 C421A polymorphisms affect exposure of the epidermal growth factor receptor inhibitor gefitinib.

ATP-binding castle protein G2 (ABCG2) is thought to inhibit the activities of certain gefitinib transporters, thereby affecting drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on the cell membrane. Previous studies have shown that proton-pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. In total, 61 patients with advanced epidermal-growth-factor-positive non-small-cell lung cancer were enrolled in this study. They were treated with gefitinib at a dose of 250mg per day. Plasma gefitinib concentration and ABCG2 C421A status were determined after 2weeks. The patients were divided into CC- and CA/AA genotype groups. We compared the trough and peak gefitinib levels and the area under the curve (AUC) values for 24-h gefitinib concentrations. We also compared these parameters among four groups distinguished according to the presence or absence of the polymorphism and PPI use. The mean trough gefitinib level and AUC value for 24-h gefitinib concentration were significantly lower in the CA/AA group compared to the CC group (mean trough level: 333.2 vs. 454.5ng/mL, respectively, P = 0.021; AUC: 9949.9 vs. 13,085.4ng・h/mL, respectively, P = 0.034). Among patients taking PPIs, the mean trough gefitinib level was significantly lower in the CA/AA group than the CC group (220.1 vs. 340.5ng/mL, respectively, P = 0.033). The CA/AA-type of ABCG2 C421A polymorphism may be associated with lower gefitinib plasma concentrations.

Effects of STAT3 polymorphisms and pharmacokinetics on the clinical outcomes of gefitinib treatment in patients with EGFR-mutation positive non-small cell lung cancer.

We investigated the correlations among signal transducer and activator of transcription 3 (STAT3) rs4796793C >G polymorphism, gefitinib pharmacokinetics and clinical responses in Japanese patients with non-small cell lung cancer receiving gefitinib therapy. Forty-five patients were enrolled in this study. Plasma trough concentrations (C0 ) of gefitinib at the steady-state were measured by high-performance liquid chromatography. Patients having a gefitinib C0 of at least ≥200ng/mL had significantly longer PFS than patients having a C0 of <200ng/mL (median [95% confidence interval (CI)] PFS: 11.0 [8.2-13.7] and 5.3 [0.0-12.0] months, respectively, P=.042). There were no significant differences in PFS between patients with STAT3 rs4796793C/C and G alleles; however, patients with STAT3 rs4796793C/C having a gefitinib C0 of ≥200ng/mL had significantly longer progression-free survival (PFS) and overall survival (OS) than those with a C0 of <200ng/mL (median [95% CI] PFS: 11.4 [4.1-18.6] and 3.0 [0.0-7.0] months, respectively, P=.008; median [95% CI] OS: 20.6 [7.4-33.7] and 12.6 [10.1-15.1] months, respectively, P=.042). In patients with the STAT3 rs4796793G allele, there were no significant differences in PFS and OS between the two gefitinib C0 groups. In addition, there were no significant differences in PFS or OS according to smoking, presence of proton pump inhibitor combination, or onset of side effects. Clinical outcomes of gefitinib in patients with the STAT3 rs4796793C/C genotype depended on plasma concentrations of gefitinib. In addition to information regarding EGFR mutations, the STAT3 rs4796793C >G polymorphism and gefitinib C0 may be potential predictors of clinical outcomes after beginning of gefitinib therapy.

Marsdenia tenacissima extract promotes gefitinib accumulation in tumor tissues of lung cancer xenograft mice via inhibiting ABCG2 activity

Ethnopharmacological relevanceMarsdenia tenacissima extract (MTE) is the water-soluble part of a traditional Chinese medicine Marsdenia tenacissima (Roxb.) Wight & Arn, and is commercially available in China for treating cancers. MTE has been revealed to be effective in improving gefitinib efficacy in treating non-small cell lung cancer (NSCLC). However, the mechanisms remain to be defined. Aim of the studyTo determine the effects of MTE on gefitinib metabolism and accumulation in vivo, and to explore the underlying mechanisms. Materials and methodsMTE or vehicle were intraperitoneally administrated to the H1975 xenograft model, followed by intragastric administration of gefitinib 12 h later. Mice plasma, tumors and liver tissues were harvested for further analysis. Hoechst 33342, a specific substrate of ATP Binding Cassette Subfamily G Member 2 (ABCG2), was used to determine the effects of MTE on activities of ABCG2 in tumor cells. ResultsA higher concentration of plasma gefitinib was detected in MTE-treated mice at 24 h after delivery of gefitinib, however, it became insignificant in another 24 h. By contrast, gefitinib levels were continuously higher in MTE-pretreated mice tumor tissues at 12–48 h post gefitinib administration. MTE suppressed plasma levels of gefitinib metabolites (M523595, M608236 and M537194) in the first 24 h after gefitinib delivery, and inhibited activities of liver CYP2D6 and CYP3A4 at early stage (within 6 h) after gefitinib treatment. Strikingly, the activities of ABCG2, the primary drug transporter for gefitinib, were significantly inhibited by MTE in H1975 lung cancer cells. Further, it was identified that tenacissoside H, but not tenacissoside I, may contribute to the ABCG2-suppressive effects of MTE. ConclusionsMTE pretreatment temporarily elevated plasma concentrations of gefitinib via inhibiting CYP450 enzymes. Most importantly, MTE promoted gefitinib accumulation in tumor tissues in a long-lasting manner via decreasing activities of ABCG2, a drug transporter responsible for gefitinib efflux.

Gefitinib exposure and occurrence of interstitial lung disease in Japanese patients with non-small-cell lung cancer

PurposeA prospective, multicenter, large-scale cohort with a nested case–control study (NCT00252759) was conducted to identify and quantify risk factors for interstitial lung disease (ILD) in Japanese patients with non-small-cell lung cancer who received gefitinib. This study reports the association between gefitinib exposure and the occurrence of ILD.MethodsA total of 1891 gefitinib plasma concentrations from 336 patients were measured after first dose, at steady state, and at time of ILD occurrence. Influences of demographic and pathophysiological factors on pharmacokinetics were investigated by non-linear mixed-effect modeling. The exposure to gefitinib was compared between patients without and with ILD occurrence to explore risks associated with gefitinib-induced ILD. Intra-patient comparison of exposure was also conducted between times at ILD development and normal states.ResultsIn the population pharmacokinetic analysis for gefitinib, α1-acid glycoprotein (AGP), age, body weight, and concomitant use of cytochrome P450 3A4 inducers were significant covariates on oral clearance (CL/F). AGP and body weight were also identified as factors affecting the volume of distribution. CL/F was significantly lower at the time of ILD occurrence than normal states. Patients who developed ILD tended to show higher exposure to gefitinib than those without ILD; however, these differences were not statistically significant. On the other hand, exposure at the time of ILD occurrence was significantly elevated compared to the time of normal state within the same patients.ConclusionsSignificant elevation of exposure of gefitinib was observed at the time of ILD occurrence, suggesting reduction of CL/F could be associated with ILD-induced AGP elevation. Increase in exposure of gefitinib is unlikely to be a robust predictor of ILD and does not warrant any dose modifications.

Alterations of Gefitinib Pharmacokinetics by Co-administration of Herbal Medications in Rats.

To evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib (Iressa®) and the oriental medications Guipi Decoction (, GPD, Guibi-tang in Korean) and Bawu Decoction (, BWD, Palmul-tang in Korean). Methylcellulose (MC, control), GPD (1,200 mg/kg), or BWD (6,000 mg/kg) was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefitinib (10 mg/kg) was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments. To examine the effects of the multiple doses of the herbal medicines, gefitinib (10 mg/kg) was orally administered following 7 consecutive days of the administration of MC or each herbal medicine. The plasma concentrations of gefitinib were determined with liquid chromatography-tandem mass spectrometry assay. The plasma concentration-time profiles of gefitinib were analyzed with a noncompartmental analysis. Gefitinib was rapidly absorbed and showed a monoexponential decline with an elimination half-life of 3.7-4.1 h. The pharmacokinetics of gefitinib was not affected by GPD pretreatment. However, a significantly lower maximum plasma concentration (Cmax, P<0.05) and area under the curve (P<0.05), and a delayed time to reach Cmax (Tmax, P<0.01) were observed in both single- and multipledose BWD-pretreated rats compared with the control rats. BWD and not GPD might delay and interfere with gefitinib absorption. Further evaluations of the clinical significance of these findings are needed.

Relationship between gastric pH and plasma concentrations of gefitinib, erlotinib and osimertinib after oral administrations in rat

Back ground: Gefitinib (Gef), erlotinib (Erl) and osimertinib (Osi), the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), are recommended as a first-line therapy for non-squamous lung cancer harboring EGFR mutations. Although drug interactions between EGFR-TKIs and gastric acid-suppressing medications are considered clinically significant, there is limited data regarding the influence of various gastric pH conditions on the pharmacokinetics of EGFR-TKIs. The aim of this study were to clarify the relationship between gastric pH and plasma concentrations of the EGFR-TKIs after oral administrations. We evaluated the pharmacokinetics of Gef, Erl and Osi in rats, due to the changes in gastric pH after administration of omeprazole (Ome) or vonoprazan (Von).

Effects of Histamine 2-receptor Antagonists and Proton Pump Inhibitors on the Pharmacokinetics of Gefitinib in Patients With Non–small-cell Lung Cancer

IntroductionIn this study, we investigated the degree of drug interactions between gefitinib and gastric acid suppressants (ie, histamine 2-receptor antagonists [H2RAs] or proton pump inhibitors [PPIs]) with a clinical standard dose in Japanese patients with non–small-cell lung cancer. MethodsRetrospectively, 47 patients were divided into 3 groups: gefitinib therapy with a PPI (15 patients) or an H2RA (8 patients) or gefitinib therapy alone (24 patients). On day 15 after beginning gefitinib therapy (administration at 08:00) with or without H2RA (administration twice daily at 08:00 and 18:30) or PPI (administration once daily at 08:00 or 18:30), whole blood samples were collected just prior to and at 1, 2, 4, 6, 8, 12, and 24 hours after administration. ResultsThe total area under the observed plasma concentration-time curve (AUC0-24) and the maximum and trough plasma concentrations of gefitinib with the PPI were significantly lower than those without the PPI. The AUC0-24 of gefitinib with PPI administration in either the morning or evening were significantly lower than those without PPI administration (P = .015 and .049, respectively); however, there were no significant differences in gefitinib AUC0-24 between patients taking PPI in the morning and evening. No significant differences were observed in gefitinib exposure among the 3 CYP2C19 genotypes. The AUC0-24 of gefitinib with H2RA tended to be lower than that without H2RA. ConclusionIf the plasma concentrations of gefitinib cannot be monitored, the combination of gefitinib and PPI should be avoided, and an H2RA should also be used carefully.

Low plasma concentration of gefitinib in patients with EGFR exon 21 L858R point mutations shortens progression-free survival.

The relationship between the pharmacokinetics and effects of gefitinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is unknown. In this study, we examined the correlation between gefitinib plasma concentration and progression-free survival (PFS) in patients with two common types of EGFR mutations: a deletion in exon 19 and point mutations in exon 21 L858R. The retrospective analysis examined 40 patients who were administered 250mg of gefitinib daily. All patients were diagnosed with and treated for advanced non-small cell lung carcinoma with sensitive EGFR mutations between January 2011 and November 2013 at Akita University Hospital, Akita, Japan. The 40 patients were divided into four groups by trough plasma concentration (high or low) and mutation type (exon 19 deletions or exon 21 L858R point mutations). PFS, response rate, and toxic effects were analyzed in all four groups. After excluding 5 patients, the remaining 35 were successfully analyzed. For the patients with exon 19 deletions, there was no significant difference in PFS between the high and low plasma concentration groups (median survival: 12.0 vs. 17.0months, P = 0.9548). In contrast, the PFS was significantly shorter for patients with exon 21 point mutations and low vs. high concentrations of gefitinib (median survival: 8.0 vs. 16.0months, P < 0.05). The results suggest that low gefitinib plasma concentrations in patients with exon 21 L858R point mutations may be associated with shorter PFS in NSCLC patients.

Effects of polymorphisms in CYP2D6 and ABC transporters and side effects induced by gefitinib on the pharmacokinetics of the gefitinib metabolite, O-desmethyl gefitinib.

We investigated the effects of polymorphisms in CYP2D6, ABCB1, and ABCG2 and the side effects induced by gefitinib on the pharmacokinetics of O-desmethyl gefitinib, the active metabolite of gefitinib. On day 14 after beginning therapy with gefitinib, plasma concentrations of gefitinib and O-desmethyl gefitinib were measured. Patients were grouped into three groups according to their combination of CYP2D6 alleles: homozygous extensive metabolisers (EMs; *1/*1, *1/*2, and *2/*2; n=13), heterozygous EMs (*1/*5, *2/*5, *1/*10, and *2/*10; n=18), and intermediate metabolisers (IMs; *5/*10 and *10/*10; n=5). The median AUC0-24 of O-desmethyl gefitinib in CYP2D6 IMs was 1460ngh/mL, whereas that in homozygous EMs was 12,523ngh/mL (P=0.021 in univariate analysis). The median AUC ratio of O-desmethyl gefitinib to gefitinib differed among homozygous EMs, heterozygous EMs, and IMs at a ratio of 1.41:0.86:0.24 (P=0.030). On the other hand, there were no significant differences in the AUC0-24 of O-desmethyl gefitinib between ABCB1 and ABCG2 genotypes. In a multivariate analysis, CYP2D6 homozygous EMs (P=0.012) were predictive for a higher AUC0-24 of O-desmethyl gefitinib. The side effects of diarrhoea, skin rash, and hepatotoxicity induced by gefitinib were unrelated to the AUC0-24 of O-desmethyl gefitinib. CYP2D6 polymorphisms were associated with the formation of O-desmethyl gefitinib from gefitinib. In CYP2D6 homozygous EMs, the plasma concentrations of O-desmethyl gefitinib were higher over 24h after taking gefitinib than those of the parent compound; however, side effects induced by gefitinib were unrelated to O-desmethyl gefitinib exposure.

Association of pharmacokinetics and pharmacogenomics with safety and efficacy of gefitinib in patients with EGFR mutation positive advanced non-small cell lung cancer

ObjectivesGefitinib is a potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is a key drug for patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). The pharmacokinetics of orally administered gefitinib varies greatly among patients. We prospectively evaluated the association of pharmacokinetics and pharmacogenomics with the safety and efficacy of gefitinib in patients with EGFR mutation-positive advanced NSCLC. Patients and methodsPharmacokinetics was evaluated with samples of peripheral blood obtained on day 1 before treatment and 1, 3, 5, 8, and 24h after gefitinib (250mg per day) was administered and on days 8 and 15 as the trough values. The plasma concentration of gefitinib was analyzed with high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, CYP3A4, CYP3A5, and CYP2D6 genes were analyzed with direct sequencing. ResultsThe subjects were 35 patients (21 women; median age, 72 years; range, 53 to 90 years) with stage IV adenocarcinoma harboring EGFR mutations. The median peak plasma concentration (Cmax) was 377 (range, 168–781)ng/mL. The median area under the curve (AUC) of the plasma concentration of gefitinib from 0 to 24h was 4893 (range, 698–13991) ng/mLh. The common adverse events were skin toxicity (68% of patients), diarrhea (46%), and liver injury (63%). One patient died of drug-induced interstitial lung disease (ILD). The overall response rate was 82.9% (95% confidence interval, 66.4%–93.4%). The median progression-free survival time was 10 months, and the median survival time was 25 months. The pharmacokinetics and pharmacogenomics were not associated with significantly different toxicities, response rates, or survival times with gefitinib. However, the AUC and Cmax were highest and the trough value on day 8 was the second highest in one patient who died of drug-induced ILD. ConclusionElevated gefitinib exposure might be associated with drug-induced ILD.

Relationship Among Gefitinib Exposure, Polymorphisms of Its Metabolizing Enzymes and Transporters, and Side Effects in Japanese Patients With Non–Small-Cell Lung Cancer

IntroductionThe present study investigated the effects of patients' genetic variations in the pharmacokinetics of gefitinib at steady-state. We analyzed 31 Japanese patients with non–small-cell lung cancer (NSCLC) who had been treated with gefitinib. We focused on common polymorphisms within important gefitinib exposure genes, including cytochromes P450 (CYPs) CYP3A4*1G, CYP3A5 (*3), and CYP2D6 (*5 and *10) and ATP-binding cassette (ABC) ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T). Materials and MethodsFourteen days after beginning 250 mg of gefitinib therapy, when the patients were in steady-state, blood samples were collected just before and 1, 2, 4, 6, 8, 12, and 24 hours after oral gefitinib administration. The plasma concentrations of gefitinib were measured using high-performance liquid chromatography. ResultsThe median area under the concentration-time curve from 0 to 24 hours (AUC0-24) and trough plasma concentration (C0) of gefitinib was 10,086 ng·h/mL (range, 3247-24,726 ng·h/mL) and 334 ng/mL (range, 77.9-813 ng/mL), respectively. No significant differences were found in the AUC0-24 or C0 for gefitinib or in the frequency of diarrhea, skin rash or hepatotoxicity among the CYP3A4, CYP3A5, CYP2D6, ABCG2 (421C>A), and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genotype groups. However, the AUC0-24 and C0 levels of gefitinib in the patients with diarrhea or hepatotoxicity were significantly greater than in those without (diarrhea: AUC0-24, 14,246 vs. 8918 ng·h/mL, P = .006; C0: 421 vs. 261 ng/mL, P = .002; hepatotoxicity: AUC0-24, 12,967 vs. 8473 ng·h/mL, P = .024; C0: 420 vs. 248 ng/mL, P = .002). ConclusionThe side effects from gefitinib were related to exposure but not genetic polymorphism. Therefore, therapeutic drug monitoring after beginning gefitinib therapy rather than the analysis of polymorphism before initiating therapy might be beneficial.

Pharmacogenetic determinants of gefitinib trough concentration in patients with non-small cell lung cancer.

e13533 Background: Some studies postulated that the plasma concentration of gefitinib may have great influence on its efficacy; meanwhile, it is well-known that polymorphisms in metabolic enzymes a...

Phase I and pharmacokinetic study of bexarotene in combination with gefitinib in the third-line treatment of non-small-cell lung cancer

Gefitinib (an epidermal growth factor receptor tyrosine kinase inhibitor) and bexarotene (a rexinoid) affect similar oncogenic pathways and are both metabolized through cytochrome P450 CYP3A4. We studied the combination of bexarotene and gefitinib in the third-line treatment of advanced non-small-cell lung cancer to examine pharmacokinetic interactions and establish the maximum tolerated dose. This was a single-institution, nonrandomized, open-label, phase I clinical trial with a standard 3+3 dose escalation. Three patients were enrolled at each dose level on the basis of pharmacokinetic analysis with dose level 1 including gefitinib (Iressa) 250 mg oral daily and bexarotene (Targretin) 400 mg/m oral daily and dose level +1 including gefitinib 500 mg oral daily and bexarotene 400 mg/m oral daily. Patients received gefitinib alone for 2 weeks to allow for steady state and thereafter, bexarotene was added. In dose level 1, two of three patients had undetectable gefitinib levels at day 15 for unknown reasons. However, the peak levels on day 29 for all three patients receiving 250 mg of gefitinib with bexarotene are lower than published peak levels. Among the three patients in dose level +1, ∼40% lower gefitinib plasma concentrations were noted on day 29 compared with day 15 along with a mean 44% reduction in area under the plasma concentration-time curve from 0 to 24 h (AUC0-24). Bexarotene appears to lower the C max and AUC0-24 of gefitinib through cytochrome P450 CYP3A4. Our results have pharmacokinetic implications for ongoing trials that combine bexarotene with other small molecules in the era of personalized cancer therapy.

Pharmacokinetics of Gefitinib Predicts Antitumor Activity for Advanced Non-small Cell Lung Cancer

We assessed the relationship between the plasma concentration of gefitinib and its efficacy in Japanese patients with advanced non-small cell lung cancer (NSCLC). Plasma trough levels of gefitinib were measured on days 3 (D3) and 8 (D8) by high-performance liquid chromatography in 44 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status < or =3, age < or = 80 years, and stages IIIB-IV cancer. Epidermal growth factor receptor mutations in 23 patients were analyzed retrospectively. The median plasma gefitinib values were 662 ng/ml on D3 and 1064 ng/ml on D8, and the D8/D3 ratio was 1.587. The median progression-free survival (PFS) was 71 days, and the median overall survival was 224 days. Adenocarcinoma, never smoking, and high D8/D3 ratio were associated with better PFS. Multivariate analysis showed that PFS was associated with never smoking and high D8/D3 ratio. Never-smokers with a high D8/D3 ratio showed the best PFS. Overall survival was not associated with the D8/D3 ratio. Epidermal growth factor receptor mutation analysis of 23 patients showed that 15 patients had exon 19 deletion and/or exon 21 point mutation. Median PFS was similar between mutation-positive and mutation-negative individuals in the high D8/D3 group, whereas mutation-negative individuals in the low D8/D3 group showed the worst median PFS. A high D8/D3 ratio was independently associated with better PFS in patients with NSCLC treated with gefitinib. Our findings suggest that the pharmacokinetics of gefitinib may be involved in its antitumor activity.

The relationship between drug exposure and clinical outcomes of non-small cell lung cancer patients treated with gefitinib

The objective of this study was to explore the relationship between gefitinib exposure and clinical outcome in gefitinib-treated patients with advanced non-small cell lung cancer. Thirty patients participated in this pharmacokinetic study and received 250-mg oral doses of gefitinib once daily. Blood samples were collected before dosing and on days 7, 14, 21, and 28. The plasma concentrations of gefitinib were evaluated using a validated high-performance liquid chromatographic method with tandem mass spectrometric detection. Univariate and multivariate analyses were performed to determine predictive factors for response and survival of patients. EGFR mutations were analyzed retrospectively. Median survival time (MST) was 9.97 months (95%CI 2.79-17.14 months). The geometric mean trough gefitinib plasma concentration (Cminss was 266 ng/ml (range 94-538 ng/ml). In the multivariate analysis, only skin rash was associated with gefitinib-induced disease control (P=0.017); Adenocarcinoma, skin rash, and 'high' Cminss (Cminss≥200 ng/ml) were independently associated with overall survival (P=0.004, 0.028,0.007, respectively). MST of EGFR wild-type patients with 'high' Cminsswas longer than that with 'low' Cminss (P=0.002). Our study results show that pharmacokinetic variability may also account for the different outcomes following treatment with gefitinib for patients with wild-type EGFR. Further studies are needed to confirm these results.

Functional characterization of gefitinib uptake in non-small cell lung cancer cell lines

Gefitinib, an inhibitor of epidermal growth factor receptor tyrosine kinase, has been developed and approved for treatment of advanced non-small cell lung cancer (NSCLC). In this study, we investigated the uptake of gefitinib in gefitinib-sensitive and -resistant NSCLC cell lines. The transport system was temperature-dependent, indicative of an active process and sodium- and potential-independent. Moreover, high cell densities and low extracellular pH significantly reduced the uptake of gefitinib. Inhibitors of the human organic cation transporter 1 (hOCT1) significantly decreased gefitinib uptake; however, gefitinib was not a substrate for hOCT1 or hOCT2 in overexpressing HEK293 cells. Interestingly, gefitinib significantly reduced uptake of the hOCT prototypical substrate MPP suggesting that gefitinib may exert an inhibitory effect on the intracellular accumulation of drugs transported by hOCT1 and hOCT2. After 15 min of treatment at 1 μM (the maximum plasma concentration of gefitinib obtained at the clinically relevant dose) gefitinib accumulated within the cell in resistant-cell lines at concentrations similar or even higher than in gefitinib-sensitive cells tending to rule out an alteration in drug uptake as a mechanism of resistance to gefitinib treatment. Moreover, our results suggest that the extrusion of lactate by crowded cells may contribute in decreasing the pH, which in turn can influence the uptake of gefinitib and as a result the inhibition of EGFR autophosphorylation.

Gefitinib–phenytoin interaction is not correlated with the 14C‐erythromycin breath test in healthy male volunteers

We aimed to describe the pharmacokinetic interaction between phenytoin, a potent CYP3A4 and P-glycoprotein (P-gp) (ABCB1) inducer, and gefitinib, a CYP3A4, CYP2D6 and P-gp substrate. An open-label, randomized, two-phase crossover study was conducted. Eighteen healthy male volunteers (nine homozygous CC and nine homozygous TT as determined by their ABCB1 C3435T polymorphism in exon 26) received a single oral dose of 250 mg gefitinib alone or after 5 days treatment with phenytoin (5 mg kg(-1) daily). Gefitinib plasma concentrations were determined by high-performance liquid chromatography. Hepatic CYP3A4 activity was evaluated by the (14)C-erythromycin breath test (ERMBT) and the ABCB1 and CYP2D6 genetic polymorphisms were determined by the TaqMan allelic discrimination assay and long polymerase chain reaction, respectively. Following treatment with phenytoin, mean gefitinib C(max) and AUC(0-infinity) decreased by 26 +/- 44% [95% confidence interval (CI) for the difference 5-48%, P= 0.005] and 47 +/- 26% (95% CI for the difference 34-60%, P= 0.001), respectively, and apparent oral clearance increased by 126 +/- 93% (95% CI for the difference 80-172%, P= 0.004). Concomitantly, phenytoin increased the mean ERMBT by 91 +/- 44% (95% CI 75-105%, P < 0.001) from baseline, but the extent of liver CYP3A4 induction was not correlated to the extent of interaction. Furthermore, this interaction was independent of ABCB1 genetic polymorphism. The CYP2D6 genotype was slightly but significantly related to gefitinib clearance (P= 0.04) during the control phase. The significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent of ABCB1 polymorphism, but may involve presystemic CYP3A-mediated intestinal first-pass.

The relative bioavailability of gefitinib administered by granular formulation

Gefitinib (IRESSA) is normally administered as a once-daily oral tablet. However, many patients with head and neck cancer have difficulty swallowing medication in a tablet form. A granular formulation has recently been developed to facilitate the administration of gefitinib to patients who are unable to swallow tablets. The aims of this study were to determine the relative bioavailability of a single dose of gefitinib when administered as 250 mg of a new granular formulation compared with the standard 250 mg tablet, and to assess the intra-subject variability of the granular formulation, in healthy subjects. This was a randomized, open-label, three-period crossover study. Healthy male subjects (n = 18) received either a single gefitinib 250 mg tablet (once), or a 250 mg granular formulation of gefitinib (on two separate occasions) over the three dosing periods, in randomized order. Plasma concentrations of gefitinib were measured up to 240 h post-dose. The treatment ratio estimates for area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C (max)) for the granular formulation when compared with the tablet were 1.05 (90% confidence intervals [CI] for the ratio 0.97-1.13) and 1.14 (90% CI for the ratio 1.01-1.28), respectively. The estimate for the intra-subject standard deviation for the granular formulation when given on 2 separate occasions was 0.143 for AUC and 0.165 for C (max), equivalent to a 1.4- and 1.7-fold intra-subject variability in AUC and C (max), compared with that observed for the tablet of two and threefold, respectively. There was little difference in exposure to gefitinib administered as the 250 mg granular formulation compared with the 250 mg standard tablet. The granular formulation of gefitinib could provide an alternative treatment regimen for patients unable or unwilling to swallow the standard tablet formulation, without compromizing exposure to gefitinib.