The present study suggested that the ABCB1 1236TT-2677TT-3435TT genotype was associated with higher plasma concentration and the risk of developing higher toxicity in patients treated with erlotinib.

1 The mechanism by which cicletanine (CIC) exerts its antihypertensive eects has not been fully elucidated. The present study was undertaken to examine the eects of in vivo and in vitro treatment with CIC on the pressor response and noradrenaline (NA) over¯ow during periarterial nerve stimulation (PNS) in perfused mesenteric arterial beds isolated from spontaneously hypertensive rats (SHR). 2 CIC at a dose of 50 mg kg 71 day 71 was administered orally to both SHR and normotensive WistarKyoto rats (WKY) from the 6th to 10th week of age. At the 10th week, the isolated mesenteric arterial bed was perfused with Krebs-Henseleit buer and changes in perfusion pressure and NA over¯ow during PNS were measured. 3 Chronic treatment with CIC suppressed the age-related elevation of systemic blood pressure in SHR but not in WKY. 4 The PNS (20 Hz)-induced mesenteric vasoconstrictor response and NA over¯ow were greater in SHR than in WKY. In the vasculature of SHR chronic treatment with CIC resulted in a signi®cant attenuation of the vasoconstriction and the NA over¯ow during PNS, whereas it did not alter vasoconstrictor responses to bolus injections of KCl and phenylephrine. 5 Treatment with 30 mM CIC in vitro diminished the PNS-induced vasoconstriction and NA over¯ow but not the NA-and KCl-induced vasoconstriction in the vasculature of untreated SHR. 6 In the vasculature of SHR PNS-induced NA over¯ow was attenuated by prostaglandin E 2 (0.05 mM), whereas it was augmented by the cyclo-oxygenase inhibitor diclofenac-Na (30 mM). In the presence of diclofenac, in vitro treatment with CIC did not attenuate the NA over¯ow during PNS. 7 The results suggest that the antihypertensive eect of CIC in SHR is partially due to the presynaptic inhibition of NA release during sympathetic nerve activation. Transjunctional inhibition of NA release by prostaglandins may contribute to the inhibitory action of CIC on NA release in the vasculature of SHR.

Erlotinib is an oral available, selective inhibitor of EGFR tyrosine kinase activity for the treatment of patients with NSCLC. Side effects, commonly seen as skin rash and diarrhea, occurred in 75% of patients. About 20% of patients needed erlotinib dose reduction from the standard dose of 150mg/day due to these toxicities. Since the severity of skin rash is strongly associated with improved clinical outcome, skin rash may be a surrogate marker of favorable clinical outcome. Erlotinib is a substrate for ABC transporters such as ABCB1 and ABCG2. However, it is unknown whether these polymorphisms affect the pharmacokinetics of erlotinib and influence the inter-individual variability in erlotinib toxicity. The purpose of this study is to evaluate the effects of ABC transporter polymorphism on erlotinib pharmacokinetics and the development of side effects, skin rash and diarrhea in Japanese patients with NSCLC. Methods: Thirty-one Patients were orally administered 150 mg erlotinib as a single treatment. Plasma levels of erlotinib were measured by high-performance liquid chromatography on days 1(D1), 8(D8), and stable phase. DNA from plasma was screened for SNPs in the ABCB1 and ABCG2 genes using TaqMan assay or direct nucleotide sequencing. Results: The mean Cmax of D1 and D8 were 1.7 and 3.1 µg/ml, respectively. Trough concentration at D1, D8 and steady state were 0.7, 1.2 and 1.4 µg/ml, respectively. Skin rash occurred in 95% of patients. One patient (Cmax, 3.0 µg/ml at D1) developed interstitial lung disease after continuous treatment with erlotinib for 3 days. The Cmax and AUC on D1 was correlated with the severity of skin rash, however, Cmin were not correlated. Patients with homozygous variant for ABCB1 1236C>T, 2677 G>(T/A), and 3435C>T genotype as compared to patients carrying the wild-type and heterozygous were associated with higher AUC and Cmin at D1 (31 vs 21, p=0.07; 1.1 vs 0.6 µg/ml, p=0.007). AGCG2 421C>A genotype were not associated with any pharmacokinetic parameters. ABCB1 polymorphism was associated with decreased ABCB1 function, resulting in the increased concentration of erlotinib. All five patients with homozygous variant for ABCB1 1236TT-2677TT-3435TT developed higher grade 2 toxicity by day 7. Patients homozygous variant for ABCB1 developed toxicity significantly faster than those with at least one T allele (p=0.002). On the other hand, all three patients carrying without T allele had not experience toxicity. Conclusions: The present study suggests that ABCB1 polymorphism affects the pharmacokinetics of erlotinib and also influence the development of erlotinib toxicity. We proposed that prior to the Erlotinib treatment, the measuring of ABCB1 polymorphism may help to identify patients with NSCLC who can develop a severe toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3588.

2506 Background: Erlotinib demonstrates substantial inter-individual differences in response and the development of skin rash (grade≥2) was correlated with efficacy. Erlotinib interacts with its target EGFR and the efflux transporter ABCB1 and ABCG2. EGFR CA repeat is associated with incidence of skin rash. A 421C>A SNP in ABCG2 and 1236C>T, 2677 G>(T/A), and 3435C>T SNPs in ABCB1 are associated with reduced protein expression. The aim of this study was to evaluate the effects of these variants and pharmacokinetics of erlotinib on toxicity grade in Japanese patients treating single agent erlotinib. Methods: Twenty-two patients with NSCLC received erlotinib orally at 150 mg/day and plasma levels of erlotinib were measured on days 1(D1), 8(D8), and stable phase (>day 14) by high-performance liquid chromatography. DNA from plasma was screened for SNPs in the EGFR, ABCB1, and ABCG2 genes using direct nucleotide sequencing or TaqMan assay. Eligibility criteria included: performance status (PS) < 3, age < 75, stage IIIB-IV, and written informed consent. Results: The mean Cmax (±SD) of D1 and D8 were 1.8 ± 1.0 and 3.1 ± 1.4 μg/ml, respectively. Trough concentration (Cmin) at D1 and steady state were 0.9 and 1.7 μg/ml, respectively. Grade 1–2 skin rash or diarrhea occurred in 95% of patients. One patient (Cmax at D1, 3.0 μg/ml) developed interstitial lung disease after continuous treatment with erlotinib for 3 days. The area under curves and Cmax on D1 were correlated with the severity of skin rash (p=0.05 and 0.01), however, Cmin were not correlated. Patients with homozygous variant and heterozygous for ABCB1 1236C>T, 2677 G>(T/A), and 3435C>T genotype as compared to patients carrying the wild-type were associated with higher Cmin at steady state (2.4 vs 1.2 μg/ml, p=0.01). EGFR CA repeat and AGCG2 421C>A genotype were not associated with any pharmacokinetic parameters. All Patients (n=4) with homozygous variant for ABCB1 1236TT- 2677TT/TA/AA-3435TT developed grade≥2 skin rash or diarrhea. Conclusions: The present study suggests that ABCB1 gene polymorphism is associated with the variable toxicity and pharmacokinetics to erlotinib treatment. No significant financial relationships to disclose.