A Randomized, Open, Single-Centre, Crossed Study of the Effect of Food on the Pharmacokinetics of One Oral Dose of Alflutinib Mesylate Tablets (AST2818) in Healthy Male Subjects

Document Type : Research article

Authors

1 Department of Clinical Pharmaceutical Research Institution, Hunan Cancer Hospital, Affliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410006, China.

2 Department of Early Clinical Trail Center, Hunan Cancer Hospital, Affliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410006, China.

3 Department of Lung Cancer and Gastroenterology, Hunan Cancer Hospital, Affliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410006, China.

Abstract

The aim of the study was to study the PK of AST2818 tablets after one oral dose in healthy
male subjects on an empty stomach and in a postprandial state and to evaluate the effect of food on
AST2818 bioavailability. Sixteen healthy Chinese male subjects were randomly divided into two
groups: a fasting-postprandial group and a postprandial-fasting group. The drug was administered
once per evaluation at a dose of 80 mg, with an interval of 22 days between the two treatments.
The LC-MS/MS method was used to determine the concentrations of AST2818 and its metabolite
AST5902. Plasma pharmacokinetic parameters were calculated by noncompartmental analysis
(NCA). WinNonlin® version 7.0 was used to analyse PK parameters, and SAS version 9.4
was used for statistical analyses. After a meal, the peak concentration of alflutinib increased by
approximately 53%, and the AUC increased by approximately 32%; The peak concentration of its
metabolite AST5902 decreased by approximately 20%, and the AUC decreased by approximately
8%. There was no signifcant change in peak time. The peak AST5902 concentration and AUC
0-∞
were 27.4% and 71.4%, respectively, of that of alflutinib. None of the subjects experienced serious
AEs, and both fasting and high-fat meal administration were safe. There was no statistically
signifcant difference between groups in AEs (
P = 0.102, RR = 1.40) or adverse reactions (P
= 0.180, RR = 1.30). The effects of food may not need to be considered for the clinical use of
alflutinib. No serious AEs occurred, and drug administration was safe and tolerable after fasting
or a high-fat meal.

Graphical Abstract

A Randomized, Open, Single-Centre, Crossed Study of the Effect of Food on the Pharmacokinetics of One Oral Dose of Alflutinib Mesylate Tablets (AST2818) in Healthy Male Subjects

Keywords


(1) Chen W, Zheng R, Baade PD, Zhang S, Zeng H, BrayF, Jemal A, Yu XQ and He J. Cancer statistics inChina, 2015. CA Cancer J. Clin. (2016) 66: 115-32.
(2) Vachani A, Sequist LV and Spira A. AJRCCM: 100-Year Anniversary. The Shifting Landscape for LungCancer: Past, Present, and Future. Am. J. Respir.
Crit. Care Med. (2017) 195: 1150-60.
(3) Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L,Ahn MJ, De Pas T, Besse B, Solomon BJ, BlackhallF, Wu YL, Thomas M, O’Byrne KJ, Moro-SibilotD, Camidge DR, Mok T, Hirsh V, Riely GJ, IyerS, Tassell V, Polli A, Wilner KD and Jänne PA.Crizotinib versus chemotherapy in advanced ALKpositive lung cancer. N. Engl. J. Med. (2013) 368:2385-94.
(4) Imai H, Kaira K, Mori K, Kotake M, Mitani M,Kawashima N, Hisada T and Minato K. Postprogression survival is highly linked to overallsurvival in patients with non-small-cell lung cancerharboring sensitive EGFR mutations treated withfirst-line epidermal growth factor receptor-tyrosinekinase inhibitors. Thorac. Cancer (2019) 10: 2200-8.
(5) Gelatti ACZ, Drilon A and Santini FC. Optimizingthe sequencing of tyrosine kinase inhibitors (TKIs) inepidermal growth factor receptor (EGFR) mutationpositive non-small cell lung cancer (NSCLC). LungCancer (2019) 137: 113-22.
(6) Ahn MJ, Tsai CM, Shepherd FA, Bazhenova L,Sequist LV, Hida T, Yang JCH, Ramalingam SS,Mitsudomi T, Jänne PA, Mann H, Cantarini Mand Goss G. Osimertinib in patients with T790Mmutation-positive, advanced non-small cell lungcancer: Long-term follow-up from a pooled analysisof 2 phase 2 studies. Cancer (2019) 125: 892-901.
(7) Aguiar PN Jr, Haaland B, Park W, San Tan P, DelGiglio A and de Lima Lopes G Jr. Cost-effectivenessof Osimertinib in the first-line treatment of patientswith EGFR-mutated advanced non-small cell lungcancer. JAMA Oncol. (2018) 4: 1080-4.
(8) Zhao H, Cao J, Chang J, Zhang Z, YangL, Wang J, Cantarini M and Zhang L.Pharmacokinetics of Osimertinib in Chinese patientswith advanced NSCLC: A phase 1 study. J. Clin.Pharmacol. (2018) 58: 504-13.
(9) Situ W, Xiang T and Liang Y. Chitosan-basedparticles for protection of proteins during storageand oral administration. Int. J. Biol. Macromol.(2018) 117: 308-14.
(10) Verkempinck SHE, Salvia-Trujillo L, Denis S andVan Loey AM. Pectin influences the kinetics of invitro lipid digestion in oil-in-water emulsions. FoodChem. (2018) 262: 150-61.
(11) Williams HD, Ford L, Han S, Tangso KJ, Lim S,Shackleford DM, Vodak DT, Benameur H, PoutonCW, Scammells PJ and Porter CJH. Enhancing theoral absorption of kinase inhibitors using lipophilicsalts and lipid-based formulations. Mol. Pharm.(2018) 15: 5678-96.
(12) Hu P, Chen J, Liu D, Zheng X, Zhao Q and Jiang J.Development of population pharmacokinetics modelof icotinib with non-linear absorption characters inhealthy Chinese volunteers to assess the CYP2C19polymorphism and food-intake effect. Eur. J. Clin.Pharmacol. (2015) 71: 843-50.
(13) Freiwald M, Schmid U, Fleury A, Wind S, StopferP and Staab A. Population pharmacokinetics ofafatinib, an irreversible ErbB family blocker,in patients with various solid tumors. Cancer Chemother. Pharmacol. (2014) 73: 759-70.
(14) Sudan S and Rupasinghe HV. Antiproliferative activity of long chain acylated esters of quercetin3-O-glucoside in hepatocellular carcinoma HepG2cells. Exp. Biol. Med. (Maywood) (2015) 240: 1452-64.
(15) Liu X, Li W, Zhang Y, Jiang Y, Zhao Q and ZhongD. Simultaneous determination of alflutinib andits active metabolite in human plasmausing liquidchromatography-tandem mass spectrometry. J.Pharm. Biomed. Anal. (2019) 176: 112735.33
(16) Guidelines for Bioequivalence Studies of GenericProducts. Pharmaceuticals and Medical DevicesAgency. 2015 Jun [cited 2019 Dec 5]. Available from:URL: http://www.pmda.go.jp/files/000157415.
(17) Vishwanathan K, Dickinson PA, Bui K, Cassier PA,Greystoke A, Lisbon E, Moreno V, So K, ThomasK, Weilert D, Yap TA and Plummer R. The effectof food or omeprazole on the pharmacokinetics ofosimertinib in patients with non-small-cell lungcancer and in healthy volunteers. J. Clin. Pharmacol (2018) 58: 474-84.