Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

被引:17
作者
Appels, N. M. G. M.
Bolijn, M. J.
Chan, K.
Stephens, T. C.
Hoctin-Boes, G.
Middleton, M.
Beijnen, J. H.
de Bono, J. S.
Harris, A. L.
Schellens, J. H. M.
机构
[1] Netherlands Canc Inst, Antoni van Leeuwenhoek Hosp, NL-1066 CX Amsterdam, Netherlands
[2] Netherlands Canc Inst, Slotervaart Hosp, Dept Pharm & Pharmacol, NL-1066 EC Amsterdam, Netherlands
[3] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England
[4] Churchill Hosp, Canc Res UK Med Oncol Unit, Oxford OX3 7L, England
[5] Univ Utrecht, Dept Biomed Anal, Div Drug Toxicol, Dept Pharmaceut,Beta Fac, NL-3508 TB Utrecht, Netherlands
[6] Royal Marsden Hosp, Sutton SM2 5PT, Surrey, England
关键词
AZD3409; prenyl transferase inhibitor; biological effect study;
D O I
10.1038/sj.bjc.6604402
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
AZD3409 is an orally active double prodrug that was developed as a novel dual prenyltransferase inhibitor. The formation of the active metabolite AZD3409 acid is mediated by esterases in plasma and cells. The aim of this phase I study was to determine the maximum tolerated dose, toxicities, pharmacokinetics and pharmacodynamics of AZD3409. AZD3409 was administered orally to patients with advanced solid malignancies using an interpatient dose-escalation scheme starting at 500 mg AZD3409 once daily. Twenty-nine patients were treated at seven dose levels. The MTD of part A was defined as 750 mg b.i.d. in the fasted state. Adverse events were mainly gastrointestinal and the severity was on average mild to moderate and reversible. The dose-limiting toxicities were vomiting, diarrhoea and uncontrolled nausea. Pharmacokinetic studies of the prodrug and the active metabolite indicated dose proportionality. Pharmacodynamic studies showed that farnesyltransferase ( FTase) was inhibited at all dose levels. In conclusion, chronic oral dosing with AZD3409 is feasible and results in significant inhibition of FTase activity. Pharmacodynamic studies revealed that the maximal FTase inhibition, estimated at 49 +/- 11%, appeared to be reached at AZD3409 acid plasma concentrations at which the occurrence of drug-related toxicity was low. This study supports the rationale to implement biological effect studies in clinical trials with biologically active anticancer drugs to define optimal dosing regimens.
引用
收藏
页码:1951 / 1958
页数:8
相关论文
共 20 条
[1]   Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma [J].
Alsina, M ;
Fonseca, R ;
Wilson, EF ;
Belle, AN ;
Gerbino, E ;
Price-Troska, T ;
Overton, RM ;
Ahmann, G ;
Bruzek, LM ;
Adjei, AA ;
Kaufmann, SH ;
Wright, JJ ;
Sullivan, D ;
Djulbegovic, B ;
Cantor, AB ;
Greipp, PR ;
Dalton, WS ;
Sebti, SM .
BLOOD, 2004, 103 (09) :3271-3277
[2]   Development of farnesyl transferase inhibitors: A review [J].
Appels, NMGM ;
Beijnen, JH ;
Schellens, JHM .
ONCOLOGIST, 2005, 10 (08) :565-578
[3]  
BOS JL, 1989, CANCER RES, V49, P4682
[4]  
Brunner TB, 2003, CANCER RES, V63, P5656
[5]   Protein prenyltransferases [J].
Casey, PJ ;
Seabra, MC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (10) :5289-5292
[6]   Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma [J].
Cohen, SJ ;
Ho, L ;
Ranganathan, S ;
Abbruzzese, JL ;
Alpaugh, RK ;
Beard, M ;
Lewis, NL ;
McLaughlin, S ;
Rogatko, A ;
Perez-Ruixo, JJ ;
Thistle, AM ;
Verhaeghe, T ;
Wang, H ;
Weiner, LM ;
Wright, JJ ;
Hudes, GR ;
Meropol, NJ .
JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (07) :1301-1306
[7]   Phase I study of BMS-214662, a farnesyl transferase inhibitor in patients with acute leukemias and high-risk myelodysplastic syndromes [J].
Cortes, J ;
Faderl, S ;
Estey, E ;
Kurzrock, R ;
Thomas, D ;
Beran, M ;
Garcia-Manero, G ;
Ferrajoli, A ;
Giles, F ;
Koller, C ;
O'Brien, S ;
Wright, J ;
Bai, SA ;
Kantarjian, H .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (12) :2805-2812
[8]   Ras biochemistry and farnesyl transferase inhibitors: a literature survey [J].
Crul, M ;
de Klerk, GJ ;
Beijnen, JH ;
Schellens, JHM .
ANTI-CANCER DRUGS, 2001, 12 (03) :163-184
[9]   Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter [J].
Delarue, F. L. ;
Adnane, J. ;
Joshi, B. ;
Blaskovich, M. A. ;
Wang, D-A ;
Hawker, J. ;
Bizouarn, F. ;
Ohkanda, J. ;
Zhu, K. ;
Hamilton, A. D. ;
Chellappan, S. ;
Sebti, S. M. .
ONCOGENE, 2007, 26 (05) :633-640
[10]  
Garrett Michelle D, 2003, Prog Cell Cycle Res, V5, P145