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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of E3024, a Novel and Selective Dipeptidyl Peptidase-IV Inhibitor, in Healthy Japanese Male Subjects: Rash Development in Men and Its Possible Mechanism

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DOI: 10.4236/pp.2013.49093    2,899 Downloads   5,380 Views   Citations

ABSTRACT

E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p < 0.001), but not by vildagliptin or valine-pyrrolidide (DPP-IV inhibitors) at the same dose. No blood histamine increases were observed in genetically mast cell-deficient Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relationship study suggested that a piperazine group N-linked to the 2-position of the 5,6-membered fused heterocyclic rings was a key structural element for triggering histamine release.

 

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Y. Takeuchi, M. Namiki, Y. Kitahara, S. Hasegawa, A. Ohnishi, N. Yasuda, T. Inoue, R. Clark and K. Yamazaki, "Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of E3024, a Novel and Selective Dipeptidyl Peptidase-IV Inhibitor, in Healthy Japanese Male Subjects: Rash Development in Men and Its Possible Mechanism," Pharmacology & Pharmacy, Vol. 4 No. 9, 2013, pp. 663-678. doi: 10.4236/pp.2013.49093.

References

[1] J. J. Holst and C. F. Deacon, “Inhibition of the Activity of Dipeptidyl-Peptidase IV as a Treatment for Type 2 Diabetes,” Diabetes, Vol. 47, No. 11, 1998, pp. 1663-1670.
http://dx.doi.org/10.2337/diabetes.47.11.1663
[2] D. J. Drucker, “Enhancing Incretin Action for the Treatment of Type 2 Diabetes,” Diabetes Care, Vol. 26, No. 10, 2003, pp. 2929-2940.
http://dx.doi.org/10.2337/diacare.26.10.2929
[3] C. F. Deacon, “Therapeutic Strategies Based on Glucagon-Like Peptide 1,” Diabetes, Vol. 53, No. 9, 2004, pp. 2181-2189. http://dx.doi.org/10.2337/diabetes.53.9.2181
[4] J. J. Holst and C. Orskov, “The Incretin Approach for Diabetes Treatment. Modulation of Islet Hormone Release by GLP-1 Agonism,” Diabetes, Vol. 53, Suppl. 3, 2004, pp. S197-S204.
http://dx.doi.org/10.2337/diabetes.53.suppl_3.S197
[5] B. Ahrén, “Dipeptidyl Peptidase-4 Inhibitors. Clinical Data and Clinical Implications,” Diabetes Care, Vol. 30, No. 6, 2007, pp. 1344-1350.
http://dx.doi.org/10.2337/dc07-0233
[6] D. Kim, L. Wang, M. Beconi, G. J. Eiermann, M. H. Fisher, H. He, G. J. Hickey, J. E. Kowalchick, B. Leiting, K. Lyons, F. Marsilio, M. E. McCann, R. A. Patel, A. Petrov, G. Scapin, S. B. Patel, R. S. Roy, J. K. Wu, M. J. Wyvratt, B. B. Zhang, L. Zhu, N. A. Thornberry and A. E. Weber, “(2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1, 2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl) butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes,” Journal of Medicinal Chemistry, Vol. 48, No. 1, 2005, pp. 141-151. http://dx.doi.org/10.1021/jm0493156
[7] E. B. Villhauer, J. A. Brinkman, G. B. Naderi, B. F. Burkey, B. E. Dunning, K. Prasad, B. L. Mangold, M. E. Russell and T. E. Hughes, “1-[[(3-Hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine: A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties,” Journal of Medicinal Chemistry, Vol. 46, No. 13, 2003, pp. 2774-2789. http://dx.doi.org/10.1021/jm030091l
[8] D. J. Augeri, J. A. Robl, D. A. Betebenner, D. R. Magnin, A. Khanna, J. G. Robertson, A. Wang, L. M. Simpkins, P. Taunk, Q. Huang, S. P. Han, B. Abboa-Offei, M. Cap, L. Xin, L. Tao, E. Tozzo, G. E. Welzel, D. M. Egan, J. Marcinkeviciene, S. Y. Chang, S. A. Biller, M. S. Kirby, R. A. Parker and L. G. Hamann, “Discovery and Preclinical Profile of Saxagliptin (BMS-477118): A Highly Potent, Long-Acting, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes,” Journal of Medicinal Chemistry, Vol. 48, No. 15, 2005, pp. 5025-5037. http://dx.doi.org/10.1021/jm050261p
[9] J. Feng, Z. Zhang, M. B. Wallace, J. A. Stafford, S. W. Kaldor, D. B. Kassel, M. Navre, L. Shi, R. J. Skene, T. Asakawa, K. Takeuchi, R. Xu, D. R. Webb and S. L. Gwaltney, II, “Discovery of Alogliptin: A Potent, Selective, Bioavailable, and Efficacious Inhibitor of Dipeptidyl Peptidase IV,” Journal of Medicinal Chemistry, Vol. 50, No. 10, 2007, pp. 2297-2300.
http://dx.doi.org/10.1021/jm070104l
[10] M. Eckhardt, E. Langkopf, M. Mark, M. Tadayyon, L. Thomas, H. Nar, W. Pfrengle, B. Guth, R. Lotz, P. Sieger, H. Fuchs and F. Himmelsbach, “8-(3-(R)-Aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinaz-olin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a Highly Potent, Selective, Long-Acting, and Orally Bioavailable DPP-4 Inhibitor for the Treatment of Type 2 Diabetes,” Journal of Medicinal Chemistry, Vol. 50, No. 26, 2007, pp. 6450-6453.
http://dx.doi.org/10.1021/jm701280z
[11] N. Kato, M. Oka, T. Murase, M. Yoshida, M. Sakairi, S. Yamashita, Y. Yasuda, A. Yoshikawa, Y. Hayashi, M. Makino, M. Takeda, Y. Mirensha and T. Kakigami, “Discovery and Pharmacological Characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methyl-propyl-2-methylpyrazolo[1,5-a]pyrimidine-6-car-boxamide Hydrochloride (Anagliptin Hydrochloride Salt) as a Potent and Selective DPP-IV Inhibitor,” Bioorganicand Medicinal Chemistry, Vol. 19, No. 23, 2011, pp. 7221-7227. http://dx.doi.org/10.1016/j.bmc.2011.09.043
[12] N. Yasuda, T. Nagakura, T. Inoue, K. Yamazaki, N. Katsutani, O. Takenaka, R. Clark, F. Matsuura, E. Emori, S. Yoshikawa, K. Kira, H. Ikuta, T. Okada, T. Saeki, O. Asano and I. Tanaka, “E3024, 3-But-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one Tosylate, Is a Novel, Selective and Competitive Dipeptidyl Peptidase-IV Inhibitor,” European Journal of Pharmacology, Vol. 548, No. 1-3, 2006, pp. 181-187.
http://dx.doi.org/10.1016/j.ejphar.2006.08.011
[13] K. Yamazaki, T. Inoue, N. Yasuda, Y. Sato, T. Nagakura, O. Takenaka, R. Clark, T. Saeki and I. Tanaka, “Comparison of Efficacies of a Dipeptidyl Peptidase IV Inhibitor and α-Glucosidase Inhibitors in Oral Carbohydrate and Meal Tolerance Tests and the Effects of Their Combination in Mice,” Journal of Pharmacological Sciences, Vol. 104, No. 1, 2007, pp. 29-38.
http://dx.doi.org/10.1254/jphs.FP0061376
[14] K. Yamazaki, N. Yasuda, T. Inoue, E. Yamamoto, Y. Sugaya, T. Nagakura, M. Shinoda, R. Clark, T. Saeki and I. Tanaka, “Effects of the Combination of a Dipeptidyl Peptidase IV Inhibitor and an Insulin Secretagogue on Glucose and Insulin Levels in Mice and Rats,” The Journal of Pharmacological and Experimental Therapeutics, Vol. 320, No. 2, 2007, pp. 738-746.
http://dx.doi.org/10.1124/jpet.106.112011
[15] T. Hashimoto, H. Kasai, M. Yamada, M. Yamada, H. Sakaki, J. Handa, T. Takizawa and A. Hirata, “Statistical Assessment of Linear Pharmacokinetics in Clinical Pharmacological Studies,” Xenobiotic Metabolism and Disposition, Vol. 16, No. 3, 2001, pp. 244-252.
[16] C. F. Deacon, T. E. Hughes and J. J. Holst, “Dipeptidyl Peptidase IV Inhibition Potentiates the Insulinotropic Effect of Glucagon-Like Peptide 1 in the Anesthetized Pig,” Diabetes, Vol. 47, No. 5, 1998, pp. 764-769.
http://dx.doi.org/10.2337/diabetes.47.5.764
[17] S. N. Pramod, Y. P. Venkatesh and P. A. Mahesh, “Potato Lectin Activates Basophils and Mast Cells of Atopic Subjects by Its Interaction with Core Chitobiose of Cell-Bound Non-Specific Immunoglobulin E,” Clinical and Experimental Immunology, Vol. 148, No. 3, 2007, pp. 391-401.
http://dx.doi.org/10.1111/j.1365-2249.2007.03368.x
[18] K. Kowal, H. Nolte, P. S. Skov and L. M. DuBuske, “Effect of Allergen-Specific Immunotherapy on Recombinant Human Interleukin 3-Mediated Amplification of Allergen-Induced Basophil Histamine Release,” Allergy and Asthma Proceedings, Vol. 26, No. 6, 2005, pp. 456-462.
[19] B. Davies and T. Morris, “Physiological Parameters in Laboratory Animals and Humans,” Pharmaceutical Research, Vol. 10, No. 7, 1993, pp. 1093-1095.
http://dx.doi.org/10.1023/A:1018943613122
[20] G. R. Lankas, B. Leiting, R. S. Roy, G. J. Eiermann, M. G. Beconi, T. Biftu, C. C. Chan, S. Edmondson, W. P. Feeney, H. He, D. E. Ippolito, D. Kim, K. A. Lyons, H. O. Ok, R. A. Patel, A. N. Petrov, K. A. Pryor, X. Qian, L. Reigle, A. Woods, J. K. Wu, D. Zaller, X. Zhang, L. Zhu, A. E. Weber and N. A. Thornberry, “Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes: Potential Importance of Selectivity over Dipeptidyl Peptidases 8 and 9,” Diabetes, Vol. 54, No. 10, 2005, pp. 2988-2994. http://dx.doi.org/10.2337/diabetes.54.10.2988
[21] Y. Niwa, T. Kasugai, K. Ohno, M. Morimoto, M. Yamazaki, K. Dohmae, Y. Nishimune, K. Kondo and Y. Kitamura, “Anemia and Mast Cell Depletion in Mutant Rats that Are Homozygous at ‘White Spotting (Ws)’ Locus,” Blood, Vol. 78, No. 8, 1991, pp. 1936-1941.
[22] T. Tsujimura, S. Hirota, S. Nomura, Y. Niwa, M. Yamazaki, T. Tono, E. Morii, H.-M. Kim, K. Kondo, Y. Nishimune and Y. Kitamura, “Characterization of Ws Mutant Allele of Rats: A 12-Base Deletion in Tyrosine Kinase Domain of c-kit Gene,” Blood, Vol. 78, No. 8, 1991, pp. 1942-1946.
[23] T. Kasugai, M. Okada, M. Morimoto, N. Arizono, K. Maeyama, M. Yamada, H. Tei, K. Dohmae, H. Onoue, G. F. Newlands, T. Watanabe, Y. Nishimune, H. R. P. Miller and Y. Kitamura, “Infection of Nippostrongylus brasiliensis Induces Normal Increase of Basophils in Mast Cell-Deficient Ws/Ws Rats with a Small Deletion at the Kinase Domain of c-kit,” Blood, Vol. 81, No. 10, 1993, pp. 2521-2529.
[24] S. Nakamura, H. Watanabe, T. Yokota, H. Matsui, M. Onji and K. Maeyama, “Effect of Rabeprazole on Histamine Synthesis in Enterochromaffin-Like Cells of Mast Cell-Deficient (Ws/Ws) Rats,” European Journal of Pharmacology, Vol. 394, No. 1, 2000, pp. 9-16.
http://dx.doi.org/10.1016/S0014-2999(00)00080-7
[25] S. Hüttner, E. U. Graefe-Mody, B. Withopf, A. Ring and K. A. Dugi, “Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of BI 1356, an Inhibitor of Dipeptidyl Peptidase 4, in Healthy Male Volunteers,” The Journal of Clinical Pharmacology, Vol. 48, No. 10, 2008, pp. 1171-1178.
http://dx.doi.org/10.1177/0091270008323753
[26] A. Sarashina, S. Sesoko, M. Nakashima, N. Hayashi, A. Taniguchi, Y. Horie, E. U. Graefe-Mody, H.-J. Woerle and K. A. Dugi, “Linagliptin, a Dipeptidyl Peptidase-4 Inhibitor in Development for the Treatment of Type 2 Diabetes Mellitus: A Phase I, Randomized, Double-Blind, Placebo-Controlled Trial of Single and Multiple Escalating Doses in Healthy Adult Male Japanese Subjects,” Clinical Therapeutics, Vol. 32, No. 6, 2010, pp. 1188-1204. http://dx.doi.org/10.1016/j.clinthera.2010.06.004
[27] G. Schernthaner, A. H. Barnett, A. Emser, S. Patel, J. Troost, H.-J. Woerle and M. von Eynatten, “Safety and Tolerability of Linagliptin: A Pooled Analysis of Data from Randomized Controlled Trials in 3572 Patients with Type 2 Diabetes Mellitus,” Diabetes, Obesity and Metabolism, Vol. 14, No. 5, 2012, pp. 470-478.
http://dx.doi.org/10.1111/j.1463-1326.2012.01565.x

  
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