Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers
| Autor: | Chintan Y. Shah, Maulik R. Patel, Rahul J. Gupta, Raghav Sukhadiya, Deven Parmar, Heather Heading, Mukul R. Jain, Devang P. Parikh, Kinjal Barot, Harilal Patel, Hardik B. Patel, Nuggehally R. Srinivas, Vyom N. Dholakia, Kevinkumar Kansagra, Rajendrakumar H. Jani, Krupi Parmar, Jason Lickliter |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Phases of clinical research Administration Oral Quinolones Gastroenterology Drug Administration Schedule law.invention 03 medical and health sciences 0302 clinical medicine Randomized controlled trial Pharmacokinetics Double-Blind Method law Oral administration Internal medicine Medicine Humans Pharmacology (medical) Dosing Original Research Article Adverse effect Pharmacology Dose-Response Relationship Drug business.industry Prolyl-Hydroxylase Inhibitors 030104 developmental biology Tolerability 030220 oncology & carcinogenesis Pharmacodynamics Area Under Curve Female business Half-Life |
| Zdroj: | Clinical Pharmacokinetics |
| ISSN: | 1179-1926 0312-5963 |
| Popis: | This phase I study of ZYAN1 was conducted to evaluate the safety, tolerability, and pharmacokinetics following oral administration in healthy volunteers. The study was a randomized, double-blind, placebo-controlled phase I study carried out in two parts in addition to a third part involving an open-label study to evaluate the food/sex effect. A total of 100 subjects were enrolled into the study as follows: part I—single-dose study with ZYAN1 10, 25, 50, 100, 150, 200, and 300 mg (n = 56); part II—multiple-dose study with every other day dosing of ZYAN1 100, 150, 200, and 300 mg (n = 32); and part III—sex and food effect study with ZYAN1 150 mg (n = 12; open-label). ZYAN1 was well-tolerated after single and multiple oral ascending doses. No drug-related serious adverse events were reported. Following a single ascending dose of ZYAN1, the maximum concentration (C max) ranged from 566.47 ± 163.03 to 17,858.33 ± 2899.19 ng/mL and the median time to C max (t max) was approximately 2.5 h for the studied 30-fold oral doses of ZYAN1. Regardless of single or multiple doses, mean C max and area under the concentration–time curve from time zero to time t (AUC t ) values generally showed a dose-proportional increase. The mean elimination half-life (t ½) of ZYAN1 ranged from 6.9 to 13 h with negligible accumulation. Following a single dose of ZYAN1, the mean serum erythropoietin (EPO) C max values showed dose response (i.e., 6.6 and 79.9 mIU/L for 10 and 300 mg ZYAN1 doses, respectively), while the time to mean maximal serum EPO concentrations ranged from 10 to 72 h. Oral single (10–300 mg) and multiple dosing (100–300 mg) of ZYAN1 in healthy subjects was found to be safe and well-tolerated. With increasing ZYAN1 dose, there was almost a proportional increase in mean C max and AUC t . The mean serum EPO concentrations showed a trend of dose response. Based on the t ½, pharmacodynamic activity, and lack of drug accumulation, a once every 2 days dosing regimen of ZYAN1 was appropriate for phase II study. Trial Registration: Australian New Zealand Clinical Trials Registry trial ID ACTRN12614001240639. |
| Databáze: | OpenAIRE |
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