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

Abstract

ObjectiveThis phase I study of ZYAN1 was conducted to evaluate the safety, tolerability, and pharmacokinetics following oral administration in healthy volunteers.MethodsThe 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).ResultsZYAN1 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 (AUCt) 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.ConclusionOral 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 AUCt. 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.

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

“…HIF-PHIs in current clinical development are potent reversible inhibitors of all 3 PHD isoforms, with in vitro halfmaximal inhibitory concentrations in the submicromolar to low micromolar range (Table 1 [68][69][70][71][72][73][74][75][76] ). 68,70,71 HIF-PHIs chelate at the catalytic-site iron, stabilizing both HIF-1a and HIF-2a and resulting in dose-dependent increases in HIF-regulated gene expression. 68 However, differences between daprodustat, molidustat, roxadustat, and vadadustat were found in the kinetics of HIF-a stabilization and relative expression levels of HIF-regulated genes in cells exposed to equimolar amounts of compound.…”

Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study

“…The safety, tolerability, and EPO stimulation of Desidustat administration have been evaluated in the phase 1 trial [24]. The doses for the phase 2 trial were based on pharmacokinetic (PK)/pharmacodynamic data from the phase 1 trial (Trial ID: AC-TRN12614001240639 and CTRI/2016/02/006665) and preclinical studies.…”

Novel methodology to perform incurred sample reanalysis on dried blood spot cards: Experimental data using darolutamide and filgotinib

“…Whole blood sample bioanalysis is cumbersome as compared with plasma/serum bioanalysis of samples and therefore, it is less preferred to be used as a matrix to generate relevant pharmacokinetic data in animals and humans. However, there are many drugs such as cyclosporin (Fahr, 1993), chloroquine (Kaewkhao et al, 2019) tacrolimus (Venkataramanan et al, 1995) and desidustat (ZYAN1) (Kansagra et al, 2018) whose pharmacokinetics have been derived using the whole blood matrix. One of the reasons for choosing whole blood as a matrix for the aforementioned drugs is due to the higher partitioning of the drug into red blood cells relative to plasma and therefore, in such instances, blood as opposed to plasma would likely represent as a key surrogate to define the pharmacokinetics of the drug.…”