Chemical formula: C₁₉H₁₆N₂O₅ Molecular mass: 352.346 g/mol PubChem compound: 11256664
Roxadustat is a hypoxia-inducible factor, prolyl hydroxylase inhibitor (HIF-PHI). The activity of HIF-PH enzymes controls intracellular levels of HIF, a transcription factor that regulates the expression of genes involved in erythropoiesis. Activation of the HIF pathway is important in the adaptative response to hypoxia to increase red blood cell production. Through the reversible inhibition of HIF-PH, roxadustat stimulates a coordinated erythropoietic response that includes the increase of plasma endogenous erythropoietin (EPO) levels, regulation of iron transporter proteins and reduction of hepcidin (an iron regulator protein that is increased during inflammation in CKD). This results in improved iron bioavailability, increased Hb production and increased red cell mass.
A thorough QT (TQT) study in healthy subjects with roxadustat at a single therapeutic dose of 2.75 mg/kg and a single supratherapeutic dose of 5 mg/kg (up to 510 mg) did not show a prolongation of the QTc interval. The same thorough QT study demonstrated a placebo-corrected heart rate increase of up to 9 to 10 bpm at 8 to 12 h post-dose for the 2.75 mg/kg dose and 15 to 18 bpm at 6 to 12 h post-dose for the dose of 5 mg/kg.
Roxadustat plasma exposure (area under the plasma drug concentration over time curve [AUC] and maximum plasma concentrations [Cmax]) is dose-proportional within the recommended therapeutic dose range. In a three times per week dosing regimen, steady-state roxadustat plasma concentrations are achieved within one week (3 doses) with minimal accumulation. The pharmacokinetics of roxadustat do not change over time.
Maximum plasma concentrations (Cmax) are usually achieved at 2 hours post dose in the fasted state. Administration of roxadustat with food decreased Cmax by 25% but did not alter AUC as compared with the fasted state. Therefore, roxadustat can be taken with or without food.
Roxadustat is highly bound to human plasma proteins (approximately 99%), predominantly to albumin. The blood-to-plasma ratio of roxadustat is 0.6. The apparent volume of distribution at steady state is 24 L.
Based on in vitro data, roxadustat is a substrate for CYP2C8 and UGT1A9 enzymes, as well as BCRP, OATP1B1, OAT1 and OAT3. Roxadustat is not a substrate for OATP1B3 or P-gp. Roxadustat is primarily metabolised to hydroxy-roxadustat and roxadustat-O-glucuronide. Unchanged roxadustat was the major circulating component in human plasma; no detectable metabolite in human plasma constituted more than 10% of total drug-related material exposure and no human specific metabolites were observed.
The mean effective half-life (t1/2) of roxadustat is approximately 15 hours in patients with CKD. The apparent total body clearance (CL/F) of roxadustat is 1.1 L/h in patients with CKD not on dialysis and 1.4 L/h in patients with CKD on dialysis. Roxadustat and its metabolites are not significantly removed by haemodialysis. When radiolabelled roxadustat was administered orally in healthy subjects, the mean recovery of radioactivity was 96% (50% in faeces, 46% in urine). In faeces, 28% of the dose was excreted as unchanged roxadustat. Less than 2% of the dose was recovered in urine as unchanged roxadustat.
No clinically relevant differences in the pharmacokinetics of roxadustat were observed based on age (≥18), sex, race, body weight, renal function (eGFR) or dialysis status in adult patients with anaemia due to CKD.
In dialysis-dependent CKD patients, no marked differences in pharmacokinetic parameter values were observed when roxadustat was administered 2 hours before or 1 hour after haemodialysis. Dialysis is a negligible route of overall clearance of roxadustat.
Following a single dose of 100 mg roxadustat, mean roxadustat AUC was 23% higher and mean Cmax was 16% lower in subjects with moderate hepatic impairment (Child-Pugh Class B) and normal renal function compared to subjects with normal hepatic and renal functions. Subjects with moderate hepatic impairment (Child-Pugh Class B) and normal renal function showed an increase in unbound roxadustat AUCinf (+70%) as compared to healthy subjects. The pharmacokinetics of roxadustat in subjects with severe hepatic impairment (Child-Pugh Class C) have not been studied.
Based on in vitro data, roxadustat is an inhibitor of CYP2C8, BCRP, OATP1B1 and OAT3. The pharmacokinetics of rosiglitazone (moderate sensitive CYP2C8 substrate) were not affected by co-administration of roxadustat. Roxadustat may be an inhibitor of intestinal but not hepatic UGT1A1 and showed no inhibition of other CYP metabolising enzymes or transporters, or induction of CYP enzymes at clinically relevant concentrations. There is no clinically significant effect of oral adsorptive charcoal or omeprazole on roxadustat pharmacokinetics. Clopidogrel has no effect on roxadustat exposure in patients with CKD.
In the 26-week intermittent repeat dose study in Sprague-Dawley or Fisher rats, roxadustat at approximately 4 to 6-fold the total AUC at Maximum Recommended Human Dose (MRHD) resulted in histopathological findings including aortic and atrioventricular valves (A-V) valvulopathies. These findings were present in surviving animals at the time of termination as well as in animals terminated early in a moribund state. Furthermore, the findings were not fully reversible as they were also present in animals at the end of a 30-day recovery period.
Exaggerated pharmacology resulting in excessive erythropoiesis has been observed in repeated-dose toxicity studies in healthy animals.
Haematological changes such as decreases in circulating platelets as well as increases in activated partial thromboplastin time and prothrombin time were noted in rats from approximately 2-fold the total AUC at MRHD. Thrombi were noted in the bone marrow (systemic exposures of approximately 7-fold the total AUC at MRHD in rats), kidneys (systemic exposures of approximately 5 to 6-fold total AUC at MRHD in rats), lungs (systemic exposures approximately 8- and 2-fold total AUC at MRHD in rats and cynomolgus monkeys, respectively), and the heart (systemic exposures of approximately 4 to 6-fold the total AUC at MRHD in rats).
In the 26-week intermittent repeat dose study in Sprague-Dawley rats, one animal, at approximately 6- fold the total AUC at MRHD showed a histologic finding of brain necrosis and gliosis. In Fisher rats, treated for the same duration, brain/hippocampal necrosis was noted in a total of four animals at the approximately 3 to 5-fold the total AUC at MRHD.
Cynomolgus monkeys intermittently administered roxadustat for 22 or 52-weeks, did not show similar findings at systemic exposures up to approximately 2-fold the total AUC at MRHD.
Roxadustat was negative in the in vitro Ames mutagenicity test, in vitro chromosome aberration test in human peripheral blood lymphocytes and an in vivo micronucleus test in mice at 40-fold the MRHD based on a human equivalent dose.
In the mouse and rat carcinogenicity studies, animals were administered roxadustat with the clinical dosing regimen of three times per week. Due to the rapid clearance of roxadustat in rodents, systemic exposures were not continuous throughout the dosing period. As such, possible off-target carcinogenic effects may be underestimated.
In the 2-year mouse carcinogenicity study, significant increases in the incidence of lung bronchoalveolar carcinoma was noted in the low and high dose groups (systemic exposures approximately 1-fold and approximately 3-fold the total AUC at MRHD). A significant increase in subcutis fibrosarcoma was seen in females at the high dose group (systemic exposures approximately 3-fold total AUC at MRHD).
In the 2-year rat carcinogenicity study, a significant increase in the incidence of mammary gland adenoma was noted at the middle dose level (systemic exposure less than 1-fold the total AUC at MRHD). However, the finding was not dose related and the incidence of this tumour type was lower at the highest dose level tested (systemic exposure approximately 2-fold the total AUC at MRHD) and was therefore not considered test article related.
Similar findings from the mouse and rat carcinogenicity studies were not observed in the clinical studies.
Roxadustat had no effect on mating or fertility in treated male or female rats at approximately 4-fold the human exposure at the MRHD. However, at the NOAEL in male rats, there were decreases in weights of the epididymis and the seminal vesicles (with fluid) without effects on male fertility. The NOEL for any male reproductive organ related findings was 1.6-fold MRHD. In female rats there were increases in the number of non-viable embryos and post-implantation losses at this dose level compared to control animals.
Results from the reproductive and developmental toxicity studies in rats and rabbits demonstrated reduction of average foetal or pup body weight, average placental weight increase, abortion and pup mortalities.
Pregnant Sprague-Dawley rats administered roxadustat daily from implantation through the closure of the hard palate (Gestation Days 7-17) showed decreased foetal body weight and increased skeletal alterations at approximately 6-fold the total AUC at MRHD. Roxadustat had no effect on post-implant foetal survival.
Pregnant New Zealand rabbits were administered roxadustat daily from Gestation Day 7 through Gestation Day 19 and Caesarian sections were performed on Gestation Day 29. Roxadustat administration at systemic exposures up to approximately 3-fold the total AUC at MRHD showed no embryo-foetal findings. However, one doe aborted at approximately 1-fold the total AUC at MRHD and 2 does aborted at approximately 3-fold the total AUC at MRHD, the aborting females showed thin body condition.
In the perinatal/postnatal development study in Sprague-Dawley rats, pregnant dams were administered roxadustat daily from Gestation Day 7 to Lactation Day 20. During the lactation period, pups from dams administered roxadustat at approximately 2-fold the total Cmax at MRHD showed high mortality during the preweaning period and were sacrificed at weaning. Pups from dams administered roxadustat at doses resulting in systemic exposures approximately 3-fold the human exposure at MRHD showed a significant decrease in 21-day survival after birth (lactation index) compared with pups from control litters.
In a cross-fostering study, the most pronounced effects on rat pup viability were noted in the pups exposed to roxadustat postnatally only, and the pup viability exposed to roxadustat until delivery was lower than that of unexposed pups.
The cross-fostering study in which pups from unexposed rats were cross fostered with dams treated with roxadustat (human equivalent dose approximately 2-fold MRHD), had roxadustat in pup plasma indicating transfer of drug via the milk. Milk from these dams had roxadustat present. The pups who were exposed to milk containing roxadustat showed a lower survival rate (85.1%) versus pups from untreated dams cross fostered with untreated dams (98.5% survival rate). The mean body weight of the surviving pups exposed to roxadustat during the lactation period was also less than the control pups (no in utero exposure – no exposure in milk).
A cardiovascular safety pharmacology study showed heart rate increases following a single administration of 100 mg/kg roxadustat to monkeys. There was no effect on hERG or ECG. Additional safety pharmacology studies in rats have shown that roxadustat reduced total peripheral resistance followed by a reflex increase in heart rate from approximately six times the exposure at the MRHD.
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