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Clinical Trials: Phase 3 Dialysis Study FGCL-4592-806: Study 806 was a randomized, multicenter, open-label, active-controlled study that demonstrated the efficacy and safety of roxadustat in correcting and maintaining Hb levels in CKD patients on dialysis (either hemodialysis or peritoneal dialysis) who had previously been treated with epoetin alfa. A total of 305 CKD patients with baseline Hb levels ranging from 90 to 120 g/L (mean ~104 g/L) were enrolled and randomized in a 2:1 ratio to receive either oral administration of roxadustat capsules (204 patients) or epoetin alfa for injection (101 patients). The initial dose of roxadustat capsules was based on body weight, with starting dose of 100 mg (for patients weighing 45-60 kg) or 120 mg (for patients weighing ≥ 60 kg), TIW. Patients receiving epoetin alfa continued their previous dose of epoetin alfa for 26 weeks of treatment. Patients in roxadustat group received the medication for a 26-week initial treatment period, followed by a 26-week extension treatment period, totaling 52 weeks.
Baseline characteristics were similar between the two treatment groups, with comparable baseline Hb levels (104.2 g/L in the roxadustat group versus 104.7 g/L in the epoetin alfa group), and similar proportions of patients with baseline Hb < 100 g/L. Both groups had a mean CKD history of 9.3 years and had been on dialysis for 4.4 to 4.5 years. Prior to enrollment, both groups had similar weekly doses of epoetin alfa (~7600 IU). Of these patients, 89% of patients were on hemodialysis, and the rest of patients were on peritoneal dialysis. Patients ranged in age from 18 to 74 years, with no significant differences in gender, height, weight, and body mass index between two groups.
The primary efficacy endpoint was the mean change in Hb level from baseline averaged over Weeks 23 to 27. This analysis used Hb values obtained from the central laboratory. Baseline Hb level was defined as the average of the last 3 central laboratory Hb values assessed prior to the first dose of the study drug.
A total of 304 patients were included in the full analysis set (FAS) population (roxadustat group: 204 patients, epoetin alfa group: 100 patients), and 294 patients were included in the per protocol set (PPS) population (roxadustat group: 196 patients, epoetin alfa group: 98 patients).
In the FAS population, roxadustat met non-inferiority criteria but not superiority criteria (p=0.0718). Notably, in patients receiving roxadustat, Hb levels increased significantly higher than in those receiving epoetin alfa (Espo) as early as Week 2 and continued throughout the study, despite similar baseline Hb levels (~104 g/L) (See Table 1 and Figure 1).
In the PPS population, roxadustat met both non-inferiority and superiority criteria, with Hb level improvements in the roxadustat group being significantly better than in the epoetin alfa group (p=0.037).
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Click on icon to see table/diagram/imageApproximately 90% of patients treated with roxadustat for 26 weeks maintained a mean Hb level ≥ 100 g/L during the final 4 weeks of treatment. The mean dose of roxadustat at Week 26 was 73 mg TIW. Approximately 96% of patients on roxadustat who completed the 52-week extension period maintained Hb ≥ 100 g/L at the end of treatment. The mean dose of roxadustat at Week 52 was 53 mg TIW.
Among ESA hyporesponsive patients with baseline Hb < 100 g/L, while on stable doses of ESA prior to randomization, 94.4% achieved Hb ≥ 100 g/L, and 83.3% achieved Hb ≥ 110 g/L after up to 26 weeks of roxadustat treatment.
In a subgroup analysis by baseline C-reactive protein (CRP), a marker of inflammation, roxadustat effectively raised and maintained Hb levels across all CRP levels, with comparable roxadustat doses, whereas epoetin alfa showed less efficacy in patients with inflammation (lower Hb levels in patients with elevated CRP levels despite higher doses of epoetin alfa; see Figure 2). The efficacy difference between roxadustat and epoetin alfa was statistically significant in patients with inflammation (subgroup with elevated CRP), p=0.0047.
Click on icon to see table/diagram/imageIron level: Iron utilization improved in roxadustat-treated patients compared to the epoetin alfa group, as indicated by higher mean serum iron levels, higher mean transferrin, and higher total iron binding capacity (TIBC). Although roxadustat-treated patients experienced greater increases in Hb levels compared to the epoetin alfa group, the reductions in mean transferrin saturation (TSAT) and ferritin levels were smaller. Roxadustat effectively achieved treatment goals regardless of baseline iron status and did not require routine use of intravenous iron.
Cholesterol level: Mean total cholesterol levels decreased in the roxadustat group in the early stage compared to the epoetin alfa group and remained throughout the treatment period (p < 0.0001). The reduction in cholesterol with roxadustat was independent of and additive to the use of lipid-lowering agents (statins) (Figure 3). Roxadustat led to a reduction in mean total cholesterol levels in both subgroups (with and without statins), whereas there was no reduction in mean total cholesterol levels among epoetin alfa-treated patients without using statins. (See Figure 3.)
Click on icon to see table/diagram/imagePhase 3 NDD CKD Study FGCL-4592-808: Study 808 was a randomized, multicenter, double-blind, placebo-controlled study designed to assess the efficacy and safety of roxadustat in treating NDD CKD patients with anemia. The study was divided into an initial 8-week double-blind, placebo-controlled period followed by an additional 18 weeks of open-label period where all patients in both treatment groups received roxadustat. A subset of patients in the roxadustat group continued into an open-label extension period, receiving up to 52 weeks of roxadustat.
The study enrolled a total of 154 patients with baseline Hb levels ranging from 70 to 100 g/L (mean ~89 g/L). These patients were randomized in a 2:1 ratio, with the treatment groups receiving either oral roxadustat (102 patients) or oral placebo (52 patients) under a double-blind protocol. With the exception of mean ferritin levels (191 and 266 µg/L, respectively), the baseline characteristics of patients in the roxadustat and placebo groups were generally similar. Both groups had mean baseline Hb levels of 88.7 and 89.3 g/L, respectively. The proportions of patients with baseline Hb levels of ≥ 80 g/L were comparable, at 83.2% and 86.3%, respectively. Patients in the roxadustat group had slightly longer CKD history (5.3 years) and higher eGFR levels (16.5 mL/min/1.73 m2) compared to the placebo arm (4.2 years and 14.5 mL/min/1.73 m2).
In terms of the primary efficacy endpoint, which assessed mean Hb level changes from baseline over weeks 7 to 9, roxadustat demonstrated superiority over placebo at 19 g/L (roxadustat) and -4 g/L (placebo), respectively, with p < 0.0000000000000001. By the end of the 8-week double-blind treatment period, the results showed that 84.2% of roxadustat-treated patients experienced an Hb level increase of ≥ 10 g/L, compared to 0% patients in the placebo group, with p < 0.000000000000001. Additionally, 67.3% of roxadustat-treated patients had mean Hb levels (averaged from weeks 7 to 9) of ≥ 100 g/L, compared to 6.0% in the placebo group, with p=0.00000000077.
Moreover, it was observed that roxadustat was effective in correcting early-stage anemia: The mean Hb level increase for patients in the roxadustat group was significantly higher than that of placebo-treated patients after one week of treatment (p < 0.00001) (see Figure 4).
Click on icon to see table/diagram/imageBy the end of Week 26, the anemia correction was achieved in 97.6% of the patients with Hb ≥ 100g/L.
For patients who initially received placebo, their mean Hb increased by 20.2 g/L (Weeks 23-27) after switching to roxadustat, compared to their mean Hb during the placebo-treated period (Weeks 7-9), with p < 0.0001 (see Figure 5).
Click on icon to see table/diagram/imageApproximately 95% of patients who completed 52 weeks of treatment maintained Hb levels ≥ 100 g/L.
Roxadustat is equally effective in patients with inflammation (CRP > 4.9 mg/L) and without inflammation (CRP ≤ 4.9 mg/L). Roxadustat led to a significant reduction in serum hepcidin levels by 56.1 ng/mL, compared to a reduction of 15.1 ng/mL in the placebo group, with a p=0.00000005.
No specific limits on iron parameters (ferritin and TSAT) were set at study enrollment. The results showed that roxadustat was effective in treating anemia even without intravenous iron.
Beyond its impact on Hb levels, roxadustat also resulted in significant reductions in mean serum lipid levels compared to placebo. During Weeks 7 to 9, the average reductions from baseline were 23% for total cholesterol, 28% for LDL cholesterol, 26% for non-HDL cholesterol, and 21% for triglycerides in the roxadustat group, whereas mean change in lipid levels in the placebo group were not significant from baseline to Week 9, with p < 0.0001. Cholesterol reductions were observed in both patients who received statins and those who did not. The LDL cholesterol/HDL cholesterol ratio was also significantly improved in the roxadustat group compared to the placebo group, with p=0.01.
Cardiovascular events in global pivotal phase 3 clinical trials: Erythropoiesis-stimulating agents (ESAs) have been reported to potentially increase the risk of cardiovascular events in CKD patients. This section describes cardiovascular events in the clinical trials of roxadustat. Cardiovascular safety was assessed using major adverse cardiovascular events (MACE, which include all-cause mortality, stroke, and myocardial infarction), MACE+ (which include all-cause mortality, stroke, myocardial infarction, hospitalization due to heart failure, and hospitalization due to unstable angina); and all-cause mortality.
DD CKD patients with anemia: The pool of the 3 open-label active-controlled studies (FGCL-4592-063, FGCL-4592-064, D5740C00002) included 3880 patients (on-treatment + 7analysis set). The cardiovascular safety of roxadustat relative to epoetin alfa in the overall dialysis population has been confirmed. Patients receiving roxadustat have a comparable risk of MACE, MACE+ or all-cause mortality compared to epoetin alfa; all three endpoints have the upper bounds of the 95% confidence interval (CI) of hazard ratios below the pre-specified non-inferiority margin of 1.3. The cardiovascular safety of roxadustat in the incident dialysis patients has been confirmed, the analysis of this subgroup showed that the patients treated with roxadustat had comparable risks of MACE, MACE+, and all-cause mortality compared to those treated with epoetin alfa, (see Table 2).
NDD CKD patients with anemia: A pooled analysis of 3 randomized, double-blind, placebo-controlled studies (FGCL-4592-060, 1517-CL-0608, and D5740C00001), which included a total of 4270 patients (intent-to-treat analysis set), confirmed the cardiovascular safety of roxadustat compared to placebo. The risks of MACE, MACE+, and all-cause mortality were similar between the roxadustat and placebo groups. For all three endpoints, the hazard ratios (HRs) were close to 1.0, with the upper limits of the 95% CI below the pre-specified non-inferiority margin of 1.3.
Click on icon to see table/diagram/imagePhase 4 Dose Optimization Study in CKD patients: Two dose optimization studies were conducted: One in DD CKD patients with anemia (FGCL-4592-818) and another in NDD CKD patients with anemia (FGCL-4592-858). These studies aimed to compare the efficacy and safety of roxadustat in both dialysis-dependent and non-dialysis-dependent patients, including those who had and had not previously received ESAs, at a one-step lower starting dose compared to the starting dose (standard starting dose) used in the phase 3 clinical study.
FGCL-4592-818: Study 818 was a 36-week, randomized, open-label, multicenter study designed to evaluate the efficacy and relative safety of different roxadustat dosing regimens in DD CKD patients. The initial 20-week was the correction/conversion period (Part 1), followed by a 16-week Hb maintenance period (Part 2).
During the correction/conversion period, both ESA-naïve and ESA-treated DD CKD subjects were enrolled and randomized in a 1:1 ratio to receive roxadustat at the following two starting doses: A lower starting dose (70 mg TIW for subjects weighing 45 to < 60 kg and 100 mg TIW for subjects weighing ≥ 60 kg) and a standard starting dose (100 mg TIW for subjects weighing 45 to < 60 kg and 120 mg TIW for subjects weighing ≥ 60 kg). Roxadustat doses were adjusted during correction/conversion period according to the approved dose adjustment guidelines in monograph.
In total, 318 subjects were randomized and entered the correction/conversion period for study treatment. The full analysis set (FAS) consisted of 316 subjects, including 113 ESA-naïve subjects (57 in the lower starting dose group and 56 in the standard starting dose group) and 203 ESA-treated subjects (103 in the lower starting dose group and 100 in the standard starting dose group). The FAS was used for efficacy data analysis.
Overall, baseline characteristics, including age, gender, and CKD duration, were comparable between the two groups. Among both ESA-naïve and ESA-treated patients, the average baseline Hb levels were similar between the two starting dose groups (87.73 g/L and 86.17 g/L in the ESA-naïve group, and 104.81 g/L and 105.47 g/L in the ESA-treated group).
For ESA-naïve subjects, the primary efficacy endpoint (proportion of subjects achieving Hb ≥ 110 g/L in the first 20 weeks) was similar in both lower and standard starting dose groups (77.2% and 73.2%, respectively) (see Table 3). For ESA-treated subjects, the primary efficacy endpoint (proportion of subjects with a mean Hb ≥ 100 g/L from the Week 17 visit to the Week 21 visit) was comparable in both lower and standard starting dose groups (82.5% and 79.0%) (see Table 4).
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Click on icon to see table/diagram/imageThe lower starting dose of roxadustat also showed similar results in the following secondary efficacy endpoints for correction of anemia compared with the standard starting dose.
In ESA-naïve subjects, the mean change from baseline in Hb levels from Week 17 visit to Week 21 visit was 20.7 (±10.41) g/L in the lower starting dose group and 21.6 (±14.91) g/L in the standard starting dose group; the proportion of subjects with a mean Hb (mean Hb from Week 17 visit to Week 21 visit) ≥ 100 g/L was slightly higher in the lower starting dose group than in the standard starting dose group (78.9% vs. 67.9%). In ESA-treated subjects, the mean change from baseline in Hb levels from Week 17 visit to Week 21 visit was 4.9 (±11.80) g/L in the lower starting dose group and 6.0 (±12.63) g/L in the standard starting dose group.
Additionally, in ESA-naïve subjects, the mean change from baseline (CFB) in Hb level at Week 5 was slightly lower in the lower starting dose group compared to the standard starting dose group (11.5 g/L vs. 16.8 g/L). From Week 9 onward, Hb CFB remained stable and similar in both groups (19.8 g/L vs. 21.6 g/L at Week 9). This trend was similar to what was observed in ESA-treated subjects (3.3 g/L vs. 8.5 g/L at Week 5; 5.9 g/L vs. 8.2 g/L at Week 9), further supporting the comparable efficacy between the two groups.
FGCL-4592-858: Study 858 was a randomized, controlled, open-label, multicenter study designed to evaluate the efficacy and safety of the lower starting dose of roxadustat in Stage 3-5 CKD subjects with anemia not on dialysis over a 16-week treatment period. The study hypothesized that the primary efficacy endpoint (mean change from baseline in hemoglobin level between Week 12 and Week 16) in the lower starting dose group would be non-inferior to that in the standard starting dose group.
Following screening for eligibility, subjects were stratified by CKD stage (Stage 3, Stage 4, Stage 5) and randomized in a 1:1 ratio to either the lower starting dose group (50 mg TIW for subjects weighing < 60 kg and 70 mg TIW for subjects weighing ≥ 60 kg) or the standard starting dose group (70 mg TIW for subjects weighing < 60 kg and 100 mg TIW for subjects weighing ≥ 60 kg). Roxadustat doses were adjusted during treatment according to the approved dose adjustment guidelines in the Package Insert.
A total of 254 subjects were randomized, of whom 250 subjects (126 in the lower starting dose group and 124 in the standard starting dose group) were treated. Of these, 249 subjects (126 in the lower starting dose group and 123 in the standard starting dose group) were included in the full analysis set (FAS), and 226 subjects (115 in the lower starting dose group and 111 in the standard starting dose group) were included in the per protocol set (PPS).
Baseline characteristics such as age, gender, and CKD duration were generally comparable between the two groups. Baseline Hb levels (89.4 ± 6.96 g/L in the lower starting dose group and 90.4 ± 6.83 g/L in the standard starting dose group) and proportions of subjects in each Hb subgroup (≥ 80 g/L, < 80 g/L) were comparable. Additionally, baseline levels of transferrin, transferrin saturation, serum iron, and total iron-binding capacity were comparable between two groups.
In the PPS, the least squares mean for the primary efficacy endpoint (change from baseline in mean hemoglobin level between Week 12 and Week 16) was 21.57 g/L for subjects in the lower starting dose group and 26.35 g/L for subjects in the standard starting dose group. The difference between groups (2-sided 95% CI) was -4.78 g/L (-7.77, -1.79), with the lower limit being less than the preset non-inferiority margin of -5 g/L (see Table 5). For the secondary efficacy endpoint (proportion of subjects with mean Hb level in the range of 100-120 g/L between Week 12 and Week 16), the proportions were comparable between the lower starting dose group and the standard starting dose group, at 47.8% (55 subjects) and 47.7% (53 subjects), respectively, with an odds ratio of 1.158 (95% CI: 0.671, 1.996), and the difference was not statistically significant (P=0.5983) (see Table 6). Other secondary endpoints indicated that the overall magnitude of hemoglobin fluctuation was smaller in the lower starting dose group compared to the standard starting dose group.
Throughout the treatment period, the number and proportion of subjects experiencing an hemoglobin (Hb) rise > 20 g/L over any 4-week period (lower starting dose group vs. standard starting dose group: 51 subjects [40.5%] vs. 72 subjects [58.5%]), the number and proportion of subjects with Hb concentration > 120 g/L (lower starting dose group vs. standard starting dose group: 54 subjects [42.9%] vs. 78 subjects [63.4%]), and the number and proportion of subjects with Hb concentration > 130 g/L (lower starting dose group vs. standard starting dose group: 19 subjects [15.1%] vs. 39 subjects [31.7%]) were lower in the lower starting dose group compared to the standard starting dose group (P < 0.05).
Subgroup analyses based on the primary endpoint showed that in the lower starting dose group, the change from baseline in mean hemoglobin level between Week 12 and Week 16 in Stage 5 CKD subjects with anemia (17.28 g/L) was numerically smaller than that in subjects with Stage 3 (25.41 g/L) and Stage 4 (23.91 g/L) CKD, and this trend was not reflected in the standard starting dose group. These results suggest that the lower starting dose may be more suitable for patients with Stage 3-4 CKD, while the standard starting dose may be more effective for achieving target hemoglobin levels in patients with Stage 5 CKD.
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Click on icon to see table/diagram/imagePharmacokinetics: Roxadustat PK data were obtained from a single- and multiple-dose escalation study in Chinese healthy subjects (dose range 40 to 200 mg), as well as from PK subgroup studies in a China phase 2 study (hemodialysis patients) and two China phase 3 studies in China (one in NDD CKD patients and one in CKD patients undergoing peritoneal dialysis). Additionally, PK data were collected from a bioequivalence (BE) study in China and a BE study conducted in Chinese subjects in Singapore. Other PK data concerning dose escalation, drug-drug interactions, human mass balance, food effects, bioequivalence, and in vitro pharmacokinetics were obtained from various studies conducted in the US, Europe, and Japan.
Absorption: Roxadustat is rapidly absorbed after oral administration, with median time for reaching the maximum plasma concentration at 2 hours post dose in the fasted state. Roxadustat plasma exposure (Cmax and AUC) is dose-proportional within the recommended therapeutic dose range.
The mean elimination half-life is approximately 8-11 hours in healthy subjects, around 12 hours in NDD CKD patients, and approximately 10-12 hours in DD patients. No significant drug accumulation was observed when roxadustat was administered three times per week at the recommended dose.
After a high-calorie, high-fat breakfast including dairy products, roxadustat AUC remained unchanged, while Cmax decreased by 25%. Roxadustat can be taken with or without food.
Distribution: Roxadustat is highly bound to human plasma proteins (> 98%), predominantly to albumin. Hemodialysis or peritoneal dialysis does not significantly affect the removal of Roxadustat.
Metabolism: Roxadustat is primarily metabolized in vivo by UGT1A9 and CYP2C8, with major metabolites including roxadustat-O-glucuronide and hydroxy-roxadustat.
In vitro studies assessing CYP450 metabolic enzyme phenotyping evaluated a range of common CYP enzymes (CYP1A1, 1A2, 2A6, 1B1, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5). Results indicated that CYP2C8 is the primary enzyme responsible for converting roxadustat to hydroxy-roxadustat in the human liver.
In vitro UGT metabolic enzyme phenotyping studies assessed a range of common UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, and 2B17). These studies found that UGT1A9 is the major enzyme responsible for the glucuronidation of roxadustat in the human liver. Additionally, in vitro studies showed that O-glucuronidation activity of roxadustat was detectable in both human liver and renal microsomes. Although in vitro studies showed that rUGT1A7 and rUGT1A8 play a role in roxadustat metabolism, given that both enzymes were usually outside the liver and their effects could not be verified by correlation analysis of human liver microsomes, it was suggested that these enzymes may be involved in the renal glucuronidation of roxadustat.
Elimination: When radiolabelled roxadustat was administered orally in healthy subjects, the mean recovery rate of radioactivity was approximately 96% (50% in feces, 46% in urine). The majority of radioactivity in plasma (≥ 83%) was attributed to unchanged roxadustat. No major metabolites were detected in plasma.
Special Population: Geriatrics: In elderly subjects (≥ 65 years old), roxadustat Cmax and AUCinf increased by 15% and 23%, respectively, compared to younger subjects (18 to 45 years old); these differences were not clinically significant. Changes in mean Hb from baseline, adverse events, and average roxadustat dose in subjects > 65 years were similar to subjects < 65 years in China Phase 3 clinical trial.
Patients with Hepatic Impairment: 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. The unbound fraction of roxadustat increased in subjects with moderate hepatic impairment compared to matched healthy subjects (1.1% vs. 0.8%), resulting in a significant increase in mean unbound exposure (70%).
The pharmacokinetics of roxadustat in patients with severe hepatic impairment (Child-Pugh Class C) have not been studied.
Cardiac Electrophysiology: In a thorough QT interval study in healthy subjects, roxadustat administered at doses of 2.75 mg/kg and 5.0 mg/kg (up to 510 mg) did not result in a prolongation of the QT interval after correction for heart rate.
Toxicology: Genotoxicity: Roxadustat was negative in the Ames test, the chromosome aberration test of human peripheral blood lymphocytes, and the bone marrow micronucleus test in mouse.
Reproductive and Developmental toxicity: In the rat fertility and early embryo developmental toxicity test, rats were orally administered Roxadustat at doses of 5, 15, and 30 mg/kg. Male rats were given the drug three times a week from 14 days before mating until the end of the study, while female rats were given the drug three times a week from 14 days before mating throughout the mating period, and once daily from day 0 to day 7 of pregnancy. At the 30 mg/kg dose, the weights of the epididymis and seminal vesicles in male rats decreased, but fertility was unaffected. Female fertility was also unaffected, although the number of stillbirths and the post-implantation loss rate increased at the 30 mg/kg dose; at 30 and 15 mg/kg doses, both male and female rats showed enlarged spleens and increases in spleen weight and coefficient, with female rats also showing increased liver weight.
In the rat embryo-fetal toxicity test, rats were orally administered with roxadustat at 5, 15, or 30 mg/kg/day from day 7 to day 17 of pregnancy. In the 30 mg/kg dose group, pregnant rats experienced reduced body weight early in dosing, decreased food intake during the dosing period, and decreased fetal weight. Additionally, the average weight of male fetal placentas increased and the incidence of cervical rib variations increased. In the rabbit embryo-fetal toxicity test, rabbits were orally administered with roxadustat at 15, 35, or 100 mg/kg/day from day 7 to day 17 of pregnancy. At the 35 and 100 mg/kg doses, the miscarriage rate increased, but no significant fetal abnormalities were observed.
In the rat perinatal toxicity study, rats were orally administered with roxadustat at doses of 5, 10, or 20 mg/kg/day from day 7 of pregnancy to day 20 of lactation. The 20 mg/kg dose led to decreased food intake and body weight in the mothers (F0 generation) during lactation period, a significant increase in hematocrit, and increased spleen weight and coefficient. At doses of 10 mg/kg and above, F1 generation offspring showed a dose-dependent increase in mortality and significant abnormal clinical signs. The evaluation of F1 generation after weaning was stopped at the 20 mg/kg dose level due to high mortality. At doses of 5 mg/kg and above, F1 generation offspring experienced reduced food intake and weight gain, delayed reflex development (e.g., righting reflex, auditory startle reflex), delayed sexual maturity, reduced passive avoidance, increased testicular weight and coefficient, and decreased spleen weight and coefficient. At the 10 mg/kg dose level, F1 generation showed decreased body weight and food intake during pregnancy. At doses of 5 and 10 mg/kg, some F2 generation offspring showed visible malformations, though the relevance to the drug remains unclear. Roxadustat can cross the placental barrier and is excreted in milk, with the concentration in milk significantly higher than maternal blood concentrations during the same period.
Carcinogenicity: Mice were orally administered with roxadustat at doses of 15, 30, or 60 mg/kg, and rats were orally administered with roxadustat at doses of 2.5, 5, or 10 mg/kg, three times a week for two consecutive years. No carcinogenic effects related to roxadustat were observed.
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