JESDUVROQ Film coated tablet Ref.[50977] Active ingredients: Daprodustat

Effects on Erythropoiesis

Daprodustat increases endogenous erythropoietin in a dose-dependent manner within 6 to 8 hours after administration. With repeat doses, peak increases in reticulocyte counts occur between 7 and 15 days, with subsequent increases in red blood cell production. New hemoglobin steady-state levels are reached several weeks (approximately 4 weeks in ESA-users and approximately 16-20 weeks in ESA-non-users) after initial administration.

Effects on Iron Metabolism and Utilization

Daprodustat increased serum transferrin and total iron binding capacity (TIBC) and decreased serum ferritin, transferrin saturation, and hepcidin when administered for 52 weeks in adults on dialysis with anemia due to CKD.

Cardiac Electrophysiology

At a dose 10 times the maximum recommended dose, daprodustat does not prolong the QTc interval to any clinically relevant extent.

Daprodustat exposure generally increases in a dose-proportional manner over the range of approved doses. Steady-state concentrations are achieved within 24-hours of dosing.

Absorption

Following oral administration, daprodustat is readily absorbed with median time to peak concentration (T_max) in healthy subjects ranging from 1 hour to 4 hours. The absolute bioavailability of daprodustat is 65%. Administration of JESDUVROQ with a high fat/high calorie meal did not significantly alter daprodustat exposure compared to administration in the fasted state.

Distribution

Daprodustat has an approximately equal distribution between plasma and blood cells (blood:plasma ratio of 1.23). Following intravenous dosing, the volume of distribution at steady-state in healthy subjects is 14.3 L. In vitro, plasma protein binding of daprodustat is >99%.

Elimination

The terminal elimination half-life of daprodustat is approximately 1 hour to 4 hours.

Metabolism

In vitro, daprodustat is primarily metabolized by CYP2C8 (95% contribution), with a minor contribution by CYP3A4 (5%).

Following oral or intravenous administration of radiolabeled daprodustat to healthy adults, approximately 40% of the total circulating radioactivity in plasma was daprodustat, and the remaining 60% was metabolites.

In patients treated with JESDUVROQ, the parent drug is the principal circulating component in plasma. Three metabolites, each accounting for more than 10% of circulating drug-related material, have been identified; in vitro and non-clinical data suggest that each may contribute to the pharmacologic response in vivo; however, the extent of this contribution is unknown.

Excretion

Mean clearance from plasma was 18.9 L/h, which correlates to blood clearance of 15 L/h and equates to a hepatic extraction of approximately 18%.

Within seven days of an oral dose of radiolabeled daprodustat, 74% of the radioactivity was recovered in the feces, and 21% in the urine. Approximately 99.5% of the dose was excreted as oxidative metabolites, with the rest accounted for by daprodustat.

Specific Populations

Elderly

Population pharmacokinetic analyses in adults with CKD (22 years to 93 years) showed that age did not influence the pharmacokinetics of daprodustat.

Renal Impairment

The steady-state exposure of daprodustat is similar in patients with normal renal function and those with varying degrees of renal impairment; daprodustat exposure is not significantly impacted by hemodialysis or peritoneal dialysis. The systemic exposure of daprodustat metabolites was higher in patients with Stage 3 to 5 CKD compared to those with normal renal function. Exposures of metabolites were higher on non-dialysis days compared to dialysis days.

Hepatic Impairment

Following administration of a single JESDUVROQ 6 mg dose, mean daprodustat C_max and AUC increased by 2-fold and unbound exposure increased by 2.3-fold in subjects with moderate hepatic impairment (Child‑Pugh Class B) compared to subjects with normal hepatic and renal function. For those with mild hepatic impairment (Child‑Pugh Class A), mean daprodustat C_max was similar while AUC increased by 1.5-fold and unbound C_max and AUC increased by 1.6 and 2.2-fold, respectively, compared to subjects with normal hepatic and renal function. The effect of severe hepatic impairment (Child‑Pugh Class C) on the pharmacokinetics of daprodustat is unknown as there have been no studies of JESDUVROQ in patients with severe hepatic impairment.

Drug Interaction Studies

Clinical Studies

Effect of CYP2C8 Inhibitors on the Pharmacokinetics of Daprodustat:

The concomitant administration of gemfibrozil 600 mg twice a day for 5 days (strong CYP2C8 inhibitor) with a single 100 mg dose of JESDUVROQ on Day 4 of gemfibrozil administration resulted in an 18.6‑fold increase in AUC_(0-∞) and a 3.9-fold increase in C_max of daprodustat [see Contraindications (4)].

The concomitant administration of trimethoprim 200 mg twice a day for 5 days (CYP2C8 weak inhibitor) and 25 mg single dose of JESDUVROQ on Day 4 of trimethoprim administration resulted in a 1.5-fold increase in AUC_(0-∞) and a 1.3‑fold increase in C_max of daprodustat.

Daprodustat AUC and C_max are expected to increase at least 4-fold and 3-fold, respectively, following concomitant administration of daprodustat with clopidogrel 75 mg once daily (moderate CYP2C8 inhibitor).

Following 4 weeks of JESDUVROQ dosing, hemoglobin changes from baseline were similar in subjects with and without concomitant use of clopidogrel.

Effect of Daprodustat on the Pharmacokinetics of Other Drugs:

Clinical drug interaction studies showed that daprodustat inhibition of CYP2C8 and OATP1B1/OATP1B3 demonstrated no clinically significant effect on pioglitazone (CYP2C8 substrate) or rosuvastatin (OATP1B1/OATP1B3 substrate) C_max or AUC.

In vitro studies

Some oxidative metabolites of daprodustat are substrates of Organic Anion Transporter (OAT)1 or OAT3; however, the clinical significance of this is unknown. Daprodustat is a substrate of Breast Cancer Resistance Protein (BCRP); however, the risk of significant drug interactions between daprodustat and BCRP inhibitors is considered low given the absorption and metabolism profile of daprodustat.

Daprodustat is not an inducer of CYP1A2, CYP2B6 and CYP3A4. Daprodustat is not an inhibitor of P-glycoprotein (P-gp) and BCRP.

Daprodustat is not a substrate of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and P-gp. The major metabolites are not substrates of OATP1B1, OATP1B3, OATP2B1, Organic Cation Transporter (OCT)1, OCT2, Multidrug and Toxin Extrusion (MATE)1 and MATE2-K. Daprodustat and its major metabolites are not inhibitors of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, OATP1B1, OATP1B3, OATP2B1, OCT1, OAT1, OAT3, OCT2, MATE1 and MATE2-K.

Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice (approximating the MRHD based on body surface area).

Daprodustat was negative for mutagenic or clastogenic potential in the in vitro bacterial reverse mutation assay, the in vitro human lymphocyte chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.

In a fertility and early embryonic development study in rats, daprodustat was administered orally at doses of 2, 7, or 100 mg/kg/day in females, resulting in maternal toxicity of reduced body weight gain and decreased mean uterine weight (in the presence of polycythemia), associated with decreased number of corpora lutea, implantations, and live fetuses, and increased post-implantation loss at the dose of 100 mg/kg/day (41 times the MRHD based on body surface area).

14.1 Anemia Due to Chronic Kidney Disease in Adults on Dialysis

The efficacy and safety of JESDUVROQ were evaluated in 2,964 adults with anemia due to CKD on dialysis and receiving an ESA at the time of study entry in a randomized, sponsor-blind, active-controlled, global, multicenter, event-driven clinical trial (ASCEND-D; NCT02879305). Patients were stratified by dialysis type and were required to be on dialysis for at least 4 months prior to the first dose of JESDUVROQ. Patients on hemodialysis (HD) were randomized 1:1 to receive oral JESDUVROQ (n=1,316) or intravenous epoetin alfa (n=1,308) while patients on peritoneal dialysis (PD) were randomized 1:1 to receive oral JESDUVROQ (n=171) or subcutaneous darbepoetin alfa (n=169).

Key exclusion criteria included: ferritin ≤100 ng/ml (≤100 mcg/L), transferrin saturation ≤20% at screening; evidence of non-renal anemia; cardiovascular abnormalities (including myocardial infarction, acute coronary syndrome, stroke or transient ischemic attack within 4 weeks of screening, New York Heart Association (NYHA) Class IV heart failure, and uncontrolled hypertension); liver disease; history of malignancy within 2 years of screening; current treatment of cancer and complex kidney cyst.

Dosing in each treatment arm followed a protocol-specified adjustment algorithm to achieve and/or maintain a hemoglobin target of 10 to 11 g/dL. The starting dose of JESDUVROQ was 4 mg, 6 mg, 8 mg, or 12 mg orally once daily, based on prior ESA dose. The starting dose of either epoetin alfa (HD patients) or darbepoetin alfa (PD patients) was the same as the patient’s current dose rounded to the nearest study dose. Patients receiving other ESAs were switched to the epoetin alfa or darbepoetin alfa equivalent starting dose. The median doses at Week 52 were 6 mg per day for JESDUVROQ, 8,000 units per week for epoetin alfa, and 150 mcg every four weeks for darbepoetin alfa. Most patients (86%) were exposed to randomized treatment for greater than 6 months (median 26 months for JESDUVROQ and 26 months for rhEPO). The median number of dose adjustments from Day 1 to Week 28 was 2 (interquartile range: 1 to 3) for JESDUVROQ and 2 (interquartile range: 1 to 3) for rhEPO. The median number of dose adjustments from Week 28 to Week 52 was 1 (interquartile range: 1 to 2) for JESDUVROQ and 2 (interquartile range: 1 to 3) for rhEPO.

The mean age of the patients in this study was 57 years (range 18-95), 57% were males, 67% were Caucasian, 16% were Black, and 12% were Asian. In the US region, 39% of patients were Black. Approximately 25% of the population was Hispanic or Latino. The largest regions of enrollment were the US (29%) and Eastern Europe/South Africa (28%). Common comorbid conditions included hypertension (92%), hyperlipidemia (50%) and diabetes mellitus (42%).

Effects on Hemoglobin

The efficacy and safety of JESDUVROQ were evaluated as co-primary endpoints: the mean change in hemoglobin from baseline to the Evaluation Period (Weeks 28 to 52) and time to first adjudicated MACE (defined as all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke), using a non-inferiority comparison to rhEPO (epoetin alfa and darbepoetin alfa) for both endpoints.

The lower limit of the 95% confidence interval (CI) for the overall hemoglobin treatment difference was greater than the pre-specified non-inferiority margin of -0.75 g/dL, demonstrating non-inferiority of JESDUVROQ to rhEPO with respect to the mean change in hemoglobin between baseline and over the Evaluation Period (see Table 6). Results were similar in patients receiving either hemodialysis or peritoneal dialysis.

Table 6. Change in Hemoglobin in Adults with Anemia Due to Chronic Kidney Disease Receiving Dialysis: ASCEND-D Trial (ITT Analysis)^a:

CI = Confidence interval; Hgb = Hemoglobin; ITT = Intent to treat; rhEPO = Recombinant human erythropoietin; SD = Standard deviation; SE = Standard error.
^a Intent to Treat (ITT) analyses included observed and imputed values on and off treatment after randomization. Eight percent of patients had no observed hemoglobin during Weeks 28 to 52.
^b Hemodialysis patients received epoetin alfa and peritoneal dialysis patients received darbepoetin alfa.
^c Adjusted for multiplicity.
^d Mean Hgb change from baseline to Evaluation Period (EP): Weeks 28 to 52.
^e Adjusted for baseline covariates.
^f Not adjusted for multiplicity.

Cardiovascular Outcomes

The hazard ratio for the time to first occurrence of MACE, a composite of all-cause mortality, non‑fatal myocardial infarction, and non-fatal stroke, comparing JESDUVROQ to rhEPO was 0.93 (95% CI 0.81, 1.07) (Table 7). Non-inferiority of JESDUVROQ to rhEPO on MACE was achieved because the upper limit of the 95% CI for the MACE hazard ratio was less than the pre‑specified non-inferiority margin of 1.25.

Table 7. Major Adverse Cardiovascular Events in the ASCEND-D Trial (ITT Analysis)^a:

CI = Confidence interval; ITT = Intent to treat; MACE = Major adverse cardiovascular events; PY = Person Years; rhEPO = Recombinant human erythropoietin.
^a ITT analyses included events on and off treatment after randomization.
^b Hemodialysis patients received epoetin alfa; peritoneal dialysis patients received darbepoetin alfa.
^c Co-primary endpoint.
^d Component of composite endpoint.
^e Adjusted for baseline covariates.