Daprodustat - Indication, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Drug Overview:

Daprodustat is prescribed to adults with chronic kidney failure (a condition in which the kidneys gradually stop functioning altogether over time) who are currently getting hemodialysis for at least four months to treat anemia (a lower-than-normal level of red blood cells). Daprodustat belongs to a group of drugs known as HIF PH (hypoxia-inducible factor propyl hydroxylase) inhibitors. It functions by raising erythropoietin, a hormone required by the human body for making more red blood cells.

For Patients:

What Is Anemia in Chronic Kidney Diseases?

A frequent side effect of chronic kidney disease (CKD) is anemia. CKD is characterized by impaired blood filtration due to damaged kidneys. Wastes and fluid might accumulate in the body as a result of this harm. Other health issues might also result from CKD. Early kidney disease is less likely to cause anemia, and as the illness advances and more kidney function is lost, anemia frequently worsens.

How Is Daprodustat Used?

Daprodustat is available as an oral tablet. It is typically taken once daily, with or without food. Take Daprodustat every day at about the same time. Ask the doctor or chemist to explain any instructions on the prescription label. Daprodustat should be taken as prescribed. Never take it in larger or smaller amounts or more frequently than directed by the doctor. Tablets are not meant to be chewed, broken, or crushed. Instead, it should be swallowed as a whole tablet. Depending on the results of the lab tests, the doctor may need to modify the Daprodustat dosage from time to time. Anemia is not cured by Daprodustat, but it can be controlled. Daprodustat should not be stopped without consulting the doctor.

What Should the Patient Inform the Doctor Before Taking Daprodustat?

• If the patient is allergic to Daprodustat or its ingredients. The patient must consult the doctor to know about the ingredients of the Daprodustat before consuming it. They must also inform about allergy reactions to other medicines.

• If the patient is pregnant or thinking of conceiving a child or breastfeeding a child. Contact the doctor if pregnancy is positive during the treatment course of this medicine, as Daprodustat might harm the fetus. Breastfeeding is prohibited if the patient is on Daprodustat. They should also avoid breastfeeding for one week after stopping the drug.

• If the patient is hypertensive, the doctor must be informed. Daprodustat is not advised for patients who have high blood pressure.

• If the patient has or ever had cancer, liver disease, stomach ulcers, esophageal damage, or damage to the lining of the intestines.

• If the patient is having surgery, including dental surgery, the doctor or the dentist should be informed about the intake of Daprodustat.

• Daprodustat should not be taken with certain medications. Before beginning Daprodustat, make sure the doctor and chemist are aware of any medications the patient is taking or intends to take. Talk to the doctor or pharmacist before starting, stopping, or changing medicines while taking Daprodustat, as it may be necessary to change the dose or monitor more closely.

What Are the Side Effects of Daprodustat?

Daprodustat might have side effects. If any of the below-mentioned symptoms are severe or do not go away, consult the doctor immediately:

• Pain in the abdomen.

• Dizziness.

Some adverse effects may be very harmful. Seek medical care immediately if any of these symptoms occur:

• Nausea or vomiting.

• Blood in the vomit or stool.

• Black and tarry stools.

• Trouble swallowing.

• Pain in the throat or chest.

Storage and Disposal of the Drug:

• Keep this medicine tightly closed in the original container and out of the reach of children. Keep it at room temperature and out of the bathroom and other places with excessive heat and moisture.

• Unused medicines should be carefully disposed of to prevent ingestion by pets, children, and other people. One should not, however, dispose of the medication in the toilet. Instead, utilizing a medicine take-back program is the best way to get rid of the medication. To find out about take-back programs in one's area, speak with the chemist or the garbage or recycling department in the city.

For Doctors:

• Color - White to off-white.

• Chemical Name - Prolyl 4-hydroxylases (PH)1, PH2, and PH3. N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine

• Molecular Weight - 393.43.

• Melting Point - 162 to 163 degrees Celsius.

• Solubility - Poor solubility.

• Components of the Drug - Colloid silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, mannitol, and microcrystalline cellulose.

Mechanism of Action:

HIF-PH1, PH2, and PH3 are reversibly inhibited by Daprodustat (IC50 = Inhibitory concentration in the low nM range). As a result of this activity, HIF-1, and HIF-2 transcription factors are stabilized and accumulate in the nucleus, increasing the transcription of HIF-responsive genes like erythropoietin.

Pharmacodynamics:

• Effects on Erythropoiesis - Within six to eight hours of administration, Daprodustat increases endogenous erythropoietin in a dose-dependent manner. Repeated doses cause reticulocyte counts to increase to their maximum levels between seven and 15 days later, followed by an increase in red blood cell production. After initial administration, steady-state for new hemoglobin levels are attained several weeks later (roughly four weeks in erythropoiesis-stimulating agent users and roughly 16 to 20 weeks in erythropoiesis nonusers).

• Effects on the Utilization and Metabolism of Iron - When given for 52 weeks to adults on dialysis with chronic kidney-related disease-related anemia, Daprodustat increases serum transferrin, total iron binding capacity (TIBC), decreased serum ferritin, transferrin saturation, and hepcidin.

• Cardiac Electrophysiology - Daprodustat does not lengthen the QTc interval to any clinically significant degree at ten times the highest advised dose.

Over the range of permitted doses, Daprodustat exposure typically increases in a dose-proportional manner. Within 24 hours of administration, steady-state concentrations are attained.

• Absorption - Daprodustat is easily absorbed after oral administration in healthy subjects with average times to peak concentration (Tmax) varying from one to four hours. Daprodustat's bioavailability is 65 percent. Administering the drug along with high-fat and high-calorie food did not change the amount of Daprodustat that was exposed to the body when administered in a fasting condition.

• Distribution - With blood: plasma ratio of 1:23, Daprodustat has a roughly equal distribution of plasma and blood cells. The total volume of the distribution at a steady state in healthy subjects after intravenous dosing is 14.3 Liters. The protein binding capacity of Daprodustat is >99 percent in vitro.

• Elimination - The final half-life of Daprodustat is around one hour to four hours.

• Metabolism - Daprodustat is primarily metabolized in vitro by CYP2C8 (95 percent contribution), with CYP3A4 making up the remaining five percent for metabolism. According to a study, when radiolabeled Daprodustat was administered orally or intravenously to healthy adults, it was found that Daprodustat constituted around 40 percent of the total circulating radioactivity in plasma. The remaining 60 percent was made up of metabolites. The parent medication Darpodustat makes up the majority of the circulating plasma components in patients receiving treatment with the drug. Three metabolites were identified, each accounting for more than ten percent of the circulating drug. In vitro and non-clinical data indicate that each metabolite may contribute to the pharmacologic response in vivo; however, the magnitude of this contribution is unknown.

• Excretion - The average plasma clearance was 18.9 Liters/hour, which is comparable to blood clearance of 15 Liters/hour and liver extraction of roughly 18 percent. After an oral dose of radiolabeled Daprodustat, 74 percent of the radioactivity was recovered in the feces and 21 percent in the urine within seven days. Around 99.5 percent of the drug dose was removed from the body as oxidative metabolites, and Daprodustat made up for the remaining dose.

Warning and Precaution:

• Increased Chances of Death, Heart Attack, Stroke, Venous Thromboembolism, and Vascular Access Thrombosis - The use of Daprodustat raises the risk of potentially fatal arterial and venous thrombotic disorders like heart attack, strokes, venous thromboembolism, and vascular access thrombosis. These events are more likely to occur in patients with cardiovascular or cerebrovascular disease. Doctors should not use Daprodustat in patients who have experienced a myocardial infarction, stroke, or acute coronary syndrome within three months before the start of treatment with Daprodustat. These risks could be increased by a rise in hemoglobin of more than 1 g/dL over the course of two weeks. The risk for fatalities and arterial and venous thrombotic conditions is anticipated to rise further if hemoglobin levels are aimed at being higher than 11 g/dL. There is no known hemoglobin target level, Daprodustat dose, or dosing regimen that does not increase these risks. Doctors should use the smallest amount of Daprodustat necessary to decrease the requirement for transfusions of blood. In order to avoid excessive erythropoiesis, it is critical to follow dosing and hemoglobin monitoring recommendations. Encourage patients to seek help immediately if they experience signs and symptoms of the above-mentioned disease condition. In case of an occurrence, a doctor should evaluate and take action right away.

• Hospitalization Risk for Heart Failure - Prescribing Daprodustat by a doctor depends on the patient's history of heart failure. Spread awareness among the patients regarding the symptoms of heart failure and urge them to contact their doctor right away if anything worsens.

• Hypertension - Daprodustat is not advised in patients with uncontrolled blood pressure. Hypertensive crises, including hypertensive encephalopathy and seizures, have also been documented in patients taking Daprodustat. A patient must get their blood pressure regularly monitored. The healthcare worker should start or adjust the anti-hypertensive therapy in such patients as when necessary.

• Gastrointestinal - In patients who were treated with Daprodustat and rhEPO (recombinant human erythropoietin), serious gastrointestinal bleeding requiring red blood cell transfusions was reported. The risk increases in patients who have a history of gastrointestinal erosion, or peptic ulcer disease, increased risk of gastrointestinal erosion due to the use of medication, and who are tobacco and alcohol abusers. Remind the patients to seek immediate medical attention if they experience the symptoms and signs of gastrointestinal bleeding, gastric and esophageal erosions, or both.

• Serious Adverse Events in Anemic Patients With Chronic Kidney Disease Not Receiving Dialysis - It is not advised to use Daprodustat in this situation because its safety has not been established for the treatment of anemia caused by CKD in adults who are not on dialysis.

• Malignancy - Daprodustat has not been studied and is not advised in patients with active malignancies due to the possibility that elevated hypoxia-inducible factor (HIF)-1 levels could have detrimental effects on cancer growth.

Monitoring Treatment Response and Dose Modification:

After the start of treatment and after every drug dose adjustment, check hemoglobin every two weeks for the first month, then every four weeks. Consider the rate of rise, rate of fall, and variability of hemoglobin when adjusting Daprodustat doses.

• Doses of Daprodustat should not be increased more frequently than once every four weeks. Increase or decrease Daprodustat dosage by one dose level at a time if necessary.

• Reduce the Daprodustat dosage if hemoglobin rises quickly (for example, more than 1 g/dL (grams per deciliter) in two weeks or more than 2 g/dL in four weeks) or when it is higher than 11 g/dL.

• Stop using Daprodustat if hemoglobin rises above 12 g/dL. Once the hemoglobin falls within the desired range, the treatment can be restarted at a lower dose.

• If a clinically significant increase in hemoglobin level is not achieved after 24 weeks of therapy, treatment with Daprodustat should not be continued beyond that point. Prior to restarting therapy, alternate causes for a poor response should be investigated and treated.

• In patients with moderate hepatic impairment, the starting dose of Daprodustat needs to be reduced in half, with the exception of those that have a starting dose of 1 mg. It is not advised to use Daprodustat in people who have severe hepatic impairment.

• For patients taking Clopidogrel or a moderate CYP2C8 inhibitor, the starting dose of Daprodustat should be reduced to half unless their starting dose is already 1 mg. When starting or stopping Clopidogrel or a moderate CYP2C8 inhibitor during treatment with Daprodustat, keep an eye on hemoglobin and adjust the dose of Daprodustat.

Adverse Reactions:

There is more information about the following clinically important adverse reactions in the labeling:

• Increased chances of death, heart attack, stroke, venous thromboembolism, and vascular access thrombosis.

• Hospitalization in case of patients with heart failure.

• Hypertension.

• Erosion of the gastrointestinal tract.

Drug Use in Specific Population:

• Geriatric Population - According to population pharmacokinetic evaluations of adults (aged 22 to 93 years) with chronic kidney disease, Daprodustat pharmacokinetics were unaffected by age.

• Kidney Impairment - Hemodialysis or peritoneal dialysis has no appreciable effect on steady-state exposure to Daprodustat, which is the same in patients with normal renal function and those who have varying degrees of renal impairment. Patients with stage 3 to stage 5 chronic kidney illness had higher systemic exposure to Daprodustat metabolic products than those with normal renal function. Non-dialysis days had higher metabolite exposures when compared to dialysis days.

• Liver Impairment -

  • Child-Pugh Class B - Upon receiving a single dose of Daprodustat of 6 mg, subjects with moderate hepatic impairment (Child-Pugh Class B) experienced mean Daprodustat Cmax and AUC (area under the curve) to increase by 2 and unbound exposure to 2.3 times when compared to subjects with normal liver and kidney function.

  • Child-Pugh Class A - In comparison to subjects with normal hepatic and renal function, patients with mild hepatic impairment, Daprodustat had an average Cmax was the same for both of them while AUC raised 1.5-fold and unbound Cmax and AUC raised by 1.6 and 2.2 fold, respectively.

  • Child-Pugh Class C - Since Daprodustat has not been studied for individuals with severe forms of liver impairment, it is unknown how the pharmacokinetics of Daprodustat will affect extreme hepatic conditions (Child-Pugh Class C).

Drug Interaction Studies:

• Clinical Studies: Impact of CYP2C8 Inhibitors on Daprodustat Pharmacokinetics

  • Gemfibrozil, a potent CYP2C8 inhibitor, was administered (600 milligrams two times a day for five days) concurrently with a single 100 mg dose of Daprodustat on day four of Gemfibrozil administration. This caused an 18.6-fold increase in AUC and a 3.9-fold increase in the Cmax of Daprodustat.

  • When Trimethoprim (CYP2C8 weak inhibitor) 200 mg was given two times a day for five consecutive days along with 25 mg of Daprodustat On the fourth day of Trimethoprim administration, it caused an increase in 1.5 times in AUC and 1.3 times in Cmax of Daprodustat.

  • Following concurrent administration of Daprodustat and Clopidogrel 75 mg once daily (moderate CYP2C8 inhibitor), Daprodustat AUC and Cmax are anticipated to rise by at least 4-fold and 3-fold, respectively.

• Impact of Daprodustat on Other Pharmacokinetics of Other Drugs - Daprodustat's inhibition of CYP2C8 and OATP1B1/OATP1B3 was shown in clinical drug interaction studies to have no clinically significant impact on the Cmax or AUC of Pioglitazone (a CYP2C8 substrate) or Rosuvastatin (an OATP1B1/OATP1B3 substrate).

• In-Vitro Studies - The clinical significance of a few oxidative metabolites of Daprodustat, which are substrates of organic anion transporter (OAT)1 or OAT3, is not known. Despite the fact that Daprodustat is a substrate of the breast cancer resistance protein (BCRP), the risk of adverse reactions between the Daprodustat and BCRP inhibitors is regarded as low, given the metabolism and absorption profile of Daprodustat.

Non-Clinical Toxicology:

• Cancer Development, Mutagenesis, and Fertility Impairment -

  • Cancer Development or Carcinogenesis - A two-year carcinogenicity study presented that Daprodustat did not cause cancer in rats when it was provided at an oral dose of 0.02, 0.1, 0.8, 7 mg/kg/day (females) or 4 mg/kg/day (males). This dose was about three times the maximum recommended human dose (MRHD) based on the body surface area. Also, the drug was found to be non-carcinogenic when administered subcutaneously with human metabolites Daprodustat at 0.2, 0.8, or 3 mg/kg/day in mice.

  • Mutagenesis - In the in vivo rat bone marrow micronucleus assay, in vitro bacterial reverse mutation assay, and the in vitro human lymphocyte chromosomal aberration assay, Daprodustat was found to have no mutagenic or clastogenic potential.

  • Impairment of Fertility - Daprodustat being given orally to female rats in a study on birth rates and early embryonic growth at dosages of 2, 7, or 100 mg/kg/day. In the presence of polycythemia, it caused maternal toxicity at an amount of 100 mg/kg/day (41 times the MRHD calculated using the surface of the body area), which resulted in lower weight gain in the body and decreased mean uterine weight., linked to a reduced number of implantations, live fetuses, corpora lutea corpo, and increased post-implantation loss.

Indications and Usage:

Daprodustat is prescribed to treat anemia in adults who have had chronic kidney disease (CKD), and the treatment for chronic kidney disease is ongoing for at least four months.

Limitations of the Drug:

• Daprodustat is not used as a substitute for red blood cell transfusions in patients who need to have their anemia corrected right away.

• Daprodustat cannot improve the life quality, exhaustion, or well-being of the patient.

• Daprodustat is not used to treat anemia in chronic kidney disease individuals who are not on hemodialysis.

Storage, Supply, and Handling:

Daprodustat is present in doses of 1, 2, 4, 6, or 8 mg per Daprodustat tablet. It is stored between 20 and 25 degrees Celsius (68 and 77 degrees Fahrenheit). Drug travel is allowed between 15 and 30 degress Celsius (59 and 86 degrees Fahrenheit).

• Tablet Strength of 1 Mg - It comes in a bottle containing 30 tablets. It is a biconvex, round, gray, film-coated tablet with "GS KF" embossed on one side. The National Drug Code number (NDC) is (NDC 0173-0897-13).

• Tablet Strength of 2 Mg - It comes in a bottle containing 30 tablets. It is a round, yellow, biconvex, film-coated tablet with "GS V7" embossed on one side. The National Drug Code number (NDC) is (NDC 0173-0903-13).

• Tablet Strength of 4 Mg - It comes in a bottle containing 30 tablets. It is a white, biconvex, round film-coated tablet with a "GS 13" embossed on one side. The National Drug Code number (NDC) is (NDC 0173-0906-13).

• Tablet Strength of 6 Mg - It comes in a bottle containing 30 tablets. It is a pink, round, biconvex film-coated tablet with "GS IM" embossed on one side. The National Drug Code number (NDC) is (NDC 0173-0911-13).

• Tablet Strength of 8 Mg - It comes in a bottle containing 30 tablets. It is a biconvex, round, orange film-coated tablet with "GS 5E" embossed on one side. The National Drug Code number (NDC) is (NDC 0173-0914-13).

Clinical Trials:

• Anemia in Adults on Dialysis Due to Chronic Kidney Disease - A study was conducted on 2,964 adults who had anemia caused by chronic kidney disease and were on dialysis and at the same time were also treated with erythropoietin stimulating agents. The study was conducted to assess the effectiveness and safety of Daprodustat.

  • Type of Trial - A global, multicenter, event-driven, randomized, sponsor-blinded clinical trial was conducted.

  • Randomization - Patients were segregated according to the type of dialysis they were receiving. Also, the prime requisite was that prior to receiving the first dose of Daprodustat, patients must have had regular dialysis for at least four months. Patients receiving hemodialysis (HD) were randomly assigned to receive either oral Daprodustat or intravenous epoetin alfa (1:1 randomization), while those receiving peritoneal dialysis (PD) were randomly assigned to either oral Daprodustat or subcutaneous darbepoetin alfa (1:1 randomization)

  • Exclusion Criteria - The important exclusion criteria in the study included:

    • Ferritin level less than 100 ng/ml (≤100 mcg/L).

    • At the time of screening for study enrolment, transferrin saturation should have been less than 20 percent.

    • Presence of anemia (non-renal).

    • Abnormalities of the heart like stroke, ischemia, myocardial infarction, uncontrolled hypertension, and acute coronary syndrome.

    • Hepatic disorders.

    • Malignancy history (within a time frame of two years post-screening).

    • Ongoing cancer treatment.

    • Complex renal cyst.

  • Dosing - Each treatment arm's dosing was adjusted in accordance with the protocol in order to reach and/or maintain a hemoglobin target of 10 to 11 g/dL. Depending on the previous ESA dose, the starting dose of Daprodustat was 4 mg, 6 mg, 8 mg, or 12 mg, administered orally once daily. For patients with hemodialysis or peritoneal dialysis, the starting dose of either Epoetin alfa or Darbepoetin alfa was equal to the patient's current dose, rounded to the nearest study dose. The equivalent starting dose of Epoetin alfa or Darbepoetin alfa was administered to patients receiving other erythropoietin-stimulating agents. At week 52, the median doses for Daprodustat, Epoetin alfa, and Darbepoetin alfa were 150 mcg every four weeks and 8,000 units per week, respectively.

  • Duration of Treatment - The median duration of randomized treatment for patients (86 percent) who received Daprodustat and rhEPO was 26 months, respectively. For both Daprodustat and rhEPO, the median wide variety of dose changes from day one to week 28 changed into 2, with an interquartile range of 1 to 3. For Daprodustat and rhEPO, the median quantity of dose modifications from week 28 to week fifty-two changed into 1 and 2, respectively.

  • Age, Sex, and Race - The patients in this study had a mean age of 57 years (ranging between 18 to 95). 57 percent were males. 67 percent Caucasian, 16 percent Black, and 12 percent Asian. 39 percent of patients in the US were Black. Latinos made up about 25 percent of the total population. Eastern Europe or South Africa (28 percent), and the United States (29 percent) had the highest enrollment rates. Hyperlipidemia (50 percent), hypertension (92 percent), and diabetes mellitus (42 percent), are very common comorbid conditions.

  • The efficacy and safety of Daprodustat were evaluated as co-primary endpoints.