Table of Contents
Overview:
Seladelpar treats primary biliary cholangitis (PBC) in adults who have not responded well to Ursodeoxycholic acid (UDCA) or as a monotherapy in patients who cannot take UDCA. This indication is granted under accelerated approval due to decreased alkaline phosphatase (ALP). There has been no evidence of improved survival or prevention of hepatic decompensation episodes. Continued approval for this indication may be subject to verification and description of clinical benefits in confirmatory trials. The exact mechanism by which Seladelpar works as a treatment for PBC is unclear.
One pharmacological activity that may have therapeutic effects is the suppression of bile acid synthesis through the activation of peroxisome proliferator-activated receptor delta (PPARδ), a nuclear receptor found in most tissues, including the liver. Through the fibroblast growth factor 21 (FGF21)-dependent downregulation of CYP7A1 (cytochrome P7A1), a crucial enzyme for bile acid synthesis from cholesterol, PPARδ activation by Seladelpar lowers bile acid synthesis.
Limitations of Use:
Seladelpar is not advised for patients with decompensated cirrhosis (ascites, variceal hemorrhage, and hepatic encephalopathy). Transaminase level increases did not follow a similar trend while using Seladelpar 10 milligrams (mg) once a day. When starting treatment with Seladelpar, get baseline clinical and laboratory evaluations. Then, follow the patient by standard patient care. If the patient experiences symptoms that are compatible with clinical hepatitis, such as jaundice, pain in the right upper quadrant, eosinophilia, or worsening liver tests (ALT (alanine transaminase), AST (aspartate aminotransferase), ALP (alkaline phosphatase)), stop Seladelpar medication. If liver tests become worse after taking Seladelpar again, think about stopping it permanently. If biliary blockage is detected, stop Seladelpar and administer treatment as the physician prescribes.
Warnings:
Fractures:
Four percent of Seladelpar-treated patients suffered fractures, but none in placebo-treated patients. Therefore, the fracture risk should be considered when managing Seladelpar-treated patients, and current guidelines should monitor bone health.
Liver Test Abnormalities:
Seladelpar has been linked to dose-related increases in serum transaminase (AST and ALT) levels greater than three times the upper limit of normal (ULN) in PBC patients receiving 50 mg (milligrams) once daily (five times the recommended dosage) and 200 mg (20 times the recommended dosage) once daily.
Biliary Obstruction:
Avoid using it in patients with complete biliary obstruction. If biliary obstruction is suspected, discontinue the current dosing and treat as clinically indicated.
For Patients:
Why Is Seladerpar Prescribed?
Primary biliary cholangitis is treated with Seladelpar. It serves as the salt for lysine dihydrate. It is an agonist of the PPARδ receptor.
What Is Primary Biliary Cholangitis?
A liver condition called primary biliary cholangitis (PBC) affects the bile ducts that pass through the liver. It gradually weakens those bile ducts, which makes bile passage more difficult. When bile builds up within the liver, the tissues sustain harm.
Considerations for Dosing:
When starting treatment, get baseline liver evaluations in the form of clinical and laboratory results. Then, follow up with regular patient management.
Side Effects:
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Serum creatinine elevated.
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Headache.
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Abdominal pain.
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Nausea.
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Abdominal distension.
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Dizziness.
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Fractures.
Oral Administration:
The medication can be taken with or without food.
Storage:
Store at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit); excursions permitted to 15 to 30 degrees (59 to 86 degrees Fahrenheit).
Overdose:
PBC patients who received five times or 20 times the authorized dosage of Seladelpar reported elevations in creatine phosphokinase, muscle soreness, and increased liver transaminases; these side effects disappeared after the medication was stopped. There is no specific Seladelpar overdose therapy. When necessary, the patient should get general supportive care. When necessary, emesis or stomach lavage should remove unabsorbed medication; standard safety procedures should be followed to keep the airway open. Seladelpar is strongly linked to plasma proteins; hence, hemodialysis is not a viable option.
For Doctors:
Indications:
Primary Biliary Cholangitis
Recommended for people with primary biliary cholangitis (PBC) who do not respond well to Ursodeoxycholic acid (UDCA) or as a monotherapy if UDCA 10 mg orally per day is intolerable.
Dosage Forms and Strengths
- Dose: 10 milligrams per capsule.
Dosage Modifications:
1. Administration Along With Bile Acid Sequestrants:
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Administer Seladelpar at least four hours before or after taking bile acid sequestrants or at the greatest possible interval.
2. Renal Impairment:
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Mild, Moderate, or Severe: No dosage adjustment is recommended.
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ESRD on Dialysis: No studies have been performed on this subject.
3. Hepatic Impairment:
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Mild (Child-Pugh A): No dosage adjustment is required.
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Decompensated Cirrhosis: Safety and efficacy are not yet established; it is not recommended for decompensated cirrhosis (ascites, variceal bleeding, hepatic encephalopathy). Monitor patients with cirrhosis for chances of decompensation. Consider discontinuing if it progresses to moderate or severe impairment (Child-Pugh B or C).
What Are the Pharmacological Aspects of Seladelpar?
Mechanism of Action
A PPAR-delta (δ) agonist, Seladelpar, is activated by peroxisome proliferators. Nonetheless, nothing is known about the exact process by which Seladelpar treats PBC patients. One pharmacological action that may have therapeutic implications is suppressing bile acid production by activating the nuclear receptor PPARδ found in most tissues, including the liver. Published research demonstrates that Seladelpar's activation of PPARδ lowers the synthesis of bile acids by downregulating CYP7A1, the primary enzyme involved in the synthesis of bile acids from cholesterol, in a manner that is dependent on Fibroblast Growth Factor 21 (FGF21).
Pharmacodynamics
Compared to the placebo group, patients with PBC treated with 10 mg of Seladelpar once daily (Trial 1) showed a larger decrease in mean ALP from baseline as early as one month into treatment, and this lower ALP was generally maintained until month 12. Another study found a dose-dependent decrease in mean ALP in PBC patients receiving Seladelpar at doses of two, five, or 10 mg once daily. For the electrophysiology of the heart, even at 20 times the prescribed dose of 10 mg, Seladelpar did not result in QTc interval prolongation, which was clinically significant.
Pharmacokinetics
CYP2C9 Poor Metabolizers:
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When taking a concurrent moderate to strong CYP3A4 inhibitor, watch for any negative side effects in CYP2C9 poor metabolizers.
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Seladelpar is a substrate for CYP2C9 and CYP3A4.
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When a moderate to strong CYP3A4 inhibitor is used concurrently with CYP2C9-poor metabolizers, patients might expect an increased Seladelpar AUC.
Absorption:
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Peak Plasma Time: 1.5 hours.
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Peak Plasma Concentration: 103 ng/mL (nanogram per milliliter).
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Steady state is achieved by day 4.
Distribution:
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Protein-bound: Greater than 99 percent.
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Volume of Distribution: 133.2 liters.
Metabolism: It is mainly metabolized in vitro by CYP2C9 and, to a lesser extent, by CYP2C8 and CYP3A4 to inactive metabolites.
Elimination
- Half-life: 3.8 to 6.7 hours (in patients with PCB).
- Clearance: 12 liters per hour.
Excretion:
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Urine: 73.4 percent (less than 0.01 percent unchanged).
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Feces: 19.5 percent (2.02 percent unchanged).
What Are the Drug Interactions of Seladelpar?
1. OAT3 inhibitors:
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The administration must be avoided.
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Organic Anion Transporter – 3 (OAT3) inhibitors may increase Seladelpar exposure.
2. Strong CYP2C9 Inhibitors:
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The administration must be avoided.
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Strong CYP2C9 inhibitors may increase Seladelpar exposure.
3. Bile Acid Sequestrants:
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The dose must be modified.
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Bile acid sequestrants can decrease Seladelpar absorption and systemic exposure, which may reduce efficacy.
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Administer Seladelpar at least four hours before or after administering a bile acid sequestrant or at the greatest possible interval.
4. Coadministration With Rifampin:
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It must be monitored.
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Rifampin may reduce Seladelpar exposure; monitor the biochemical response of Seladelpar if Rifampin is to be started during treatment.
5. Dual CYP2C9 and CYP3A4 Inhibitors:
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It must be monitored.
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Medications that are both a moderate CYP2C9 inhibitor and a moderate-to-strong CYP3A4 inhibitor may increase Seladelpar exposure.
6. CYP2C9 Poor Metabolizers Using Moderate-to-Strong CYP3A4 Inhibitors:
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It must be monitored.
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Coadministration of a moderate-to-strong CYP3A4 inhibitor in patients who are CYP2C9-poor metabolizers may increase Seladelpar exposure.
7. BCRP Inhibitors
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It must be monitored.
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BCRP (breast cancer resistance protein) inhibitors may increase Seladelpar exposure.
Specific Considerations:
1. Pregnancy:
There is not enough information available from human pregnancies involving Seladelpar to evaluate the drug's potential association with serious birth abnormalities, miscarriages, or other unfavorable outcomes for either the mother or the fetus. Based on AUC (area under the plasma concentration-time curve), Seladelpar administration in pregnant rats or rabbits resulted in no abnormalities or impacts on embryo-fetal survival up to 176 and 49 times, respectively, the recommended dose. Based on AUC, pregnant rabbits showed a reduction in fetal growth linked to maternal toxicity at 49 times the acceptable dose but not at three times the recommended level. In a study on rats' prenatal and postnatal development, postnatal growth and preweaning survival of offspring were decreased when the mother administered Seladelpar during organogenesis through lactation. Postnatal growth and preweaning survival of offspring were reduced at 115 times the recommended dose based on AUC in a prenatal and postnatal development study in rats with maternal dosing of Seladelpar during organogenesis through lactation, but not at the lower exposure of 16 times the recommended dose.
2. Lactation:
The effects of Seladelpar or its metabolite on the nursing infant, the production of milk, or the presence of these substances in human or animal milk are all undocumented. In addition to the mother's clinical requirement for Seladelpar and any potential negative effects on the breastfed newborn from Seladelpar or the underlying maternal ailment, it is important to take into account the developmental and health benefits of breastfeeding.
3. Use in Pediatrics:
It is unknown if Seladelpar is safe and effective for pediatric patients.
4. Use in Elderly:
Of the 128 patients in Trial 1 who received Seladelpar treatment, 29 (23 percent) were 65 or older, and two (two percent) were 75 or older. There were no discernible variations in safety or efficacy between patients aged 65 to 75 and younger adults. For patients 65 years of age and above, there is no need to change the dosage.
5. Renal Impairment:
The recommended dosage for individuals with normal renal function is the same for those with mild, moderate, or severe renal impairment. No research has been done on dialysis patients with end-stage renal disease. For PBC patients with mild hepatic impairment (Child-Pugh A), no dosage change is advised. It is unknown if Seladelpar is safe and effective in treating people with decompensated cirrhosis. It is not advised for individuals with decompensated cirrhosis (e.g., ascites, variceal hemorrhage, hepatic encephalopathy) to use Seladelpar.
Clinical Trials
Seladelpar is a selective PPAR-delta agonist. PPAR-delta activation in hepatocytes, Kupffer cells, and hepatic stellate cells is linked to decreased bile acid production, reduction of inflammatory cytokines, and inhibition of hepatic stellate cell proliferation and activation, among other key metabolic consequences.
In an international, open-label phase 2 trial, 121 patients with PBC who had an incomplete response or intolerance to UDCA were randomly assigned to Seladelpar five mg/day or 10 mg/day for 52 weeks. The study found dose-dependent decreases in serum ALP.
Surprisingly, 31 percent of patients in the 10 mg/day sample had normalized ALP levels, a response seen as early as week 12, with a 43 percent mean drop from baseline. The POISE criteria (ALP <1.67 × ULN, ≥15 percent decrease in ALP, and normal bilirubin) were met by 67 percent of patients on 10 mg/day. Total bilirubin levels remained steady, whereas transaminase activity decreased. As expected with PPAR agonists, median levels of bile acid precursor C4 were lower than baseline, as were mean low-density lipoprotein cholesterol and triglyceride levels. There were no significant safety signals, but two individuals had reversible transaminase increases.
Seladelpar is a strong and selective PPAR-δ agonist with anti-inflammatory and anti-cholestatic effects. An international open-label phase II research included 119 patients who received Seladelpar at doses of five mg or 10 mg/day for 52 weeks. Patients in the 5-mg group might be increased to 10 mg after the first 12 weeks (for noncirrhotic patients) or 26 weeks (for cirrhotic subjects). At 12 weeks, ALP had dropped by 34 and 43 percent from baseline in the 5- and 10-mg groups, respectively. These effects persisted after one year of treatment, resulting in 41 and 45 percent decreases.
After one year of treatment, 55 and 69 percent of patients achieved the composite endpoint (ALP < 1.67x ULN, with at least 15 percent reduction from baseline and normal TB level) in the 5-mg and 10-mg groups, respectively. ALP levels were normalized in 14 percent of patients in the 5-mg group and 33 percent in the 10-mg group. Significant moderate to severe itching improvements were observed, particularly in the 10-mg group. Data on 2-year follow-ups for 103 patients who entered this long-term follow-up phase show continuing improvement, with a mean ALP percent change from the baseline of 50 percent in the 10-mg group, although no safety signals were seen.
