Formulary Drug Review: Odevixibat

Abstract

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Pharmacy and Therapeutics Review

Generic Name: ODEVIXIBAT

Proprietary Name: Bylvay (Albireo Pharma, Inc)

Approval Rating: 1P (Orphan)

Therapeutic Class: Ileal Bile Acid Transporter Inhibitor

Similar Drugs: None

Sound-/Look-Alike Names: Byetta, Byvalson, Obeticholic Acid, Odefsey, Odesivimab

Indications

Odevixibat is indicated for the treatment of pruritus in patients 3 months and older with progressive familial intrahepatic cholestasis (PFIC).^1,2 Odevixibat may not be effective in PFIC type 2 (PFIC2) patients with ABCB11 variants resulting in nonfunctional or complete absence of bile salt export pump protein (BSEP-3). ²

Odevixibat is also being evaluated for the treatment of biliary atresia and pruritus associated with Alagille syndrome or primary biliary cholangitis.^3-6

PFIC is a heterogenous group of autosomal recessive disorders characterized by defective secretion of bile acids. PFIC typically presents during infancy or early childhood with pruritus, jaundice, elevated liver tests, and growth failure.^7-9 PFIC type 1 (PFIC1), also known as Byler disease, is caused by mutations in the ATP8B1 (FIC1) gene, while PFIC2 and PFIC type 3 (PFIC3) occur due to mutations in the ABCB11 (BSEP) and ABCB4 (MDR3) genes, respectively. ⁷ PFIC can progress to cirrhosis leading to liver failure and need for liver transplantation.^7-9 Mortality estimates range from 0% to 87%, with lower mortality rates largely dependent upon higher liver transplantation rates. ⁹ Pruritus is a common symptom of PFIC and can negatively impact patient sleep and quality of life.^6,7 Treatment options include ursodeoxycholic acid to improve biochemical parameters and pruritus and bile acid sequestrants (eg, cholestyramine), rifampicin, naltrexone, sertraline, and UV-B phototherapy for cholestatic pruritus.^7,10,11 Sedating antihistamines may be used for their sedative effects in nocturnal pruritus. ¹¹ Treatment-resistant pruritus is an indication for biliary diversion surgery and liver transplantation, even in the absence of end-stage liver disease.^6,7

Clinical Pharmacology

Odevixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT) (also known as apical sodium-dependent bile salt transporter [ASBT]). IBAT, a brush border membrane glycoprotein primarily expressed in the distal ileum, is responsible for the reabsorption of about 95% of intestinal bile acids that are then recirculated to the liver via portal venous blood. ⁵ IBAT inhibition decreases reabsorption of bile acids from the terminal ileum, resulting in a decrease in serum bile acids.^2,5

In animal models, odevixibat improved sclerosing cholangitis, reduced bile duct injury, reduced transaminase levels, reduced biliary bile acid secretion, and increased fecal biliary acid excretion. ¹²

Following administration of odevixibat 3 mg once daily for 1 week in healthy adults, plasma bile acids were reduced by 47% and fibroblast growth factor 19 was reduced by 76%. Plasma 7α-hydroxy-4-cholesten-3-one (C4) and fecal bile acids were also increased. ¹³ In patients with PFIC, serum bile acids were reduced from baseline within 4 to 8 weeks of initiation of odevixibat therapy, with decreased concentrations generally maintained over 24 weeks. The extent of decrease in serum bile acids was similar between odevixibat 40and 120 µg/kg doses. ²

The precise pathogenesis of cholestatic pruritus is unknown. Possible underlying mechanisms have been proposed, including bile acid accumulation, increased endogenous opioid levels, and elevations in lysophosphatidic acid. Genetic, environmental, and dietary factors may also be involved. ¹¹

Pharmacokinetics

Odevixibat is minimally absorbed following oral administration. Following oral administration of odevixibat 40 or 120 µg/kg once daily with food in pediatric patients 6 months to 17 years of age with PFIC, measurable odevixibat concentrations ranged from 0.06 to 0.72 ng/mL and were below the level of quantification (0.05 ng/mL) in the majority of plasma samples. Following single and repeated oral administration of odevixibat 0.1 to 3 mg in healthy adults, plasma concentrations were mostly below the limit of quantification, precluding calculation of AUC and C_max. Following a single 7.2 mg dose in healthy adults, mean C_max was 0.47 ng/mL and mean AUC_0-24 was 2.19 ng•h/mL; C_max was reached in 1 to 5 hours. Administration of either the capsules or oral pellets with food resulted in a delay in median T_max from 3 to 4.5 hours. Administration of the oral pellets with applesauce decreased C_max and AUC_0-24 by 39% and 35%, respectively, compared with administration of whole capsules under fasted conditions, effects regarded as not clinically significant. Administration of the oral capsules with a high-fat meal decreased C_max and AUC_0-24 by 72% and 62%, respectively, compared with administration under fasted conditions, effects regarded as not clinically significant. ²

Human plasma protein binding of odevixibat is greater than 99% in vitro. ²

Following a single oral dose of odevixibat 7.2 mg in healthy adults, mean half-life was 2.36 hours. In vitro, odevixibat was metabolized by monohydroxylation. Following a single radiolabeled odevixibat dose in healthy adults, 82.9% of the dose was recovered in the feces (97% unchanged) and less than 0.002% was recovered in the urine. ²

Comparative Efficacy

Indication: Pruritus Associated With Progressive Familial Intrahepatic Cholestasis

Guidelines

• Guideline: Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases

• Reference: American Association for the Study of Liver Diseases, 2019 ¹⁰

• Comments: The guidelines on management of primary biliary cholangitis include recommendations for symptomatic management of cholestatic pruritus. Bile acid sequestrants (cholestyramine, colestipol, and colesevelam) are recommended as initial therapy. For pruritus refractory to bile acid sequestrants, rifampicin, an oral opiate antagonist (eg, naltrexone), or sertraline can be used. The guideline notes that newer agents under evaluation for the treatment of cholestatic pruritus include peroxisome proliferator activator receptor (PPAR) agonists, IBAT inhibitors, and autotaxin inhibitors. Guidelines for the management of PFIC or cholestatic pruritus associated specifically with PFIC are not available.

Studies

• Drug: Odevixibat vs Placebo

• Reference: FDA 2021; Thompson RJ, et al, 2020 (PEDFIC 1 trial; A4250-005)^2,8,14,15

• Study Design: Phase 3, randomized, double-blind, placebo-controlled, multicenter study

• Study Funding: Albireo

• Patients: 62 pediatric patients (6 months-17 years of age) with genetically confirmed PFIC1 or PFIC2, elevated serum bile acid levels (at least 100 µmol/L), and significant pruritus (defined as a mean scratching score of at least 2 on the observer-reported 5-point ordinal response scale, with 0 indicating no scratching and 4 indicating worse possible scratching). Exclusion criteria included variants in the ABCB11 gene that predict nonfunction or complete absence of the BSEP protein; prior hepatic decompensation events; liver transplant; other concomitant liver disease; international normalized ratio (INR) greater than 1.4; or ALT or total bilirubin greater than 10 times the ULN. Median patient age was 3.2 years (mean age, 4.3 years; range, 0.5-15.9 years); 3 patients were older than 12 years; 50% were male; 84% were White; and 27% had PFIC1 and 73% had PFIC2.

• Intervention: Patients were randomized 1:1:1 to placebo (n = 20), odevixibat 40 µg/kg (n = 23), or odevixibat 120 µg/kg (n = 19) administered once daily with a meal in the morning for 24 weeks. For patients weighing less than 19.5 kg or who could not swallow the whole capsule, study drug was sprinkled on soft food. Randomization was stratified by PFIC class (types 1 and 2) and age (6 months-5 years, 6-12 years, or 13-17 years). Patients who completed the 24-week treatment period and the day 168 visit could enroll in a 72-week open-label extension trial in which all patients received odevixibat 120 µg/kg/day.

• Results:

• Primary End Point(s):

  • ● Mean proportion of positive pruritus assessments over the 24-week treatment period based on the manufacturer’s observer-reported outcome instrument:

    • ○ Defined as a scratching score of 1 or less or at least a 1-point decrease from baseline (protocol-specified primary end point): 58.3% with odevixibat 40 µg/kg (mean difference from placebo, 28.2% [95% CI, 9.8%-46.6%]; P = .003), 51.8% with odevixibat 120 µg/kg (mean difference from placebo, 21.7% [95% CI, 1.9%-41.5%]; P = .033), and 30.1% with placebo.
    • ○ Defined as a score of 0 (no scratching) or 1 (a little scratching) (FDA alternative primary end point): 35.4% with odevixibat 40 µg/kg (mean difference from placebo, 22.2% [95% CI, 4.7%-39.6%]; P = .0069), 30.1% with odevixibat 120 µg/kg (mean difference from placebo, 16.9% [95% CI, −2% to 35.7%]; P = .039), and 13.2% with placebo.
  • ● Proportion of patients with a serum bile acid response (defined as at least a 70% reduction in serum bile acid level from baseline or a serum bile acid level of 70 µmol/L or less) at week 24: 43.5% with odevixibat 40 µg/kg (P < .001 vs placebo), 21.1% with odevixibat 120 µg/kg (P = .035), and 0% with placebo. Bile acid reduction was the primary outcome for Europe and the rest of the world but a secondary outcome in the United States.
• Secondary End Point(s):

  • ● Mean change in serum bile acid level from baseline to weeks 22/24: −114.3 µmol/L (−38%) with odevixibat (both dose groups combined) and +13.1 µmol/L (+8%) with placebo. Mean change was −141.5 µmol/L (−54.5%) with odevixibat 40 µg/kg and −83.7 µmol (−19.4%) with odevixibat 120 µg/kg.
  • ● Mean change in pruritus score from baseline to end of treatment: −1.13 with odevixibat and −0.25 with placebo.
  • ● Mean change in worst weekly scratching score from baseline to month 6 (weeks 21-24): −1.1 with odevixibat 40 µg/kg (difference from placebo, −0.7 [95% CI, −1.4 to 0]), −1.1 with odevixibat 120 µg/kg (difference from placebo, −0.8 [95% CI, −1.5 to −0.1]), and −0.3 with placebo.
  • ● Change in serum ALT concentration: Not reported.
  • ● Change in growth: No difference in height increments was observed from baseline to week 24 in the 3 treatment groups; however, the study duration was insufficient to adequately assess changes in height.
  • ● Change in sleep disturbances: Not reported.
  • ● Number of patients undergoing biliary diversion surgery or liver transplantation: Not reported. One patient in the placebo group averted a scheduled biliary diversion surgery after switching to odevixibat 120 µg/kg in the extension trial and experiencing a response. Another patient originally in the placebo group did not experience a response to odevixibat 120 µg/kg in the extension trial and underwent elective liver transplantation.
• Other End Point(s):

  • ● Mean change in monthly average of daytime and nighttime scratching scores from baseline to month 6 (weeks 21-24): −1.2 with odevixibat 40 µg/kg (difference from placebo, −0.9 [95% CI, −1.5 to −0.2]), −0.8 with odevixibat 120 µg/kg (difference from placebo, −0.5 [95% CI, −1.2 to 0.2]), and −0.3 with placebo.
  • ● Mean change in monthly average of nighttime scratching scores from baseline to month 6 (weeks 21-24): −1.3 with odevixibat 40 µg/kg (difference from placebo, −0.8 [95% CI, −1.5 to −0.1]), −1.1 with odevixibat 120 µg/kg (difference from placebo, −0.6 [95% CI, −1.3 to 0.1]), and −0.5 with placebo.
  • ● Mean change in monthly average of daytime scratching scores from baseline to month 6 (weeks 21-24): −1.2 with odevixibat 40 µg/kg (difference from placebo, −0.9 [95% CI, −1.6 to −0.2]), −0.7 with odevixibat 120 µg/kg (difference from placebo, −0.4 [95% CI, −1.2 to 0.3]), and −0.2 with placebo.
  • ● Mean change in monthly average of worst daily scratching scores from baseline to month 6 (weeks 21-24): −1.3 with odevixibat 40 µg/kg (difference from placebo, −0.8 [95% CI, −1.5 to −0.1]), −1.1 with odevixibat 120 µg/kg (difference from placebo, −0.7 [95% CI, −1.4 to 0.1]), and −0.4 with placebo.
  • ● Change in Pediatric Quality of Life Inventory (PedsQL) questionnaire score: Mean total score improved with odevixibat compared with placebo (7.8 vs 0.5). Improvements were observed in all 4 PedsQL domains with odevixibat, while worsening was observed in 3 of 4 domains with placebo (physical: 7.8 vs −5.9; emotional: 14.1 vs 13.5; social: 3.6 vs −1; school functioning: 2.3 vs −5.3). Greater mean improvements were observed with odevixibat compared to placebo in family impact total score (14.5 vs 5.6) and domain scores (physical: 18.9 vs 8.1; emotional: 13.4 vs 7.9; social: 13.5 vs 8.5; cognitive: 16.4 vs 3.2; communication: 8.3 vs −4.4; worry: 12.8 vs 7.9; daily activities: 21.1 vs 9.3; and family relationships: 10.9 vs 2.1). ¹⁶

• Comments: Patients were enrolled at 33 sites in Australia, Belgium, Canada, France, Germany, Israel, Italy, the Netherlands, Poland, Saudi Arabia, Spain, Sweden, Turkey, the United Kingdom, and the United States; most patients were enrolled at sites in Europe. A single-item observer-reported instrument was used to measure severity of patients’ scratching as observed by their caregiver twice daily (once in the morning and once in the evening); scratching was assessed on a 5-point scale, with scores ranging from 0 (no scratching) to 4 (worst possible scratching). While both the 40 and 120 µg/kg doses met the prespecified end point over placebo, there was no evidence of a greater response with the higher odevixibat dose compared with the lower dose and no evidence that patients without a response to the 40 µg/kg dose responded to the 120 µg/kg dose. In an analysis that evaluated whether pretreatment serum bile acid parameters could predict response to odevixibat, the proportion of patients with treatment response (defined as a serum bile acid of 70 µmol/L or less or at least a 70% reduction in serum bile acid from baseline and/or at least a 1-point decrease in observer-reported pruritus score from baseline to end of treatment) was 69.6% (16 of 23 patients) with odevixibat 40 µg/kg and 42.1% (8 of 19) with odevixibat 120 µg/kg. The overall response rate was 57% (24 of 42). Before starting odevixibat, responders and nonresponders had a median total serum bile acid level of 194.1 and 269.3 µmol/L, respectively. Response was similar among patients receiving and not receiving ursodeoxycholic acid (56% vs 60%). The authors concluded that response rates in patients with PFIC type 1 or 2 were not associated with pretreatment serum bile acids concentrations or ursodeoxycholic acid use. ¹⁷

• An ongoing open-label extension study (PEDFIC 2; A4250-008) with a planned enrollment of 120 patients is evaluating odevixibat 120 µg/kg once daily for 72 weeks in children with PFIC1 or PFIC2 previously enrolled in PEDFIC 1 or children or adults with any type of genetically confirmed PFIC, elevated serum bile acid levels, and a history of significant pruritus. The primary outcome measures are change in pruritus and change in serum bile acids; secondary outcome measures include all-cause mortality, number of patients undergoing biliary diversion surgery or liver transplantation, change in growth, change in use of antipruritic medication, and change in measures of liver function (eg, AST). The estimated primary completion date is December 2021. ¹⁸ At the time of an interim report, 69 patients had received odevixibat in the extension study (19 treated with placebo in the original study, 34 who received odevixibat in the original study, and 16 newly enrolled patients) and 77 patients total had received odevixibat during either study with a median exposure of 37 weeks.^19-22 In pooled analysis of the 2 studies, patients with a bile acid response or pruritus response had greater changes from baseline in ALT and greater improvements in sleep parameters than nonresponders.^19,20 Improvements in serum bile acid levels, pruritus, growth, sleep parameters, and autotaxin and plasma C4 levels were sustained through 48 weeks of odevixibat treatment.^21,22

• Limitations: Study results of PEDFIC 1 are only available in the odevixibat prescribing information, on the ClinicalTrials.gov website, in an FDA review document, and as meeting abstracts. The PEDFIC 2 study is ongoing and interim results have only been reported in meeting abstracts. The primary end point has not been validated.

• Drug: Odevixibat

• Reference: Baumann U, et al, 2021 (A4250-003 study)^6,8

• Study Design: Phase 2, open-label, nonrandomized, dose-ranging, multicenter study

• Study Funding: Albireo AB

• Patients: 20 pediatric patients (1-18 years of age) with a diagnosis of pruritus due to chronic cholestatic disease (eg, PFIC, Alagille syndrome, primary sclerosing cholangitis, biliary atresia), elevated serum total bile acids at least 2 times the ULN, and a score of at least 3 on an 11-point visual analog scale (VAS) for itch averaged over 7 days. Patients with decompensated liver disease, liver transplant, structural abnormality of the GI tract, or pruritus caused by any condition other than chronic cholestasis were excluded. Patients could reenroll after completion of a dosing cohort. For the entire study cohort (24 enrollments of 20 patients), mean patient age was 6.5 years (range, 1-17 years); 62.5% were male; 8.3% had PFIC1 and 37.5% had PFIC2; 79.2% were receiving concomitant ursodeoxycholic acid and 58.3% were receiving rifampicin; and mean serum bile acid level was 235 µmol/L. The PFIC subgroup consisted of 10 patients with PFIC1, PFIC2, or PFIC3, of whom 3 reenrolled in a second dosing cohort for a total of 13 PFIC patient enrollments.

• Intervention: Odevixibat was administered first as a single dose; following a 14-day observation period, odevixibat was then administered once daily for 4 weeks at the same dose as the initial single dose. Six dose cohorts were planned: 10 µg/kg (n = 4), 30 µg/kg (n = 6), 60 µg/kg (n = 4), 100 µg/kg (n = 6), 200 µg/kg (n = 4), and 300 µg/kg. Each cohort was evaluated by a Data Safety and Monitoring Board (DSMB) before the cohort at the next higher dose was opened. After review of the fifth cohort (200 µg/kg), the DSMB recommended that further dose escalation beyond 200 µg/kg be discontinued; the sixth cohort opened but patients received doses less than 200 µg/kg. Patients in the first 3 cohorts could reenroll after completion of the initial cohort if they met eligibility criteria; there was a washout period of least 17 weeks between the last dose at the initial dose level and the first dose at the reenrolled dose level. Use of agents with effects on bile acid concentration in the GI tract or on GI motility (eg, bile acid sequestrants, sucralfate, opioid derivatives) was prohibited. Use of other agents or products with possible effects on GI motility (eg, selective serotonin reuptake inhibitors, tricyclic antidepressants, fiber supplementation, yogurt variants) and treatment with ursodeoxycholic acid, rifampicin, and antihistamines was allowed if the dose was stable for at least 4 weeks prior to screening and throughout the study.

• Results:

• Primary End Point(s):

  • ● Change in serum bile acid levels: 235 µmol/L at baseline to 112 µmol/L at end of treatment (mean change from baseline, −123 µmol/L; range, −394 to 15 µmol/L). Mean change was −31% in the 10 µg/kg cohort, −56% in the 30 µg/kg cohort, −63% in the 60 µg/kg cohort, −48% in the 100 µg/kg cohort, and −51% in the 200 µg/kg cohort.

    • ○ Mean change in the PFIC subgroup was −165.1 µmol/L (range, −394 to −1.2 µmol/L).
• Secondary End Point(s):

  • ● Change in VAS itch score (0 = no itching; 10 = worst possible itching): 6.2 at baseline to 3.9 at the end of treatment (mean change from baseline, −2.2; range, −6.1 to 1.7). Mean change from baseline was −1.5 in the 10 µg/kg cohort, −2 in the 30 µg/kg cohort, −1.9 in the 60 µg/kg cohort, −2.8 in the 100 µg/kg cohort, and −2.3 in the 200 µg/kg cohort. Correlation was observed between the change in serum bile acids and VAS itch score (P = .007).

    • ○ Mean change in the PFIC subgroup was −2.7 (range, −5.9 to 0.4).
  • ● Change in Whitington itch score (0 = no itching; 4 = cutaneous mutilation, hemorrhage, and scarring evident): 2.6 at baseline to 1.7 at the end of treatment (mean change from baseline, −0.8; range, −3 to 0.8). Mean change from baseline was 0 in the 10 µg/kg cohort, −0.8 in the 30 µg/kg cohort, −1.1 in the 60 µg/kg cohort, −1.4 in the 100 µg/kg cohort, and −0.5 in the 200 µg/kg cohort. Correlation was observed between the change in serum bile acids and the Whitington itch score (P = .005).

    • ○ Mean change in the PFIC subgroup was −1.1 (range, −3 to 0.1).
  • ● Change in Partial Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD) itch score (0 = no problem at all with itching; 10 = unbearable problem with itching): 6 at baseline to 3.8 at the end of treatment (mean change from baseline, −2; range, −6.7 to 1.6). Correlation was observed between the change in serum bile acids and PO-SCORAD itch score (P = .005).

    • ○ Mean change in the PFIC subgroup was −2.5 (range, −6 to 0.3).
  • ● Change in PO-SCORAD sleep disturbance score (0 = no problem at all with sleeping; 10 = unbearable problem with sleeping): 5.3 at baseline to 3.4 at the end of treatment (mean change from baseline, −1.8; range, −5.8 to 1.2). Correlation was observed between the change in serum bile acids and the PO-SCORAD sleep disturbance score (P = .004).

    • ○ Mean change in the PFIC subgroup was −2.4 (range, −5.8 to 0.4).
• Other End Point(s):

  • ● Change in level of autotaxin, an enzyme involved in the production of lysophosphatidic acid (a possible mediator of pruritus): 1890 ng/mL at baseline to 1483 ng/mL at the end of treatment (mean change from baseline, −389 ng/mL; range, 1996-1200 µmol/L). Correlation was observed between changes in plasma autotaxin levels and PO-SCORAD itch (P = .029) and sleep disturbance (P = .012) scores, but not VAS itch (P = .082) and Whitington itch (P = .073) scores.
  • ● Change in plasma C4 level: 6.6 ng/mL at baseline to 17.1 ng/mL at the end of treatment (mean change from baseline, +7.7 ng/mL; range, −1.4 to 60 ng/mL).
  • ● Change in fibroblast growth factor 19: 109 pg/mL at baseline to 85 pg/mL at the end of treatment (mean change from baseline, −30.7 pg/mL; range, −194 to 166 pg/mL).
  • ● Comments: The study was conducted at 7 centers in Germany, France, Sweden, Denmark, and the United Kingdom. One patient had an intronic splice site mutation in ABCB11 that was predicted to result in a complete absence of BSEP protein; this patient had a minimal response to the 100 µg/kg dose, suggesting that patients with little to no BSEP activity may be less likely to respond to therapy.

• Limitations: This was a nonrandomized study with a short duration; the study lacked a placebo or active comparator; enrollment included patients with various cholestatic liver diseases and was not specific to patients with PFIC; and baseline serum bile acid levels were highly variable.

Contraindications, Warnings, and Precautions

Contraindications

The odevixibat prescribing information states there are no contraindications to its use. ² Though not stated in the product labeling, a potential contraindication is hypersensitivity to odevixibat or any of its inactive ingredients (ie, hypromellose, microcrystalline cellulose, titanium dioxide, yellow iron oxide, red iron oxide [capsules only], ferrosoferric oxide/black iron oxide, shellac glaze).

Warnings and Precautions

Treatment-emergent elevations in liver tests or worsening of liver tests relative to baseline were observed with odevixibat in a clinical trial (PEDFIC 1). Elevations in AST, ALT, or total and direct bilirubin were most common (see Table 1). Obtain liver function tests at baseline and monitor during therapy. Dose reduction, treatment interruption, or discontinuation may be necessary for liver test abnormalities or clinical hepatitis. In the clinical trial, treatment interruption due to liver test abnormalities ranged from 3 to 124 days; no patient required permanent discontinuation of odevixibat due to liver test abnormalities. Odevixibat was not evaluated in patients with cirrhosis or clinically significant portal hypertension. Treatment with odevixibat should be permanently discontinued if a patient progresses to portal hypertension or experiences a hepatic decompensation event. ²

Table 1.

Treatment-Emergent Liver Test Abnormalities in the PEDFIC 1 Study. ²

Abnormality relative to baseline	Placebo (n = 20)	Odevixibat 40 µg/kg (n = 23)	Odevixibat 120 µg/kg (n = 19)	Total odevixibat (n = 42)
ALT increased by ≥150 units/L	0%	8.7%	10.5%	9.5%
AST increased by ≥150 units/L	0%	4.3%	15.8%	9.5%
Total bilirubin increased by ≥2 mg/dL	5%	17.4%	5.3%	11.9%
Direct bilirubin increased by ≥1 mg/dL	10%	21.7%	10.5%	16.7%

Diarrhea occurred more frequently in odevixibat-treated patients than placebo-treated patients (39% of patients in the odevixibat 40 µg/kg/day group and 21% in the odevixibat 120 µg/kg/day group compared with 10% of the placebo group). Treatment interruption due to diarrhea occurred in 2 patients experiencing 3 events during treatment with 120 µg/kg/day; treatment interruption ranged from 3 to 7 days. One patient withdrew from the study due to persistent diarrhea. If diarrhea occurs, monitor patients for dehydration and treat promptly. Interrupt odevixibat therapy if a patient experiences persistent diarrhea. When diarrhea resolves, therapy can be restarted at 40 µg/kg/day and the dose increased as tolerated. If diarrhea persists and no alternate etiology is identified, discontinue odevixibat. ²

Patients with PFIC may have fat-soluble deficiency at baseline, and odevixibat may affect absorption of fat-soluble vitamins. In the PEDFIC 1 clinical study, new-onset or worsening of existing fat-soluble vitamin deficiency was reported in 1 (5%) placebo-treated patient and 3 (16%) odevixibat 120 µg/kg/day-treated patients; no patients treated with odevixibat 40 µg/kg/day had new-onset or worsening of existing fat-soluble vitamin deficiency. Obtain serum fat-soluble vitamin levels (A, D, E, and K [measured using INR levels]) at baseline and monitor during therapy, along with clinical manifestations of fat-soluble vitamin deficiency. If deficiency persists or worsens despite adequate fat-soluble vitamin supplementation, discontinue odevixibat. ²

There are no adequate and well-controlled studies of odevixibat use during pregnancy. Based on findings from animal studies, odevixibat may cause fetal ham, including cardiac malformations, when administered during pregnancy. ²

As a condition of its approval, the manufacturer is required to conduct a worldwide descriptive study collecting prospective and retrospective data in patients prescribed odevixibat during pregnancy and/or breastfeeding to assess risk of maternal complications, adverse effects on the developing fetus and neonate, and adverse effects on the infant. Infant outcomes are to be assessed at least through the first year of life. The study will collect information for a minimum of 10 years. ¹

There are no data regarding the presence of odevixibat in human milk or its effects on breastfeeding infants or milk production. However, odevixibat has low absorption following oral administration, and breastfeeding is not expected to result in exposure of the infant to odevixibat at recommended doses. The manufacturer recommends that the developmental and health benefits of breastfeeding should be considered along with the patient’s clinical need for odevixibat and any potential adverse effects on the breastfeeding child from odevixibat or from the underlying maternal condition. Odevixibat may reduce absorption of fat-soluble vitamins; monitor fat-soluble vitamin levels and increase intake if a maternal deficiency is observed during breastfeeding. ²

Safety and effectiveness of odevixibat have been established in pediatric patients 3 months to 17 years of age for the treatment of pruritus in PFIC. The safety and effectiveness of odevixibat have not been established in patients younger than 3 months. ²

Adverse Reactions

The most common adverse reactions (incidence at least 10%) associated with odevixibat in the PEDFIC 1 trial were liver test abnormalities, diarrhea, abdominal pain, vomiting, and fat-soluble vitamin deficiency. ² See Table 2 for adverse reactions reported in at least 2% of patients treated with odevixibat and at a higher incidence than with placebo.

Table 2.

Adverse Reactions with Odevixibat (Occurring in ≥2% of Patients and More Frequently Than With Placebo) in PEDFIC 1 Trial. ²

Adverse reaction	Odevixibat 40 µg/kg/day (n = 23)	Odevixibat 120 µg/kg/day (n = 19)	Placebo (n = 20)
Diarrhea	39.1%	21.1%	10%
Vomiting	17.4%	15.8%	0%
Transaminases increased	13%	21.1%	5%
Abdominal pain	13%	15.8%	0%
Blood bilirubin increased	13%	10.5%	10%
Fracture	4.3%	0%	0%
Fat-soluble vitamin deficiency	0%	15.8%	5%
Splenomegaly	0%	10.5%	0%
Cholelithiasis	0%	5.3%	0%
Dehydration	0%	5.3%	0%

Drug Interactions

Bile acid sequestrants (eg, cholestyramine, colesevelam, or colestipol) should be administered at least 4 hours before or 4 hours after administration of odevixibat. Bile acid sequestrants may bind odevixibat in the gut, reducing efficacy. ²

Odevixibat is a substrate of P-gp but is not a substrate of BCRP. Administration with itraconazole, a strong P-gp inhibitor, increased odevixibat C_max by 52% and AUC by 66%, effects not expected to be clinically meaningful.^2,23 In in vitro studies, odevixibat was not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6, was not an inducer of CYP1A2, 2B6, or 3A4, and did not inhibit P-gp, BCRP, OAT1B1, OAT1B3, OAT1, OAT3, OCT2, MATE1, or MATE2K transporters. Administration with oral midazolam, a CYP3A4 substrate, decreased midazolam AUC by 29%, which is not expected to have a clinically meaningful effect. ²

Recommended Monitoring

Obtain liver tests (eg, ALT, AST, total bilirubin, direct bilirubin, INR) at baseline and monitor during treatment with odevixibat. Establish the baseline pattern of variability of liver tests prior to initiating therapy so that potential signs of liver injury can be identified. Therapy should be interrupted if new-onset liver test abnormalities occur or symptoms consistent with hepatitis are observed. Obtain serum fat-soluble vitamin levels at baseline and monitor during treatment. ²

Dosing

The recommended odevixibat dosage is 40 µg/kg once daily in the morning with a meal. If there is no improvement in pruritus after 3 months, the dosage may be increased in 40 µg/kg increments up to 120 µg/kg once daily. The total daily dose should not exceed 6 mg. ² See Table 3 for the recommended weight-based total daily dose for the 40 µg/kg once daily dosage.

Table 3.

Recommended Weight-Based Total Daily Dosage for Odevixibat 40 µg/kg/day. ²

Body weight	Total daily dose
≤7.4 kg	200 mg
7.5-12.4 kg	400 mg
12.5-17.4 kg	600 mg
17.5-25.4 kg	800 mg
25.5-35.4 kg	1200 mg
35.5-45.4 kg	1600 mg
45.5-55.4 kg	2000 mg
≥55.5 kg	2400 mg

Odevixibat is available as oral pellets and capsules. The oral pellets are intended for use in patients who weigh less than 19.5 kg and the capsules are intended for use in patients who weigh at least 19.5 kg. ²

The oral pellets should be mixed into a small amount (up to 30 mL) of room temperature or colder soft food (applesauce, oatmeal, banana or carrot puree, or chocolate or rice pudding). Open the shell containing the oral pellets and empty the contents into a bowl of soft food, tapping the shell to ensure all the contents are dispersed; mix until well dispersed and administer the entire dose immediately, followed by water. The shell containing the oral pellets should not be swallowed. Do not mix in liquids (eg, breast milk, formula, water); patients who are exclusively on liquid food should not receive odevixibat. ²

The oral capsules should be swallowed whole with a glass of water; do not crush or chew. For patients unable to swallow the capsules whole, the capsules may be opened and the contents sprinkled and mixed with a small amount of soft food (following the same process used for the oral pellets). ²

For patients taking bile acid sequestrants, odevixibat should be taken at least 4 hours before or 4 hours after taking a bile acid sequestrant. ²

Interrupt odevixibat therapy if new-onset liver test abnormalities occur or symptoms consistent with hepatitis develop. Once liver test abnormalities return to baseline or stabilize at a new baseline value, odevixibat may be restarted at 40 µg/kg and increased as tolerated. If liver test abnormalities return, consider permanently discontinuing odevixibat. Permanently discontinue odevixibat therapy if a patient experiences a hepatic decompensation event (eg, variceal hemorrhage, ascites, hepatic encephalopathy). ²

Product Availability and Storage

Odevixibat was approved by the FDA on July 20, 2021. ¹ Odevixibat is available as 400 and 1200 µg capsules supplied in bottles of 30 and as 200 and 600 µg oral pellets supplied in bottles of 30. ²

Store odevixibat capsules and oral pellets at 20°C to 25°C (68°F-77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). ²

Drug Safety/REMS

No REMS is required for odevixibat. ¹

Postmarketing safety studies required as a condition of approval include a prospective observational study to assess long-term safety of odevixibat over a 72-week treatment period and a 5-year registry-based study to collect data on the course of liver disease in patients treated long-term with odevixibat. ¹

Conclusion

Odevixibat, a reversible IBAT inhibitor, is indicated for the treatment of pruritus in patients 3 months and older with PFIC. It offers a treatment alternative, with a unique mechanism of action, in the treatment of cholestatic pruritus. Although improvement in pruritus and bile acid levels were observed, the precise mechanism by which odevixibat improves pruritus is not known, and efficacy was not observed in all forms of PFIC. In addition, dose-related responses were not observed. Additional efficacy information is necessary to determine an optimal dosage and the patient population most likely to respond to odevixibat therapy.