Description for Bylvay Test
BYLVAY (odevixibat) is a medication available in two different formulations: capsules and oral pellets. It is used for oral administration and contains the active ingredient odevixibat, which is an ileal bile acid transporter (IBAT) inhibitor. This active ingredient helps regulate the flow of bile acids in the body.
The chemical structure of odevixibat is (2S)-2-{[(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1λ6,2,5-benzothiadiazepin-8yl]oxy}acetamido)-2-(4-hydroxyphenyl)acetly]amino}butanoic acid. It is formulated as the sesquihydrate, which means it contains 1.5 molecules of water for every molecule of odevixibat sesquihydrate. The molecular formula is C37H48N4O8S2 x 1.5 H2O, and its molecular weight is 768.0 g/mol (anhydrous) or 740.9 g/mol (with water).
Odevixibat sesquihydrate appears as a white to off-white solid. Its solubility in aqueous solutions varies depending on the pH level, increasing with higher pH levels.
The available formulations of BYLVAY are:
Oral Pellets: These pellets contain odevixibat sesquihydrate and are equivalent to either 200 mcg or 600 mcg of odevixibat. The oral pellets also contain excipients such as hypromellose and microcrystalline cellulose. The capsule shells of the oral pellets are composed of hypromellose, titanium dioxide, and yellow iron oxide.
Capsules: The capsules also contain odevixibat sesquihydrate, but in different strengths. They are available in formulations equivalent to 400 mcg or 1200 mcg of odevixibat. The capsule shells consist of hypromellose, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink used on the capsules contains ferrosoferric oxide/black iron oxide and shellac glaze.
It's important to note that the specific dosage and usage instructions for BYLVAY should be determined by a healthcare professional. This information is provided for general knowledge and should not replace medical advice or guidance.
Warnings for Bylvay Test
Included as part of the PRECAUTIONS section.
Precautions for Bylvay Test
Based on the information provided, here are some warnings and precautions for the use of BYLVAY (odevixibat):
1. Liver Test Abnormalities: Patients enrolled in the PFIC and ALGS trials had abnormal liver tests at baseline. Treatment with BYLVAY may cause elevations in liver tests or worsening of liver tests compared to baseline. Liver tests should be obtained before starting BYLVAY and monitored periodically during treatment. Dose reduction or treatment interruption may be required if abnormalities occur. Persistent or recurrent liver test abnormalities may necessitate treatment discontinuation.
2. Diarrhea: Diarrhea was reported in patients receiving BYLVAY. If diarrhea occurs, it is important to monitor for dehydration and promptly treat it. BYLVAY dosing should be interrupted if a patient experiences persistent diarrhea. Treatment can be restarted at a lower dose when diarrhea resolves and increased as tolerated if appropriate. If diarrhea persists without an alternate cause identified, BYLVAY treatment should be stopped.
3. Fat-Soluble Vitamin (FSV) Deficiency: BYLVAY may affect the absorption of fat-soluble vitamins (vitamin A, D, E, and K). Patients with PFIC and ALGS may already have FSV deficiency at baseline. Serum FSV levels should be obtained before starting BYLVAY and monitored during treatment, along with any clinical manifestations. If FSV deficiency is diagnosed, supplementation with FSV should be initiated. BYLVAY should be discontinued if FSV deficiency persists or worsens despite adequate supplementation.
4. Pregnancy: BYLVAY may cause cardiac malformations when a fetus is exposed during pregnancy, based on findings from animal reproduction studies. There are no human data on the use of BYLVAY in pregnant individuals. Pregnant women exposed to BYLVAY, or their healthcare providers, should report BYLVAY exposure by calling the provided phone number.
5. Lactation: Odevixibat (the active ingredient in BYLVAY) has low absorption following oral administration, and breastfeeding is not expected to result in exposure of the infant to BYLVAY at recommended doses. However, there are no data on the presence of odevixibat in human milk or its effects on the breastfed infant. Monitoring of fat-soluble vitamin levels and increasing intake if deficiency is observed is recommended during lactation. The decision to use BYLVAY during breastfeeding should consider the benefits of breastfeeding and the mother's clinical need for the medication.
6. Pediatric Use: BYLVAY has been studied and approved for use in pediatric patients (3 months to 17 years of age) with pruritus associated with PFIC or ALGS. The safety and effectiveness of BYLVAY have not been established in pediatric patients less than 3 months of age (for PFIC) or less than 12 months of age (for ALGS).
7. Geriatric Use: Clinical studies of BYLVAY did not include patients aged 65 years and older. PFIC and ALGS are primarily diseases affecting pediatric and young adult patients.
8. Hepatic Impairment: The efficacy and safety of BYLVAY have not been established in PFIC and ALGS patients with clinically significant portal hypertension or decompensated cirrhosis.
It's important to note that this information is based on the provided text and may not encompass the full prescribing information for BYLVAY. For complete and accurate guidance, it is recommended to consult the medication's official prescribing information or consult a healthcare professional.
Clinical Pharmacology for Bylvay Test
Mechanism Of Action
Odevixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids (primarily the salt forms) from the terminal ileum.
Pruritus is a common symptom in patients with PFIC and ALGS; the pathophysiology of pruritus in patients with PFIC is not completely understood. Although the complete mechanism by which odevixibat improves pruritus in both PFIC and ALGS patients is unknown, it may involve inhibition of the IBAT, which results in decreased reuptake of bile salts, as observed by a decrease in serum bile acids [see CLINICAL PHARMACOLOGY].
Pharmacodynamics
Odevixibat reduces serum bile acids in patients with PFIC and ALGS.
In Trial 1, a 24-week, randomized, double-blind, placebo-controlled trial conducted in 62 patients with a confirmed diagnosis of PFIC type 1 or type 2, the majority of patients (88.7%) had elevated serum bile acids above 100 mcmol/L at baseline [see Clinical Studies]. Serum bile acids concentrations were reduced from baseline within 4-8 weeks of odevixibat treatment compared to placebo treatment. The decreased concentrations of serum bile acids fluctuated over time but generally were maintained during the treatment over 24 weeks. The extent of decrease in serum bile acids was similar between 40 and 120 mcg/kg.
Trial 3 is a 24-week, randomized, double-blind, placebo-controlled trial conducted in 52 patients with a confirmed diagnosis of ALGS who were administered treatment with BYLVAY 120 mcg/kg once daily [see Clinical Studies]. At baseline, serum bile acids were variable ranging from 93 to 510 mcmol/L. Serum bile acid concentrations were reduced from baseline as early as Week 4 of odevixibat treatment and the reduction was generally maintained during treatment over 24 weeks.
Pharmacokinetics
In pediatric patients with PFIC, 6 months to 17 years of age who received BYLVAY 40 mcg/kg or 120 mcg/kg once daily with food in the morning, the measurable odevixibat concentrations ranged from 0.06 to 0.72 ng/mL, and odevixibat concentrations were below the limit of quantification (0.05 ng/mL) in the majority of plasma samples.
In pediatric patients with ALGS who received BYLVAY 120 mcg/kg once daily with food in the morning, the measurable odevixibat concentrations ranged from 0.05 to 3.4 ng/mL.
Following single and repeated oral administration of odevixibat from 0.1 to 3 mg in healthy adults, plasma concentrations of odevixibat were mostly below the limit of quantification (0.05 ng/mL); therefore, AUC and peak plasma concentration (Cmax) could not be calculated.
Following a single administration of odevixibat 7.2 mg in healthy adults, the mean (%CV) Cmax and AUC0-24h were 0.47 ng/mL (34.8) and 2.19 ng·h/mL (36.2), respectively. No accumulation of odevixibat was observed following once-daily dosing.
Absorption
Odevixibat is minimally absorbed following oral administration. Following a single administration of odevixibat 7.2 mg in healthy adults, odevixibat Cmax is reached between 1 to 5 hours.
Sprinkle On Applesauce
When odevixibat 9.6 mg was administered after sprinkling the pellets on applesauce, decreases of 39% and 35% in Cmax and AUC0-24h, respectively, and delayed median Tmax from 3 hours to 4.5 hours were observed compared to administration of whole capsules (eight 1200 mcg capsules) under fasted conditions. The effect of sprinkling on soft food on systemic exposure is not clinically significant [see DOSAGE AND ADMINISTRATION].
Effect Of Food
Concomitant administration of a high-fat meal (800-1000 calories with approximately 50% of total caloric content of the meal from fat) with a single dose of odevixibat 9.6 mg delayed median Tmax from 3 hours to 4.5 hours and resulted in decreases of 72% and 62% in Cmax and AUC0-24h, respectively, compared to administration under fasted conditions in healthy adults. The effect of food on the changes of systemic exposures to odevixibat is not clinically significant [see DOSAGE AND ADMINISTRATION].
Distribution
Human plasma protein binding of odevixibat is greater than 99% in vitro.
Elimination
Following a single oral dose of 7.2 mg odevixibat in healthy adults, the mean half-life (t½) was 2.36 hours.
In vitro, odevixibat was metabolized via mono-hydroxylation.
Excretion
Following a single radiolabeled odevixibat 3 mg oral dose in healthy adults, 82.9% of the dose was recovered in feces (97% unchanged) and less than 0.002% in the urine.
Drug Interaction Studies
Effect Of Other Drugs On Odevixibat
Odevixibat is a substrate of P-glycoprotein (P-gp) but not a substrate of breast cancer resistance protein (BCRP).
Coadministration of itraconazole (a strong P-gp inhibitor) with a single dose of BYLVAY 7.2 mg increased odevixibat AUC0-24h by 66% and Cmax by 52%, which is not expected to have a clinically significant effect.
Effect Of Odevixibat On Other Drugs
In in vitro studies, odevixibat was not an inhibitor of CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 nor an inducer of CYP isoforms 1A2, 2B6, or 3A4.
Concomitant use of BYLVAY 7.2 mg once daily for 4 days with oral midazolam (a CYP3A4 substrate) in healthy adults decreased the AUC0-24h of midazolam and 1-OH midazolam by 29% and 13%, respectively, which is not expected to have a clinically relevant effect.
In in vitro studies, odevixibat did not inhibit the transporters P-gp; BCRP; organic anion transporter polypeptide 1B1 and 1B3(OATP1B1 and OATP1B3); organic anion transporter (OAT)1, OAT3; organic cation transporter 2 (OCT2), multidrug and toxin extrusion transporter 1 and 2K (MATE1 and MATE2K).
Pharmacogenomics
PFIC is a heterogenous disease caused by homozygous or compound heterozygous variants, with different PFIC subtypes occurring in the general population. PFIC2 is the most common subtype accounting for 37-90% of PFIC patients. PFIC1 is caused by variants in the aminophospholipid flippase (ATP8B1) gene, which encodes the Familial Intrahepatic Cholestasis 1 (FIC1) protein, while PFIC2 results from variants in the ABCB11 gene, which encodes the Bile Salt Export Pump (BSEP) protein. PFIC2 patients are further categorized into BSEP subgroups based on their specific variants. The BSEP-1 subgroup includes patients with at least one p.D482G (c.1445A>G) or p.E297G (c.890A>G) variant, BSEP-2 includes patients with at least one missense variant other than p.D482G or p.E297G (non BSEP-1), and BSEP-3 includes patients with variants that are predicted to encode a non-functional protein. No BSEP-3 patients were studied in clinical Trial 1 (NCT03566238). The prevalence of BSEP-1, BSEP-2, and BSEP-3 subgroups are approximately 27.3%, 51.5%, and 21.2%, respectively, based on data from a global consortium characterizing the natural history of severe BSEP deficiency.
Clinical Studies
PFIC
The efficacy of BYLVAY was evaluated in Trial 1 (NCT03566238), a 24-week, randomized, double-blind, placebo-controlled trial. Trial 1 was conducted in 62 pediatric patients, aged 6 months to 17 years, with a confirmed molecular diagnosis of PFIC type 1 or type 2, and presence of pruritus at baseline. Patients with variants in the ABCB11 gene that predict non-function or complete absence of the bile salt export pump (BSEP) protein, who had experienced prior hepatic decompensation events, who had other concomitant liver disease, whose INR was greater than 1.4, whose ALT or total bilirubin was greater than 10-times the upper limit of normal (ULN), or who had received a liver transplant were excluded in Trial 1.
Patients were randomized to placebo (n=20), 40 mcg/kg (n=23), or 120 mcg/kg (n=19). Study drug was administered once daily with a meal in the morning. In patients weighing less than 19.5 kg or patients who could not swallow the whole capsule, study drug was sprinkled on soft food and then administered orally.
Median age (range) of the patients in Trial 1 was 3.2 (0.5 to 15.9) years; 3 patients were older than 12 years of age. Of the 62 patients, 50% were male and 84% were white; 27% had PFIC type 1, and 73% had PFIC type 2. The mean (standard error [SE]) scratching score in the 2 weeks prior to baseline was 2.9 (0.08). Baseline mean (SE) eGFR was 164 (30.6) mL/min/1.73 m². Baseline median (range) ALT, AST, and total bilirubin were 65 (16-798) U/L, 83.5 (32-405) U/L, and 2.2 (0.2-18.6) mg/dL, respectively.
In Trial 1, a total of 13 patients discontinued from trial prematurely either due to no improvement in pruritus (n=11) or due to adverse reactions (n=2); 5/20 (25%) patients discontinued from the placebo arm and 8/42 (19%) patients discontinued from the BYLVAY arms. A total of 11 of the 13 patients rolled over to Trial 2 to receive BYLVAY 120 mcg/kg/day. One patient treated with BYLVAY 120 mcg/kg/day withdrew from the trial due to a treatment-emergent adverse reaction of diarrhea [see ADVERSE REACTIONS].
Given the patients’ young age, a single-item observer-reported outcome (ObsRO) was used to measure patients’ scratching severity as observed by their caregiver twice daily (once in the morning and once in the evening). Scratching severity was assessed on a 5-point ordinal response scale, with scores ranging from 0 (no scratching) to 4 (worst possible scratching). Patients were included in Trial 1 if their average scratching score was greater than or equal to 2 (medium scratching) in the 2 weeks prior to baseline.
Table 7 presents the results of the comparison between BYLVAY and placebo on the mean of patients’ percentage of ObsRO assessments over the 24-week treatment period that were scored as 0 (no scratching) or 1 (a little scratching). Patients treated with BYLVAY demonstrated greater improvement in pruritus compared with placebo. Figure 1 displays the mean of patients’ worst weekly average scratching scores in each treatment group for each month, where the weekly average utilized the worst score from each day (morning or evening score).
Table 7: Efficacy Results Over the 24-Week Treatment Period in Patients with PFIC Type 1 or 2 in Trial 1
Placebo
(n=20)BYLVAY
40 mcg/kg/day
(n=23)120 mcg/kg/day
(n=19)
Meana Percentage of Assessments Over the Treatment Period Scored as 0 (No Scratching) or 1 (A Little Scratching) (%)
Mean (SE)13.2 (8.7)35.4 (8.1)30.1 (9.0)
Mean Difference vs Placebo (95% CI) 22.2
(4.7, 39.6)16.9
(-2.0, 35.7)
a Based on least squares means from analysis of covariance model with daytime and nighttime baseline pruritus scores as covariates and treatment group and stratification factors (i.e., PFIC type and age category) as fixed effects.
Figure 1: Mean* of the Worst Weekly Average Scratching Scores for Each Month in Trial 1
*Figure 1 presents least squares means
Based on a mixed model repeated measure (MMRM) analysis accounting for baseline score, treatment group, time (in months), treatment-by-baseline interaction, treatment-by-time interaction, and stratification factors (i.e., PFIC type and age category). Missing data were accounted for using placebo-reference multiple imputation.
ALGS
The efficacy of BYLVAY was evaluated in Trial 3 (NCT04674761), a 24-week, randomized, double-blind, placebo-controlled trial. Trial 3 was conducted in 52 pediatric patients, aged 6 months to 15 years, with a confirmed diagnosis of ALGS and presence of pruritus at baseline. Patients who had decompensated liver disease, who had other concomitant liver disease, whose INR was greater than 1.4, whose ALT was greater than 10-times the upper limit of normal (ULN) at screening, whose total bilirubin was greater than 15-times the ULN at screening, or who had received a liver transplant were excluded from Trial 3.
Patients were randomized to placebo (n=17) or 120 mcg/kg (n=35). Study drug was administered once daily with a meal in the morning. In patients weighing less than 19.5 kg or patients who could not swallow the whole capsule, study drug was sprinkled on soft food and then administered orally.
Median age (range) of the patients in Trial 3 was 6.1 (1.7 to 15.5) years in the BYLVAY group and 4.2
(0.5 to 14.3) years in the placebo group; 5 patients were older than 12 years of age. Of the 52 patients, 52% were male and 83% were white; 92% of patients had the JAG1 mutation and 8% had the NOTCH2 mutation. The mean (standard deviation [SD]) scratching score in the 2 weeks prior to baseline was 2.9 (0.6). Baseline mean (SD) eGFR was 159 (51.4) mL/min/1.73 m². Baseline median (range) ALT, AST, and total bilirubin were 152 (39-403) U/L, 135 (57-427) U/L, and 2.0 (0.4-11.4) mg/dL, respectively.
Given the patients’ young ages, a single-item observer-reported outcome (ObsRO) was used to measure patients’ scratching severity as observed by their caregiver twice daily (once in the morning and once in the evening). Scratching severity was assessed on a 5-point ordinal response scale, with scores ranging from 0 (no scratching) to 4 (worst possible scratching). Patients were included in Trial 3 if the average scratching score was greater than or equal to 2 (medium scratching) in the 14 days prior to baseline.
Table 8 presents the results of the comparison between BYLVAY and placebo on the change from baseline in average scratching score based on ObsRO assessments to Month 6 (Weeks 21 to 24). The average scratching score for each patient for each month post-baseline was calculated by: (Step 1) averaging the morning scores and averaging the evening scores within a week; (Step 2) averaging the morning and evening weekly scores to yield a single weekly score; and finally (Step 3) averaging the 4 weekly scores within the month. The baseline average scratching score for each patient was calculated by averaging the weekly scores obtained in Step 2 across the 2 weeks prior to randomization and initiation of blinded treatment. Patients treated with BYLVAY demonstrated greater improvement in pruritus compared with placebo. Figure 2 displays the means (95% confidence interval) of patients’ average scratching scores in each treatment group for each month.
Table 8: Efficacy Results in Patients with ALGS in Trial 3
Placebo
(n=17)BYLVAY 120 mcg/kg/day
(n=35)
Baseline Average Scratching Score
Mean (SD)3.0 (0.6)2.8 (0.5)
Change from Baseline in Average Scratching Score to Month 6 (Weeks 21 to 24)a
Mean (SE)-0.8 (0.2)-1.7 (0.2)
Mean Difference vs Placebo (95% CI)-0.9 (-1.4, -0.3)
p-value0.002
a Based on least square means from a mixed-effect model for repeated measures (MMRM) for change from baseline to each month accounting for baseline average scratching score, baseline age stratification (<10, ≥10 years), baseline direct bilirubin, treatment group, time (in months), and treatment-by-time interaction.
Figure 2: Mean* of the Average Scratching Scoresfor Each Month in Trial 3
*Figure 2 presents means for baseline and least squares means for Month 1 to 6
Least squares means are based on a mixed model repeated measure (MMRM) analysis accounting for baseline average scratching score, baseline age stratification (<10, ≥10 years), baseline direct bilirubin, treatment group, time (in months), and treatment-by-time interaction.
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