Berotralstat

Introduction Overview

Generic Name

berotralstat

Brand Name

Orladeyo

Dosage Form

capsules (150 mg, 110 mg)

Drug Class

Hereditary angioedema agents

Pharmacokinetics

Absorption:
Berotralstat (Orladeyo) exhibits oral bioavailability optimized for once-daily dosing when taken with food. Peak plasma concentrations are typically achieved approximately 5 to 7 hours after oral administration, which supports its suitability for chronic prophylactic use in hereditary angioedema (HAE). The absorption process appears to be influenced by food intake, with a significant increase in drug exposure when administered with meals compared to fasting conditions. This food effect is clinically relevant as the recommended administration includes taking Orladeyo with food to maximize systemic absorption and minimize gastrointestinal adverse effects.

Distribution:
Following absorption, berotralstat demonstrates moderate plasma protein binding, estimated to be approximately 99%. The high plasma protein binding suggests extensive distribution predominantly within the vascular compartment. Volumes of distribution noted in clinical pharmacology studies indicate distribution beyond plasma into peripheral tissues, likely targeting sites implicated in kallikrein activity. The drug's lipophilicity favors tissue penetration but remains sufficient to maintain effective plasma concentrations for kallikrein inhibition.

Metabolism:
Berotralstat undergoes hepatic metabolism principally mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4, which contribute to its biotransformation. The metabolic pathways yield several inactive metabolites. The involvement of these enzymes necessitates consideration of potential drug-drug interactions with concomitant medications that induce or inhibit CYP2D6 and CYP3A4, affecting berotralstat plasma levels. Metabolism is a key determinant of the drug’s elimination half-life, and genetic polymorphisms in CYP2D6 may modulate individual pharmacokinetic variability.

Elimination:
The elimination half-life of berotralstat ranges typically from 93 to 120 hours, supporting once-daily dosing. The drug is primarily eliminated via feces, with renal excretion playing a minor role. Less than 10% of the dose is recovered unchanged in urine, indicating limited renal clearance. The extended half-life allows for steady plasma concentrations, reducing peak-to-trough fluctuations. In patients with mild hepatic impairment, no dosage adjustments are necessary, whereas in moderate to severe impairment, dose reduction is recommended due to decreased metabolic clearance. Renal impairment has less impact on elimination, but caution is advised with severe dysfunction. The prolonged elimination phase highlights the importance of adherence to dosing schedules to maintain therapeutic efficacy.

Dosage Forms

Available Dosage Forms:
- Oral capsules containing 150 mg of berotralstat
- Oral capsules containing 110 mg of berotralstat

Dosages for Adults and Adolescents:
- The recommended dose for hereditary angioedema prophylaxis in adults and pediatric patients aged 12 years and older is one 150 mg capsule taken orally once daily with food.
- In cases of persistent gastrointestinal side effects, a dose reduction to one 110 mg capsule once daily with food may be considered.

Specific Patient Populations:
- For patients with mild hepatic impairment (Child-Pugh Class A), no dose adjustment is required.
- In patients with moderate to severe hepatic impairment (Child-Pugh Class B or C), the recommended dose is one 110 mg capsule once daily with food to mitigate risk of drug accumulation and related adverse effects.
- The safety and efficacy of Orladeyo have not been established in patients under 12 years of age; thus, its use is not approved for this pediatric population.
- No specific dose adjustment guidelines exist for renal impairment, but caution is advised in severe cases.
- The capsules should not be opened or crushed, as this may affect drug release and absorption characteristics.

Clinical Guidelines and Administration:
- Administration with food is critical to enhance absorption and reduce gastrointestinal adverse events such as nausea, vomiting, and abdominal pain.
- Patients should be instructed to adhere strictly to the once-daily dosing schedule to maintain steady kallikrein inhibition and prevent breakthrough HAE attacks.
- Missed doses should be taken as soon as remembered unless close to the next scheduled dose; double dosing should be avoided.

Storage and Handling:
- Orladeyo capsules should be stored at controlled room temperature (20°C to 25°C / 68°F to 77°F).
- Capsules should be kept out of reach of children and stored in the original package until use to preserve integrity.

Mechanism Of Action

Orladeyo (berotralstat) is an oral selective inhibitor of plasma kallikrein, a serine protease that plays a central role in the pathophysiology of hereditary angioedema (HAE). In HAE, dysregulation of the plasma contact system occurs due to C1 esterase inhibitor deficiency or dysfunction, leading to unchecked activity of plasma kallikrein. This enzymatic overactivity converts high molecular weight kininogen into bradykinin, a potent vasodilator that increases vascular permeability and causes the characteristic episodes of swelling seen in HAE.

Berotralstat binds selectively and reversibly to the active site of plasma kallikrein, thereby inhibiting its enzymatic action and subsequent bradykinin production. By reducing bradykinin levels, Orladeyo decreases vascular leakage and swelling. This targeted mechanism effectively interrupts the central mediator pathway of hereditary angioedema attacks without broadly suppressing immune function or other enzymatic pathways.

The selectivity of berotralstat for plasma kallikrein minimizes off-target effects commonly associated with other kallikrein inhibitors. At the molecular level, berotralstat exhibits high affinity binding that stabilizes the enzyme in an inactive conformation, which has been demonstrated in preclinical crystallography and enzymatic assays. Clinically, this translates into sustained prophylactic efficacy with once-daily dosing.

Compared to injectable kallikrein inhibitors or C1 esterase replacement therapies, Orladeyo offers a convenient oral dosing alternative with a comparable effect in reducing HAE attack frequency. Ongoing clinical studies continue to elucidate the pharmacodynamic effect of berotralstat on plasma kallikrein activity and bradykinin levels, supporting its approval for prevention of HAE attacks in both adults and pediatric populations aged 12 years and older.

Pharmacological Actions

Selective inhibition of plasma kallikrein enzyme activity.
Reduction of bradykinin production leading to decreased vascular permeability.
Prevention of swelling and pain associated with hereditary angioedema attacks.
Oral once-daily administration providing convenient prophylactic therapy.
Modulation of the plasma contact system to restore vascular homeostasis.
Non-immunosuppressive mechanism that does not compromise immune defenses.
Sustained kallikrein inhibition due to long half-life supporting steady plasma concentrations.
Reduction in frequency and severity of hereditary angioedema attacks demonstrated in clinical trials.
Minimal off-target activity reducing risk of adverse drug reactions.
Potential dose-dependent gastrointestinal side effects related to mechanism of drug absorption.
Advantage over injectable therapies by providing an oral alternative with favorable safety profile.
Does not treat acute HAE attacks but effectively prevents their occurrence.
Modulates biochemical pathways central to the bradykinin-mediated angioedema cascade.
Interferes specifically with the enzymatic activation step in the kallikrein-kinin pathway.

Therapeutic Or Clinical Uses

Prophylactic treatment to prevent attacks of hereditary angioedema in adults aged 18 years and older.
Prevention of hereditary angioedema attacks in pediatric patients aged 12 years and older.
Reduction of frequency and severity of HAE attacks to improve patient quality of life.
Suitable for long-term management of hereditary angioedema with consistent dosing.
Oral therapy option for patients who prefer to avoid injectable preventive treatments.
Use in patients with C1 esterase inhibitor deficiency leading to recurrent angioedema.
Prevention of potentially life-threatening swelling episodes in face, throat, extremities, and abdomen.
Adjunctive therapy in patients with hereditary angioedema who inadequately respond to other prophylactic agents.
Management of HAE in patients with comorbid conditions limiting access to injectable therapies.
Suitable for patients with mild hepatic impairment without dose adjustment.
Dose-adjusted prophylaxis in moderate to severe hepatic impairment for safe use.
Not indicated for treatment of acute hereditary angioedema attacks but exclusively for prevention.
Orphan drug designation for treatment of rare hereditary angioedema disorder.
FDA-approved oral agent since 2020 for HAE prophylaxis.

Side Or Adverse Effects

Stomach pain, reported in approximately 10% of patients, often early in treatment.
Indigestion (dyspepsia) occurring in about 10% of patients during initial therapy.
Vomiting experienced by roughly 10% of patients, typically transient and early onset.
Diarrhea reported in 10% of patients, frequently resolving over continued dosing.
Back pain occurring in a smaller subset (~2%) of treated individuals.
Potential risk of allergic reactions including hives, facial swelling, and respiratory distress.
QT interval prolongation risk if more than the recommended 150 mg daily dose is taken.
Gastrointestinal side effects tend to decrease in frequency over time with continued therapy.
Serious allergic reactions warrant immediate medical attention due to risk of airway compromise.
No significant immunosuppression or increased infection risk documented with Orladeyo.
Side effects generally manageable with dose adjustment to 110 mg in sensitive patients.
Possible mild elevation in liver enzymes noted but not typically clinically significant.
No reports of serious hematologic toxicity from clinical trial data.
Rare incidences of cardiac arrhythmias related to overdose or dosing errors.
Potential interaction-related adverse effects when co-administered with CYP enzyme modulators.

Precautions

Do not exceed 150 mg per day to avoid serious heart rhythm issues.
Administer Orladeyo with food to minimize gastrointestinal adverse effects.
Monitor patients for signs of allergic reactions, especially with first doses.
Use caution in patients with pre-existing liver disease; dose adjustments may be required.
Exercise caution in patients with renal impairment, although no specific dose adjustment is established.
Not recommended for use in patients under 12 years due to lack of safety and efficacy data.
Careful monitoring required when co-administered with drugs metabolized by CYP2D6, CYP3A4, or transported by P-glycoprotein.
Report any worsening or new symptoms promptly, as Orladeyo does not treat acute HAE attacks.
Pregnancy safety has not been established; discuss risks vs benefits with healthcare provider.
Breastfeeding safety is unknown; consult healthcare professional about feeding options.
Patients should be advised against using unapproved doses or doubling missed doses.
Medication adherence is important to maintain steady state plasma levels and prevent breakthrough attacks.
Regular cardiac monitoring may be warranted in patients at risk for QT prolongation.
Disclose all concomitant medications to healthcare providers to avoid interactions.
Avoid abrupt discontinuation without medical guidance to prevent possible rebound increase in attacks.

Warnings

QT prolongation risk at doses exceeding 150 mg per day can lead to serious cardiac arrhythmias.
Do not take more than one capsule daily to prevent heart rhythm abnormalities.
Serious allergic reactions, including angioedema and anaphylaxis, require immediate emergency treatment.
Orladeyo is not indicated for treatment of acute HAE attacks and should not replace acute therapy.
Patients with hepatic impairment require dose modification to reduce toxicity risk.
Potential for drug interactions with CYP2D6, CYP3A4, and P-glycoprotein substrates and inducers warrants careful monitoring.
Use caution in patients with history of cardiac conduction abnormalities or arrhythmias.
Pregnancy and breastfeeding safety profiles are unclear, caution recommended when prescribing.
Gastrointestinal side effects may impair tolerance if not properly managed with food and dose adjustment.
Avoid abrupt cessation to decrease risk of exacerbation of hereditary angioedema.
Overdose may result in serious adverse events including cardiac arrhythmias and gastrointestinal distress.
Careful patient education is essential to avoid dosing errors leading to toxicity.
Warning about interacting substances such as P-glycoprotein inducers that can reduce drug efficacy.
Not recommended for pediatric patients below 12 due to lack of safety data.
Storage below recommended temperature ranges may reduce capsule stability and effectiveness.

Contraindication

Known hypersensitivity or allergic reaction to berotralstat or any components of the capsule formulation.
Use exceeding the recommended once-daily dosing regimen (i.e., more than one capsule per day).
Concurrent administration of P-glycoprotein inducers that significantly decrease berotralstat concentrations.
Not approved or recommended in pediatric patients under 12 years of age.
Severe uncontrolled cardiac arrhythmias or known QT interval prolongation prior to therapy initiation.
Use in patients with history of severe allergic reactions to kallikrein inhibitors.
Concurrent use with drugs highly dependent on CYP2D6 or CYP3A4 with narrow therapeutic index without appropriate monitoring.
Patients with severe hepatic impairment who cannot tolerate dose adjustments.
Contraindicated in situations where oral administration is not feasible or absorption is compromised.
Avoid use in patients with acute hereditary angioedema attacks; not indicated for acute treatment.
Patients with known severe gastrointestinal disorders that prevent oral capsule intake.
Use in lactating women unless the potential benefit outweighs risks, due to unknown excretion in breast milk.
Pregnant women unless clearly necessary, due to insufficient safety data.
Hypersensitivity reactions to any hereditary angioedema agents with a similar mechanism causing cross-reactivity.

Drug Interactions

P-glycoprotein (P-gp) inducers significantly reduce plasma levels of berotralstat and should be avoided.
CYP3A4 enzyme inducers may decrease berotralstat efficacy by increasing its metabolism.
CYP2D6 enzyme inhibitors or inducers can alter berotralstat plasma concentrations requiring dose adjustments or close monitoring.
Drugs that prolong the QT interval combined with berotralstat increase the risk of cardiac arrhythmias.
Narrow therapeutic index drugs metabolized by CYP3A4 or CYP2D6 require monitoring and possible dose modification when co-administered.
P-gp substrates may have altered plasma levels when used concurrently with Orladeyo.
No significant interaction with common medications such as antihypertensives or antidiabetics observed in trials, but clinical vigilance warranted.
Concomitant use of strong CYP3A4 inhibitors may elevate berotralstat levels increasing risk of toxicity.
Drugs affecting gastrointestinal motility could impact absorption and efficacy of berotralstat capsules.
Immunosuppressants and biologics have not demonstrated direct interactions, but clinical efficacy should be monitored.
Combination with other hereditary angioedema prophylactic agents must be considered carefully considering overlapping mechanisms.
Herbal supplements like St. John's Wort, a CYP3A4 inducer, should be avoided due to reduced berotralstat efficacy.
Monitoring liver function tests is advisable when combining with agents hepatically metabolized in similar pathways.
Dose titration may be necessary when initiating or discontinuing interacting drugs to maintain therapeutic control.
Patients should inform healthcare providers of all medications including over-the-counter and supplements to avoid unanticipated interactions.

Preparations Of The Drug

Berotralstat is formulated as oral capsules designed for once-daily administration.
Commercially available capsule strengths include 150 mg and 110 mg formulations.
Capsules contain inactive excipients tailored to optimize gastrointestinal tolerability and bioavailability.
Packaging typically features blister packs or bottles suitable for outpatient dispensing.
Capsules are contraindicated for crushing, opening, or dissolving to preserve pharmacokinetic properties.
Storage instructions specify maintaining controlled room temperature to preserve chemical stability.
Manufactured by BioCryst Pharmaceuticals, Inc., located in Durham, NC, USA.
Approved by FDA in December 2020 with marketing exclusivity extending to 2027 under orphan drug status.
Patient information leaflets accompany packaging to educate on dosing, side effects, and precautions.
Special packaging features to prevent moisture ingress and maintain capsule integrity.
Distinctive capsule coloration aids in product identification and compliance.
Supplied in quantities adequate for monthly treatment cycles with adherence support materials.
Included in professional prescribing databases and monographs to assist healthcare providers.
Available through specialty pharmacies with patient assistance programs given orphan drug classification.
Detailed prescribing information and package inserts are accessible through manufacturer and FDA channels.