Overview
Thrombotic thrombocytopenic purpura (TTP) is an uncommon blood clotting illness characterized by thrombocytopenia (a condition characterized by an abnormally low platelet count), microangiopathic hemolytic anemia (a type of hemolytic anemia characterized by fragmentation and hemolysis caused by erythrocyte destruction in tiny blood vessels), and organ destruction (a significant impairment of major body organs caused by high blood pressure or inadequate blood flow events). Autoantibodies can cause it to be inherited or acquired. cTTP is responsible for less than five percent of cases. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), a plasma metalloproteinase responsible for breaking down von Willebrand factor multimers and inhibiting microthrombi formation, is severely deficient in cTTP patients. Prophylactic plasma infusions are the standard treatment for cTTP. The FDA authorized ADAMTS13, recombinant-krhn, as an enzyme replacement treatment for cTTP patients in November 2023.
Drug Group
ADAMTS13, recombinant-krhn, is a human recombinant ADAMTS13 enzyme essential for blood clotting control. A mutation in the gene responsible for generating this enzyme causes its deficiency in patients with congenital thrombotic thrombocytopenic purpura (cTTP), causing blood clots to develop in small blood vessels. It acts by replacing the faulty ADAMTS13 enzyme, addressing the underlying cause of cTTP.
Indications
ADAMTS13, recombinant-krhn is a human recombinant ADAMTS13 enzyme replacement therapy (ERT) intended for use in children as well as adults with congenital thrombotic thrombocytopenic purpura (cTTP) for preventive and on-demand purposes.
Contraindications
Patients who have encountered life-threatening hypersensitivity reactions to ADAMTS13, recombinant-krhn or its ingredients should not take it.
Dosage Forms and Available Strengths
ADAMTS13, recombinant-krhn is a powder that has been lyophilized in single-dose vials containing 500 or 1500 International Units (IU) and 5 mL of sterile water for injection, with potency on each label.
Warnings and Precautions
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Hypersensitivity: Hypersensitivity reactions of ADAMTS13, recombinant-krhn are possible. If hypersensitivity symptoms occur, discontinue ADAMTS13, recombinant-krhn, and offer necessary emergency treatment.
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Immunogenicity: Patients may develop antibodies against rADAMTS13, resulting in a decreased or lacking response to rADAMTS13. Patients may acquire antibodies to host cell proteins, which may cause unpleasant effects. There is no information regarding the risk for previously untreated patients.
For Patients
What Is Congenital Thrombotic Thrombocytopenic Purpura?
Congenital thrombotic thrombocytopenic purpura (cTTP), also referred to as Upshaw-Schulman syndrome, is a very uncommon thrombotic microangiopathy arising from an inherited deficiency of ADAMTS13, a von Willebrand factor (VWF)-cleaving metalloprotease. This deficit results from the unusual presence of ultra-large VWF multimers and the production of circulating platelet-rich microthrombi. The condition is characterized by periodic instances of microangiopathy, hemolytic anemia, thrombocytopenia, and organ destruction of varying severity. Symptoms can appear during the newborn period or later in life.
How Does ADAMTS13, Recombinant-Krhn Work?
ADAMTS13, recombinant-krhn is a synthetically produced form of the ADAMTS13 enzyme, essential for regulating blood clotting. By replacing the missing ADAMTS13 enzyme, it serves to prevent or treat blood clots in individuals with congenital thrombotic thrombocytopenic purpura.
What Are the Clinical Uses of ADAMTS13, Recombinant-Krhn?
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Prophylactic Enzyme Replacement Therapy (ERT): ADAMTS13, recombinant-krhn, serves as a preventive therapy in both adults and children with congenital thrombotic thrombocytopenic purpura (cTTP), 40 IU/kg (International Units per kilogram) body weight, injected intravenously at a rate of 2 to 4 mL per minute once every other week.
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On-Demand ERT: ADAMTS13, recombinant-krhn, is an on-demand therapy for acute events that is delivered intravenously at a rate of two to four mL per minute. The recommended dose is 40 IU/kg body weight on day 1, 20 IU/kg body weight on day 2, and 15 IU/kg on day three and beyond until the occurrence ends, a period of two days.
How Is ADAMTS13, Recombinant-Krhn Administered?
Suitable for intravenous administration following reconstitution.
Prophylactic Therapy
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Every other week, 40 IU/kg body weight is administered intravenously at 2 mL to 4 mL each minute.
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Based on a prior prophylactic dosage regimen or clinical response, the prophylaxis dosage schedule may be modified to 40 IU/kg body weight once a week.
On-Demand Therapy
Administration of ADAMTS13, recombinant-krhn intravenously, at an intensity of 2 to 4 mL per minute:
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On the first day, administer 40 IU/kg of body weight.
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On day two, administer 20 IU/kg of body weight.
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On day three and every day after that, provide 15 IU/kg body weight until two days after the acute episode ends.
What Are the Side Effects of ADAMTS13, Recombinant-Krhn?
ADAMTS13, recombinant-krhn has the potential to trigger an allergic reaction. If patients experience a rash or hives, itching, throat tightness, chest pain or tightness, difficulty breathing, lightheadedness, dizziness, nausea, or fainting, contact the doctor immediately.
The most common side effects reported with ADAMTS13, recombinant-krhn, include headache, diarrhea, migraine, stomach discomfort, nausea, upper respiratory tract infection, dizziness, and vomiting, affecting over five percent of patients.
Inform the physician if any side effects bother patients or do not go away. These are not the only ADAMTS13, recombinant-krhn adverse effects that could occur.
What Are the Things to Inform the Doctor Before Taking ADAMTS13, Recombinant-Krhn?
If a patient has had a fatal adverse reaction or if there are any inactive chemicals in the vial, ADAMTS13, recombinant-krhn should not be utilized. Inform the doctor about any medical concerns, such as allergies, pregnancy, or breastfeeding, and the plans to get pregnant or breastfeed.
Missed Dose
If patients miss a dose of ADAMTS13, recombinant-krhn, contact the healthcare practitioner immediately. Healthcare professionals can offer advice and make changes to the treatment schedule. ADAMTS13, recombinant-krhn is a vital treatment for congenital thrombotic thrombocytopenic purpura, and it must be taken regularly.
Overdose
The existing information on ADAMTS13, recombinant-krhn does not directly identify the precise signs or effects of an overdose. It is critical to seek prompt medical assistance if an overdose of ADAMTS13, recombinant-krhn is suspected.
Storage and Handling
ADAMTS13, recombinant-krhn is a medicine that can be stored at ambient temperature for up to six months or refrigerated at temperatures ranging from 2 °C (degree Celsius) to 8 °C for as long as 36 months. It should not be restored to the refrigerator, used after expiration, or improperly stored. It should not be frozen and should be kept in its original package. Reconstituted products should be used immediately or within three hours of reconstitution if stored at room temperature. The solution should be clear and particle-free. Unused reconstituted materials should be discarded after three hours.
For Doctors
What Are the Pharmacological Actions of ADAMTS13, Recombinant-Krhn?
Pharmacodynamics
A plasma ADAMTS13 activity below 10 IU/dL (or 10 percent of normal ADAMTS13 activity) is a defining feature of cTTP. The overall average duration for ADAMTS13 activity remained above 10 percent after intravenous injection of 40 IU/kg of rADAMTS13 was 5.3 days. Surrogate measurements of von Willebrand factor platelet binding activity showed temporary reductions of fifteen to twenty-five percent from baseline after intravenous treatment for 1 or 2 days.
Chemical Taxonomy
ADAMTS13, recombinant-krhnis a chemical molecule that belongs to the Super Class of Organic Compounds, which includes amino acids, peptides, and analogs.
Mechanism of Action
A significant lack of plasma ADAMTS13 can induce congenital thrombocytopenic purpura (cTTP). ADAMTS13 is a zinc metalloprotease found in plasma that controls the activity of von Willebrand factor (VWF) by breaking down ultra-large VWF multimers into smaller units, lowering VWF's platelet binding capabilities and the production of microthrombi. ADAMTS13, recombinant-krhn is a recombinant version of endogenous ADAMTS13. It is used in patients with cTTP as an enzyme replacement therapy to partially restore ADAMTS13 function to prevent thromboses.
Pharmacokinetics
Absorption: Following intravenous treatment with 40 IU/kg, the average (Cave) and maximum (Cmax) serum concentrations of rADAMTS13 were 0.30 IU/mL and 1.15 IU/mL, respectively. The area under the ADAMTS13 activity-time curve from 0 to infinity (AUC0-inf) and the area under the ADAMTS13 activity-time curve from 0 to 168 hours (AUC0-168h) values were 57.6 and 57.2 IU/h/mL, respectively.
Metabolism: rADAMTS13, like other therapeutic proteins, is likely reduced to smaller peptides and amino acids by catabolic mechanisms.
Half-Life: The mean half-life (t1/2) after intravenous injection of 40 IU/kg rADAMTS13 is 47.8 hours. The average length of stay (mean residence time from 0 to infinity (MRT0-inf)) is 63.8 hours.
What Are the Drug Interactions of ADAMTS13, Recombinant-Krhn?
Inform the healthcare provider about all of the medications that patients are taking, including prescription and over-the-counter medications, vitamins, and herbal supplements, asADAMTS13, recombinant-krhn may interact with these medications.
Clinical Studies
ADAMTS13, recombinant-krhn was studied in a worldwide, prospective, randomized, active-controlled, open-label, multicenter, two-period crossover study comparing the efficacy and safety of prophylactic and on-demand ERT with ADAMTS13, recombinant-krhn to plasma-based therapies in patients with cTTP.
Prophylactic Enzyme Replacement Therapy in cTTP Patients:
The clinical trial looked at the effectiveness of ADAMTS13, recombinant-krhn as a preventative therapy for people with cTTP. The trial included 46 patients randomly assigned to receive either 40 IU/kg of ADAMTS13, recombinant-krhn or plasma-based therapy for six months before switching to the other medication for another six months. Thirty-five individuals were enrolled in the 6-month single-arm study with ADAMTS13, recombinant-krhn. The patients' median age was 32.5 years, and their average weight was 67.6 kg. Most patients (65.2%) were white, 80.4% were neither Hispanic nor Latino, and 58.7% were female. Twenty of the twenty female patients (74.1%) were child-bearing age. Over six months, the efficacy of ADAMTS13, recombinant-krhn was established by the incidence of protocol-specified acute and subacute TTP events and TTP symptoms and the incidence of additional doses induced by subacute TTP events. Throughout the research, including Period 3, no patients receiving ADAMTS13, recombinant-krhn experienced an acute TTP episode. Two patients receiving ADAMTS13, recombinant-krhn prophylaxis experienced two subacute episodes in Period 3, which were managed with four extra doses. Overall, ADAMTS13, recombinant-krhn efficacy results were similar over the research, including Period 3 and across age groups.
On-Demand Enzyme Replacement Therapy: For the course of the trial, the proportion of acute TTP events responding to ADAMTS13, recombinant-krhn in both the Prophylactic and on-demand (OD) groups was utilized to assess the efficacy of on-demand (OD) enzyme replacement treatment. A resolved TTP incident in response to ADAMTS13, recombinant-krhn was defined as a platelet count of 150,000/L or within 25 percent of baseline, whichever occurred first, and LDH of 1.5 times baseline or 1.5 times the ULN, without the requirement for another ADAMTS13-containing medication. The OD cohort consisted of five adult patients (18 years old) who had six acute TTP events. Two of the five patients were given ADAMTS13, recombinant-krhn on-demand medicine, while the remaining three were given a placebo.
Specific Considerations
Pregnancy: The safety of ADAMTS13, recombinant-krhn during pregnancy is unknown due to a lack of data on unfavorable developmental consequences. When considering whether to use ADAMTS13, recombinant-krhn during pregnancy, healthcare practitioners should weigh the potential advantages against the hazards. The baseline rate of significant birth abnormalities and miscarriage in the indicated demographic is unclear, but in the general population of the United States, the rates are expected to be between two and four percent and between 15 and 20 percent, respectively.
ADAMTS13, recombinant-krhn was administered to four cTTP patients during pregnancy. While undergoing ADAMTS13, recombinant-krhn prophylaxis, two patients became pregnant early in the first trimester. To meet protocol standards, both were removed from the study. The first patient had no more exposure and miscarried in the first trimester. The second patient returned to treatment through a compassionate use program and gave birth to a healthy full-term baby with no safety issues. During a compassionate use program, two more cTTP patients were treated with ADAMTS13, recombinant-krhn. The first patient had a stroke and thrombocytopenia that were resistant to daily plasmapheresis and ADAMTS13, recombinant-krhn therapy restored ADAMTS13 activity and cleared thrombocytopenia. The second patient experienced an aggravation of the cTTP during the second trimester and did not respond well to plasma-based therapy. The ADAMTS13, recombinant-krhn medication resulted in clinical remission, and the baby was born via cesarean section at week 29. The usage of ADAMTS13, recombinant-krhn during pregnancy is at the discretion of the healthcare professional.
ADAMTS13, recombinant-krhn, a hormone used in rat embryo-fetal development, was given to female rats every third day starting from 2 weeks before mating until Day 16 of gestation at doses of 80, 200, or 400 IU/kg. The medication was not linked to any negative maternal findings or treatment-related impacts on embryo-fetal development. ADAMTS13, recombinant-krhn was given intravenous bolus injections every three days starting from Day 6 of gestation until weaning on Day 21 of lactation in a pre- and post-natal development trial.
Breastfeeding: The study lacks data on ADAMTS13, recombinant-krhn in human milk, and its effects on milk production or the breastfed infant, suggesting that breastfeeding's developmental and health benefits should be considered alongside the mother's clinical requirement.
Pediatric Use: ADAMTS13, recombinant-krhn is safe and effective in pediatric patients. Patients aged two years and up were eligible for clinical trials. Based on population pharmacokinetic (PK) statistics, no additional dose changes beyond body weight are needed for this age group. The recommended body-weight-based dosage schedule in juvenile patients is the same as in adults.
Geriatric Use: ADAMTS13, recombinant-krhn clinical trials did not involve individuals 65 and older to see if these individuals responded differently than younger people. According to the findings of population pharmacokinetics studies, no dose change is necessary for senior people.
