Compositions and methods for treating transplant-associated thrombotic microangiopathy in bleeding patients - Patents.com

Abstract

The present disclosure relates to a method for the treatment of an individual with TA-TMA. In one aspect, the method comprises the administration of a C5 inhibitor, more specifically eculizumab, or an antigen-binding fragment thereof. The disclosed method may be used in one aspect for the treatment of an individual with TA-TMA and clinically significant bleeding.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 292,188, entitled "Eculizumab Precision Dosing Algorithm for Thrombotic Microangiopathy in Children and Young Adults Undergoing HSCT," filed December 21, 2021, the contents of each of which are incorporated in their entirety for all purposes. [Background technology]

[0002] Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal post-transplant complication of hematopoietic stem cell transplantation (HSCT). Untreated patients have a very high mortality rate (16.7% and 9% overall survival at 1 year after HSCT). TA-TMA survival has been improved by early intervention with eculizumab, a complement C5 inhibitor, guided by precise dosing based on pharmacokinetic / pharmacodynamic (PK / PD) models. However, not all patients respond to complement C5 inhibition in the same manner and may not be effectively treated using standard dosing recommendations. Thus, targeted therapies are needed to more effectively treat TA-TMA patients, especially those who may suffer from concurrent blood loss. The present disclosure seeks to address one or more of the aforementioned needs in the art. Summary of the Invention

[0003] The present disclosure relates to methods for the treatment of individuals with TA-TMA, particularly via administration of a C5 inhibitor, more particularly eculizumab or a fragment thereof. The disclosed methods may, in one aspect, be used for the treatment of individuals determined to have clinically significant bleeding. [Brief description of the drawings]

[0004] Those skilled in the art will understand that the drawings, described below, are for illustration purposes only and are not intended to limit the scope of the present teachings in any way.

[0005] [Figure 1] Figure 1 shows eculizumab concentration-time profiles in TA-TMA patients with and without bleeding complications. The Y-axis shows the observed concentrations of eculizumab, and the X-axis shows the time after each dose. Black circles represent data from non-bleeding patients (n=38), and red circles represent data from bleeding patients (n=19). Data collected from the same patient are connected by dotted lines. [Diagram 2] Changes in eculizumab clearance and sC5b-9 across treatment doses are shown. PK and PD changes across treatment doses were assessed using individual eculizumab clearance estimates (A) and pre-dose sC5b-9 levels (B). Red and black circles represent data in bleeding and non-bleeding patients, respectively. Individual clearance values ​​of eculizumab at each week were estimated by Bayesian estimation methods to account for between-chance variability and adjusted by a relative scaled body weight of 70 kg. As the study included a wide age range (0.5-29.9 years), the effect of increasing body size on eculizumab clearance was taken into account by adjusting it by a relative scaling to a body weight of 70 kg to allow comparison across pediatric and young adult patients with different body sizes as previously described. 7 Eculizumab clearance estimates and changes in sC5b-9 levels over time were statistically analyzed using one-way ANOVA (R 3.0.3). [Diagram 3] Simulation of eculizumab concentration-time profiles. Eculizumab concentration-time profiles over 7 days after the first dose were simulated based on the model developed by the inventors for non-bleeding and bleeding patients shown in Table 2. Population PK parameter estimates were used for the simulation. Eculizumab concentration-time curves are shown in different colors, representing different pre-dose sC5b-9 levels ranging from 200 to 800 ng / mL. The horizontal pink dotted line represents the proposed eculizumab target concentration of 100 μg / mL. [Figure 4] Simulation of the optimal dosing algorithm for nonbleeding patients with TA-TMA is shown. The y-axis indicates the probability of target achievement, determined as the proportion of patients who achieved eculizumab concentrations above the target, and the y-axis indicates each weight cohort. A total of 12,000 age- and weight-matched subjects were randomly sampled from the CDC-NHANES database. Six weight cohorts were defined as follows: <10 kg, 10 to <20 kg, 20 to <30 kg, 30 to <40 kg, 40 to <70, and 70 to <100 kg. Actual pre-dosing sC5b-9 levels were generated using simulation to match the observed sC5b-9 distribution. Monte Carlo simulation analysis was performed to predict eculizumab trough concentrations for each dosing scenario using NONMEM. [Diagram 5] Figure 4 shows the probability of target achievement for various dosing schedules. The x-axis shows the eculizumab dosing intervals ranging from 1 to 7 days. The y-axis shows the % probability of target achievement to reach an eculizumab target trough concentration >100 μg / mL. The probability of target achievement is predicted for dosing protocols with different doses (mg) ranging from 300 to 2100 mg and is shown by lines of different colors. A PTA% close to 100% could be achieved by increasing the dose by 300 mg (1 vial) in each weight cohort for protocol 4 shown in Figure 4. [Figure 6A] Population PK model evaluation for the final model. Goodness-of-fit plots (A and C) and predictor-corrected visual predictive checks (pcVPC) (B and D) for the final population PK models for non-bleeding and bleeding patients shown in Table 2. Open circles represent observed results. A, C: Goodness-of-fit plots include four figures: observed eculizumab concentrations vs. population model predicted concentrations, observed concentrations vs. individual predicted concentrations estimated using Bayesian estimation methods, conditional weighted residuals vs. population predicted concentrations, and conditional weighted residuals vs. time post-dose. [Figure 6B]Population PK model evaluation for the final model is shown. Goodness-of-fit plots (A and C) and predictor-corrected visual predictive check (pcVPC) (B and D) for the final population PK models for non-bleeding and bleeding patients shown in Table 2. Open circles represent observed results. B, D: Red lines indicate the 5th (dashed), 50th (solid), and 95th (dashed) percentiles of observed eculizumab concentrations. Shaded areas indicate the 5th (blue), 50th (red), and 95th (blue) percentiles for simulated data based on the final model. Goodness-of-fit plots demonstrated model stability for the final model. Predictor-corrected visual predictive check (pcVPC) showed that the median and 5th and 95th percentile prediction intervals were in good agreement with observations. [Figure 6C] Population PK model evaluation for the final model. Goodness-of-fit plots (A and C) and predictor-corrected visual predictive checks (pcVPC) (B and D) for the final population PK models for non-bleeding and bleeding patients shown in Table 2. Open circles represent observed results. A, C: Goodness-of-fit plots include four figures: observed eculizumab concentrations vs. population model predicted concentrations, observed concentrations vs. individual predicted concentrations estimated using Bayesian estimation methods, conditional weighted residuals vs. population predicted concentrations, and conditional weighted residuals vs. time post-dose. [Figure 6D] Population PK model evaluation for the final model is shown. Goodness-of-fit plots (A and C) and predictor-corrected visual predictive check (pcVPC) (B and D) for the final population PK models for non-bleeding and bleeding patients shown in Table 2. Open circles represent observed results. B, D: Red lines indicate the 5th (dashed), 50th (solid), and 95th (dashed) percentiles of observed eculizumab concentrations. Shaded areas indicate the 5th (blue), 50th (red), and 95th (blue) percentiles for simulated data based on the final model. Goodness-of-fit plots demonstrated model stability for the final model. Predictor-corrected visual predictive check (pcVPC) showed that the median and 5th and 95th percentile prediction intervals were in good agreement with observations. [Figure 7A]Schematic diagrams showing the number of red blood cell (RBC) (7A) and platelet transfusions (7B) during the first five doses of treatment in bleeding and non-bleeding patients are shown. The y-axis shows the sum (mg / kg / day) of each platelet transfusion during each dosing cycle. Each transfusion during each dosing interval is shown in a different color. Fifteen to sixteen of the 38 bleeding patients received a transfusion, whereas only two of the 38 non-bleeding patients received a transfusion after starting eculizumab therapy. The maximum number of RBC and platelet transfusions was 12 and 32, respectively. Bleeding patients received significantly higher transfusions over all first five doses of treatment compared to non-bleeding patients. [Figure 7B] Schematic diagrams showing the number of red blood cell (RBC) (7A) and platelet transfusions (7B) during the first five doses of treatment in bleeding and non-bleeding patients are shown. The y-axis shows the sum (mg / kg / day) of each platelet transfusion during each dosing cycle. Each transfusion during each dosing interval is shown in a different color. Fifteen to sixteen of the 38 bleeding patients received a transfusion, whereas only two of the 38 non-bleeding patients received a transfusion after starting eculizumab therapy. The maximum number of RBC and platelet transfusions was 12 and 32, respectively. Bleeding patients received significantly higher transfusions over all first five doses of treatment compared to non-bleeding patients. [Figure 8] Figure 1 shows a graph depicting the effect of red blood cell (RBC) transfusion on eculizumab clearance in bleeding patients. The x-axis shows the total amount of red blood cell transfusion during the dosing interval. Because body weight and pretreatment sC5b-9 were significant covariates for eculizumab clearance, eculizumab clearance on the y-axis was adjusted by a relative scaled body weight of 70 kg and a pretreatment sC5b-9 of 244 ng / mL. Linear regression analysis showed a weak correlation between eculizumab clearance and RBC transfusion (R2=0.13, p<0.01) or platelet transfusion (R2=0.20, p<0.01). A correlation between RBC and platelet transfusion was observed. [Figure 9]5 is a graph showing the probability of target achievement for protocol 4 considering pre-dosing sC5b-9 levels. The probability of target achievement for protocol 4 shown in FIG. 5 is stratified by different sC5b-9 cohorts (<250, 250-<500, 500-<750 and >750 ng / mL) and shown in different colors. The x-axis shows the different weight cohorts and the y-axis shows the probability of target achievement for reaching eculizumab trough concentrations ≧100 μg / mL. [Figure 10]Selection of loading dose duration for TA-TMA patients with active GI bleeding. Panel A shows the change in sC5b-9 over the first 3 weeks of eculizumab therapy. Blue circles with lines represent measured sC5b-9 levels over the first 3 weeks of eculizumab therapy for nonbleeding patients (top panel), and magenta for bleeding patients (bottom panel). Data were stratified by pretreatment sC5b9 levels below normal <244 ng / mL (left panel), intermediate levels above target but less than twice normal (244 to <488 ng / mL, middle panel), or higher ≥488 ng / mL (right panel). Each connecting line represents data from an individual patient. The significant delayed sC5b-9 decline observed in nonbleeding patients (top right) was not observed in bleeding patients (bottom right) because of the limited number of patients who had very high sC5b-9 at the start of treatment (bottom right). However, considering the comparable overall sC5b-9 distribution regardless of bleeding, a loading dose for active bleeding was proposed for at least the first 14 days, as proposed for non-bleeding patients by taking the worst case scenario. Panel B shows the frequency of patients who achieved sC5b-9 levels <244 ng / mL over the first 3 weeks of treatment. Blue represents data for non-bleeding and magenta represents data for bleeding patients. The frequency of patients who achieved sC5b-9 below normal <244 ng / mL was calculated by dividing the number of patients who achieved normal values ​​by the total number of patients with available sC5b-9 levels on each day. 20% of bleeding patients showed sC5b-9 <244 ng / mL at the start of treatment, and this increased over time to 90% by 14 days of eculizumab therapy. These suggest that a loading dose for the first 14 days of treatment may benefit bleeding patients. [Figure 11]The loading dose protocol for non-bleeding patients predicts lower target achievement for bleeding patients. Option A (Q72h dosing option) proposed for non-bleeding patients predicts a significantly lower probability of target achievement in bleeding patients than in non-bleeding patients, especially at higher body weight, as indicated by the arrow. With option B (more flexible dosing interval option) for non-bleeding patients, the probability of target achievement reaches more than 80% in bleeding patients, except for patients 40 to <70 kg. For TA-TMA patients with low body weight <20 kg, the dosing protocol for non-bleeding patients can be proposed for patients with active GI bleeding. [Figure 12] Optimal "loading dose" simulation of eculizumab for TA-TMA with active GI bleeding. Based on a population PK model developed for bleeding patients, assuming a sC5b-9 distribution similar to that observed in bleeding patients in the applicant's published data, the probability of target achievement was simulated for a selection of "loading" mg doses and dosing intervals (Mizuno et al. 2022). Simulations were performed at various mg doses ranging from 300 mg to 2100 mg, with dosing intervals ranging from 1 to 7 days. Different mg ​​doses are shown. The optimal dosing option was selected to achieve a probability of target achievement of 80% or more. The dashed optimal loading dose protocol was selected and is summarized in Tables 1 and 3. [Figure 13]Selection of optimal "induction dosing" of eculizumab for TA-TMA with active gastrointestinal (GI) bleeding. Optimal dosing simulation was performed by simulating eculizumab C trough using a Monte Carlo simulation approach based on a published population PK / PD model (Mizuno et al, Blood Adv 2022). The y-axis shows the simulated C trough of eculizumab and the x-axis shows the weight cohort. Different eculizumab mg doses are shown, ranging from 300 mg to 1500 mg in 300 mg (1 vial) increments. Significantly higher C trough levels were achieved when bleeding patients received the proposed loading dose of eculizumab proposed for active bleeding during the induction phase (left panel). The lower interquartile C trough decreases to the target level by 1-2 days interval at the same dose, except for patients with the highest weight over 70 kg. The highest weight group required an additional 1 vial (300 mg) to achieve lower interquartile C trough levels above the target level of 100 μg / mL. The optimized protocol shown in the right panel was summarized in the full dosing protocol in Table 1. [Figure 14] Optimal "induction dose" simulation of eculizumab for TA-TMA with active GI bleeding to explore additional dosing options. PK simulations were performed using the same method as above in FIG. 12, but sC5b-9 distribution was observed for the "induction" dose phase instead of the "loading" dose phase. Additional potential dosing protocols are proposed as dashed lines and summarized in Table S3(B) as induction dosing options. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] definition Unless otherwise stated, terms should be understood according to conventional usage by those skilled in the art. In case of conflict, the present specification, including definitions, will control. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present invention, exemplary methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods and examples disclosed herein are illustrative only and are not intended to be limiting.

[0007] As used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes a plurality of such methods, reference to "a dose" includes reference to one or more doses and equivalents thereof known to those skilled in the art, and so forth.

[0008] The term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, "about" may mean within one standard deviation or more than one standard deviation, as is customary in the art. Alternatively, "about" may mean within a range of up to 20%, or up to 10%, or up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. When a particular value is described in the present application and claims, unless otherwise indicated, the term "about" should be assumed to mean within an acceptable error range of the particular value.

[0009] As used herein, the term "antibody fragment," "antigen-binding fragment," or similar terms refer to a fragment of an antibody that retains the ability to bind to an antigen (e.g., complement component C5 protein), such as a single chain antibody, a single chain Fv fragment (scFv), an Fd fragment, a Fab fragment, a Fab' fragment, or a F(ab')2 fragment. An scFv fragment is a single polypeptide chain that contains both the heavy and light chain variable regions of the antibody from which the scFv is derived. Additionally, diabodies and intrabodies that bind complement component C5 protein can be incorporated into compositions and used in the methods described herein.

[0010] As used herein, the term "effective amount" refers to an amount of one or more active ingredients sufficient to produce a desired effect. This includes both therapeutic and prophylactic effects. When applied to an individual active ingredient administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to the combined amount of active ingredients that results in a therapeutic effect, regardless of whether they are administered in combination, sequentially, or simultaneously.

[0011] The terms "individual," "host," "subject," and "patient" are used interchangeably to refer to an animal that is the object of treatment, observation, and / or experiment. Generally, the term refers to a human patient, although the methods and compositions may be equally applicable to non-human subjects, such as other mammals. In some embodiments, the term refers to a human. In further embodiments, the term may refer to a child.

[0012] The methods may include, consist of, or consist essentially of the elements of the methods described herein, as well as any additional or optional elements described herein or otherwise useful in methods of treating individuals with transplant-associated thrombotic microangiopathy (TA-TMA) resulting from hematopoietic stem cell transplantation (HSCT) and bleeding complications.

[0013] Patients with TA-TMA and clinically significant intestinal bleeding require individualized eculizumab dosing. In certain clinical situations, real-time drug PK values ​​are not readily available. A "fixed" dosing regimen or dosing schedule for TA-TMA therapy using eculizumab for patients with gastrointestinal bleeding based is disclosed. The present disclosure relates to complement C5 inhibitors, particularly eculizumab, pharmacokinetics / pharmacodynamics (PK / PD), and dosing regimens of complement inhibitors. Eculizumab is a C5 inhibitor sold under the trade name Soliris™ manufactured by Alexion Pharmaceuticals, Inc. (Boston, Massachusetts) and described in Kaplan (2002) Curr Opin Investig Drugs 3(7):1017-23, Hill (2005) Clin Adv Hematol Oncol 3(11):849-50, and Rother et al. (2007) Nature Biotechnology 25(11):1256-1488), in particular the administration of eculizumab to individuals with TA-TMA who may further be diagnosed as having clinically significant bleeding. The disclosed methods may be used to treat both TA-TMA patients with active gastrointestinal bleeding and / or TA-TMA patients with resolved gastrointestinal bleeding. For example, the methods disclosed herein encompass the dosing schedules set forth in Table 1.

[0014] In one aspect, a method of treating an individual with transplant-associated thrombotic microangiopathy (TA-TMA) and active gastrointestinal bleeding is disclosed. In this aspect, the method may include administering eculizumab or an antigen-binding fragment thereof to the individual, where the eculizumab or antigen-binding fragment thereof is administered via a loading dose and an induction dose. In one aspect, the loading dose is about 1200 milligrams every 24 hours for four doses, followed by about 1500 milligrams every 48 hours for five doses (wherein the individual is 70 kilograms or more), or about 900 milligrams every 24 hours for four doses, followed by about 900 milligrams every 48 hours for five doses (wherein the individual has a body weight of between 40 kilograms and less than 70 kilograms), or about 900 milligrams every 48 hours for two doses, followed by about 900 milligrams every 72 hours for three doses (wherein the individual is 30 kilograms or more). or about 900 milligrams every 48 hours for two doses, followed by about 900 milligrams every 72 hours for three doses (individuals having a body weight of 20 kilograms to less than 30 kilograms), or about 600 milligrams every 72 hours for five doses (individuals having a body weight of 10 kilograms to less than 20 kilograms), or about 300 milligrams every 72 hours for five doses (individuals having a body weight of less than 10 kilograms). Induction doses may include about 1500 milligrams every 48 hours for three weeks (individuals having a body weight of 70 kilograms or more), or about 900 milligrams every 48 hours for three weeks (individuals having a body weight of 40 kilograms to less than 70 kilograms), or about 900 milligrams every 72 hours for three weeks (individuals having a body weight of 30 kilograms to less than 40 kilograms), or about 900 milligrams every 96 hours for three weeks (individuals having a body weight of 20 kilograms to less than 30 kilograms), or about 600 milligrams every 96 hours for three weeks (individuals having a body weight of 10 kilograms to less than 20 kilograms), or about 300 milligrams every 96 hours for three weeks (individuals having a body weight of less than 10 kilograms).

[0015] In one aspect, a method of treating an individual with transplant-associated thrombotic microangiopathy (TA-TMA) and resolved gastrointestinal bleeding is disclosed. In this aspect, the method can include administering eculizumab or an antigen-binding fragment thereof to the individual, where the eculizumab or antigen-binding fragment thereof is administered via an induction dose and a maintenance dose. In one embodiment, the induction dose may comprise about 1500 milligrams twice a week every 3-4 days for 4 weeks (individual has a body weight of 70 kilograms or more), or 1500 milligrams per week for 4 weeks (individual has a body weight of 40 kilograms to less than 70 kilograms), or about 1200 milligrams per week for 4 weeks (individual has a body weight of 30 kilograms to less than 40 kilograms), or about 900 milligrams per week for 4 weeks (individual has a body weight of 20 kilograms to less than 30 kilograms), or about 600 milligrams per week for 4 weeks (individual has a body weight of 10 kilograms to less than 20 kilograms), or about 300 milligrams per week for 4 weeks (individual has a body weight of less than 10 kilograms). Maintenance doses may include about 1200 milligrams twice a week every 3-4 days for 4-5 weeks (individual is 70 kilograms or more), or about 1200 milligrams per week for 4-5 weeks (individual has a body weight between 40 kilograms and less than 70 kilograms), or about 900 milligrams per week for 4-5 weeks (individual has a body weight between 30 kilograms and less than 40 kilograms), or about 600 milligrams per week for 4-5 weeks (individual has a body weight between 20 kilograms and less than 30 kilograms), or about 600 mg per week for 4-5 weeks (individual has a body weight between 10 kilograms and less than 20 kilograms), or about 300 milligrams every two weeks for 4-5 weeks (individual has a body weight less than 10 kilograms).

[0016] In a further aspect, a method of treating an individual having transplant-associated thrombotic microangiopathy (TA-TMA) is disclosed comprising administering eculizumab or an antigen-binding fragment thereof to the individual, wherein the eculizumab or antigen-binding fragment thereof is administered at a dose of about 300 milligrams to a patient weighing <10 kilograms, or about 600 milligrams to a patient weighing 10 kilograms to <20 kilograms, or about 900 milligrams to a patient weighing 20 to <30 kilograms, or about 1200 milligrams to a patient weighing 30 to <40 kilograms, or about 1500 milligrams to a patient weighing 40 to <70 kilograms, or about 2100 milligrams to a patient weighing 70 to <100 kilograms, wherein the dose is administered every three days, and wherein the patient is a non-bleeding patient.

[0017] In a further aspect, a method of treating an individual with TA-TMA is disclosed comprising administering eculizumab or an antigen-binding fragment thereof to the individual, wherein the eculizumab or antigen-binding fragment thereof is administered at a dose of about 300 milligrams every 3 days to a patient weighing <10 kilograms, or about 600 milligrams every 3 days to a patient weighing 10 kilograms to <20 kilograms, or about 600 milligrams every 2 days to a patient weighing 20 to <30 kilograms, or about 600 milligrams per day to a patient weighing 30 to <40 kilograms, or about 900 milligrams per day to a patient weighing 40 to <70 kilograms, or about 900 milligrams per day to a patient weighing 70 to <100 kilograms.

[0018] In a further aspect, a method of treating an individual with TA-TMA is disclosed comprising administering eculizumab or an antigen-binding fragment thereof to the individual, wherein the eculizumab or antigen-binding fragment thereof is administered at a dose of about 300 milligrams every 3 days to a patient weighing <10 kilograms, or about 600 milligrams every 3 days to a patient weighing 10 kilograms to <20 kilograms, or about 900 milligrams every 3 days to a patient weighing 20 to <30 kilograms, or about 900 milligrams every 2 days to a patient weighing 30 to <40 kilograms, or about 1200 milligrams every 2 days to a patient weighing 40 to <70 kilograms, or about 1200 milligrams per day to a patient weighing 70 to <100 kilograms.

[0019] In a further aspect, a method of treating an individual with TA-TMA is disclosed comprising administering eculizumab or an antigen-binding fragment thereof to the individual, wherein the eculizumab or antigen-binding fragment thereof is administered at a dose of about 40 milligrams / kilogram every three days for patients weighing <10 kilograms, or 30 milligrams / kilogram every two days for patients weighing <10 kilograms to <100 kilograms.

[0020] In one embodiment, an individual with TA-TMA has high-risk TMA with MODS. In one embodiment, TA-TMA may be characterized by an sC5b-9 level that is at least twice the baseline level measured in the individual and / or by an sC5b-9 level of greater than about 244 nanograms per milliliter.

[0021] Administration of any of the aforementioned therapeutic regimens (dosing schedules) may be initiated upon TA-TMA diagnosis in an individual. In one aspect, administration may be via intravenous administration. The method may be administered until a hematological TA-TMA response selected from one or more of normalization of LDH, elimination of the need for red blood cell (RBC) and platelet transfusions, and disappearance of schistocytes is achieved in the individual being treated. In one aspect, induction doses may be administered until a hematological TA-TMA response of normalization of LDH, elimination of the need for red blood cell (RBC) and platelet transfusions, and disappearance of schistocytes is achieved in the individual being treated. In further aspects, induction doses may be administered until normalized sC5b-9 is achieved, which is one or both of sC5b-9 levels below 244 ng / mL or sC5b-9 levels that are substantially baseline (pre-transplant), or until elevated sC5b-9 levels are normalized.

[0022] In certain embodiments, the method may include determining whether the individual has clinically significant gastrointestinal bleeding prior to selecting an appropriate dosing regimen. In one embodiment, the individual may be determined to have resolved gastrointestinal bleeding. In certain embodiments, the individual treated using the dosing regimen may not have clinically significant bleeding (i.e., a "non-bleeding" individual). In some embodiments, the individual may be selected from a young child, a prepubertal individual, or an adult (over 18 years of age).

[0023] In a further aspect, a precision dosing tool for determining a course of treatment in an individual diagnosed with TA-TMA is disclosed, in which the tool detects one or more patient-specific variables and determines a therapeutically effective amount of eculizumab therapy, the determination comprising: CL=CL L +CL NL , C.L. L =CL L、pop ×(WT / 70) 0.97 , C.L. NL =CL NL、pop ×(sC5b-9 / 244) 0.53 ×(WT / 70) 0.97 , Vd=Vd pop ×(WT / 70) 0.63 (for non-bleeding patients), and CL=CL L +CL NL , C.L. L =CL L、pop ×(WT / 70) 1.03 , C.L. NL =CL NL、pop ×(sC5b-9 / 244) 0.52 ×(WT / 70) 1.03 , Vd=Vd pop ×(WT / 70) 0.74 (For bleeding patients) (Here, CL NL is the eculizumab population average nonlinear clearance for a 70 kg patient, which represents the target-mediated component of clearance, and CL L、popis the eculizumab population mean linear clearance for a 70 kg patient, which represents the nonspecific component of clearance mediated by neonatal Fc receptors, and CL tot、pop CL NL、pop and C.L. L、pop is the population average total clearance, defined as the sum of Vd pop is the population average volume of distribution for a 70 kg patient, and WT is the actual body weight (kg); and administering a therapeutically effective amount of eculizumab to an individual as described herein according to an algorithm. Such methods may be performed using a computerized device, for example a handheld device that may be used at the point of care "bedside."

[0024] The disclosed methods may include one or more of a loading dose, an induction dose, and a maintenance dose.

[0025] Loading dose. In one embodiment, a loading dose may be used to control complement activation by achieving normalization of sC5b-9. A concentrated loading dose may be used to normalize sC5b-9 as quickly as possible by providing a sufficient eculizumab dose to completely suppress complement activity in the blood. The loading dose may use the maximum dose (mg) relative to the patient's weight, since a TA-TMA clinical response is unlikely to be achieved unless sC5b-9 is normalized. In one embodiment, the loading dose is administered until normalization sC5b-9 is normalized. In one embodiment, eculizumab may be administered to a patient with elevated sC5b-9 for a period of about 11 to about 13 days. Elevated sC5b-9 may be one or both of >244 ng / mL or doubling compared to the patient's baseline value.

[0026] In one embodiment, the disclosed method may use a 72 hour dosing schedule, or a 48 hour dosing schedule, or a 24 hour dosing schedule. In one embodiment, each dose (mg) is administered at intervals of 72 hours or less in subjects with elevated sC5b-9. In one embodiment, the loading dose may be multiple doses that may be administered with a loading dose interval of at least about, or may be about, 2 weeks.

[0027] Induction dose. An induction dose may be used to control sC5b-9 activation while achieving a clinical TA-TMA response. In one embodiment, the induction dosing time is at least about 3 weeks, or at least about 4 weeks, or about 4 weeks. In one embodiment, the induction dose may be 3 weeks, but can be shortened or extended based on the bleeding status of the patient being treated. In one embodiment, the total treatment time with loading and induction is at least about 6 weeks, and the loading dose includes about 2 weeks of the total loading dose and induction dose treatment period. In one embodiment, sC5b-9 activation is controlled with the loading dose period such that sC5b-9 levels are normalized (below about 244 ng / mL or substantially returned to patient baseline) when induction dosing is initiated. In one embodiment, the induction period is administered to a patient with normalized sC5b-9 levels and is administered every 7 days, or every 6 days, or every 5 days, or every 4 days, or every 3 days, or every 2 days, or every day, or twice daily. In one embodiment, the induction dose is administered for 7 days or less. In one embodiment, the patient has a body weight >70 kg and is administered two doses per week during the induction period.

[0028] Maintenance dosing. Eculizumab clearance in patients with TA-TMA remained 23% higher in the maintenance phase compared to patients with aHUS. A maintenance dosing period may be used to maintain TA-TMA control and normalized sC5b-9 levels. Complement activation may be assessed during the maintenance dosing period. In one embodiment, eculizumab therapy can be safely stopped once complement activation has resolved. In one embodiment, the maintenance dosing period is at least or about 4 weeks. Thus, applicants proposed a weekly drug dosing option for all weight groups, except for those >70 kg who required twice weekly dosing and those <10 kg who required dosing only every 2 weeks using weight-based drug (mg) dosing to maintain therapeutic eculizumab drug levels of >75 μg / mL that resulted in the desired clinical response.

[0029] In one aspect, the dosing schedule comprises about 9.5 weeks total dosing time, with about 5 to about 6 weeks of loading and induction therapy, and about 4 to about 5 weeks of maintenance therapy. In one aspect, after 4 weeks of maintenance therapy, treatment can be discontinued if sC5b-9 remains normalized and eculizumab drug concentrations (trough) are >100 μg / mL and / or increasing with each dose.

[0030] In some embodiments, the patient has not been previously treated with a complement inhibitor (e.g., the patient is a complement inhibitor treatment naive patient). In some embodiments, the patient may have been previously treated with a complement blocker, but may have cleared such previous treatment.

[0031] In some embodiments, the individual is a toddler. The individual may be, for example, 0.5 (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, or 9.5) years old. The toddler may be less than 10 years old (e.g., 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1 year old, or less than 1 year old). In some embodiments, the individual is a toddler. The individual may be, for example, 0.5 (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, or 9.5) years old. An infant can be under 10 years of age (e.g., 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1 year old, or under 1 year old). In one aspect, the individual is a newborn (from birth to 28 days after birth), or an infant (29 days to under 2 years old), a child (2 years to under 12 years old), or an adolescent (12 to 21 years old, up to their 22nd birthday).

[0032] In one aspect, a method of treating an individual with TA-TMA is disclosed, wherein the individual is administered a C5 inhibitor, or eculizumab, or a fragment thereof, according to the following dosing schedule:

[0033] [Table 1] * 1: Bleeding status of TA-TMA patients who experienced GI bleeding; active and resolved bleeding episodes are expected during treatment of bleeding patients. Criteria for active gastrointestinal (GI) bleeding are described in the patent literature. *2: Loading dose and induction dose-1: The loading dose and induction dose-1 were designed for "active" GI bleeding. Considering the continuous high clearance prediction in TA-TMA patients with "active" bleeding (Mizuno et al. 2022), it is a lower mg dose with more frequent dosing than non-bleeding patients shown in Table 2 to maintain the target Ctrough > 100 μg / mL. This induction dose was selected from the two proposed induction dosing options shown in Table 3, taking into account the economic and pharmacological benefits. A detailed explanation of the selection is described in Table 3. Following the decline of sC5b-9, the dosing interval for patients with active bleeding can be spaced apart, but is limited to intervals of up to 96 hours for patients < 30 kg, up to 72 hours for patients 30 to < 40 kg, and up to 48 hours for patients > = 40 kg to achieve the target Ctrough > 100 μg / mL. The induction dose-1 treatment course is proposed to be 3 weeks based on PK modeling using clinical data in treated patients, but may be shortened or extended based on the bleeding status of the treated patient. * 3: Induction Dose-2 and Maintenance Dose: Induction Dose-2 followed by a maintenance dose is given to the patient after the bleed has resolved. These protocols were developed using data from non-bleeding patients as shown in Table 3.

[0034] The dosing regimens in Table 1 may be used for two categories of bleeding patients: active bleeding and resolved bleeding. A "loading dose and induction dose-1" may be used for "active" GI bleeding, and an "induction dose-2 followed by a maintenance dose" may be used for patients after the bleeding has resolved.

[0035] Persistently high clearance is predicted in TA-TMA patients with "active" bleeding (Mizuno et al., 2022). Bleeding patients require smaller mg doses and more frequent dosing than non-bleeding patients to maintain Ctrough above target levels (Table 1 vs. Table 2).

[0036] [Table 2]

[0037] Economically effective dosing options were selected as the complete dosing regimen for TA-TMA with active GI bleeding (Table 3-A and B).

[0038] [Table 3] The loading dose options were selected based on the simulations in Figure 12. Option A was selected for the full dosing proposal in Table 1, taking into account the economic benefits.

[0039] (A) Induction Medication Options Table 3B. Eculizumab Dosing Options for TA-TMA with GI Bleeding

[0040] [Table 4]

[0041] Table 3C. Eculizumab Dosing Options for TA-TMA with GI Bleeding

[0042] [Table 5] * Only one induction dosing option was suggested for patients over 70 kg, as the higher doses of 1800 mg or 2100 mg doses with a 3-day dosing interval do not reach 80% target achievement. Option A is designed as dosing using a lower dose of drug (mg) but with more frequent dosing, and option B utilizes an increased dose (mg) but with minimally frequent dosing. Option A may be used as a dosing regimen for patients with active bleeding, considering the economic and pharmacological benefits. Option A requires fewer vials for treatment compared to option B, making it economically effective. Overall, option A achieves a higher probability of target achievement than option B (Figure 14).** The induction dose-1 treatment course is proposed to be 3 weeks based on PK modeling using clinical data in treated patients, but may be shortened or extended based on the bleeding status of the treated patient.

[0043] Following the decline in sC5b-9, dosing intervals for patients with active bleeding can be spaced apart, but are limited to intervals of up to 96 hours for patients <30 kg, up to 72 hours for patients 30 to <40 kg, and up to 48 hours for patients >=40 kg, to achieve a target Ctrough >100 μg / mL.

[0044] Medication for Patients with Active GI Bleeding loading dose Loading dosing time (2 weeks) (Figure 10). As described for non-bleeding, normalization of sC5b-9 should occur within 2 weeks (14 days), since sustained complement activation longer than 2 weeks has been shown to be associated with multi-organ injury in TA-TMA. Applicants have found that in non-bleeding patients with double normal sC5b-9, even with sufficient (therapeutic eculizumab dose) and fully suppressed whole blood complement activity (CH50 < normal lower limit 10%), it may take about 11 to about 13 days to normalize sC5b-9. A limited number of patients showed double normal sC5b-9 at the start of treatment in bleeding patients. Given the comparable sC5b-9 distribution throughout treatment, the loading dose duration observed in non-bleeding can be applied to bleeding patients.

[0045] Each dose (mg): (Figures 11 and 12). Assuming a similar sC5b-9 distribution to that observed in bleeding patients, optimal dosing simulations were performed based on the model published in Mizuno et al. 2022. If patients with active bleeding receive dosing protocol option A for non-bleeding patients (Table 2), a significantly lower probability of target achievement is predicted for the higher weight cohorts above 20 kg. The simulation in Figure 12 derived an optimized dosing protocol for patients >20 kg with active GI bleeding by shortening the dosing interval and / or mg dose adjustment.

[0046] Dosing options A and B (Table 3-A). For patients weighing 20 to <40 kg, two dosing options were proposed: 900 mg IV Q48h (option A) versus 600 mg IV Q24h (option B). Considering the economic benefits, option A was selected for the optimal dosing proposal for patients with active bleeding. The high clearance in TA-TMA patients with bleeding did not result in an economically and pharmacologically beneficial dosing option for patients weighing >40 kg.

[0047] induction dose 1 Induction Dose-1 (2-3 weeks). In the applicant's patient cohort, bleeding patients received eculizumab treatment for a median of 13.0 weeks (IQR: 7.3-17.6), whereas non-bleeding patients received it for 9.8 weeks (IQR 5.9-16.6). Compared with non-bleeding patients, bleeding patients required longer treatment, a median of 3 weeks. Partial therapy of induction dose-1 may be used in patients who continue to have clinically significant GI bleeding after loading therapy is completed. The dosing regimen may be administered for 3 weeks or until active bleeding is controlled (the induction dose-1 treatment course may be shortened or extended based on the bleeding status of the patient being treated).

[0048] Each dose (mg) and dosing interval (Figures 13 and 14). sC5b-9 activation is controlled with the loading dose, so sC5b-9 is normal when induction dose-1 is started. Doses given every 7 days are not appropriate for patients >20 kg due to insufficient Ctrough target achievement. When bleeding patients receive the proposed loading dose of eculizumab during the induction phase, predicted Ctrough levels are reached above therapeutic levels. Interquartile Ctrough levels were optimized to appropriate target levels by spacing the doses by 1-2 days at the same mg dose. Further dose adjustment for the highest weight group by adding 1 vial (300 mg) was required to achieve interquartile Ctrough levels above the target level of 100 μg / mL.

[0049] The patient is taken off medication after the bleed. The patient can proceed to "Induction Medication-2" after the GI bleed is controlled and has undergone the stress and induction-1 medication portion. Maintenance medication may then be administered after induction 2. EXAMPLES

[0050] The following non-limiting examples are provided to further illustrate the embodiments disclosed herein. It should be understood by those skilled in the art that the techniques disclosed in the following examples only represent exemplary aspects of the present disclosure.

[0051] Example 1. Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication following hematopoietic stem cell transplantation (HSCT) in pediatric patients and young adults. Patients with high-risk TA-TMA features, including activated terminal complement as measured by elevated blood sC5b-9 and proteinuria, have dismal outcomes with a 1-year post-transplant overall survival rate of 16.7%. Although there is no uniformly agreed upon therapeutic approach for TA-TMA, complement dysregulation is an important pathogenic pathway with potential for clinical intervention. Eculizumab, the first available monoclonal antibody against complement C5, has shown promising efficacy for TA-TMA treatment. In HSCT recipients with high-risk complement-mediated TA-TMA, blood soluble terminal complement complex activity (sC5b-9) serves as a surrogate pharmacodynamic biomarker for enhanced C5 production. The population PK model of eculizumab after the first dose of treatment allows prediction of the optimal initial dose and the optimal timing of subsequent doses based on the individual's pre-treatment sC5b-9 level and body weight. However, this model (described in Jodele S. et al. Variable Eculizumab Clearance Requires Pharmacodynamic Monitoring to Optimize Therapy for Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation. Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2016; 22(2): 307-315) only considers the elevated sC5b-9 levels at the start of treatment and cannot reflect the changes in the status of disease progression and subsequent improvements during the course of treatment.

[0052] The significant impact of gastrointestinal bleeding on eculizumab PK / PD is another factor to consider as part of dose individualization. TA-TMA patients with bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs. 9, p=0.0015), and had a lower 1-year survival rate than patients without bleeding (44% vs. 78%, p=0.01). Applicants identified HSCT subjects with TA-TMA and clinically significant bleeding as an ultra-high risk group that requires individualized drug dosing to improve survival.

[0053] Model-informed precision dosing can be used to improve treatment success by optimizing drug target exposure. Development of PK / PD model-informed precision dosing of eculizumab across treatment promises to improve treatment outcomes as well as cost-effectiveness. Patients with gastrointestinal (GI) bleeding exhibit poor survival even when dosed at more frequent doses. Eculizumab PK / PD was analyzed in 19 bleeding and 38 non-bleeding patients (0.5-29.9 years old). Complement activation biomarker (sC5b-9) and body weight were identified as important determinants of eculizumab clearance regardless of bleeding. Eculizumab clearance after the first dose was higher in bleeding patients than in non-bleeding patients (83.8 vs. 61.3 mL / hr / 70 kg, p=0.07). High clearance was maintained across therapeutic doses in bleeding patients, whereas non-bleeding patients showed a time-dependent decrease in clearance. sC5b-9 levels were highest before the first dosing and decreased over time regardless of bleeding complications. Monte Carlo simulation analysis showed that the current dosing protocol recommended for aHUS has a <15% probability of achieving eculizumab target concentrations >100 μg / mL in nonbleeding patients.

[0054] method Test subjects A clinical cohort of 64 patients with high-risk TA-TMA treated with eculizumab was available for analysis. All study subjects were prospectively and uniformly monitored for TA-TMA and underwent real-time eculizumab PK / PD monitoring. Clinical outcomes of this cohort were recently published in Blood by Jodele et al, Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Jodele S, Dandoy CE, Lane A, Laskin BL, Teusink-Cross A, Myers KC, Wallace G, Nelson A, Bleesing J, Chima RS, Hirsch R, Ryan TD, Benoit S, Mizuno K, Warren M, Davies SM. Blood. 2020 Mar 26;135(13):1049-1057. doi:10.1182 / blood.2019004218. PMID:31932840. Informed consent was obtained from all study subjects participating in the Bone Marrow Transplant Tissue Repository. The Institutional Review Board approved the retrospective analysis of PK / PD data.

[0055] Patient demographics, transplant information, clinical data, and laboratory studies were obtained from the electronic medical record and transplant data repository. Red blood cell (RBC) and platelet transfusions were reviewed for each day of eculizumab therapy and recorded as mL / kg / day administered for each study subject. Patients with any clinical evidence of lower intestinal bleeding were marked as having clinically significant bleeding and assigned to the bleeding patient group for analysis.

[0056] Subjects with incomplete eculizumab concentrations and / or incomplete sC5b-9 data were excluded from the analysis. Eculizumab concentrations >1000 μg / mL and eculizumab measurements where the patient was treated with therapeutic plasma exchange (TPE) were excluded from the analysis.

[0057] Eculizumab treatment and treatment monitoring Details of eculizumab dosing, response monitoring methods, and clinical outcome assessments are described in Jodele S, Dandoy CE, Lane A, et al. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020;135(13):1049-1057. Briefly, the initial eculizumab dose (mg) was based on body weight as suggested in the eculizumab drug label and published data. During the loading and induction phases of treatment, dosing intervals were adjusted based on eculizumab concentrations and CH50 levels to maintain blood eculizumab trough concentrations ≥100 μg / mL and trough CH50 levels <10% of normal. Eculizumab loading doses were given at least every 72 hours to subjects with elevated blood sC5b-9 levels at the start of eculizumab treatment, and loading doses were continued until blood sC5b-9 levels normalized (normal < 244 ng / mL). Maintenance and tapering schedules were considered only after maintaining therapeutic eculizumab concentrations and CH50 < 10% for at least two consecutive dosing intervals after normalization of sC5b-9. If therapeutic eculizumab concentrations and normal sC5b-9 levels were recorded for two consecutive doses after initiating a tapering schedule, eculizumab therapy was discontinued after resolution of blood TA-TMA and stabilization / improvement of affected organ function.

[0058] Eculizumab PK / PD modeling Nonlinear mixed-effects modeling (NONMEM version 7.4, ICON Development Solutions, Ellicott City, MD, USA) coupled with Perl-speaks-NONMEM (PsN 4.9.0) and Pirana 2.9.9 was used to develop pharmacokinetic (PK) models for non-bleeding and bleeding TA-TMA patients. Following standards of good modeling practice, observations with Iconditional weighted residuals > 6 were excluded from modeling. The effect of potential covariates on eculizumab PK was evaluated using age, sex, weight, albumin, glomerular filtration rate (GFR), eculizumab dosing frequency, and sC5b-9 levels. The effect of increasing body size on eculizumab clearance was evaluated using relative scaling to a body weight of 70 kg. Inter-occasion variability was also considered. Missing sC5b-9 levels were replaced by an interpolated value between the previous and subsequent values, assuming linear change. Covariate selection was based on a significant decrease in the objective function value by stepwise forward inclusion (p<0.05), backward exclusion (p<0.01), and graphical evaluation of the goodness-of-fit plots. Model evaluation was performed by bootstrap analysis and predictor-corrected visual prediction checks (Figures 6A-6D).

[0059] Simulation of eculizumab concentration-time profiles for non-bleeding and bleeding patients Based on the population PK model developed for bleeding and non-bleeding patients, Edsim++ version 1.9 was used to simulate eculizumab concentration-time profiles after the first dose to predict the optimal timing of subsequent doses in representative patients. Considering the currently recommended starting doses approved for aHUS (300 mg for <10 kg, 600 mg for 10 to <40 kg, and 900 mg for ≥40 kg), representative patients were selected for PK simulation to cover the weight ranges of young, middle-aged, and older pediatric / young adult cohorts as follows: an 8-kg patient receiving 300 mg, a 25-kg patient receiving 600 mg, and a 70-kg patient receiving 900 mg.

[0060] Simulation of optimal loading dose schedules The optimal loading dose schedule for TA-TMA non-bleeding patients was investigated by assessing the probability of achieving target trough concentration achievement (PTA%) using Monte Carlo simulation (MCS) analysis. PTA% was defined as the percentage of patients achieving a pre-dose eculizumab concentration goal of >100 μg / mL. A total of 12,000 age- and weight-matched subjects were randomly sampled from the CDC-NHANES database with weight cohorts of <10 kg, 10 to <20 kg, 20 to <30 kg, 30 to <40 kg, 40 to <70, and 70 to <100 kg. Under the assumption of a data distribution similar to that observed in this study, realistic pre-dose sC5b-9 levels were generated using MCS to match the sC5b-9 distribution observed in this study. Based on the simulation results for the currently recommended loading dose scenario labeled for aHUS, five optimal dosing scenarios were selected (300 mg for patients <10 kg, 600 mg for 10 <-40 kg, and 900 mg for 40-<100 kg). Considering a dose strength of 300 mg per vial, five different dosing scenarios were tested as follows: 1; the currently recommended dosing for each weight cohort approved for aHUS but with a shortened dosing interval of 3 days (protocol 1), 2; an increased dosing with a dosing interval of 3 days (protocol 2), 3; the currently recommended dosing for each weight cohort approved for aHUS but with an adjusted dosing interval according to weight cohort (protocol 3), 4; a combination of an increased dosing and a shortened dosing interval to avoid extremely high doses (protocol 4), and 5; mg / kg-based dosing (protocol 5).

[0061] result Test subjects Complete eculizumab PK / PD data throughout multiple dose treatment were available in 19 bleeding and 38 non-bleeding patients for model development. Relevant demographic data for population PK model development are summarized in Table 1.

[0062] Bleeding patients received significantly more RBC and platelet transfusions during eculizumab therapy than nonbleeding patients (79-84% of bleeding patients vs. 5% of nonbleeding patients). Pretreatment sC5b-9 levels in this population were highly variable, with a median of 217 ng / mL (range 107-1641 ng / mL). Bleeding patients had significantly lower albumin and AST values ​​than nonbleeding patients. All other laboratory parameters, including age, weight, and predose sC5b-9 levels, were not significantly different between bleeding and nonbleeding patients (Table 1).

[0063] Table 1. Patient demographics GFR, glomerular filtration rate adjusted for body surface area 1.73 m2; SCR, serum creatinine; BIL, serum bilirubin; ALB, albumin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; RBC, red blood cells; PLTS, platelets; * 1, total, sum of RBC / PLTS transfusions during the first 5 therapeutic doses (mg / kg / day); * 2. Number of transfusions, total RBC / PLTS transfusion days during the first 5 therapeutic doses

[0064] [Table 6]

[0065] [Table 7]

[0066] The final model for non-bleeding patients is as follows: CL=CL L +CL NL , C.L. L =CL L、pop ×(WT / 70) 0.97 , C.L. NL =CL NL、pop ×(sC5b-9 / 244) 0.53 ×(WT / 7O) 0.97 , Vd=Vd pop ×(WT / 70) 0.63 .

[0067] The final model for the bleeding patient is as follows: CL=CL L +CL NL , C.L. L =CL L、pop ×(WT / 7O) 1.03 , C.L. NL =CL NL、pop ×(sC5b-9 / 244) 0.52 ×(WT / 7O) 1.03 , Vd=Vd pop ×(WT / 70) 0.74 . Here, CL NL、pop is the eculizumab population mean nonlinear clearance for a 70 kg patient, CL L、pop is the eculizumab population mean linear clearance for a 70 kg patient, CL tot、pop CL NL、pop and C.L. L、pop is the population average total clearance, defined as the sum of Vd pop is the population average volume of distribution for a 70 kg patient, and WT is the actual body weight (kg).

[0068] Eculizumab PK / PD Differences between Non-Bleeding and Bleeding Patients Changes in eculizumab concentration-time profiles were visualized during the first 5 doses of treatment in non-bleeding and bleeding patients (Figure 1). In bleeding patients, eculizumab concentrations fell below target levels more rapidly over the treatment dose compared to non-bleeding patients. Drug elimination decreased gradually over the treatment dose in non-bleeding patients. In contrast, bleeding patients maintained high drug elimination over all 5 doses. Bleeding patients received higher RBC and platelet transfusions over the first 5 doses of treatment compared to non-bleeding patients (Figures 7A, 7B).

[0069] Eculizumab PK / PD differences between non-bleeding and bleeding patients were also evaluated by using individual eculizumab clearance estimates and observed pre-dose sC5b-9 levels. Median eculizumab clearance after the first dose tended to be higher in bleeding patients than in non-bleeding patients (83.8 vs. 61.3 mL / hr / 70 kg, p=0.07). It is important to note that high clearance was maintained over time in bleeding patients, whereas non-bleeding patients showed a decrease in clearance over time. Pre-dose sC5b-9 levels were highest during the first week of treatment and decreased over time regardless of bleeding events (Figure 2, B). Pre-dose sC5b-9 levels were higher in bleeding patients during the first week and then tended to suppress to levels comparable to non-bleeding patients during subsequent treatments.

[0070] Eculizumab population PK modeling Separate population PK models were developed for non-bleeding and bleeding patients. A one-compartment model best explained the data. Eculizumab clearance (CL) was calculated as a nonspecific linear clearance (CL ) representing neonatal Fc receptor-mediated clearance. L ) components and nonlinear clearance (CL NL ) listed by ingredients. 22~24 In bleeding patients, CL L and C.L. NL The difference in eculizumab clearance between bleeding and non-bleeding patients could not be estimated independently because no change in eculizumab clearance over time was observed. Given the very high total clearance observed in bleeding patients, the difference in CL between bleeding and non-bleeding patients was not significant. L The effect of the difference was negligible. Therefore, the estimated CL in non-bleeding patients L was used for PK modeling in bleeding patients.

[0071] Regardless of bleeding events, sC5b-9 levels and body weight were significant covariates predicting eculizumab clearance with comparable index estimates.

[0072] Nonbleeding patients showed a mean eculizumab clearance estimate of 58.5 mL / h in a 70-kg patient after the first dose (CL NL ;31.3mL / hour, CL L 27.2 mL / hr), with an upper normal range for sC5b-9 levels of 244 ng / mL. These estimates are comparable to Applicant's previously published model, which derived a mean eculizumab clearance of 66.0 mL / hr in a 70-kg patient with an sC5b-9 level of 244 ng / mL. The eculizumab nonlinear time-dependent decrease in clearance was a function of dosing number in addition to sC5b-9 changes. The mean volume of distribution after the first dose for the 70-kg patient was 5.5 L. The volume of distribution increased by 63% across the therapeutic doses.

[0073] Bleeding patients had a mean eculizumab clearance of 87.2 mL / hour after the first dose in a 70-kg patient with an sC5b-9 level of 244 ng / mL (CL NL ;60.0L / hour, CL L 27.2 L / hr), which was 50% higher than the mean clearance estimate in nonbleeding patients. Eculizumab nonlinear clearance remained constant over multiple doses of treatment when body weight and sC5b-9 levels did not change. Bleeding patients had a volume of distribution of 4.4 L (normalized for a 70-kg patient) over the different dosing intervals, which was 20% lower than the volume of distribution after the first dose in nonbleeding patients. The amount of RBC correlated with the amount of platelet transfusion. Patients who received RBC and / or platelet transfusions were more likely to have higher eculizumab clearance (R for RBCs). 2 = 0.13 and R for platelet transfusions 2 = 0.20, Figure 8). However, this effect was not significant and was not retained in the final model.

[0074] Eculizumab PK simulation A previously reported eculizumab concentration-time simulation over 7 days after the first dose of treatment was extended based on a newly developed PK model for patients with bleeding complications (Figure 3). The simulation predicted the timing of the next dose required to maintain eculizumab target concentrations at ≥100 μg / mL in representative cases. Figure 3 provides an overview of the simulated eculizumab concentration-time profiles for dosing scenarios in an 8-kg patient receiving 300 mg, a 25-kg patient receiving 600 mg, and a 70-kg patient receiving 900 mg.

[0075] In 25-kg nonbleeding patients receiving 600 mg eculizumab with a predose sC5b-9 level of 400 ng / mL, the mean eculizumab concentration was predicted to fall to less than 100 μg / mL approximately 4 days after the first dose. The mean eculizumab concentration was maintained above the target for 5 days during which a lower pretreatment sC5b-9 level of 200 ng / mL would be present. 8-kg nonbleeding patients receiving 300 mg eculizumab were predicted to maintain eculizumab concentrations above the target for a period ranging from 5 to 7 days depending on the predose sC5b-9 level. This target achievement period was longer than that observed in 25-kg patients receiving 600 mg eculizumab. In contrast, 70-kg nonbleeding patients receiving 900 mg were predicted to have eculizumab concentrations below the target within 3 days after the first dose. In bleeding patients, eculizumab concentrations were predicted to fall below target approximately 0.5 to 1 day earlier than those predicted in nonbleeding patients.

[0076] Simulation of optimal medication schedule The currently recommended weekly induction dosing approved for aHUS resulted in a maximum probability of target achievement (PTA%) of 50% in non-bleeding patients. A lower PTA% was predicted for patients with a heavier body weight (≥20 kg) compared to patients <20 kg. When intensifying eculizumab dosing by using the same amount of drug (mg) per dose but dosing every 3 days (Protocol 1), a PTA% of at least 80% was achieved in subjects <20 kg. The PTA% was less than 50% in patients ≥20 kg. Thus, Protocol 2 evaluated the optimal dose to reach at least 80% PTA by subdividing the body weight cohorts, especially for patients ≥20 kg with a fixed 3-day dosing interval. With a 3-day dosing interval, the optimal dose was 900 mg for patients with body weight 20 to <30 kg, 1200 mg for 30 to <40 kg, and 1500 mg for 40 to <70 kg. For patients ≥70 kg, the optimal dose was predicted to be 2100 mg, which is significantly more than the currently recommended maximum induction dose of 900 mg. Protocol 3 evaluated the best dosing interval to reach 80% PTA when the recommended aHUS dose (mg) was selected for each weight cohort. The predicted optimal interval was 3 days for patients weighing <20 kg, 2 days for 20-<30 kg, and 1 day for ≥30 kg. The currently recommended 900 mg dose only resulted in a maximum PTA of 60% in patients weighing 70-100 kg, even if that dose was administered daily. Protocol 4 evaluated the optimal dosing protocol by combining increased dosage (mg) and dose intensification. The predicted optimal dose protocols were 900 mg every 3 days for patients weighing 20 to <30 kg, 900 mg every 2 days for 30 to <40 kg, 1200 mg every 2 days for 40 to <70 kg, 1200 mg every 2 days for 40 to <70 kg, and 1200 mg daily for >70 kg. Finally, an optimal mg / kg-based dose to reach 80% PTA is proposed as an option in protocol 5.The optimal dose for patients weighing less than 10 kg was 40 mg / kg every 3 days and 30 mg / kg every 2 days for patients weighing 10 kg or more. An overview of dosing protocols achieving various PTA% targets can be found in Figure 4. PTA% is described for dosing schedules where the dose ranged from 300 to 2100 mg and the dosing interval ranged from 1 to 7 days. Figure 5 shows that a PTA% approaching 100% could be achieved by increasing the dose by 300 mg (1 vial) in each weight cohort in protocol 4. The effect of pre-dosing sC5b-9 levels on PTA% is summarized in Figure 9. PTA% predictions for dosing protocol 4 were stratified by sC5b-9 cohorts of <250, 250 to <500, 500 to <750, and >750 ng / mL. PTA% decreased with increasing sC5b-9 levels. PTA% was predicted to be less than 80% in patients with high sC5b-9 levels ≥ 500 ng / mL.

[0077] Consideration Sustained excessive complement activation can damage the endothelium, resulting in multiple organ damage and death. The applicant's previous clinical observations clearly demonstrate that rapid complement blockade is necessary to improve clinical outcomes in HSCT recipients with high-risk TA-TMA. The most precise drug dosing is required during the loading and induction phases of treatment, when complement and TA-TMA activity are highest. This newly developed eculizumab loading, induction, and maintenance dosing algorithm confirms that the dosing regimens currently approved for patients with aHUS are not suitable for HSCT recipients with TA-TMA due to significantly lower target achievement. These results strongly suggest that eculizumab dosing for HSCT patients with TA-TMA needs to be optimized.

[0078] A population PK model is disclosed that uses an enriched eculizumab PK / PD dataset collected through multiple eculizumab treatment doses in the largest TA-TMA cohort of HSCT recipients. The model update adds several features for future clinical applications to the previously published model. The updated model can be used for precise dosing of eculizumab, not only for the first dose but also for subsequent doses. The enriched eculizumab PK / PD dataset enabled the development of a model that takes into account the mechanistic operating concepts of the monoclonal antibody elimination pathways: namely, Brambell receptor-mediated elimination and target-mediated elimination pathways. The currently approved aHUS dosing guidelines use the same induction dose in patients with body weights ranging from 10 to 40 kg. Simulations in HSCT patients showed that target achievement for patients ≥20 kg was significantly lower compared to patients <20 kg when treated with the same dosing protocol. These observations suggest that further subdivided body weight groups would be beneficial in HSCT patients to avoid sub-target concentrations in patients with higher body weights.

[0079] Bleeding patients have a much higher eculizumab drug clearance. Preliminary analysis showed that bleeding patients exhibit different pharmacological and disease characteristics than those observed in nonbleeding patients, so there is great benefit in optimizing eculizumab dose according to bleeding complications.

[0080] This newly developed model is also applicable to eculizumab dose optimization during the maintenance phase. The predicted eculizumab clearance during the maintenance phase was 27.2 mL / h when sC5b-9 levels were in the normal range, which was still 23% higher than the clearance reported for aHUS. This suggests that more frequent dosing may be required in TA-TMA patients than the currently recommended dosing intervals approved for aHUS suggest for the maintenance phase.

[0081] Bleeding patients had a significantly lower survival rate compared to non-bleeding patients (44% vs. 78%). Applicant compared eculizumab PK / PD in bleeding patients with that in non-bleeding patients. RBC and platelet transfusion requirements were used as surrogate markers of microangiopathy-hemolytic activity and blood loss. Strikingly, only 5% of non-bleeding patients required transfusion after initiation of eculizumab therapy, indicating good control of hemolysis and platelet consumption, whereas 84% ​​of bleeding patients were transfusion dependent. Consistent with the higher transfusion requirements over the therapeutic dosing interval observed in bleeding patients, eculizumab clearance remained high over the therapeutic dose, although clearance decreased over time in non-bleeding patients. Interestingly, there was no significant difference in the time-dependent decline in sC5b-9 between bleeding and non-bleeding patients. This can be explained by the more frequent dosing applied to bleeding patients, as the therapeutic study used real-time eculizumab concentration and CH50 monitoring for dose adjustment. These results suggest that a model-informed, precise dosing strategy that takes bleeding into account can rapidly and effectively reduce sC5b-9 by achieving eculizumab target concentrations. Appropriate complement blockade in patients with intestinal bleeding may still not be sufficient to improve survival, as these patients often have other transplant-related complications such as graft-versus-host disease (GVHD) or infection. Early interventions that maintain vascular endothelial health and rapid complement activation control, along with effective GVHD prevention or treatment and infection control, are likely required to further improve clinical outcomes.

[0082] Applicants sought to elucidate the mechanism of high eculizumab clearance in bleeding patients. In this study, pre-dose sC5b-9 levels and patient weight remained significant covariates predicting high drug clearance, without new covariates being identified. One possibility was that patients with severe blood loss had high eculizumab clearance due to drug loss from the body. Our covariate analysis suggested that red blood cell transfusion, as a surrogate marker for bleeding severity in bleeding patients, may partially explain the high clearance, but it was not retained in the final model. Another potential mechanism is persistent excess C5 generation from damaged intestinal tissue, providing multiple targets for eculizumab to bind. PK / PD analysis showed that higher pre-treatment sC5b-9 at the start of treatment reflected high drug clearance. However, eculizumab clearance in bleeding patients remains high even after sC5b-9 values ​​normalize, potentially indicating ongoing C5 generation that continues to require eculizumab for blockade to maintain normal sC5b-9 levels. Lower albumin levels in bleeding patients may be partially responsible for the high clearance, as reported for other monoclonal antibodies (mAbs), such as infliximab and anti-PD-L1 antibodies. Indeed, the applicant's study showed that baseline albumin levels in bleeding patients were significantly lower than in non-bleeding patients. However, low albumin may cause increased protein turnover, leading to accelerated degradation of IgG, including mAbs, and increased neonatal Fc receptor-mediated clearance of mAbs. In this study, there was no significant effect of albumin on the pharmacokinetics of eculizumab, possibly because bleeding patients received total parenteral nutrition containing albumin, which may have masked the effect. This suggests that high drug clearance is likely multifactorial in bleeding patients and that such patients require individualized PK / PD-based dosing of eculizumab.

[0083] In summary, our study shows that HSCT recipients require a dedicated drug dosing schedule appropriate for this population. We identified several dosing strategies that can be incorporated into clinical care. Prior to our invention, "fixed" dose or "blanket" dosing regimens could be derived for eculizumab dosing in non-bleeding HSCT recipients, but were not satisfactory for those with clinically significant bleeding. Although we have shown that TA-TMA patients with bleeding would benefit from individualized dose adjustments using continuous PK / PD dose modifications to provide adequate eculizumab exposure based on disease activity, "fixed" dosing tables could be created specifically for bleeding patients to be used by caregivers who do not have access to individualized dosing tools. Bleeding patients require a more intense loading and induction treatment course, likely due to sustained C5 production from damaged intestine and some drug loss due to bleeding. Such individualized dosing tools could be used in clinical practice for bleeding patients to further improve post-transplant outcomes.

[0084] All percentages and ratios are calculated by weight unless otherwise indicated.

[0085] All percentages and ratios are calculated based on the total composition unless otherwise indicated.

[0086] It should be understood that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification includes every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0087] The dimensions and values ​​disclosed herein should not be understood as being strictly limited to the exact numerical values ​​recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as "20 mm" is intended to mean "about 20 mm."

[0088] All documents cited herein, including any cross-references or related patents or applications, are incorporated herein by reference in their entirety unless expressly excluded or otherwise limited. All accession information (e.g., identified by PUBMED, PUBCHEM, NCBI, UNIPROT, or EBI accession number) and publications in their entirety are incorporated by reference into this disclosure to more fully describe the state of the art as known to those of skill in the art as of the date of this disclosure. The citation of any document is not an admission that it is prior art with respect to any invention disclosed or claimed herein, or that it alone, or in any combination with any other reference(s), teaches, suggests, or discloses any such invention. Furthermore, if any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall control.

[0089] While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

1. 1. A pharmaceutical composition comprising eculizumab or an antigen-binding fragment thereof for treating an individual with transplant-associated thrombotic microangiopathy (TA-TMA) and active gastrointestinal bleeding, wherein the pharmaceutical composition is administered to the individual at a loading dose and an induction dose; The loading dose is 1200 milligrams every 24 hours for four doses, followed by 1500 milligrams every 48 hours for five doses (said individual is 70 kilograms or more), or 900 milligrams every 24 hours for four doses, followed by 900 milligrams every 48 hours for five doses (said individual has a body weight of 40 kilograms to less than 70 kilograms), or 900 milligrams every 48 hours for two doses, followed by 900 milligrams every 72 hours for three doses (said individual has a body weight of 30 kilograms to less than 40 kilograms), or 900 milligrams every 48 hours for two doses, followed by 900 milligrams every 72 hours for three doses (said individual has a body weight of 20 kilograms to less than 30 kilograms), or 600 milligrams every 72 hours for five doses (said individual has a body weight of 10 kilograms to less than 20 kilograms), or 300 milligrams every 72 hours for five doses (said individual has a body weight of less than 10 kilograms); The induction dose is 1500 milligrams every 48 hours (said individual having a body weight of 70 kilograms or more), or 900 milligrams every 48 hours (said individual having a body weight of 40 kilograms to less than 70 kilograms), or 900 milligrams every 72 hours (said individual having a body weight of 30 kilograms to less than 40 kilograms), or 900 milligrams every 96 hours (said individual having a body weight of 20 kilograms to less than 30 kilograms), or 600 milligrams every 96 hours (said individual having a body weight of 10 kilograms to less than 20 kilograms), or 300 milligrams every 96 hours (said individual having a body weight of less than 10 kilograms).

2. 1. A pharmaceutical composition comprising eculizumab or an antigen-binding fragment thereof for treating an individual with transplant-associated thrombotic microangiopathy (TA-TMA) and resolved gastrointestinal bleeding, wherein the pharmaceutical composition is administered to the individual at an induction dose and a maintenance dose; The induction dose is 1500 milligrams twice a week, every 3-4 days for 4 weeks (said individual having a body weight of 70 kilograms or more), or 1500 milligrams per week for 4 weeks (said individual having a body weight of 40 kilograms to less than 70 kilograms), or 1200 milligrams per week for 4 weeks (said individual having a body weight of 30 kilograms to less than 40 kilograms), or 900 milligrams per week for 4 weeks (said individual having a body weight of 20 kilograms to less than 30 kilograms), or 600 milligrams per week for 4 weeks (said individual having a body weight of 10 kilograms to less than 20 kilograms), or 300 milligrams per week for 4 weeks (said individual having a body weight of less than 10 kilograms); The maintenance dose is 1200 milligrams twice a week every 3 to 4 days for 4 to 5 weeks (said individual is 70 kilograms or more), or 1200 milligrams per week for 4 to 5 weeks (said individual has a body weight of 40 kilograms to less than 70 kilograms), or 900 milligrams per week for 4 to 5 weeks (said individual has a body weight of 30 kilograms to less than 40 kilograms), or 600 milligrams per week for 4 to 5 weeks (said individual has a body weight of 20 kilograms to less than 30 kilograms), or 600 mg per week for 4 to 5 weeks (said individual has a body weight of 10 kilograms to less than 20 kilograms), or 300 milligrams every two weeks for 4 to 5 weeks (said individual has a body weight of less than 10 kilograms).

3. 1. A pharmaceutical composition comprising eculizumab or an antigen-binding fragment thereof for treating an individual with transplant-associated thrombotic microangiopathy (TA-TMA), wherein the pharmaceutical composition is administered at a dose of 300 milligrams to a patient weighing <10 kilograms, or 600 milligrams to a patient weighing 10 kilograms to <20 kilograms, or 900 milligrams to a patient weighing 20 to <30 kilograms, or 1200 milligrams to a patient weighing 30 to <40 kilograms, or 1500 milligrams to a patient weighing 40 to <70 kilograms, or 2100 milligrams to a patient weighing 70 to <100 kilograms, wherein the dose is administered every three days, and wherein the patient is a non-bleeding patient.

4. 1. A pharmaceutical composition comprising eculizumab or an antigen-binding fragment thereof for treating an individual with TA-TMA, wherein the pharmaceutical composition is administered at a dose of 300 milligrams every three days to a patient weighing <10 kilograms, or 600 milligrams every three days to a patient weighing 10 kilograms to <20 kilograms, or 600 milligrams every two days to a patient weighing 20 to <30 kilograms, or 600 milligrams per day to a patient weighing 30 to <40 kilograms, or 900 milligrams per day to a patient weighing 40 to <70 kilograms, or 900 milligrams per day to a patient weighing 70 to <100 kilograms.

5. 1. A pharmaceutical composition comprising eculizumab or an antigen-binding fragment thereof for treating an individual with TA-TMA, wherein the pharmaceutical composition is administered at a dose of 300 milligrams every three days to a patient weighing <10 kilograms, or 600 milligrams every three days to a patient weighing 10 kilograms to <20 kilograms, or 900 milligrams every three days to a patient weighing 20 to <30 kilograms, or 900 milligrams every two days to a patient weighing 30 to <40 kilograms, or 1200 milligrams every two days to a patient weighing 40 to <70 kilograms, or 1200 milligrams per day to a patient weighing 70 to <100 kilograms.

6. A pharmaceutical composition comprising eculizumab or an antigen-binding fragment thereof for treating an individual with TA-TMA, wherein the pharmaceutical composition is administered at a dose of 40 milligrams / kilogram every three days to a patient weighing <10 kilograms, or 30 milligrams / kilogram every two days to a patient weighing 10 kilograms to <100 kilograms.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the TA-TMA is a high-risk TMA associated with MODS.

8. The pharmaceutical composition of any one of claims 1 to 6, wherein the TA-TMA is characterized by sC5b-9 levels that are at least twice the baseline level measured in the individual.

9. The pharmaceutical composition of any one of claims 1 to 6, wherein the TA-TMA is characterized by an sC5b-9 level greater than 244 nanograms per milliliter.

10. The pharmaceutical composition of any one of claims 1 to 6, wherein the administration is initiated at the time of HSCT-TMA diagnosis in the individual.

11. The pharmaceutical composition according to any one of claims 1 to 6, wherein the administration is intravenous administration.

12. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the administration is performed until a hematological TMA response selected from one or more of: normalization of LDH, elimination of the need for red blood cell (RBC) and platelet transfusions, and disappearance of schistocytes is achieved.

13. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the method includes an induction dose, the induction dose being administered until a hematological TMA response of normalization of LDH, elimination of the need for red blood cell (RBC) and platelet transfusions, and disappearance of schistocytes is achieved.

14. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the method includes an induction dose, and the induction dose is administered until normalized sC5b-9 is achieved, which is one or both of sC5b-9 levels below 244 ng / mL or sC5b-9 levels that are substantially baseline (pre-transplant), or until elevated CH50 (whole blood complement) levels are normalized.

15. The pharmaceutical composition of any one of claims 1 to 6, wherein the individual has clinically significant bleeding.

16. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual does not have clinically significant bleeding (a non-bleeding individual).

17. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual is an infant.

18. The pharmaceutical composition of any one of claims 1 to 6, wherein the individual is prepubertal.

19. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual is an adult.

20. 1. A precision dosing tool for determining a course of treatment in an individual diagnosed with TA-TMA, comprising detecting one or more patient-specific variables and determining a therapeutically effective amount of eculizumab therapy, said determining comprising: CL=CL Ｌ +CL ＮＬ 、CL Ｌ =CL Ｌ、ｐｏｐ ×(WT / 70) ０．９７ 、CL ＮＬ =CL ＮＬ、ｐｏｐ ×(sC5b-9 / 244) ０．５３ ×(WT / 70) ０．９７ 、 Vd = Vd ｐｏｐ × (WT / 70) ０．６３ (for non-bleeding patients), and CL = CL Ｌ +CL ＮＬ , C.L. Ｌ =CL Ｌ、ｐｏｐ × (WT / 70) １．０３ , C.L. ＮＬ =CL ＮＬ、ｐｏｐ ×(sC5b-9 / 244) ０．５２ × (WT / 70) １．０３ , Vd=Vd ｐｏｐ × (WT / 70) ０．７４ (For bleeding patients) (Here, CL ＮＬ、ｐｏｐ is the eculizumab population average nonlinear clearance for a 70 kg patient, which represents the target-mediated component of clearance, and CL Ｌ、ｐｏｐ is the eculizumab population mean linear clearance for a 70 kg patient, representing the nonspecific component of clearance mediated by neonatal Fc receptors, and CL Ｌ、ｐｏｐ is the eculizumab population mean linear clearance for 70 kg patients, CL ｔｏｔ、ｐｏｐ CL ＮＬ、ｐｏｐ and C.L. Ｌ、ｐｏｐ and Vd ｐｏｐ is the population mean volume of distribution for a 70 kg patient, and WT is the actual body weight (kg); and administering a therapeutically effective amount of eculizumab to the individual in accordance with the algorithm.

21. 21. The precision dosing tool of claim 20, wherein the determination is performed by a computerized device.

Images