Population Pharmacokinetics and Exposure–Response of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With Myelodysplastic Syndromes

Chen, Nianhang; Kassir, Nastya; Laadem, Abderrahmane; Maxwell, Stephen E.; Sriraman, Priya; Giuseppi, Ana Carolina; Ritland, S; Linde, Peter G.; Budda, Balasubrahmanyam; Reynolds, Joseph G.; Zhou, Simon; Palmisano, Maria

doi:10.1002/psp4.12521

Cited by 7 publications

(7 citation statements)

References 23 publications

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“…Inspection of cumulative events for the 2 TEAEs over time during the entire study found that the increased TEAEs were mainly observed in the lower‐exposure groups; the incidence of the event was substantially lower in the highest AUC TEAE group compared with the lowest AUC TEAE group at most times. An inverse exposure‐TEAE relationship for luspatercept was also observed in other study populations 11 . The exposure‐TEAE relationship for the entire study could be confounded by dose increases over time or by individual variations in the treatment duration, during which certain adverse events manifest.…”

Section: Discussionsupporting

confidence: 59%

“…An inverse exposure-TEAE relationship for luspatercept was also observed in other study populations. 11 The exposure-TEAE relationship for the entire study could be confounded by dose increases over time or by individual variations in the treatment duration, during which certain adverse events manifest. Such an explanation is not considered likely for the current analysis, as the small dose increase (25%) fell within the individual exposure variability (36%) and the number of patients across AUC TEAE groups during the entire evaluation period was similar.…”

Section: Discussionmentioning

confidence: 99%

“…The true exposure‐efficacy relationship for binary end points, however, could be obscured by selection bias because of dose escalation (eg, patients who received higher dose levels were more likely to be nonresponders compared with patients who remained at lower dose levels). Such selection bias was observed in the exposure‐efficacy analysis for patients with myelodysplastic syndromes 11 . However, this bias was considered minimum in the current exposure‐efficacy analysis for patients with β‐thalassemia, as the luspatercept AUC largely overlapped between 1 and 1.25 mg/kg given a 36% IIV.…”

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics and Exposure‐Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With β‐Thalassemia

Chen

Kassir²,

Laadem

et al. 2020

The Journal of Clinical Pharma

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β-Thalassemia is an inherited blood disorder resulting from defects in hemoglobin production, leading to premature death of red blood cells (RBCs) or their precursors. Patients with transfusion-dependent β-thalassemia often need lifelong regular RBC transfusions to maintain adequate hemoglobin levels. Frequent transfusions may lead to iron overload and organ damage. Thus, there is a large unmet need for alternative therapies. Luspatercept, a first-in-class erythroid maturation agent, is the first approved therapy in the United States for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. The population pharmacokinetics and exposure-response relationship of luspatercept were evaluated in 285 patients with β-thalassemia. Luspatercept displayed linear and time-invariant pharmacokinetics when administered subcutaneously once every 3 weeks. Body weight was the only clinically relevant covariate of luspatercept clearance, favoring weight-based dosing. Magnitude and frequency of hemoglobin increase, if not influenced by RBC transfusions, was positively correlated with luspatercept area under the serum concentration-time curve (AUC), 0.2-1.25 mg/kg, whereas a significant reduction in RBC units transfused was observed in frequently transfused patients. The probability of achieving ≥33% or ≥50% reduction in RBC transfusion burden was similar across the time-averaged AUC (0.6-1.25 mg/kg), with the 1 mg/kg starting dose sufficient for most early responders (71%-80%). Increasing luspatercept AUC (0.2-1.25 mg/kg) did not increase incidence or severity of treatment-emergent adverse events. These results provide a positive benefit-risk profile for the recommended luspatercept doses (1-1.25 mg/kg) in treating adult patients with β-thalassemia who require regular RBC transfusions.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics and Exposure‐Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With β‐Thalassemia

Chen

Kassir²,

Laadem

et al. 2020

The Journal of Clinical Pharma

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“…9,13 Interestingly, apparent CL was strongly associated with efficacy for luspatercept, a therapeutic protein investigated in the MDS population, suggesting possible CL associations with severity of disease/anemia in MDS and providing support for these postulations. 43 However, it cannot be excluded that the identified time effect in this analysis may reflect fitting criteria to improve model description of the available data. The identification of dose as a covariate likely reflects additional nonlinearity in The simulated imetelstat concentration-time characterizes a biphasic elimination profile and shows an overall rapid disappearance plasma with an apparent t 1/2 , defined as the model estimated time for imetelstat concentrations to decrease by 50%, of 4.9 h, thus likely reflecting the rapid initial disposition phase (Figure S18).…”

Section: Discussionmentioning

confidence: 98%

Population pharmacokinetics of imetelstat, a first‐in‐class oligonucleotide telomerase inhibitor

González‐Sales,

Lennox,

Huang

et al. 2024

CPT Pharmacom & Syst Pharma

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Imetelstat is a novel, first‐in‐class, oligonucleotide telomerase inhibitor in development for the treatment of hematologic malignancies including lower‐risk myelodysplastic syndromes and myelofibrosis. A nonlinear mixed‐effects model was developed to characterize the population pharmacokinetics of imetelstat and identify and quantify covariates that contribute to its pharmacokinetic variability. The model was developed using plasma concentrations from 7 clinical studies including 424 patients with solid tumors or hematologic malignancies who received single‐agent imetelstat via intravenous infusion at various dose levels (0.4–11.7 mg/kg) and schedules (every week to every 4 weeks). Covariate analysis included factors related to demographics, disease, laboratory results, renal and hepatic function, and antidrug antibodies. Imetelstat was described by a two‐compartment, nonlinear disposition model with saturable binding/distribution and dose‐ and time‐dependent elimination from the central compartment. Theory‐based allometric scaling for body weight was included in disposition parameters. The final covariates included sex, time, malignancy, and dose on clearance; malignancy and sex on volume of the central compartment; and malignancy and spleen volume on concentration of target. Clearance in females was modestly lower, resulting in nonclinically relevant increases in predicted exposure relative to males. No effects on imetelstat pharmacokinetics were identified for mild‐to‐moderate hepatic or renal impairment, age, race, and antidrug antibody status. All model parameters were estimated with adequate precision (relative standard error < 29%). Visual predictive checks confirmed the capacity of the model to describe the data. The analysis supports the imetelstat body‐weight–based dosing approach and lack of need for dose individualizations for imetelstat‐treated patients.

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“…Additionally, a near-maximal response was correlated with AUC avg values ≥150 day•μg/ml irrespective of dose escalation status. 8…”

Section: Pharmacodynamics/pharmacokineticsmentioning

confidence: 99%

Novel agents for myelodysplastic syndromes

Hansen

2021

J Oncol Pharm Pract

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Review objective There have been several advances in the field of myelodysplastic syndromes over the past year, yielding two new US Food and Drug Administration drug approvals. The pharmacology, pharmacokinetics, clinical trials, therapeutic use, adverse effects, clinical use controversies, product description, and upcoming trials for myelodysplastic syndromes novel agents luspatercept-aamt and decitabine/cedazuridine are reviewed. Data sources This review article utilized primary information obtained from both the published studies involved in the approval of luspatercept-aamt and decitabine/cedazuridine and package inserts for the respective medications. This review article utilized secondary information obtained from National Comprehensive Cancer Network guidelines using filters and keywords to sustain information relevancy as well as key studies using the keywords, “luspatercept-aamt, myelodysplastic syndromes, decitabine, cedazuridine, hypomethylating agent, ASTX727” from scholarly journal database PubMed. Data summary Myelodysplastic syndromes consist of myeloid clonal hemopathies with a diverse range of presentation. Until recently, there have been relatively few new therapies in the myelodysplastic syndromes treatment landscape. On April 3, 2020 the US Food and Drug Administration approved Reblozyl®(luspatercept-aamt), then on July 7, 2020, the US Food and Drug Administration approved INQOVI® (decitabine and cedazuridine). Luspatercept-aamt acts as a erythroid maturation agent through differentiation of late-stage erythroid precursors. The safety and efficacy of luspatercept-aamt was demonstrated in the MEDALIST trial, a phase III trial in patients with very low-intermediate risk refractory myelodysplastic syndromes and ring sideroblasts. Luspatercept-aamt met both primary and secondary endpoints of transfusion independence of 8 weeks or longer and transfusion independence of 12 weeks or longer, respectively. Decitabine/cedazuridine has a unique mechanism of action in which decitabine acts as a nucleoside metabolic inhibitor promoting DNA hypomethylation and cedazuridine then prevents degradation of decitabine. The safety and efficacy of decitabine/cedazuridine was shown in the ASCERTAIN study, a phase III trial in patients with intermediate or high risk myelodysplastic syndromes or chronic myelomonocytic leukemia. The primary outcome evaluated was 5-day cumulative area under the curve between decitabine/cedazuridine and IV decitabine as well as additional outcomes including safety. Decitabine/cedazuridine met primary outcome and had a similar safety profile to IV decitabine. Conclusion The novel myelodysplastic syndromes agents luspatercept-aamt and decitabine/cedazuridine provide a clinical benefit in the studied populations.

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Population Pharmacokinetics and Exposure–Response of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With Myelodysplastic Syndromes

Cited by 7 publications

References 23 publications

Population Pharmacokinetics and Exposure‐Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With β‐Thalassemia

Population Pharmacokinetics and Exposure‐Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With β‐Thalassemia

Population pharmacokinetics of imetelstat, a first‐in‐class oligonucleotide telomerase inhibitor

Novel agents for myelodysplastic syndromes

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