Population Pharmacokinetics of Asciminib in Tyrosine Kinase Inhibitor-Treated Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic and Acute Phases

Li, Ying Fei; Combes, Francois Pierre; Hoch, Matthias; Lorenzo, Sebastien; Sy, Sherwin K. B.; Ho, Yu-Yun

doi:10.1007/s40262-022-01148-9

Cited by 12 publications

(11 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Philadelphia chromosome, which is formed by a reciprocal translocation that results in a prolonged chromosome 9 and a shorter chromosome 22, is the cause of this illness. The dysregulated BCR-ABL1 fusion carcinogen protein is developed as a result of the translocation, which contributes to the uncontrolled proliferating of white blood cells [ 17 ]. Multiple processes involved in cell growth and division, including receptor endocytosis, autophagy, remodeling of the cytoskeleton and actin, cell motility and adhesion, and cell adhesion, depend on ABL1.…”

Section: Discussionmentioning

confidence: 99%

“…Asciminib works as a therapeutic agent by blocking an oncogenic protein that promotes the growth of CML. It functions to inhibit both the wild-type as well as some mutation forms of BCR-ABL1, along with the T315I mutation [ 17 ]. Upon its administration, it recognizes and attaches to the myristoyl pocket of the BCR-ABL1 fusion protein, which is distinctive from the ATP-binding domain.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Artificial Intelligence Assisted Pharmacophore Design for Philadelphia Chromosome-Positive Leukemia with Gamma-Tocotrienol: A Toxicity Comparison Approach with Asciminib

et al. 2023

View full text Add to dashboard Cite

BCR-ABL1 is a fusion protein as a result of a unique chromosomal translocation (producing the so-called Philadelphia chromosome) that serves as a clinical biomarker primarily for chronic myeloid leukemia (CML); the Philadelphia chromosome also occurs, albeit rather rarely, in other types of leukemia. This fusion protein has proven itself to be a promising therapeutic target. Exploiting the natural vitamin E molecule gamma-tocotrienol as a BCR-ABL1 inhibitor with deep learning artificial intelligence (AI) drug design, this study aims to overcome the present toxicity that embodies the currently provided medications for (Ph+) leukemia, especially asciminib. Gamma-tocotrienol was employed in an AI server for drug design to construct three effective de novo drug compounds for the BCR-ABL1 fusion protein. The AIGT’s (Artificial Intelligence Gamma-Tocotrienol) drug-likeliness analysis among the three led to its nomination as a target possibility. The toxicity assessment research comparing AIGT and asciminib demonstrates that AIGT, in addition to being more effective nonetheless, is also hepatoprotective. While almost all CML patients can achieve remission with tyrosine kinase inhibitors (such as asciminib), they are not cured in the strict sense. Hence it is important to develop new avenues to treat CML. We present in this study new formulations of AIGT. The docking of the AIGT with BCR-ABL1 exhibited a binding affinity of −7.486 kcal/mol, highlighting the AIGT’s feasibility as a pharmaceutical option. Since current medical care only exclusively cures a small number of patients of CML with utter toxicity as a pressing consequence, a new possibility to tackle adverse instances is therefore presented in this study by new formulations of natural compounds of vitamin E, gamma-tocotrienol, thoroughly designed by AI. Even though AI-designed AIGT is effective and adequately safe as computed, in vivo testing is mandatory for the verification of the in vitro results.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Artificial Intelligence Assisted Pharmacophore Design for Philadelphia Chromosome-Positive Leukemia with Gamma-Tocotrienol: A Toxicity Comparison Approach with Asciminib

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Individual asciminib exposure metrics over time were predicted as daily metrics based on actual dosing records from a previously developed population PK model 10,11 . The final PK/PD model was then used through simulations to provide further justification for the recommended dosing regimen.…”

Section: Methodsmentioning

confidence: 99%

“…For each category of a significant covariate, 100 virtual trials consisting of 100 patients were simulated for each dose regimen without the consideration of dropout, dose reduction, or dose interruption. For each of the simulated dosing regimens, daily AUC 0–24 , C min , and C max were simulated until reaching steady state using the population PK model 10,11 …”

Section: Methodsmentioning

confidence: 99%

“…simulated dosing regimens, daily AUC 0-24 , C min , and C max were simulated until reaching steady state using the population PK model. 10,11 For each trial, the individual BCR::ABL1 values were then generated and summary statistics including the mean, median, standard deviation (SD), 10th, 25th, 75th, and 90th percentiles of the weekly BCR::ABL1 timepoints of the 100 trials were computed.…”

Section: Articlementioning

confidence: 99%

See 1 more Smart Citation

Exposure–Efficacy Analysis of Asciminib in Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase

Combes

Hoch

et al. 2022

Clin Pharma and Therapeutics

Self Cite

View full text Add to dashboard Cite

Asciminib (Scemblix) is a first-in-class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP) and has potent activity against the T315I mutation. This study aimed to characterize the effect of asciminib exposure on disease progression and to elucidate factors influencing efficacy. Our analysis included 303 patients with chronic myeloid leukemia in chronic phase recruited in a phase I study with dose ranging from 10 to 200 mg twice a day (b.i.d.) or 40 to 200 mg once a day (q.d.) (NCT02081378) and in the phase III ASCEMBL (Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs) study receiving asciminib 40 mg b.i.d. (NCT03106779). A total of 67 patients harbored the T315I mutation. A longitudinal pharmacokinetic/pharmacodynamic model was developed to characterize the exposure-efficacy relationship, in which the efficacy was assessed through BCR::ABL1 transcript levels over time. Specifically, a three-compartment model representing quiescent leukemic stem cells, proliferating bone marrow cells, and resistant cells was developed. Drug killing of the proliferating cells by asciminib was characterized by a power model. A subgroup analysis was performed on the patients with the T315I mutation using a maximum drug effect model to characterize the drug effect. The model demonstrated the appropriateness of a total daily dose of asciminib 80 mg in patients without the T315I mutation and 200 mg b.i.d. in patients with the T315I mutation with further validation in light of safety data. This model captured key characteristics of patients' response to asciminib and helped inform dosing rationale for resistant and difficult-to-treat populations.Chronic myeloid leukemia (CML) is driven by the constitutively active ABL1 tyrosine kinase domain of BCR::ABL1, 1 and studies have shown that BCR::ABL1 transcript levels are correlated with long-term outcomes to tyrosine kinase inhibitors (TKIs) among patients with CML. 2,3 Therefore, BCR::ABL1 and its derived major molecular response (MMR) rate (proportion of patients with BCR::ABL1 ≤ 0.1%), used in phase III studies as a primary end point, is an established surrogate marker to evaluate

show abstract

Population modeling of bosutinib exposure‐response in patients with newly diagnosed chronic phase chronic myeloid leukemia

et al. 2023

View full text Add to dashboard Cite

BackgroundThe BELA and BFORE trials compared bosutinib starting doses of 500 mg once daily (QD) and 400 mg QD, respectively, with imatinib in adults with newly diagnosed chronic phase chronic myeloid leukemia (CP‐CML). The B1871048 trial evaluated bosutinib 400 mg QD in Japanese patients with newly diagnosed CP‐CML.AimThis analysis assessed the impact of a lower bosutinib starting dose on key efficacy and safety outcomes.Materials & MethodsA pharmacokinetic model was used to estimate metrics of bosutinib exposure, and logistic regression was used to investigate relationships with efficacy (cumulative major molecular response [MMR] and cumulative complete cytogenetic response [CCyR]) and safety outcomes (eight prespecified adverse events).ResultsTotals of 573 and 574 patients were included in the efficacy and safety endpoint analyses, respectively. Cumulative MMR and CCyR were similar across studies. Log(Ctrough) and log(Cavg) were significant predictors of MMR and CCyR, and the probability of achieving MMR or CCyR increased 1.3‐fold or 2.7‐fold for every 1 unit increase in log(Ctrough) or log(Cavg), respectively. An exposure–response relationship was identified between time‐to‐event and risk of diarrhea, nausea, and vomiting. Significant relationships were also observed between time‐to‐event and log(Cavg), Ctrough, and Cavg with diarrhea, nausea, and vomiting, respectively.DiscussionA bosutinib exposure‐response relationship with safety and efficacy was observed.ConclusionCompared with 500 mg QD, a bosutinib starting dose of 400 mg QD improved tolerability in some patients with newly diagnosed CP‐CML without compromising efficacy. ClinicalTrials.gov identifiers: NCT00574873; NCT02130557; NCT03128411.

show abstract

Population Pharmacokinetics of Asciminib in Tyrosine Kinase Inhibitor-Treated Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic and Acute Phases

Cited by 12 publications

References 14 publications

Artificial Intelligence Assisted Pharmacophore Design for Philadelphia Chromosome-Positive Leukemia with Gamma-Tocotrienol: A Toxicity Comparison Approach with Asciminib

Artificial Intelligence Assisted Pharmacophore Design for Philadelphia Chromosome-Positive Leukemia with Gamma-Tocotrienol: A Toxicity Comparison Approach with Asciminib

Exposure–Efficacy Analysis of Asciminib in Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase

Population modeling of bosutinib exposure‐response in patients with newly diagnosed chronic phase chronic myeloid leukemia

Contact Info

Product

Resources

About