Starting dose selection of palbociclib in Chinese patients with breast cancer based on population kinetic–pharmacodynamic model of neutropenia

Jian, Weizhe; Xue, Jing; Yao, Qingyu; Chen, Rong; Yao, Yijun; Wang, Mopei; Zhou, Tianyan

doi:10.1007/s00280-022-04484-6

Cited by 3 publications

(4 citation statements)

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“…The pharmacokinetic interaction between amcenestrant and palbociclib may also help explain the safety findings, consistent with the previously demonstrated positive correlation between palbociclib and neutropenia. 21,22 HRQoL improvements were generally similar between amcenestrant 1 palbociclib and letrozole 1 palbociclib, with patients in both arms reporting improved global health status and QoL, increased physical, role, and emotional functioning, and fewer symptoms.…”

Section: Discussionmentioning

confidence: 85%

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Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Primary Results From AMEERA-5

Cortés,

Hurvitz,

O'Shaughnessy

et al. 2024

JCO

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PURPOSE AMEERA-5 investigated amcenestrant (oral selective estrogen receptor [ER] degrader) plus palbociclib versus letrozole plus palbociclib as first-line treatment for ER-positive/human epidermal growth factor receptor 2–negative (ER+/HER2–) advanced/metastatic breast cancer (aBC). MATERIALS AND METHODS In AMEERA-5 (ClinicalTrials.gov identifier: NCT04478266 ), a double-blind, double-dummy, international phase III trial, adult pre-/post-menopausal women and men without previous systemic therapy for ER+/HER2– aBC were randomly assigned 1:1 to amcenestrant 200 mg once daily + standard palbociclib dosage (125 mg once daily, 21 days on/7 days off) or letrozole 2.5 mg once daily + standard palbociclib dosage, stratified by de novo metastatic disease, postmenopausal women, and visceral metastasis. The primary end point was progression-free survival (PFS), compared using a stratified log-rank test with one-sided type I error rate of 2.5%. Secondary end points included overall survival (key secondary), pharmacokinetics, and safety. RESULTS Between October 14, 2020, and December 2, 2021, 1,068 patients were randomly assigned to amcenestrant + palbociclib (N = 534) or letrozole + palbociclib (N = 534). At the interim analysis (median follow-up 8.4 months), the stratified hazard ratio for PFS was 1.209 (95% CI, 0.939 to 1.557; one-sided P value = .9304); therefore, the study was stopped for futility. The 6-month PFS rate was 82.7% (95% CI, 79.0 to 85.8) with amcenestrant + palbociclib versus 86.9% (95% CI, 83.5 to 89.6) with letrozole + palbociclib. In the amcenestrant + palbociclib versus letrozole + palbociclib groups, treatment-emergent adverse events (any grade) occurred in 85.6% versus 85.4% of patients and grade ≥3 events in 46.3% versus 60.8%, respectively. CONCLUSION The AMEERA-5 study was discontinued on the basis of the recommendation of the data monitoring committee at the interim futility analysis. No new safety signals were identified.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Primary Results From AMEERA-5

Cortés,

Hurvitz,

O'Shaughnessy

et al. 2024

JCO

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“…When pharmacokinetic data are lacking, the dose-response relationship can be evaluated using kinetic-pharmacodynamic (K-PD) models that describe the relationship between the drug dose and response, which can also be used to optimize dose regimens through model simulation. 11,12 This study aimed to develop a K-PD model for oxytocininduced uterine contractions using real-world data and analyze the significant covariates influencing the drug effect. The objective of this study was to optimize the starting dosing regimen of intravenous oxytocin and provide valuable insights into its clinical application.…”

Section: Introductionmentioning

confidence: 99%

“…During labor induction, the oxytocin concentration in the maternal plasma is significantly low, and the presence of oxytocinase in the maternal blood makes oxytocin highly unstable in plasma samples. When pharmacokinetic data are lacking, the dose‐response relationship can be evaluated using kinetic‐pharmacodynamic (K‐PD) models that describe the relationship between the drug dose and response, which can also be used to optimize dose regimens through model simulation 11,12 …”

Section: Introductionmentioning

confidence: 99%

Optimal starting dosing regimen of intravenous oxytocin for labor induction based on the population kinetic‐pharmacodynamic model of uterine contraction frequency

Yu,

Chen,

Zhao

et al. 2024

Pharmacotherapy

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BackgroundIntravenous oxytocin is commonly used for labor induction. However, a consensus on the initial dosing regimen is lac with conflicting research findings and varying guidelines. This study aimed to develop a population kinetic‐pharmacodynamic (K‐PD) model for oxytocin‐induced uterine contractions considering real‐world data and relevant influencing factors to establish an optimal starting dosing regimen for intravenous oxytocin.MethodsThis retrospective study included pregnant women who underwent labor induction with intravenous oxytocin at Peking University Third Hospital in 2020. A population K‐PD model was developed to depict the time course of uterine contraction frequency (UCF), and covariate screening identified significant factors affecting the pharmacokinetics and pharmacodynamics of oxytocin. Model‐based simulations were used to optimize the current starting regimen based on specific guidelines.ResultsData from 77 pregnant women with 1095 UCF observations were described well by the K‐PD model. Parity, cervical dilation, and membrane integrity are significant factors influencing the effectiveness of oxytocin. Based on the model‐based simulations, the current regimens showed prolonged onset times and high infusion rates. This study proposed a revised approach, beginning with a rapid infusion followed by a reduced infusion rate, enabling most women to achieve the target UCF within approximately 30 min with the lowest possible infusion rate.ConclusionThe K‐PD model of oxytocin effectively described the changes in UCF during labor induction. Furthermore, it revealed that parity, cervical dilation, and membrane integrity are key factors that influence the effectiveness of oxytocin. The optimal starting dosing regimens obtained through model simulations provide valuable clinical references for oxytocin treatment.

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Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors

Panetta,

Selvo,

Mater

et al. 2024

Pharmaceutics

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Background/Objectives: Palbociclib, an oral CDK 4/6 inhibitor, was evaluated in a Pediatric Brain Tumor Consortium (PBTC) phase 1 (NCT02255461; PBTC-042) study to treat children and young adults with recurrent, progressive, or refractory brain tumors. The objectives of this study were to characterize the palbociclib population pharmacokinetics in children enrolled on PBTC-042, to conduct a population pharmacodynamic analysis in this patient population, and to perform a simulation study to assess the role of palbociclib exposure on neutropenia and thrombocytopenia. Methods: The palbociclib population pharmacokinetics and pharmacodynamics were characterized in this patient population (n = 34 patients; 4.9–21.6 years old). Population pharmacokinetics were modeled using a one-compartment model with first-order absorption and elimination. Covariate analysis was performed, evaluating demographics, laboratory values, and concomitant medications. A pharmacodynamic model was used to describe the relation between palbociclib plasma exposure and changes in the ANC and platelet counts. Results: The population estimates for the apparent oral volume, apparent oral clearance, and absorption rate constant were 664.5 L/m2, 36.8 L/h/m2, and 0.48 h−1, respectively. The palbociclib apparent oral clearance was decreased in patients with higher AST values (p = 0.0066). The ANC and platelet pharmacodynamic models estimated that the median (5th–95th percentile) time individuals had grade 3 or greater neutropenia was 4 (0, 21) days. Simulations showed that given 75 mg/m2 palbociclib, 49% of the individuals were expected to have grade 3 or greater neutropenia. Conclusions: Palbociclib pharmacokinetics and pharmacodynamics were adequately characterized in this patient population, no unexpected adverse reactions were noted, and the drug was well tolerated.

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Starting dose selection of palbociclib in Chinese patients with breast cancer based on population kinetic–pharmacodynamic model of neutropenia

Cited by 3 publications

References 23 publications

Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Primary Results From AMEERA-5

Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Primary Results From AMEERA-5

Optimal starting dosing regimen of intravenous oxytocin for labor induction based on the population kinetic‐pharmacodynamic model of uterine contraction frequency

Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors

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