ArticleClinical pharmacokinetics2026
Quantitative Pharmacology Justifying Ribociclib Dose in Early Breast Cancer.
Article in Clinical pharmacokinetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 8 registered trials, which are not on this map. Not yet cited in PubMed.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A phase1 Multi-center, Open Label, Dose-escalation Study of Oral LEE011 in Patients With Advanced Solid Tumors or Lymphoma
A Phase Ib/II, Multicenter Study of the Combination of LEE011 and BYL719 With Letrozole in Adult Patients With Advanced ER+ Breast Cancer
A Phase I Study of LEE011 in Asian Patients With Advanced Solid Tumors
A Randomized Double-blind, Placebo-controlled Study of LEE011 in Combination With Letrozole for the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative, Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease
A Phase III Randomized, Double-blind, Placebo-controlled Study of LEE011 or Placebo in Combination With Tamoxifen and Goserelin or a Non-steroidal Aromatase Inhibitor (NSAI) and Goserelin for the Treatment of Premenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer
A Randomized Double-blind, Placebo-controlled Study of Ribociclib in Combination With Fulvestrant for the Treatment of Men and Postmenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer Who Have Received no or Only One Line of Prior Endocrine Treatment
A Phase III Multi-center, Randomized, Open-label Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as an Adjuvant Treatment in Patients With Hormone Receptor-positive, HER2-negative Early Breast Cancer (New Adjuvant TriAl With Ribociclib [LEE011]: NATALEE)
A Phase II, Multicenter, Randomized, Open-label Study to Evaluate the Safety and Efficacy of 400 mg of Ribociclib in Combination With Non-steroidal Aromatase Inhibitors for the Treatment of Pre- and Postmenopausal Women With Hormone Receptor-positive, HER2-negative Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease
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8 authors.
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Abstract
BACKGROUND AND
objectiveRibociclib was recently approved for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer (EBC) at the starting dose of 400 mg orally once daily (3 weeks on/1 week off), following previous approval in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer at the starting dose of 600 mg orally once daily (3 weeks on/1 week off). This study aims to characterize ribociclib pharmacokinetics and its relationship with QT interval corrected according to Fridericia's formula (QTcF) in patients with EBC and justify the dose in EBC.
methodsData from several studies, including the pivotal phase III trial in patients with EBC and phase I-III trials in patients with advanced breast cancer and advanced cancer were analyzed. Ribociclib pharmacokinetics was characterized by non-compartmental or population pharmacokinetic analyses. The exposure-QTcF relationship was assessed by linear mixed-effects modeling. Neutropenia and QTcF data were compared by dose and population.
resultsAt the 400-mg dose, ribociclib steady-state clearance was ~ 20% higher in patients with EBC than patients with advanced cancer, suggesting differences in pharmacokinetics between populations. Steady-state mean area under the plasma concentration-time curve and maximum (peak) plasma drug concentration were ~ 50% lower and steady-state clearance was ~ 50% higher in patients with EBC receiving 400 mg compared with patients with advanced cancer and advanced breast cancer receiving 600 mg, attributed to differences in both dose and population. The pharmacokinetic-QTcF analysis showed that the patient population was a significant covariate in QTcF response. The model-estimated mean change from baseline in QTcF at steady-state maximum (peak) plasma drug concentration was substantially lower in patients with EBC receiving 400 mg (10.0 ms) versus in patients with advanced breast cancer receiving 600 mg (20.7-23.7 ms), likely due to the dose and pharmacokinetic exposure effect and the population effect. Patients with EBC receiving 400 mg experienced lower rates and severity of both neutropenia and QTcF prolongation than patients with advanced breast cancer receiving 600 mg.
conclusionsThis integrative analysis characterized the ribociclib pharmacokinetic and exposure-QTcF relationship, revealed the population effect on both pharmacokinetic and QTcF response, and justified the 400-mg dose in EBC. This work illustrates the utility and impact of quantitative pharmacology in justifying different doses across different patient populations for oncology therapies. CLINICAL
trial registrationNATALEE (NCT03701334, 2018-09-21); AMALEE (NCT03822468, 2019-01-28); MONALEESA-2 (NCT01958021, 2013-10-04); MONALEESA-3 (NCT02422615, 2015-04-01); MONALEESA-7 (NCT02278120, 2014-10-22); X1101 (NCT01898845, 2013-07-01); X2101 (NCT01237236, 2010-11-05); X2107 (NCT01872260, 2013-05-30).
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