Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients

Re, Marzia Del; Omarini, Claudia; Diodati, Lucrezia; Palleschi, Michela; Meattini, Icro; Crucitta, Stefania; Lorenzini, Giulia; Isca, Chrystel; Fontana, A.; Livi, Lorenzo; Piacentini, Federico; Fogli, Stefano; Giorgi, Ugo De; Danesi, Romano

doi:10.1016/j.esmoop.2021.100231

Cited by 41 publications

(48 citation statements)

References 34 publications

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“…Gastric pH changes by proton pump inhibitors (PPIs) may alter the oral bioavailability of targeted agents that exhibit pH-dependent solubility [ 3 , 4 ]; however, the clinical impact of such interaction remains a controversial topic that is currently debated [ 12 ]. In line with findings showing that co-administration of rabeprazole reduced palbociclib bioavailability [ 13 ], we recently demonstrated that concomitant PPIs substantially decreased progression-free survival (PFS) in metastatic breast cancer patients treated with palbociclib [ 13 ].…”

Section: Introductionsupporting

confidence: 64%

Concomitant administration of proton pump inhibitors does not significantly affect clinical outcomes in metastatic breast cancer patients treated with ribociclib

Crucitta

Omarini

et al. 2022

The Breast

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Section: Introductionsupporting

confidence: 64%

Concomitant administration of proton pump inhibitors does not significantly affect clinical outcomes in metastatic breast cancer patients treated with ribociclib

Crucitta

Omarini

et al. 2022

The Breast

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“…In the study by Re et al, PFS was 14 months versus 37.9 months in patients who received and did not receive concominant PPIs with palbociclib, respectively. Additionally, no other significant variable affecting PFS was detected in the multivariate analysis [ 28 ]. In the results we presented, PFS was similar to that in this trial in patients who received PPIs, but PFS could not be reached yet in patients who did not receive PPIs.…”

Section: Discussionmentioning

confidence: 99%

Proton pump inhibitors may reduce the efficacy of ribociclib and palbociclib in metastatic breast cancer patients based on an observational study

et al. 2022

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Introduction Approximately 20–33% of all cancer patients are treated with acid-reducing agents (ARAs), most commonly proton pump inhibitors (PPIs), to reduce gastroesophageal reflux disease symptoms. Palbociclib and ribociclib are weak bases so their solubility depends on different pH. The solubility of palbociclib dramatically decreases to < 0.5 mg/ml when pH is above 4,5 but ribociclibs’ solubility decreases when pH increases above 6,5. In the current study, we aimed to investigate the effects of concurrent PPIs on palbociclib and ribociclib efficacy in terms of progression-free survival in metastatic breast cancer (mBC) patients. Patients and methods We enrolled hormone receptor-positive, HER2-negative mBC patients treated with endocrine treatment (letrozole or fulvestrant) combined palbociclib or ribociclib alone or with PPI accompanying our observational study. During palbociclib/ribociclib therapy, patients should be treated with "concurrent PPIs" defined as all or more than half of treatment with palbociclib/ribociclib, If no PPI was applied, it was defined as ‘no concurrent PPI’, those who used PPI but less than half were excluded from the study. All data was collected from real-life retrospectively. Results Our study included 217 patients, 105 of whom received palbociclib and 112 received ribociclib treatment. In the study population CDK inhibitor treatment was added to fulvestrant 102 patients ( 47%), to letrozole 115 patients (53%). In the Palbociclib arm fulvestrant/letrozole ratio was 53.3/46.7%, in the ribociclib arm it was 41.07/58.93%. Of 105 patients who received palbociclib, 65 were on concomitant PPI therapy, 40 were not. Of the 112 patients who received ribociclib, 61 were on concomitant PPI therapy, 51 were not. In the palbociclib group, the PFS of the patients using PPIs was shorter than the PFS of the patients not using (13.04 months vs. unreachable, p < 0.001). It was determined that taking PPIs was an independent predictor of shortening PFS (p < 0.001) in the multivariate analysis, In the ribociclib group, the PFS of the patients using PPIs was shorter than the PFS of the patients not using (12.64 months vs. unreachable, p = 0.003). It was determined that taking PPIs was single statistically independent predictor of shortening PFS (p = 0.003, univariate analysis). Conclusions Our study demonstrated that concomitant usage of PPIs was associated with shorter PFS in mBC treated with both ribociclib and especially palbociclib. If it needs to be used, PPI selection should be made carefully and low-strength PPI or other ARAs (eg H2 antagonists, antacids) should be preferred.

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“…The impact of these co-treatments in terms of survival will be evaluated later, especially because the correlation between palbociclib plasma concentration and hematologic toxicity can lead to dose reductions. Recent studies suggest a link between co-medication (statin use) and neutropenia occurrence (n = 78), and a negative influence of antacids on the survival of patients treated with palbociclib (p < 0.0001) [22,26]. It would be relevant to analyze the various PK/PD correlations and specifically the modulation of palbociclib concentration on treatment efficacy in our cohort.…”

Section: Discussionmentioning

confidence: 97%

Pharmacokinetic Variability Drives Palbociclib-Induced Neutropenia in Metastatic Breast Cancer Patients: Drug–Drug Interactions Are the Usual Suspects

et al. 2022

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Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, bicentric clinical trial, we evaluated the palbociclib exposure–toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug–drug interactions (DDI). We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies.

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Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients

Cited by 41 publications

References 34 publications

Concomitant administration of proton pump inhibitors does not significantly affect clinical outcomes in metastatic breast cancer patients treated with ribociclib

Concomitant administration of proton pump inhibitors does not significantly affect clinical outcomes in metastatic breast cancer patients treated with ribociclib

Proton pump inhibitors may reduce the efficacy of ribociclib and palbociclib in metastatic breast cancer patients based on an observational study

Pharmacokinetic Variability Drives Palbociclib-Induced Neutropenia in Metastatic Breast Cancer Patients: Drug–Drug Interactions Are the Usual Suspects

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