The cyclin-dependent kinase (CDK4/6) inhibitor, palbociclib, is an OCA indicated for the treatment of advanced breast cancer (BC) with either initial endocrine-based therapy or in patients with disease progression following endocrine therapy. While there are advantages to the use of OCAs compared with parenteral products, including convenience and timesaving, there are also concerns about potential nonadherence and its adverse effects on survival.

The Optimizing Targeted Anticancer Therapies (OpTAT) study consisted of an open-label, 12-month, randomized, controlled adherence study and an OCA pharmacokinetic-pharmacodynamic relationship study. The purpose of this study was twofold: to evaluate and compare adherence to palbociclib with a focus on implementation (i.e., the extent to which a patient takes the medication as prescribed) and 12-month persistence (i.e., time between initiation and discontinuation) and to determine the influence of nonadherence on simulated palbociclib pharmacokinetics and neutropenia.

To achieve the main outcome of medication implementation, an electronic monitor (EM) was built into the medication vial that would record when the vial was open. This served as a surrogate indicator of adherence along with pill counts to support the findings. Patients were included in the parent study if they were adults receiving an OCA for a solid cancer. Patients were excluded if they did not manage their own medications or if they had cognitive disorders. There was a total of 130 patients included in the medication adherence part of the OpTAT study, but this paper focuses on the 38 patients receiving palbociclib for metastatic BC.

The patients were stratified by cancer type and times since OAC initiation (i.e., less than or greater than 30 days). They were randomized into intervention and control groups after a baseline period of EM use of at least 21 days. Those who were randomized to the intervention group attended the Interprofessional Medication Adherence Program, a theory-based intervention model that included information and motivation and behavioral skills. The pharmacist conducted monthly motivational medication adherence interviews. Palbociclib cycle dates were determined based on the electronic medical record reports and prescription information, the EM pill bottle label, and the patient’s report, of which the latter was considered the most updated information. The reasons for suboptimal implementation were recorded. The typical study patient was aged 65 years, was diagnosed with metastatic BC 2 years prior, and had received five palbociclib cycles before inclusion in the study.

Pharmacokinetic modeling was based on three scenarios of cyclical dosing of palbociclib, which involved a 21-day “ON” medication cycle and a 7-day “OFF” medication period. In this study, optimal implementation (scenario A) was defined as one dose taken daily during the 21-day ON period followed by a 7-day treatment break (OFF period). In the B1 scenario, one dose was missed at Day 18 during the 21-day ON period and was not caught up at cycle end (i.e., the OFF period is initiated 7 days from Day 22). In scenario B2, one dose was missed at Day 18 during the 21-day ON period and was caught up at cycle end at Day 22 (i.e., the OFF period is initiated from Day 23 for 6 days, resulting in a shorter OFF period prior to the next cycle). In scenario C, during the 21-day ON cycle, two first doses are missed at Days 1 and 2, which were caught up at cycle end at Day 22 and Day 23, resulting in only 5 OFF days between the current and next cycle instead of 7 days. Palbociclib pharmacokinetics were simulated for a dosage of 125 mg once daily for 21 days followed by a 7-day medication-free period. Simulated palbociclib plasma concentrations in ng/mL were correlated with absolute neutrophil counts in g/L over three palbociclib cycles in 1,000 patients.

Among the 38 substudy patients, half were in the intervention group and half were in the control. Of the 19 patients in the intervention group, eight stopped treatment because of disease progression or adverse events and four dropped out. Of the 19 control patients, four stopped treatment because of disease progression or adverse events and four dropped out. One patient in the intervention and the control group discontinued study participation due to adverse events. At 6 months, implementation was 99.2% in the intervention group and 97.3% in the control group (95% CI, 1.1-2.9).

Lower implementation was observed in the control group among patients aged older than 65 years who were diagnosed with metastatic BC >2 years earlier and who had received more than four cycles of palbociclib prior to inclusion; however, this was not found in the intervention group. The impact of the intervention on implementation was larger in patients diagnosed with metastatic BC >2 years prior in both groups. Among the control group, 83% missed at least one dose compared with 53% of the intervention group (P = .046). Significantly more cycles were impacted by missed doses in the control group (24% vs. 12%, respectively; P = .004). Although patients are instructed to not catchup missed doses, among patients who missed at least one dose, 70% of the intervention and 67% of the control group caught up the missed dose (P = 1.0).

Prescribing information for palbociclib specifically states, “If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.” Adherence behavior was often inconsistent, with some missed doses being caught up and others not taken at a later time. The difference in the number of patients who required a dose reduction due to neutropenia was similar between the two groups. None of the dose reductions were due to shortened OFF periods associated with nonadherence and playing catchup. However, when data from the pharmacokinetic simulation were analyzed, they showed that grade >3 neutropenia would occur in 25% in the optimal implementation model, and this increased to 30% in adherence model C in which two missed doses from the 21-day cycle are caught up at the end, thereby shortening the drug-free period between cycles. Therapy was interrupted more often in the intervention group than in the control group; this was most often due to infection.

The researchers concluded that the intervention did not impact persistence of palbociclib therapy but that missing doses of palbociclib and catching up at the end of the cycle was associated with a higher risk of severe neutropenia during the following cycle.

This is the first study that has examined the impact that improperly catching up on missed doses of palbociclib has on the risk of developing neutropenia and serves as a bellwether to pharmacists that patients need to be counseled to not only skip a missed dose during the treatment cycle but also to avoid playing catchup at the end of the treatment cycle.

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