Adherence to the CDK 4/6 Inhibitor Palbociclib and Omission of Dose Management Supported by Pharmacometric Modelling as Part of the OpTAT Study

Abstract

The cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib is administered orally and cyclically, causing medication adherence challenges. We evaluated components of adherence to palbociclib, its relationship with pharmacokinetics (PK), and drug-induced neutropenia. Patients with metastatic breast cancer (MBC) receiving palbociclib, delivered in electronic monitors (EM), were randomized 1:1 to an intervention and a control group. The intervention was a 12-month interprofessional medication adherence program (IMAP) along with monthly motivational interviews by a pharmacist. Implementation adherence was compared between groups using generalized estimating equation models, in which covariates were included. Model-based palbociclib PK and neutrophil profiles were simulated under real-life implementation scenarios: (1) optimal, (2) 2 doses omitted and caught up at cycle end. At 6 months, implementation was slightly higher and more stable in the intervention (n = 19) than in the control (n = 19) group, 99.2% and 97.3% (Δ1.95%, 95% CI 1.1–2.9%), respectively. The impact of the intervention was larger in patients diagnosed with MBC for >2 years (Δ3.6%, 95% CI 2.1–5.4%), patients who received >4 cycles before inclusion (Δ3.1%, 95% CI 1.7–4.8%) and patients >65 (Δ2.3%, 95% CI 0.8–3.6%). Simulations showed that 25% of patients had neutropenia grade ≥3 during the next cycle in scenario 1 versus 30% in scenario 2. Education and monitoring of patient CDK4/6i cycle management and adherence along with therapeutic drug monitoring can help clinicians improve prescription and decrease toxicity.

Digging in real-word electronic database for assessing CDK 4/6 inhibitors adherence in breast cancer patients from Romania

“…Few studies were published regarding CDK 4/6i non-adherence negatively effects. Regarding palbociclib adherence, it was measured its impact on pharmacokinetic and pharmacodynamic profiles and proved that catching up on a missed dose at the end of the cycle increases the risk of severe neutropenia in the next cycle (Bandiera et al, 2023).…”

“…CDK 4/6i are also utilized together with endocrine therapy for male patients diagnosed with HR+/HER2metastatic breast cancer (Kraus et al, 2022). It is crucial to note that approval dates and availability can vary by country, and new applications and indications for these drugs may have emerged (Bandiera et al, 2023).…”

Palbociclib Adherence and Persistence in Patients with Hormone Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Metastatic Breast Cancer

“…Our results represent one of the first efforts to provide current data on variations in palbociclib treatment patterns in the real-world practice setting and point to factors needed to aid identification of patient subgroups at risk for early discontinuation and non-adherence and to understand drivers of low adherence. An understanding of these factors is required to design programs such as the medication adherence monitoring and counseling programs 32 used in the Optimizing Oral Targeted Anticancer Therapies studies 33 to mitigate barriers to adequate adherence and persistence, and to improve patient outcomes. 34 …”

Population Pharmacokinetics of Trametinib and Impact of Nonadherence on Drug Exposure in Oncology Patients as Part of the Optimizing Oral Targeted Anticancer Therapies Study

“…The effective dose history was integrated into the database for 11 patients, who used a digital bulk pillbox (MEMS and MEMS AS, AARDEX Group) to monitor the date and the time of each opening of the trametinib bottle; these data were cross-checked with information from the adherence interviews reports and the case report forms (“The full adherence information group”) [ 14 ]. The digital monitor allowed us to provide accurate information on treatment implementation (i.e., the extent to which the patient’s dosing history is in line with the prescription—the correct dosing regimen, at the correct time and in the right condition) and temporary or long-term discontinuation of treatment (i.e., when the patient stops taking the treatment prematurely) [ 42 ].…”

“…The variability in adherence to treatment is also a major concern, as 46% to 100% of patients take their medications as prescribed [ 13 ]. There are several reasons for nonadherence, including side effects, daily administration that can be difficult to fit into a patient’s schedule, the conditions of the intake (e.g., fasting conditions), and the length of the treatment, which can lead to patient fatigue and invisible results [ 14 ]. The outpatient care reduces contact with healthcare professionals, and there may be less opportunity for patients to report their concerns regarding their medications, which sometimes results in patients temporarily discontinuing their treatments without informing their prescribers.…”