The cyclin-dependent kinase (CDK) 4/6 inhibitors belong to a new class of drugs that interrupt proliferation of malignant cells by inhibiting progression through the cell cycle. Three such inhibitors, palbociclib, ribociclib, and abemaciclib were recently approved for breast cancer treatment in various settings and combination regimens. On the basis of their impressive efficacy, all three CDK4/6 inhibitors now play an important role in the treatment of patients with HR+, HER2− breast cancer; however, their optimal use still needs to be established. The three drugs have many similarities in both pharmacokinetics and pharmacodynamics. However, there are some differences on the basis of which the choice for a particular CDK4/6 inhibitor for an individual patient can be important. In this article, the clinical pharmacokinetic and pharmacodynamic profiles of the three CDK4/6 inhibitors are reviewed and important future directions of the clinical applicability of CDK4/6 inhibitors will be discussed.
Background
Endoxifen is the most important active metabolite of tamoxifen. Several retrospective studies have suggested a minimal or threshold endoxifen systemic concentration of 14–16 nM is required for a lower recurrence rate. The aim of this study was to investigate the feasibility of reaching a predefined endoxifen level of ≥ 16 nM (5.97 ng/mL) over time using therapeutic drug monitoring (TDM).
Methods
This prospective open-label intervention study enrolled patients who started treatment with a standard dose of tamoxifen 20 mg once daily for early breast cancer. An outpatient visit was combined with a TDM sample at 3, 4.5, and 6 months after initiation of the tamoxifen treatment. The tamoxifen dose was escalated to a maximum of 40 mg if patients had an endoxifen concentration < 16 nM. The primary endpoint of the study was the percentage of patients with an endoxifen level ≥ 16 nM at 6 months after the start of therapy compared with historical data, in other words, 80% of patients with endoxifen levels ≥ 16 nM with standard therapy.
Results
In total, 145 patients were included. After 6 months, 89% of the patients had endoxifen levels ≥ 16 nM, compared with a literature-based 80% of patients with endoxifen levels ≥ 16 nM at baseline (95% confidence interval 82–94;
P
= 0.007). In patients with an affected CYP2D6 allele, it was not always feasible to reach the predefined endoxifen level of ≥ 16 nM. No increase in tamoxifen-related adverse events was reported after dose escalation.
Conclusion
This study demonstrated that it is feasible to increase the percentage of patients with endoxifen levels ≥ 16 nM using TDM. TDM is a safe strategy that offers the possibility of nearly halving the number of patients with endoxifen levels < 16 nM.
We read the article by Sanchez-Spitman et al 1 reporting on their CYPTAM study about the association between CYP2D6 genotype and clinical outcome in the adjuvant treatment of breast cancer with tamoxifen. We acknowledge that a lack of association was shown and that solely the determination of CYP2D6 genotype has limited relevance for clinical practice in this setting.
Batch-to-batch variability is a challenge for the industrial scale production of ointments. Therefore the current investigation focussed on identifying and understanding critical process parameters (CPPs) for cetomacrogol ointment. This was evaluated using a definitive screening design (DSD) approach in which fourteen batches were produced under predefined and controlled conditions using the following variables: addition of SiO nanoparticles, mixing speed, cooling rate, heating temperature, container filling temperature and isothermal mixing at the filling temperature. Ointment structure was evaluated using a number of rheological parameters. One of these parameters, yield stress was found to be strongly influenced by filling temperature and mixing speed (p=0.0065 and p=0.0013 respectively). Both significantly affect ointment structure and they also have a significant interaction (p<0.05). Understanding the ointment production process can help in defining a processing window to produce ointment of constant quality.
Background
Many cancer patients use additional herbs or supplements in combination with their anti-cancer therapy. Green tea—active ingredient epigallocatechin-3-gallate (EGCG)—is one of the most commonly used dietary supplements among breast cancer patients. EGCG may alter the metabolism of tamoxifen. Therefore, the aim of this study was to investigate the influence of green tea supplements on the pharmacokinetics of endoxifen; the most relevant active metabolite of tamoxifen.
Methods
In this single-center, randomized cross-over trial, effects of green tea capsules on endoxifen levels were evaluated. Patients treated with tamoxifen for at least 3 months were eligible for this study. After inclusion, patients were consecutively treated with tamoxifen monotherapy for 28 days and in combination with green tea supplements (1 g twice daily; containing 300 mg EGCG) for 14 days (or vice versa). Blood samples were collected on the last day of monotherapy or combination therapy. Area under the curve (AUC0–24h), maximum concentration (Cmax) and minimum concentration (Ctrough) were obtained from individual plasma concentration–time curves.
Results
No difference was found in geometric mean endoxifen AUC0–24h in the period with green tea versus tamoxifen monotherapy (− 0.4%; 95% CI − 8.6 to 8.5%; p = 0.92). Furthermore, no differences in Cmax (− 2.8%; − 10.6 to 5.6%; p = 0.47) nor Ctrough (1.2%; − 7.3 to 10.5%; p = 0.77) were found. Moreover, no severe toxicity was reported during the whole study period.
Conclusions
This study demonstrated the absence of a pharmacokinetic interaction between green tea supplements and tamoxifen. Therefore, the use of green tea by patients with tamoxifen does not have to be discouraged.
Introduction
Endoxifen—the principal metabolite of tamoxifen—is subject to a high inter-individual variability in serum concentration. Numerous attempts have been made to explain this, but thus far only with limited success. By applying predictive modeling, we aimed to identify factors that determine the inter-individual variability. Our purpose was to develop a prediction model for endoxifen concentrations, as a strategy to individualize tamoxifen treatment by model-informed dosing in order to prevent subtherapeutic exposure (endoxifen < 16 nmol/L) and thus potential failure of therapy.
Methods
Tamoxifen pharmacokinetics with demographic and pharmacogenetic data of 303 participants of the prospective TOTAM study were used. The inter-individual variability in endoxifen was analyzed according to multiple regression techniques in combination with multiple imputations to adjust for missing data and bootstrapping to adjust for the over-optimism of parameter estimates used for internal model validation.
Results
Key predictors of endoxifen concentration were CYP2D6 genotype, age and weight, explaining altogether an average-based optimism corrected 57% (95% CI 0.49–0.64) of the inter-individual variability. CYP2D6 genotype explained 54% of the variability. The remaining 3% could be explained by age and weight. Predictors of risk for subtherapeutic endoxifen (< 16 nmol/L) were CYP2D6 genotype and age. The model showed an optimism-corrected discrimination of 90% (95% CI 0.86–0.95) and sensitivity and specificity of 66% and 98%, respectively. Consecutively, there is a high probability of misclassifying patients with subtherapeutic endoxifen concentrations based on the prediction rule.
Conclusion
The inter-individual variability of endoxifen concentration could largely be explained by CYP2D6 genotype and for a small proportion by age and weight. The model showed a sensitivity and specificity of 66 and 98%, respectively, indicating a high probability of (misclassification) error for the patients with subtherapeutic endoxifen concentrations (< 16 nmol/L). The remaining unexplained inter-individual variability is still high and therefore model-informed tamoxifen dosing should be accompanied by therapeutic drug monitoring.
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