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Tamoxifen is widely used in patients with hormone receptor‐positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z‐endoxifen. The Z‐endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z‐endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z‐endoxifen concentration and tamoxifen treatment outcomes, and identify a Z‐endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed‐effect (NLME) model for tamoxifen and Z‐endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z‐endoxifen. The final parent‐metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co‐medication with CYP2D6 inhibitors, on Z‐endoxifen pharmacokinetics. Future work will use the model to simulate Z‐endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long‐term survival to identify the Z‐endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor‐positive breast cancer. [ABSTRACT FROM AUTHOR]

Palbociclib is an oral inhibitor of cyclin‐dependent kinases 4 and 6 used in the treatment of locally advanced and metastatic breast cancer, and is extensively metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). A pharmacokinetic/pharmacodynamic relationship between palbociclib exposure and neutropenia is well known. This study aimed to investigate the effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib. We performed a randomized crossover trial comparing the pharmacokinetics of palbociclib monotherapy 125 mg once daily (q.d.) with palbociclib 125 mg q.d. plus oral erythromycin 500 mg three times daily for seven days. Pharmacokinetic sampling was performed at steady‐state for both dosing schedules. Eleven evaluable patients have been enrolled. For palbociclib monotherapy, geometric mean area under the plasma concentration‐time curve from zero to infinity (AUC0–24h), maximum plasma concentration (Cmax), and minimum plasma concentration (Cmin) were 1.46 × 103 ng•h/mL (coefficient of variation (CV) 45.0%), 80.5 ng/mL (CV 48.5%), and 48.4 ng/mL (CV 38.8%), respectively, compared with 2.09 × 103 ng•h/mL (CV 49.3%, P = 0.000977), 115 ng/mL (CV 53.7%, P = 0.00562), and 70.7 ng/mL (CV 47.5%, P = 0.000488) when palbociclib was administered concomitantly with erythromycin. Geometric mean ratios (90% confidence intervals) of AUC0–24h, Cmax, and Cmin for palbociclib plus erythromycin vs. palbociclib monotherapy were 1.43 (1.24–1.66), 1.43 (1.20–1.69), and 1.46 (1.30–1.63). Minor differences in adverse events were observed, and only one grade ≥ 3 toxicity was observed in this short period of time. To conclude, concomitant intake of palbociclib with the moderate CYP3A4 inhibitor erythromycin resulted in an increase in palbociclib AUC0–24h and Cmax of both 43%. Therefore, a dose reduction of palbociclib to 75 mg q.d. is rational, when palbociclib and moderate CYP3A4 inhibitors are used concomitantly. [ABSTRACT FROM AUTHOR]

Preclinical data suggests that protein and calorie restriction (PCR) might improve treatment tolerability without impairing antitumor efficacy. Therefore, we have studied the influence of PCR on irinotecan pharmacokinetics and toxicity. In this crossover trial, patients with liver metastases of solid tumors were included and randomized to treatment with irinotecan preceded by 5 days of PCR (~ 30% caloric and ~ 70% protein restriction) during the first cycle and a second cycle preceded by a normal diet or vice versa. Pharmacokinetic blood sampling and biopsies of both healthy liver and liver metastases were performed. The primary end point was the relative difference in geometric means for the active metabolite SN‐38 concentration in healthy liver analyzed by a linear mixed model. No significant differences were seen in irinotecan (+ 16.8%, P = 0.22) and SN‐38 (+ 9.8%, P = 0.48) concentrations between PCR and normal diet in healthy liver, as well as in liver metastases (irinotecan: −38.8%, P = 0.05 and SN‐38: −13.8%, P = 0.50). PCR increased irinotecan plasma area under the curve from zero to 24 hours (AUC0–24h) with 7.1% (P = 0.04) compared with normal diet, whereas the SN‐38 plasma AUC0–24h increased with 50.3% (P < 0.001). Grade ≥ 3 toxicity was not increased during PCR vs. normal diet (P = 0.69). No difference was seen in neutropenia grade ≥ 3 (47% vs. 32% P = 0.38), diarrhea grade ≥ 3 (5% vs. 21% P = 0.25), and febrile neutropenia (5% vs. 16% P = 0.50) during PCR vs. normal diet. In conclusion, plasma SN‐38 exposure increased dramatically after PCR, whereas toxicity did not change. PCR did not alter the irinotecan and SN‐38 exposure in healthy liver and liver metastases. PCR might therefore potentially improve the therapeutic window in patients treated with irinotecan. [ABSTRACT FROM AUTHOR]

Regorafenib exposure could potentially be influenced by an interaction with acid‐reducing drugs. In this crossover trial, patients were randomized into two sequence groups consisting of three phases: regorafenib intake alone, regorafenib with concomitant esomeprazole, and regorafenib with esomeprazole 3 hours prior. The primary end point was the relative difference (RD) in geometric means for regorafenib 0–24‐hour area under the concentration‐time curve (AUC0–24h) and was analyzed by a linear mixed model in 14 patients. AUC0–24h for regorafenib alone was 55.9 μg·hour/mL (coefficient of variance (CV): 40%), and for regorafenib with concomitant esomeprazole or with esomeprazole 3 hours prior AUC0–24h was 53.7 μg·hour/mL (CV: 34%) and 53.6 μg·hour/mL (CV: 43%), respectively. No significant differences were identified when regorafenib alone was compared with regorafenib with concomitant esomeprazole (RD: −3.9%; 95% confidence interval (CI): −20.5 to 16.1%; P = 1.0) or regorafenib with esomeprazole 3 hours prior (RD: −4.1%; 95% CI: −22.8 to 19.2%; P = 1.0). These findings indicate that regorafenib and esomeprazole can be safely combined in clinical practice. [ABSTRACT FROM AUTHOR]