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Aims: Carboplatin is generally dosed based on a modified Calvert formula, in which the Cockcroft–Gault‐based creatinine clearance (CRCL) is used as proxy for the glomerular filtration rate (GFR). The Cockcroft–Gault formula (CG) overpredicts CRCL in patients with an aberrant body composition. The CT‐enhanced estimate of RenAl FuncTion (CRAFT) was developed to compensate for this overprediction. We aimed to evaluate whether carboplatin clearance is better predicted by CRCL based on the CRAFT compared to the CG. Methods: Data of four previously conducted trials was used. The CRAFT was divided by serum creatinine to derive CRCL. The difference between CRAFT‐ and CG‐based CRCL was assessed by population pharmacokinetic modelling. Furthermore, the difference in calculated carboplatin dose was assessed in a heterogeneous dataset. Results: In total, 108 patients were included in the analysis. Addition of the CRAFT‐ and CG‐based CRCL as covariate on carboplatin clearance led, respectively, to an improved model fit with a 26‐point drop in objective function value and a worsened model fit with an increase of 8 points. In 19 subjects with serum creatinine <50 μmol/L, the calculated carboplatin dose was 233 mg higher using the CG. Conclusions: Carboplatin clearance is better predicted by CRAFT vs. CG‐based CRCL. In subjects with low serum creatinine, the calculated carboplatin dose using CG exceeds the dose using CRAFT, which might explain the need for dose capping when using the CG. Therefore, the CRAFT might be an alternative for dose capping while still dosing accurately. [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]