Optimizing carboplatin dosing by an improved prediction of carboplatin clearance using a CT-enhanced estimate of renal function.

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.

Everolimus Concentration in Saliva to Predict Stomatitis: A Feasibility Study in Patients with Cancer.

BACKGROUND: Most patients with cancer treated with everolimus experience stomatitis, which seriously affects the quality of life. The salivary concentrations of everolimus may predict the incidence and severity of stomatitis. The authors aimed to examine whether it was feasible to quantify the everolimus concentration in saliva and subsequently use it to predict stomatitis. METHODS: Saliva and whole blood samples were taken from patients with cancer, who were treated with everolimus in the dosage of either 10 mg once a day or 5 mg twice a day. Everolimus concentrations in saliva samples were measured by liquid chromatography-tandem mass spectrometry. A published population pharmacokinetic model was extended with the everolimus concentration in saliva to assess any association between everolimus in the blood and saliva. Subsequently, the association between the occurrence of stomatitis and the everolimus concentration in saliva was studied. RESULTS: Eleven patients were included in this study; saliva samples were available from 10 patients, including 3 patients with low-grade stomatitis. Everolimus concentrations were more than 100-fold lower in saliva than in whole blood (accumulation ratio 0.00801 and relative standard error 32.5%). Interindividual variability (67.7%) and residual unexplained variability (84.0%) were high. The salivary concentration of everolimus tended to be higher in patients with stomatitis, 1 hour postdose ( P = 0.14). CONCLUSIONS: Quantification of the everolimus concentration in saliva was feasible and revealed a nonsignificant correlation between everolimus concentration in the saliva and the occurrence of stomatitis. If future research proves this relationship to be significant, the everolimus concentration in the saliva may be used as an early predictor of stomatitis without invasive sampling. Thereby, in patients with high salivary everolimus concentrations, precautions can be taken to decrease the incidence and severity of stomatitis.

The association of cisplatin pharmacokinetics and skeletal muscle mass in patients with head and neck cancer: The prospective PLATISMA study.

BACKGROUND: Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with cisplatin-based chemoradiotherapy (CRT). Cisplatin is associated with severe toxicity, which negatively affects survival. In recent years, a relationship between low skeletal muscle mass (SMM) and increased toxicity has been described. This increased toxicity may be related to altered cisplatin distribution and binding in the fat-free body mass of which SMM is the largest contributor. This study aims to investigate the association between cisplatin pharmacokinetics and SMM in patients with HNSCC. METHODS: We performed a prospective observational study in patients with HNSCC treated with CRT. Patients received standard-of-care chemotherapy with three cycles of cisplatin at a dose of 100 mg/m2 per cycle. Quantitative data on SMM, measured on computed tomography scans and cisplatin pharmacokinetics (total and ultrafilterable plasma concentrations) were collected, as well as data on toxicity. RESULTS: A total of 45 evaluable patients were included in the study. A large proportion of the study population had a low SMM (46.7%). The majority of patients (57.8%) experienced cisplatin dose-limiting toxicities. Pharmacokinetic analysis showed a significant relationship between cisplatin pharmacokinetics and SMM, weight, fat-free mass and body surface area (p < 0.005). In a simulation, patients with a low SMM (<25.8 kg) were predicted to reach higher-bound cisplatin concentrations. CONCLUSION: We found an association between cisplatin pharmacokinetics and SMM; however, this relationship was also seen between cisplatin pharmacokinetics and other body composition descriptors.

Effects of the Moderate CYP3A4 Inhibitor Erythromycin on the Pharmacokinetics of Palbociclib: A Randomized Crossover Trial in Patients With Breast Cancer.

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.

Intra-Tumoral Pharmacokinetics of Pazopanib in Combination with Radiotherapy in Patients with Non-Metastatic Soft-Tissue Sarcoma.

There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149-200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib (ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells (p > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.

A Review of CYP3A Drug-Drug Interaction Studies: Practical Guidelines for Patients Using Targeted Oral Anticancer Drugs.

Many oral anticancer drugs are metabolized by CYP3A. Clinical drug-drug interaction (DDI) studies often only examine the effect of strong CYP3A inhibitors and inducers. The effect of moderate or weak inhibitors or inducers can be examined using physiologically based pharmacokinetic simulations, but data from these simulations are not always available early after approval of a drug. In this review we provide recommendations for clinical practice on how to deal with DDIs of oral anticancer drugs if only data from strong CYP3A inhibitors or inducers is available. These recommendations were based on reviewed data of oral anticancer drugs primarily metabolized by CYP3A and approved for the treatment of solid tumors from January 1st, 2013 to December 31st, 2015. In addition, three drugs that were registered before the new EMA guideline was issued (i.e., everolimus, imatinib, and sunitinib), were reviewed. DDIs are often complex, but if no data is available from moderate CYP3A inhibitors/inducers, a change in exposure of 50% compared with strong inhibitors/inducers can be assumed. No a priori dose adaptations are indicated for weak inhibitors/inducers, because their interacting effect is small. In case pharmacologically active metabolites are involved, the metabolic pathway, the ratio of the parent to the metabolites, and the potency of the metabolites should be taken into account.

Worse capecitabine treatment outcome in patients with a low skeletal muscle mass is not explained by altered pharmacokinetics.

BACKGROUND: A low skeletal muscle mass (SMM) has been associated with increased toxicity and shorter survival in cancer patients treated with capecitabine, an oral prodrug of 5-fluorouracil (5-FU). Capecitabine and its metabolites are highly water-soluble and, therefore, more likely to distribute to lean tissues. The pharmacokinetics (PK) in patients with a low SMM could be changed, for example, by reaching higher maximum plasma concentrations. In this study, we aimed to examine whether the association between a low SMM and increased toxicity and shorter survival could be explained by altered PK of capecitabine and its metabolites. METHODS: Previously, a population PK model of capecitabine and metabolites in patients with solid tumors was developed. In our analysis, we included patients from this previous analysis for which evaluable abdominal computed tomography (CT)-scans were available. SMM was measured on CT-scans, by single slice evaluation at the third lumbar vertebra, using the Slice-o-Matic software. The previously developed population PK model was extended with SMM as a covariate, to assess the association between SMM and capecitabine and metabolite PK. RESULTS: PK and SMM data were available from 151 cancer patients with solid tumors. From the included patients, 55% had a low SMM. No relevant relationships were found between SMM and the PK parameters of capecitabine and, the active and toxic metabolite, 5-FU. SMM only correlated with the PK of the, most hydrophilic, but inactive and non-toxic, metabolite α-fluoro-ß-alanine (FBAL). Patients with a low SMM had a smaller apparent volume of distribution and lower apparent clearance of FBAL. CONCLUSIONS: No alterations in PK of capecitabine and the active and toxic metabolite 5-FU were observed in patients with a low SMM. Therefore, the previously identified increased toxicity and shorter survival in patients with a low SMM, could not be explained by changes in pharmacokinetic characteristics of capecitabine and metabolites.