Search

Currently, several oral androgen receptor signalling inhibitors are available for the treatment of advanced prostate cancer. Quantification of plasma concentrations of these drugs is highly relevant for various purposes, such as Therapeutic Drug Monitoring (TDM) in oncology. Here, we report a liquid chromatography/tandem mass spectrometric (LC-MS/MS) method for the simultaneous quantification of abiraterone, enzalutamide, and darolutamide. The validation was performed according to the requirements of the U.S. Food and Drug Administration and European Medicine Agency. We also demonstrate the clinical applicability of the quantification of enzalutamide and darolutamide in patients with metastatic castration-resistant prostate cancer.

Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity.Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239).Results: Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001).Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment. Clin Cancer Res; 19(12); 3316–24. ©2013 AACR.

PDF file - 45K, Hardy Weinberg equilibrium.

PDF file - 244K, Amplification plot.

Supplementary figure 1

Purpose:CPC634 is a novel nanoparticle entrapping docetaxel, developed to enhance the intratumoral chemotherapy exposure. This randomized cross-over study compared the intratumoral and plasma pharmacokinetics of CPC634 with conventional docetaxel.Patients and Methods:Adult patients with solid tumors were randomized to receive CPC634 (75 mg/m2) in cycle 1, and conventional docetaxel (75 mg/m2) in cycle 2 or vice versa. The study was powered to identify a 25% increase of intratumoral total docetaxel exposure after CPC634 infusion compared with conventional docetaxel. Four patients were allocated per tumor sampling time point, that is, 24, 48, 72, and 96 hours, 7 and 14 days after infusion during both cycles. Total docetaxel and released docetaxel from the nanoparticle were determined in tumor tissue derived from a metastatic lesion and in plasma. Pharmacokinetic data were analyzed using linear mixed modeling.Results:In total, 24 evaluable patients were included. In the tumor, CPC634 exhibited a 461% higher total docetaxel (P < 0.001) and a comparable released docetaxel concentration (P = 0.43). Plasma AUCinf was 27% higher (P = 0.001) and Cmax was 91% lower (P < 0.001) for CPC634 released docetaxel. The median observed neutrophil count nadir after conventional docetaxel treatment was lower (0.50 × 109/L) compared with CPC634 (4.30 × 109/L; P < 0.001).Conclusions:Here, we demonstrated that CPC634 enhanced the intratumoral total docetaxel exposure compared with conventional docetaxel. The lower incidence of neutropenia during CPC634 treatment is presumably related to lower plasma Cmax of released docetaxel. The unique pharmacokinetic profile of CPC634 nanoparticles has the potential to improve docetaxel treatment. A phase II efficacy trial of CPC634 is currently ongoing.

Purpose: Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination.Experimental Design: Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wild-type), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n = 213).Results: Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P = 0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P > 0.05).Conclusions: The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure–toxicity relationships for docetaxel, we suggest that caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3. Clin Cancer Res; 18(16); 4433–40. ©2012 AACR.

Purpose: RGB-286638 is a multitargeted inhibitor with targets comprising the family of cyclin-dependent kinases (CDK) and a range of other cancer-relevant tyrosine and serine/threonine kinases. The objectives of this first in human trial of RGB-286638, given i.v. on days 1 to 5 every 28 days, were to determine the maximum tolerated dose (MTD) and to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of this new drug.Experimental Design: Sequential cohorts of 3 to 6 patients were treated per dose level. Blood, urine samples, and skin biopsies for full PK and/or PD analyses were collected.Results: Twenty-six patients were enrolled in 6-dose levels from 10 to 160 mg/d. Four dose-limiting toxicities were observed in 2 of the 6 patients enrolled at the highest dose level. These toxicities were AST/ALT elevations in 1 patient, paroxysmal supraventricular tachycardias (SVTs), hypotension, and an increase in troponin T in another patient. The plasma PK of RGB-286638 was shown to be linear over the studied doses. The interpatient variability in clearance was moderate (variation coefficient 7%–36%). The PD analyses in peripheral blood mononuclear cells, serum (apoptosis induction) and skin biopsies (Rb, p-Rb, Ki-67, and p27KIP1 expression) did not demonstrate a consistent modulation of mechanism-related biomarkers with the exception of lowered Ki-67 levels at the MTD level. The recommended MTD for phase II studies is 120 mg/d.Conclusions: RGB-286638 is tolerated when administered at 120 mg/d for 5 days every 28 days. Prolonged disease stabilization (range, 2–14 months) was seen across different dose levels. Clin Cancer Res; 20(18); 4776–83. ©2014 AACR.

Supplementary Figure S2: Relationship between area under the curves (AUC) and the administered dose on day 1 of drug intake.

Supplementary Figure legend

Supplementary Table 1 tracked changes

Supplementary Table 1 clean version

PDF file, 437KB, Description of determination of docetaxel concentrations; influence of phenol red on OATP1B1-mediated transport of docetaxel; characterization of paclitaxel concentration-dependent transport by OATP1B1 and OATP1B3; docetaxel clearance as a function of observed OATP1B1 (SLCO1B1) or OATP1B3 (SLCO1B3) diplotypes and genotypes; description of genotyped variants in OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3); summary of patient demographics; and examples of OATP1B1 and OATP1B3 inhibitors.

PDF file - 61KB

PDF file - 77KB, Plasma pharmacokinetic parameters of paclitaxel (10 mg/kg) in mice using different formulations.

PDF file - 151KB, The uptake of paclitaxel by human OATP1B1, human OATP1B3 in CHO cells (1 microM; 2-min), or mouse OATP1B2 in HEK293 cells (0.1 microM; 15-min) evaluated in the absence (none) or presence of 1 percent (w/v) Cremophor EL (CrEL).

PDF file - 58KB

PDF file - 636KB, In vitro transport of paclitaxel by OATP1B1 and OATP1B3.

Retrospective data suggest that gastric acid reduction by proton pump inhibitors (PPIs) impairs the dissolution and subsequent absorption of capecitabine, and thus potentially reduces the capecitabine exposure. Therefore, we examined prospectively the effect of esomeprazole on the pharmacokinetics of capecitabine. In this randomized crossover study, patients with cancer were assigned to 2 sequence groups, each consisting of 3 phases: capecitabine with esomeprazole administration 3 hours before (phase A), capecitabine alone (phase B), and capecitabine concomitant with cola and esomeprazole co-administration 3 hours before (phase C). The primary end point was the relative difference (RD) in exposure to capecitabine assessed by the area under the plasma concentration-time curve from zero to infinity (AUC0-inf) and analyzed by a linear mixed effect model. Twenty-two evaluable patients were included in the analysis. After esomeprazole, there was a 18.9% increase in AUC0-inf of capecitabine (95% confidence interval (CI) −10.0% to 57.0%, P = 0.36). In addition, capecitabine half-life was significantly longer after esomeprazole (median 0.63 hours vs. 0.46 hours, P = 0.005). Concomitant cola did not completely reverse the effects observed after esomeprazole (RD 3.3% (95% CI −16.3 to 27.4%, P = 1.00). Capecitabine exposure is not negatively influenced by esomeprazole cotreatment. Therefore, altered capecitabine pharmacokinetics do not explain the assumed worse clinical outcome of PPI-cotreated patients with cancer.

Peptide receptor radionuclide therapy (PRRT), a form of internal targeted radiation treatment using [177Lu]Lu [DOTA0-Tyr3]octreotate, is used to treat patients with metastasized neuroendocrine tumors (NETs). Even though PRRT is now the second line of treatment for patients with metastasized NETs, the majority of patients will not be cured by the treatment. PRRT functions by inducing DNA damage upon radioactive decay and inhibition of DNA damage repair proteins could therefore be used as a strategy to potentiate PRRT. Previous work has shown promising results on the combination of PRRT with the PARP inhibitor olaparib in cell lines and mice and we have been taken the next step for further in vivo validation using two different xenografted mouse models. We observed that this combination therapy resulted in increased therapeutic efficacy only in one model and not the other. Overall, our findings indicate a tumor-type dependent anti-tumor response to the combination of PRRT and olaparib. These data emphasize the unmet need for the molecular stratification of tumors to predetermine the potential clinical value of combining PARP inhibition with PRRT.

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

Introduction: The CodeBreaK 200 trial showed that in patients (pts) with advanced KRAS G12C mutated (KRAS+) NSCLC sotorasib, a KRAS G12C-specific inhibitor, is superior to docetaxel for progression free survival (PFS) (HR 0.66) with a one-year PFS of 25%. We hypothesized that the detection of circulating tumor DNA (ctDNA) in plasma could allow for treatment response prediction and longitudinal monitoring. We analyzed serial plasma samples at baseline and within 3 months of start of sotorasib to evaluate ctDNA changes and correlation with clinical response. Methods: Pts with sotorasib treated KRAS+ NSCLC were prospectively enrolled in our biomarker START-TKI study (NCT05221372) after written informed consent. Plasma samples were collected prior to treatment (T0) and at first response evaluation (T1). The TruSight Oncology 500 ctDNA panel was used for mutation detection in cell-free DNA (cfDNA). cfDNA KRAS/TP53/STK11/KEAP1 status was determined and compared to tumor tissue pathology reports to filter out false positives. Radiological response and PFS was assessed per RECIST 1.1. Results: Between May 2021 and August 2022, 35 pts were included (table 1). Of these, 29 (83%) had detectable ctDNA KRAS G12C at T0, and 24 had both T0 and T1 samples. A decrease in variant allele frequency (VAF) at T1 compared to T0 was observed in 88% (n=21); 42% (n=10) showed complete clearance of ctDNA KRAS G12C. Six-months PFS was 83% in T0 negative pts (n=6) versus 43% in T0 positive pts (n=29); and 65% in pts with complete clearance (n=10) versus 14% in pts with incomplete clearance (n=11). VAF increase was seen in 3 pts, of which 1 had progression at T1. Conclusions: In pts with KRAS+ NSCLC treated with sotorasib, baseline ctDNA and ctDNA clearance within 3 months of treatment correlated with treatment response. Pts with undetectable KRAS ctDNA at baseline, or with complete clearance at first evaluation, had superior PFS. PFS will be updated as follow-up duration extends. Table 1. Patient cohort Liver metastasis KRAS p.G12C ctDNA at T0, median VAF % (range) KRAS p.G12C ctDNA at T1, median VAF % (range) Median change in VAF % (range) TP53/STK11/KEAP1 ctDNA T0 T1 response Reason EOT ꝉ Time on treatment (months) * Negative at T0 (n=6) No = 6 0 NE NE NE 1x PR; 4x SD; 1x PD 2x PD; 4x ongoing >8 months 6 (1 - 11) Positive at T0 (n=29) No = 20; Yes = 9 2.6 (0.1 - 46.7) 0.6 (0.1 - 38.9) -95% (-100 - +39) 4x TP53; 2x STK11; 1x STK11●; 2x KEAP1; 2x KEAP1●; 2x TP53 + KEAP1; 1x TP53 + STK11● 4x PR; 21x SD; 2x PD; 2x NE 19x PD; 3x toxicity; 6x ongoing >4 months; 1x loss to follow up 3 (1 - 15) Complete clearance at T1 (n=10) No = 6; Yes = 4 1.4 (0.1 - 8.4) 0 100% 2x TP53; 1x TP53 + KEAP1; 1x KEAP1; 1x KEAP1● 1x PR; 9x SD 6x PD; 1x toxicity; 2x ongoing >6 months; 1x loss to follow up 5 (1 - 11) Incomplete clearance at T1 (n=11) No = 7; Yes = 4 3.6 (1.3 - 46.7) 0.4 (0.1 - 29.4) -89% (-23 - -99) 2x TP53; 1x STK11; 1x STK11●; 2x TP53 + STK11●; 1x TP53 + STK11 + KEAP1; 1x STK11 + KEAP1 3x PR; 7x SD; 1x PD 8x PD; 2x toxicity; 1x ongoing >4 months 3 (1 - 8) Increase in VAF at T1 (n=3) No = 2; Yes = 1 1.0 (0.5 - 35.2) 1.1 (0.6 - 38.9) +11% (+10 - +39) 1x TP53●; 1x TP53 + KEAP1; 1x STK11● + KEAP1● 1x PD; 2x SD 3x PD 3 (1 - 15) Positive T0, no T1 available (n=5) No = 5 6.2 (0.3 - 24.6) NE NE 1x TP53; 1x TP53●; 1x KEAP1; 1x STK11 + KEAP1 3x SD; 2x NE 2x PD; 3x ongoing >3 months 2 (1 - 3) NE = Not evaluated; ● = Positive cell-free DNA (cfDNA), not tested in tumor tissue; PR = Partial response; SD = Stable disease; PD = Progressive disease; EOT = End of treatment; ꝉ for PFS analysis patients who discontinued treatment due to toxicity were censored at treatment discontinuation, and patients with ongoing sotorasib treatment were censored at data cut off (16-Nov-2022); * = excluding ongoing patients. Citation Format: Sophie M. Ernst, Ronald van Marion, Peggy N. Atmodimedjo, Evert de Jonge, Ron H. Mathijssen, Marthe S. Paats, Peter de Bruijn, Ron H.N. van Schaik, Hendrikus J. Dubbink, Anne-Marie C. Dingemans. Clinical utility of circulating tumor DNA in patients with advanced KRAS G12C-mutated NSCLC treated with sotorasib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2137.

Hepatocellular carcinoma (HCC) recurrence after liver transplantation occurs in approximately 20% of patients. Most of these patients use immunosuppressant drugs. Meanwhile, patients with HCC recurrence are frequently treated with the small molecule kinase inhibitor (SMKI) sorafenib. However, sorafenib and many immunosuppressants are substrates of the same enzymatic pathways (e.g., CYP3A4), which may potentially result in altered SMKI or immunosuppressant plasma levels. Therefore, we investigated changes in drug exposure of both sorafenib and immunosuppressants over time in four patients with systemic immunosuppressant and sorafenib treatment after HCC recurrence. In this study, sorafenib exposure declined over time during combined treatment with immunosuppressants, while two patients also experienced declining tacrolimus plasma levels. Importantly, patients were unable to increase the sorafenib dose higher than 200 mg b.i.d. without experiencing significant toxicity. We recommend to treat patients using both sorafenib and immunosuppressants with a sorafenib starting dose of 200 mg b.i.d.

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

Introduction CYP2D6 protein activity can be inferred from the ratio of N-desmethyl-tamoxifen (NDMT) to endoxifen (E). CYP2D6 polymorphisms are common and can affect CYP2D6 protein activity and E level. Some retrospective studies indicate that E 35; N = 44) groups. The ratio was independently validated by a validation cohort. The simplified system was better in predicting patients without slow metabolism, with specificity and sensitivity of 96% and 44% respectively, compared with the standard method - sensitivity 81% and specificity 83%. Conclusions The simplified classification system based on whether any variant was present better identified patients who were truly not CYP2D6 slow metabolizers more accurately than the current system. However, as CYP2D6 genotype is not the only determinant of endoxifen level, we recommend that direct measurement of endoxifen should also be considered., Highlights • We used a ratio of two tamoxifen metabolites to categorize CYP2D6 metabolizer groups. • We developed a simplified system to identify slow metabolizers based on genotype. • The simplified system was more accurate than the standard complex system.

Purpose: CPC634 is a novel nanoparticle entrapping docetaxel, developed to enhance the intratumoral chemotherapy exposure. This randomized cross-over study compared the intratumoral and plasma pharmacokinetics of CPC634 with conventional docetaxel. Patients and Methods: Adult patients with solid tumors were randomized to receive CPC634 (75 mg/m2) in cycle 1, and conventional docetaxel (75 mg/m2) in cycle 2 or vice versa. The study was powered to identify a 25% increase of intratumoral total docetaxel exposure after CPC634 infusion compared with conventional docetaxel. Four patients were allocated per tumor sampling time point, that is, 24, 48, 72, and 96 hours, 7 and 14 days after infusion during both cycles. Total docetaxel and released docetaxel from the nanoparticle were determined in tumor tissue derived from a metastatic lesion and in plasma. Pharmacokinetic data were analyzed using linear mixed modeling. Results: In total, 24 evaluable patients were included. In the tumor, CPC634 exhibited a 461% higher total docetaxel (P < 0.001) and a comparable released docetaxel concentration (P = 0.43). Plasma AUCinf was 27% higher (P = 0.001) and Cmax was 91% lower (P < 0.001) for CPC634 released docetaxel. The median observed neutrophil count nadir after conventional docetaxel treatment was lower (0.50 × 109/L) compared with CPC634 (4.30 × 109/L; P < 0.001). Conclusions: Here, we demonstrated that CPC634 enhanced the intratumoral total docetaxel exposure compared with conventional docetaxel. The lower incidence of neutropenia during CPC634 treatment is presumably related to lower plasma Cmax of released docetaxel. The unique pharmacokinetic profile of CPC634 nanoparticles has the potential to improve docetaxel treatment. A phase II efficacy trial of CPC634 is currently ongoing.

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).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.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.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.

Simple Summary This study investigated the correlation between scalp cooling used to prevent chemotherapy-induced alopecia and the pharmacokinetics of paclitaxel in female cancer patients with a solid tumor. In a prospective cohort study, 14 patients who were treated with weekly paclitaxel and scalp cooling were able to undergo pharmacokinetic sampling of paclitaxel during one cycle of treatment. In comparison to a control cohort of 24 patients treated with weekly paclitaxel without scalp cooling, our data showed that scalp cooling used concomitantly with one course of paclitaxel did not reduce or increase the clearance of paclitaxel. Therefore, it is unlikely that scalp cooling influences paclitaxel efficacy or toxicity. Finally, despite scalp cooling, half of the patients in our study developed a form of hair loss. Importantly, neither an association with difference in paclitaxel clearance nor change in hair loss was found. Abstract Chemotherapy-induced alopecia (CIA), a side effect with high impact, can be prevented by cooling the scalp during the administration of some cytotoxic drugs. However, the effects of this prolonged scalp cooling on the pharmacokinetics of chemotherapy have never been investigated. In this study, we compared the pharmacokinetics of the widely used chemotherapeutic agent paclitaxel (weekly dose of 80–100 mg/m2) in female patients with solid tumors using concomitant scalp cooling (n = 14) or not (n = 24). Blood samples were collected in all patients for pharmacokinetic analyses up to 6 h after one course of paclitaxel administration. The primary endpoint was the clearance (L/h) of paclitaxel. Paclitaxel clearance—expressed as relative difference in geometric means—was 6.8% (90% CI: −16.7% to 4.4%) lower when paclitaxel was administered with concomitant scalp cooling versus paclitaxel infusions without scalp cooling. Within the subgroup of patients using scalp cooling, paclitaxel clearance was not statistically significantly different between patients with CIA (alopecia grade 1 or 2) and those without CIA. Hence, scalp cooling did not negatively influence the clearance of paclitaxel treatment.

A reliable, specific, selective and robust liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed for the determination of ribociclib in both dried blood spot (DBS) samples and potassium EDTA plasma. DBS samples were obtained simultaneously with a plasma sample in advanced breast cancer patients treated with ribociclib. A 6 mm disk from the central part of the dried blood spot sample was punched, followed by extraction of ribociclib using liquid-liquid extraction spiked with ribociclib-d6 as internal standard. Concentrations of ribociclib in DBS samples were correlated with corresponding plasma concentrations. From the blood sample also hematocrit was determined. The method was validated for selectivity, sensitivity, precision, lower limit of detection, linearity, stability and accuracy according to the food and drug administration (FDA) guideline. The within- and between-run precisions were ≤10.6 and ≤1.07 %, respectively; while the average accuracy ranged from 100 to 103 %. The influence of hematocrit on validation parameters was tested in the range of 0.20 – 0.40 L/L. No influence of hematocrit on validation parameters was observed. Regression analysis and a Bland-Altman plot indicated correlation between the results obtained from DBS and plasma samples. A strong correlation (R2 >0.97) between DBS samples and plasma concentration from 17 breast cancer patients was found. A number of 12 out of 17 processed DBS samples (71 %) fell inside the acceptable range of 20 % difference of simultaneously obtained plasma samples. The lower limit of quantification in DBS is 10.0 ng/mL and linearity was demonstrated up to 1000 ng/mL. In conclusion, the newly developed assay met the required standard for validation. The methods were used to study ribociclib disposition in patients with advanced breast cancer.

Simple Summary CPC634 is a nanoparticle entrapping docetaxel that is associated with skin toxicity that resembles conventional docetaxel-related skin toxicity. In this randomised cross-over study, the cutaneous pharmacokinetics and pharmacodynamics of docetaxel and CPC634 were compared to unravel the mechanisms behind the cutaneous toxicity. The total docetaxel concentration in the skin was almost four-fold higher after CPC634 administration compared to conventional docetaxel. Both CPC634 and conventional docetaxel administration resulted in anti-mitotic effects in the skin such as micronucleation. Micronucleation can induce an inflammatory reaction, which could lead to skin toxicity. Abstract Docetaxel entrapped nanoparticle CPC634 is associated with dose-related skin toxicity that resembles conventional docetaxel (Cd)-related skin toxicity. This study compared the cutaneous pharmacokinetics and pharmacodynamics of docetaxel and CPC634. In this randomised cross-over study, patients with solid tumours received one cycle of CPC634 and Cd (both at 75 mg/m2). Skin biopsies were taken at baseline and at day 8 of both cycles. Released and total docetaxel (released docetaxel plus entrapped docetaxel) concentrations and histopathological changes in the skin biopsies were evaluated. Twenty patients underwent paired skin biopsies for pharmacokinetic analysis and 10 patients had biopsies available for histopathological assessment. The total skin docetaxel concentration was 369% (95%CI: 229% to 569%, p < 0.001) higher after CPC634 administration compared to Cd while the released docetaxel concentrations were not statistically different (95%CI: −9% to 63%, p = 0.169). The CPC634 released docetaxel concentration in the skin was positively correlated with plasma concentrations (Pearson’s correlation 0.48, p = 0.03). Histopathological examination revealed increased apoptosis, mitotic cells with nuclear atypia, and micronucleation with an enhanced Ki-67 index for both compounds. In conclusion, both CPC634 and Cd treatment result in docetaxel exposure in the skin causing cutaneous anti-mitotic effects such as micronucleation, which could induce an inflammatory reaction leading to skin toxicity.

Aims: Docetaxel has been approved for the treatment of metastatic prostate cancer in combination with prednisone. Since prednisone is known to induce the cytochrome P450 iso-enzyme CYP3A4, which is the main metabolizing enzyme of docetaxel in the liver, a potential drug–drug interaction may occur. In this prospective randomized pharmacokinetic cross-over study we investigated docetaxel exposure with concomitant prednisone, compared to docetaxel monotherapy in men with metastatic prostate cancer. Methods: Patients scheduled to receive at least 6 cycles of docetaxel (75 mg/m2) and who gave written informed consent were randomized to receive either the 1st 3 cycles, or the last 3 consecutive cycles with prednisone (twice daily 5 mg). Pharmacokinetic blood sampling was performed during cycle 3 and cycle 6. Primary endpoint was difference in docetaxel exposure, calculated as area under the curve (AUC0-inf) and analysed by means of a linear mixed model. Given the cross-over design the study was powered on 18 patients to answer the primary, pharmacokinetic, endpoint. Results: Eighteen evaluable patients were included in the trial. Docetaxel concentration with concomitant prednisone (AUC0-inf 2784 ng*h/mL, 95% confidence interval 2436–3183 ng*h/mL) was similar to the concentration of docetaxel monotherapy (AUC0-inf 2647 ng*h/mL, 95% confidence interval 2377–2949 ng*h/mL). Exploratory analysis showed no toxicity differences between docetaxel monotherapy and docetaxel cycles with prednisone. Conclusion: No significant difference in docetaxel concentrations was observed. In addition, we found similar toxicity profiles in absence and presence of prednisone. Therefore, from a pharmacokinetic point of view, docetaxel may be administrated with or without prednisone.

5038 Background: Taxane efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients is limited due to resistance development. In preclinical models it has been shown that addition of the androgen receptor signalling inhibitor (ARSI) enzalutamide improves cabazitaxel efficacy. However, we have previously shown that the clinical utility of this combination is hampered by a strong CYP3A4 drug-drug interaction with enzalutamide, resulting in a 22% reduced cabazitaxel systemic exposure. Darolutamide has much weaker CYP3A4 inducing effects and therefore may affect cabazitaxel systemic exposure to a lesser extent. Methods: We investigated the influence of darolutamide on cabazitaxel plasma exposure. mCRPC patients were enrolled on cabazitaxel monotherapy (20 mg/m2 Q3W) on day 1 and received concomitant darolutamide (600 mg b.i.d.) from day 2 onwards for maximal 12 weeks. During cabazitaxel infusion on day 1, and after 6 and 12 weeks of darolutamide treatment, we measured cabazitaxel systemic exposure via Area Under the Curve from 0 to 24 hours (AUC0-24h). Results: Cabazitaxel systemic exposure in 18 patients after 6 weeks of darolutamide was not significantly different compared to prior to darolutamide treatment (AUC0-24h: -4%; 95%CI -19 – +13%; p = 0.58). Also, after 12 weeks of darolutamide treatment, cabazitaxel systemic exposure was unaltered (AUC0-24h: +4%; 95%CI -10 – +20%; p = 0.54). Darolutamide plasma concentrations were constant throughout the study (Table). Conclusions: From a pharmacokinetic perspective cabazitaxel and darolutamide can be safely combined in mCRPC patients. Our findings pave the way for testing the efficacy of this promising combination in an era of combination regimens for prostate cancer. Clinical trial information: NL8611. [Table: see text]

A novel metabolic pathway for anaerobic ammonium oxidation with nitrite as the electron acceptor has been elucidated using

Multiple small-molecule kinase inhibitors with specific molecular targets have recently been developed for the treatment of cancer. This article reports the development and validation of an ultra-performance liquid chromatography/tandem mass spectrometry (UPLC–MS/MS) method to simultaneously analyse the small-molecule kinase inhibitors dacomitinib, ceritinib, lorlatinib, and nintedanib in human plasma. For chromatographic analyte separation, an Acquity UPLC® BEH C18 column 1.7 μm, 50 mm x 2.1 mm was used with a binary gradient of pure water/formic acid/ammonium formate (100:0.1:0.02, v/v/v) and methanol/formic acid (100:0.1, v/v). Calibration curves for all small-molecule kinase inhibitors were 5.00–500 ng/mL. Validation of this method met all requirements of the Food and Drug administration. Additionally, clinical applicability was demonstrated by quantification of multiple samples from a pharmacokinetic study in patients with lung cancer.

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.