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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 (R 2 >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., Competing Interests: Declaration of Competing Interest This work was supported through an unrestricted grant by Novartis, the Netherlands. Stijn L.W. Koolen has received this research grant from Novartis. C. Louwrens Braal, Mei H. Lam, Tineke Rienks, Claudia van Tilborg, Wendy Heuts, Joan B. Heijns, Monique E.M.M. Bos, Ron H.J. Mathijssen and Peter de Bruijn declare they have no conflicts of interest that might be relevant to the contents of this manuscript., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Oxycodone is frequently used for treating cancer-related pain, while not much is known about the factors that influence treatment outcomes in these patients. We aim to unravel these factors by developing a population-pharmacokinetic model to assess the pharmacokinetics of oxycodone and its metabolites in cancer patients, and to associate this with pain scores, and adverse events. Hospitalized patients with cancer-related pain, who were treated with oral oxycodone, could participate. Pharmacokinetic samples and patient-reported pain scores and occurrence and severity of nine adverse events were taken every 12 h. In 28 patients, 302 pharmacokinetic samples were collected. A one-compartment model for oxycodone and each metabolite best described oxycodone, nor-oxycodone, and nor-oxymorphone pharmacokinetics. Furthermore, oxycodone exposure was not associated with average and maximal pain scores, and oxycodone, nor-oxycodone, and nor-oxymorphone exposure were not associated with adverse events (all p > 0.05). This is the first model to describe the pharmacokinetics of oxycodone including the metabolites nor-oxycodone and nor-oxymorphone in hospitalized patients with cancer pain. Additional research, including more patients and a more timely collection of pharmacodynamic data, is needed to further elucidate oxycodone (metabolite) pharmacokinetic/pharmacodynamic relationships. This model is an important starting point for further studies to optimize oxycodone dosing regiments in patients with cancer-related pain.

Background: Dosing schemes of pembrolizumab (anti-programmed cell death protein 1 monoclonal antibody) are solely based on pharmacokinetic (PK) modelling derived from phase I-III trials. The current study aimed to determine factors affecting PK and its relationship with clinical outcome in the real-world setting., Methods: Advanced-stage cancer patients, who were treated with pembrolizumab monotherapy (2 mg/kg Q3W or 200 mg flat Q3W), were prospectively included for serial sampling to obtain trough concentrations. A PK model was generated, covariate effects assessed and internally validated by a bootstrap procedure. PK parameters were related to overall survival (OS) and the occurrence of immune-related adverse events (irAEs)., Results: 588 serum samples derived from 122 patients with (non-)small-cell lung cancer ([N]SCLC), malignant pleural mesothelioma (MPM), melanoma and urothelial cell cancer (UCC) were analyzed. Median follow-up was 2.2 years. A one-compartment PK model was generated: body surface area (BSA) and serum albumin had a significant effect on drug clearance (CL; covariate estimate 1.46 and -1.43, respectively), and serum lactate dehydrogenase (LDH) on the distribution volume(V d ; 0.34). A significant inverse CL-OS relationship was determined for NSCLC (HR:1.69; 95%CI1.07-2.68; p=0.024) and MPM (HR: 3.29; 95% CI 1.08 to 10.09; p=0.037), after correction for prognostic factors, which could not confirmed for melanoma (p=0.22) or UCC (p=0.34). No relationship could be determined between CL and grade > 3 irAEs (p=0.70)., Conclusions: High interpatient variability of pembrolizumab PK is determined by BSA and serum albumin (on CL) and LDH (on V d ). A strong inverse CL-OS relationship was demonstrated for NSCLC and MPM, which could not be observed for melanoma and UCC. The findings suggest that personalized dosing should be prospectively explored., Competing Interests: Competing interests: JGJVA reports personal fees from MSD, BMS, Amphera, Eli-Lilly, Takeda, Bayer, Roche, Boehringer Ingelheim, AstraZeneca outside the submitted work, and has a patent allogenic tumor cell lysate licensed to Amphera, a patent combination immunotherapy in cancer and a patent biomarker for immunotherapy pending. RHJM reports grants and non-financial support from Astellas, Bayer and Boehringer Ingelheim, grants from Cristal Therapeutics and Pamgene, grants and personal fees from Novartis, Servier, grants and non-financial support from Pfizer, grants from Roche, Sanofi, outside the submitted work. AAMvdV has a consultancy role at BMS, MSD, Merck, Pfizer, Novartis, Roche, Pierre Fabre, Sanofi, Ipsen, Eisai, outside the submitted work. All remaining authors declare no potential conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 (AUC 0-24h ) with 7.1% (P = 0.04) compared with normal diet, whereas the SN-38 plasma AUC 0-24h 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., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

The treatment landscape of advanced prostate cancer has widely expanded over the past years with androgen receptor signaling inhibitors (ARSIs) and taxane chemotherapy moving to earlier disease stages in the treatment of prostate cancer. With the increasing use of ARSIs in earlier disease stages, cross-resistance between treatments has emerged, which is a dominant impediment in current clinical practice. To overcome cross-resistance in the treatment of prostate cancer, it is of paramount importance to decipher the mechanisms of cross-resistance between ARSIs and between ARSIs and chemotherapy. Here, molecular mechanisms of resistance to the available therapies including androgen receptor (AR) splice variants, AR overexpression, AR mutations and glucocorticoid receptor upregulation are described. Based on these underlying mechanisms, clinical data of cross-resistance between ARSIs and chemotherapy have been reported. Only recently these data have been confirmed in prospective randomized trials. From these studies, it has become clear that sequential ARSI treatment has no place in the treatment of advanced prostate cancer due to emerging drug resistance. In addition, based on prospective evidence, we argue that it is worth considering an early switch to cabazitaxel treatment in case of lack of benefit on docetaxel regimen after an ARSI treatment. Based on these new insights from randomized trials, several recommendations for treatment sequence are proposed., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Erlotinib's gastrointestinal solubility and absorption are decreased by proton pump inhibitors (PPIs). Since erlotinib is a lipophilic drug, we hypothesized that concomitant intake with the fatty beverage milk may be a feasible way to increase erlotinib uptake. We performed a two-period, randomized, crossover study to investigate the influence of cow's milk with 3.9% fat on the exposure of erlotinib with and without the PPI esomeprazole in patients with non-small cell lung cancer (NSCLC). The effect of esomeprazole was studied in an additional intrapatient comparison., Method: Pharmacokinetic sampling was performed on days 7 and 14 during 24 consecutive hours. During the 7 days prior to pharmacokinetic sampling, erlotinib was taken daily with 250 mL of either water or milk. In the PPI arm, esomeprazole (40 mg once daily 3 h prior to erlotinib) was taken for 3 days., Results: Erlotinib area under the curve from time zero to 24 h (AUC 24 ) did not significantly change when administered with milk, compared with water, in both non-PPI users (n = 14; - 3%; 95% confidence interval [CI] - 12 to 8%; p = 0.57) and patients who used esomeprazole (n = 15; 0%; 95% CI - 15 to 17%; p = 0.95). Esomeprazole decreased erlotinib AUC 24 by 47% (n = 9; 95% CI - 57 to - 34%; p < 0.001) and C max by 56% (95% CI - 64 to - 46%; p < 0.001). No differences in toxicities were observed between milk and water., Conclusion: Milk with 3.9% fat has no effect on the exposure to erlotinib in NSCLC patients, independent of PPI use. The combination with milk is safe and well tolerated. Concomitant esomeprazole treatment strongly decreased both erlotinib AUC 24 and C max and should be avoided if possible.

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 < 16 nM may relate to worse outcome., Materials and Methods: A target NDMT/E ratio was defined as associated with an E level of 15 nM in the 161 patient Test cohort of tamoxifen-treated patients, dichotomizing them into 'Normal' (NM) and 'Slow' (SM) CYP2D6 metabolizer groups. This ratio was then tested on a validation cohort of 52 patients. Patients were phenotyped based on the standard method (ultrarapid/extensive, intermediate or poor metabolizers; UM/EM, IM, PM) or a simplified system based on whether any variant allele (V) vs wildtype (wt) was present (wt/wt, wt/V, V/V). Comprehensive CYP2D6 genotyping was undertaken on germline DNA., Results: A target NDMT/E ratio of 35 correlated with the 15 nM E level, dichotomizing patients into NM (<35; N = 117) and SM (>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., Competing Interests: Declaration of competing interest Clara Inkyung Lee, Peter Fox, Bavanthi Balakrishnar, Bo Gao, Sally Coulter, Christopher Liddle, Mark Wong, and Nicholas Wilcken have no conflicts of interest to declare. Rina Hui has conflicts to declare including: Advisory board member for Merck Sharp and Dohme, Astra Zeneca, Novartis, Roche and Bristol-Myers Squib, speaker honorarium for Merk Sharp and Dohme. Howard Gurney has conflicts to declare including: Advisory board/consulting role for Bristol-Myers Squib, Ipsen, Merck Sharp and Dohme, Astra Zeneca, Janssen-Cilag. Honorarium for Pfizer. Ron H.J. Mathijssen has conflicts to declare including: Speakers’ Bureau: Novartis. Research Funding: Roche (Inst), Sanofi (Inst), Astellas Pharma (Inst), Bayer Holding (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst), Cristal Therapeutics (Inst), Pamgene (Inst). Travel, Accommodations, Expenses: Pfizer, Astellas Pharma. Stijn L.W. Koolen has conflicts to declare including: Speakers’ Bureau: Novartis, Pfizer, Research Funding: Cristal Therapeutics (Inst), Novartis (Inst), Travel, Accommodations, Expenses: Ipsen., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Conventional taxanes are used as cornerstone of the chemotherapeutical treatment for a variety of malignancies. Nevertheless, a large proportion of patients do not benefit from their treatment while they do suffer from severe adverse events related to the solvent or to the active compound. Cremophor EL and polysorbate 80 free formulations, conjugates, oral formulations and different types of drug delivery systems are some examples of the several attempts to improve the treatment with taxanes. In this review article, we discuss recent clinical developments of nanomediated drug delivery systems of taxanes for the treatment of cancer. Targeting mechanisms of drug delivery systems and characteristics of the most commonly used taxane-containing drug delivery systems in the clinical setting will be discussed in this review., Competing Interests: This review was performed without external funding. Ron HJ Mathijssen and Stijn LW Koolen received an unrestricted grant of Cristal Therapeutics (producer of CPC634) for a phase I clinical trial with this nanomedicine agent. The authors report no other conflicts of interest in this work., (© 2020 van Eerden et al.)

Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (C SS,min ENDX ) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on C SS,min ENDX using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact C SS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget C SS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget C SS,min ENDX compared with elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing., (© 2020 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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/m 2 ) in cycle 1, and conventional docetaxel (75 mg/m 2 ) 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 AUC inf was 27% higher ( P = 0.001) and C max was 91% lower ( P /L) compared with CPC634 (4.30 × 10 9 /L; 9 /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 C max 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., (©2020 American Association for Cancer Research.)

Background: Thyroid dysfunction is among the most common adverse effects during anti-programmed cell death 1 (PD-1) immunotherapy, and alongside correlations with elevated anti-thyroid antibodies (ATAb), studies have found correlations with survival. However, the exact relations remain to be clarified. We, therefore, aimed at clarifying the relationship between thyroid dysfunction, ATAbs, and survival in anti-PD-1 treated cancer patients. Methods: We included 168 patients with nonsmall-cell lung carcinoma, renal cell carcinoma, and metastatic melanoma treated with nivolumab or pembrolizumab. Thyrotropin and free T4 (fT4) levels were measured before each anti-PD-1 infusion. ATAb levels (anti-thyroid peroxidase [TPO] and anti-thyroglobulin [Tg]) were measured at baseline and after two months of treatment. Although the vast majority of patients had detectable levels of ATABs, only a few patients had positive ATAbs when using conventional cut-offs. To study the consequences of detectable ATABs, the cut-off levels were a priori set at the median concentrations at baseline in the study population. Tumor progression was classified according to RECIST v1.1. Results: Patients who acquired overt thyroid dysfunction during treatment had significantly higher overall survival (OS) (hazard ratio [HR] = 0.18 confidence interval [CI: 0.04-0.76]; p  = 0.020) and progression-free survival (PFS) (HR = 0.39 [0.15-0.998]; p  = 0.050) than patients without thyroid dysfunction with 1-year OS rates of 94% vs. 59% and 1-year PFS rates of 64% vs. 34%. During treatment, patients with ATAb levels above the median had a higher OS (HR = 0.39 [0.21-0.72]; p  = 0.003) and PFS (HR = 0.52 [0.33-0.81]; p  = 0.004) than patients with ATAb levels below the median, with 1-year OS rates of 83% vs. 49% and PFS rates of 54% vs. 20%, respectively. When analyzing ATAb levels over time, patients with a persistent ATAb level above the median had a higher OS (HR = 0.41 [0.19-0.89], p  = 0.025) and PFS (HR = 0.54 [0.31-0.95], p  = 0.032) compared with patients with a persistent ATAb level below the median. Patients whose ATAb levels increased above the median during treatment had an improved OS (HR = 0.27 [0.06-1.22], p  = 0.088) and PFS (HR = 0.24 [0.07-0.77], p  = 0.017) compared with patients whose ATAb levels decreased below the median. Conclusions: Acquired overt thyroid toxicity and above median ATAb levels during anti-PD-1 treatment are associated with improved PFS and OS. In addition, our results suggest that ATAb levels at baseline are of clinical relevance for PFS and OS.

Cisplatin is a chemotherapeutic agent widely used for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin, dose-limiting acute kidney injury (AKI) occurs. Here, we assessed the association of 3 catechol-O-methyltransferase ( COMT) single nucleotide polymorphisms (SNPs) with increased cisplatin-induced nephrotoxicity. In total, 551 patients were genotyped for the 1947 G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316), and c.616 - 367 C>T (rs9332377) polymorphisms. Associations between these variants and AKI grade ≥3 were studied. The presence of a homozygous variant of c.616-367C>T was associated with a decreased occurrence of AKI grade 3 toxicity ( p = 0.014, odds ratio (OR) 0.201, 95% confidence interval (CI) (0.047-0.861)). However, we could not exclude the role of dehydration as a potential cause of AKI in 25 of the 27 patients with AKI grade 3, which potentially affected the results substantially. As a result of the low incidence of AKI grade 3 in this dataset, the lack of patients with a COMT variant, and the high number of patients with dehydration, the association between COMT variants and AKI does not seem clinically relevant.

Purpose: Oral bioavailability of docetaxel is poor. Absorption could be improved by development of pharmaceutical formulations based on docetaxel solid dispersions, denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg) and coadministration of ritonavir, an inhibitor of CYP3A4 and P-glycoprotein. In this study, the safety, MTD, recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of oral docetaxel combined with ritonavir in a once-weekly continuous schedule was investigated., Patients and Methods: Patients with metastatic solid tumors were included. Dose escalation was performed using a classical 3+3 design. Pharmacokinetic sampling was performed for up to 48 hours after drug administration. Safety was evaluated using CTCAE v3.0. Antitumor activity was assessed according to RECIST v1.0., Results: Sixty-seven patients were treated at weekly docetaxel dosages ranging from 30 to 80 mg in combination with 100- or 200-mg ritonavir. Most common toxicities were nausea, vomiting, diarrhea and fatigue, mostly of grade 1-2 severity. No hypersensitivity reactions were observed. The area under the plasma concentration-time curve (AUC 0-48 ) of docetaxel at the RP2D of once-weekly 60-mg ModraDoc001 capsule with 100-mg ritonavir was 1,000 ± 687 ng/mL/hour and for once-weekly 60-mg ModraDoc006 tablet with 100-mg ritonavir, the AUC 0-48 was 1,790 ± 819 ng/mL/hour. Nine partial responses were reported as best response to treatment., Conclusions: Oral administration of once-weekly docetaxel as ModraDoc001 capsule or ModraDoc006 tablet in combination with ritonavir is feasible. The RP2D for both formulations is 60-mg ModraDoc with 100-mg ritonavir. Antitumor activity is considered promising., (©2019 American Association for Cancer Research.)

An LC-MS/MS method was developed and validated to quantify the tyrosine kinase inhibitor erlotinib in human scalp hair, as alternative matrix to monitor long-term erlotinib exposure. Hair samples from 10 lung cancer patients were measured and correlated with plasma concentrations. Hair segments of 1 ± 0.1 cm each were pulverized and for at least 18 h incubated in methanol at ambient temperature. A liquid-liquid extraction purified the extracts and they were analyzed with LC-MS/MS, using erlotinib-d6 as internal standard. The procedure method was validated for selectivity, sensitivity, precision, lower limit of detection, linearity and accuracy. The within and between run precisions including the lower limit of quantification did not exceed 12.5%, while the accuracy ranged from 103 to 106%. A weak correlation between hair and plasma concentration was found (R 2  = 0.48). Furthermore, a large inter-individual variability was noted in the disposition of both plasma and hair samples. The highest hair concentrations were observed in black hair compared with other (grey and brown) hair colors. Generally, a linear reduction in hair concentration was found from proximal to distal hair segments. Additional in vitro experiments suggest an accelerated degradation of erlotinib in hair by artificial UV light and also wash-out by shampoo mixtures pretreatment compared with control samples. In conclusion, a reliable and robust LC-MS/MS method was developed to quantify erlotinib in hair. However, clinical and in vitro evaluations showed that the method is not suitable for monitoring long-term erlotinib exposure. The pitfalls of this application outweigh the current benefits., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The development and full validation of a sensitive and selective ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method are described for the simultaneous analysis of afatinib, alectinib, crizotinib and osimertinib in human lithium heparinized plasma. Afatinib-d6, crizotinib-d5 and erlotinib-d6 were used as internal standards. Given osimertinib's instability in plasma and whole blood at ambient temperature, samples should be solely processed on ice (T = 0 °C). Chromatographic separation was obtained on an Acquity UPLC ® BEH C18; 2.1 × 50 mm, 1.7 μm column, which was eluted with 0.400 mL/minute flow on a linear gradient, consisting of 10 mM ammonium formate (pH 4.5) and acetonitrile. Calibration curves for all compounds were linear for concentration ranges of 1.00 to 100 ng/mL for afatinib and 10.0 to 1000 ng/mL for alectinib, crizotinib and osimertinib, herewith validating the lower limits of quantification at 1.00 ng/mL for afatinib and 10.0 ng/mL for alectinib, crizotinib and osimertinib. Within-run and between-run precision measurements fell within 10.2%, with accuracy ranging from 89.2 to 110%., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Nivolumab treatment is subject to large interpatient variability in both efficacy and toxicity, which may partly be explained by differences in nivolumab exposure. Exposure-response relationships in regular healthcare have not been extensively investigated for nivolumab. Therefore, we aimed to identify possible exposure-response relationships in nivolumab-treated patients with non-small-cell lung cancer (NSCLC)., Methods: Patients with NSCLC who started second-line nivolumab therapy (3 mg/kg Q2W) between May 5th 2016 and August 1st 2017, and from whom serial blood samples, toxicity data and outcome data were prospectively collected, were included. Follow-up was carried out until November 1st 2017. Patients were classified according to the best overall response (BOR) based on the Response Evaluation Criteria in Solid Tumours, v1.1, and toxicities according to the Common Terminology Criteria for Adverse Events. Nivolumab trough concentrations were measured after 2, 4 and 10 weeks of treatment, excluding dose delays, and calculated geometric means were tested versus BOR or toxicity using analysis of variance and an independent samples t-test, respectively. Overall survival (OS) and progression-free survival were compared between high and low trough concentration groups., Results: Seventy-six patients were evaluable for analyses. Responders (n = 15) had higher mean trough concentrations than patients with progression (n = 33): 47% higher after 2 weeks (p = 0.001), 53% higher after 4 weeks (p = 0.008) and 73% higher after 10 weeks (p = 0.002). Higher trough concentrations were associated with longer OS (p = 0.001)., Conclusions: This study shows that patients with NSCLC with a response to nivolumab had a higher nivolumab exposure than patients with progression, indicating a potential exposure-response relationship. Further clinical research should focus on clarifying these exposure-response relationships., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Limited available data suggest that older patients are more prone to develop paclitaxel-induced toxicity than their younger peers. It remains unclear whether this is related to age-dependent pharmacokinetics (PK) of paclitaxel. Primary objective of this study was to determine the influence of older age on the PK of paclitaxel., Methods: PK data of patients aged ≥70 years who received paclitaxel intravenously at the Netherlands Cancer Institute (NKI) and the Radboud University Medical Center between September 2012 and May 2017 were collected. These prospectively collected data were pooled with previously published databases from multiple clinical trials conducted at the NKI and Erasmus MC Cancer Institute. A previously developed 3-compartment population PK model with saturable distribution and elimination was used to describe paclitaxel plasma concentration-time data. Hereafter, influence of age on paclitaxel PK was assessed in a previously established full covariate model., Results: In total, paclitaxel PK data from 684 patients were available, consisting of 166 patients ≥70 years (24%). Median age of the cohort was 61 years (range 18 to 84 years). The impact of age, either treated as a continuous or dichotomous covariate (<70 versus ≥70 years), on the elimination of paclitaxel was only marginal but statistically significant (both p < 0.001 with no clinically relevant decrease in interindividual variability). For a typical patient, maximal elimination capacity decreased by only 5% for a 10-year increment of age., Conclusion: In this extensive multi-center dataset, which included a considerable number of older patients, older age had no clinically relevant impact on paclitaxel PK.

The aim of this study was to develop an assay for the quantification of hydromorphone, morphine, fentanyl and the metabolites norfentanyl, morphine-3ß-glucuronide and morphine-6ß-glucuronide in human plasma to support pharmacokinetic studies investigating the large interpatient variability in response to opioid treatment. For the quantitation of hydromorphone, morphine, fentanyl and its metabolite norfentanyl aliquots of 200μL human potassium EDTA plasma were deproteinized with deuterated internal standards in a mixture of acetonitrile and acetone, followed by a liquid-liquid extraction with 4% ammonium hydroxide and ethyl acetate. Morphine-3ß-glucuronide and morphine-6ß-glucuronide were extracted by a solid phase extraction using 10mM ammonium carbonate pH 8.8 and a deuterated internal standards solution. Morphine, hydromorphone, fentanyl and norfentanyl were separated on an Aquity UPLC ® BEH C18 column 1.7μm, 100mm×2.1mm at 50°C. Separation, was achieved on a gradient of methanol with an overall run time of 6min. The compounds were quantified by triple-quadrupole mass spectrometry in the positive ion electrospray ionization mode. Morphine-3ß-glucuronide and morphine-6ß-glucuronide were separated on a VisionHT C18-P; 3μm 2.1×50mm, column at 40°C on a gradient of acetonitrile, with an overall run time of 10min. Both methods were precise and accurate, with within-run and between-run precisions within acceptable limits and accuracy ranging from 84.0 to 105.5%. The methods were successfully applied to support clinical pharmacological studies in patients treated with opioids for the treatment of moderate to severe cancer-related pain., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Previously, we demonstrated that oral docetaxel plus the P-glycoprotein (Pgp; ABCB1) inhibitor cyclosporin A (CsA) is safe and results in adequate exposure to docetaxel. This phase II study evaluates the anti-tumor activity, safety and pharmacokinetics of oral docetaxel in combination with CsA in women with advanced breast cancer., Materials and Methods: Patients with measurable advanced breast cancer were given one flat dose of 100 mg oral docetaxel, preceded by one single dose of 15 mg/kg CsA, weekly for 6 weeks in a cycle of 8 weeks. Pharmacokinetic monitoring of docetaxel and CsA was performed in week 1 and 9., Results: Thirty-three patients with a median age of 50 years were recruited. Thirty patients were evaluable for toxicity and twenty-six for response. All had received prior anthracycline treatment. The treatment was generally well tolerated with manageable toxicity although many patients needed a dose reduction, most commonly because of fatigue and uncomplicated neutropenia. The median treatment duration was 16 weeks (range 6 - 32). The overall response rate in evaluable patients was 42% (95% CI: 23 - 63) and the median overall survival was 12.2 months (8.4 - 23.1). The interpatient variability in the area under the curve of 100 mg orally administered docetaxel was moderate, respectively 49 and 30% in week 1 and 9., Conclusion: Weekly oral docetaxel, combined with the booster drug CsA, is an active and safe treatment in anthracycline pre-treated patients with advanced breast cancer.

Background/aims: Usually, the appropriate dosage of low-molecular-weight heparin during haemodialysis is empirically based on the clinical effect. We studied the pharmacokinetics of dalteparin during standard haemodialysis in different groups of patients to assess the added value of measuring the anti-Xa activity for dose monitoring and adjustments., Methods: The pharmacokinetics of intravenously administered dalteparin during haemodialysis was studied in 9 patients during 27 haemodialysis sessions. Six patients received a single bolus dose of dalteparin (group 1), and 3 patients received a higher initial bolus dose of dalteparin followed by a second bolus dose after 2 h (group 2). The clinical effect was evaluated by visual inspection for clot formation in the extracorporeal circuit., Results: The pharmacokinetic curve suggests a zero-order process of elimination. The mean decrease in anti-Xa activity (slope) was comparable in all patients. The mean anti-Xa activity at the end of haemodialysis (Clast) was 0.15 IU/ml in group 1 and 0.60 IU/ml in group 2., Conclusion: We conclude that measuring anti-Xa activity can be used to monitor the elimination of dalteparin during haemodialysis and is highly reproducible., (© 2013 S. Karger AG, Basel.)

Purpose: LY2334737 is an orally available prodrug of gemcitabine. The objective of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of daily administration of LY2334737 with or without erlotinib., Experimental Design: Patients with advanced or metastatic cancer were treated with escalating doses of LY2334737 monotherapy or in combination with continuous daily administration of 100 mg erlotinib. LY2334737 was given once daily for 14 days of a 21-day cycle. The study was extended with a bioequivalence trial to investigate a novel LY2334737 drug formulation., Results: A total of 65 patients were treated in this study. The MTD was 40 mg LY2334737. Fatigue was the most frequent DLT for LY2334737 monotherapy (4 patients) followed by elevated transaminase levels (2 patients), both observed at the 40- to 50-mg dose levels. Among the 10 patients in the combination arm, 2 had DLTs at the 40-mg dose level. These were fatigue and elevated liver enzyme levels. The most common adverse events were fatigue (n = 38), nausea (n = 27), vomiting (n = 24), diarrhea (n = 23), anorexia (n = 20), pyrexia (n = 18), and elevated transaminase levels (n = 14). The pharmacokinetics showed dose proportional increase in LY2334737 and gemcitabine exposure. The metabolite 2',2'-difluorodeoxyuridine accumulated with an accumulation index of 4.3 (coefficient of variation: 20%). In one patient, complete response in prostate-specific antigen was observed for 4 cycles, and stable disease was achieved in 22 patients overall. Pharmacokinetic analysis showed that the 2 investigated LY2334737 drug formulations were bioequivalent., Conclusions: LY2334737 displays linear pharmacokinetics and the MTD is 40 mg with or without daily administration of 100 mg erlotinib. Signs of antitumor activity warrant further development., (©2011 AACR)

Case: A patient with complete renal failure as a result of urothelial cell carcinoma-related nephrectomy of both kidneys received palliative chemotherapy with carboplatin and gemcitabine., Treatment: The patient received gemcitabine at 1,000 mg/m(2) followed by carboplatin at 100 mg. Shortly after, he underwent hemodialysis. The pharmacokinetics of gemcitabine and metabolites in plasma and in peripheral blood mononuclear cells were monitored., Results: Double-sided nephrectomy and hemodialysis had no influence on gemcitabine pharmacokinetics; however, a high exposure was seen for the main metabolite, difluordeoxyuridine (dFdU) (area under the concentration-time curve, 0-51 hours, 844 microg/ml.hour). During hemodialysis, plasma concentrations of dFdU were reduced by 50%. High concentrations of intracellular phosphorylated metabolites (gemcitabine triphosphate and dFdU triphosphate) were observed: 228 pmol/10(6) cells and 47 pmol/10(6) cells, respectively. The patient tolerated the regimen poorly; adverse events included grade 4 thrombocytopenia., Conclusion: Hemodialysis effectively reduced plasma concentrations of dFdU. Furthermore, high concentrations of intracellular phosphorylated metabolites may be related to double-sided nephrectomy, resulting in poor tolerability of gemcitabine.