Publications by authors named "Jos H Beijnen"

765 Publications

ABCB1 and ABCG2 restrict brain and testis accumulation and, alongside CYP3A, limit oral availability of the novel TRK inhibitor selitrectinib.

Mol Cancer Ther 2021 Mar 30. Epub 2021 Mar 30.

Division of Pharmacology, The Netherlands Cancer Institute

Selitrectinib (BAY2731954; LOXO-195) is a promising oral tropomyosin receptor kinase (TRK) inhibitor currently in Phase I/II clinical trials for treatment of histology-agnostic cancers positive for TRK fusions. With therapeutic resistance eventually developing with first-generation TRK inhibitors, selitrectinib was designed to overcome resistance mediated by acquired kinase domain mutations. Using genetically modified mouse models and pharmacological inhibitors, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing CYP3A enzyme complex in selitrectinib pharmacokinetics. In vitro, selitrectinib was markedly transported by mouse Abcg2 and human ABCB1, and modestly by human ABCG2. Following oral administration at 10 mg/kg, selitrectinib brain-to-plasma ratios were increased in Abcb1a/1b-/- (2-fold) and Abcb1a/1b;Abcg2-/- (5.8-fold) compared to wild-type mice, but not in single Abcg2-/- mice. Testis distribution showed similar results. mAbcb1a/1b and mAbcg2 each restricted the plasma exposure of selitrectinib: with both systems absent oral availability increased by 1.7-fold. Oral administration of the ABCB1/ABCG2 inhibitor elacridar boosted plasma exposure and brain accumulation in wild-type mice to the same levels as seen in Abcb1a/1b;Abcg2-/- mice. In Cyp3a-/- mice, selitrectinib plasma AUC0-4h was increased by 1.4-fold, and subsequently reduced by 2.3-fold upon transgenic overexpression of human CYP3A4 in liver and intestine. The relative tissue distribution of selitrectinib remained unaltered. Thus, selitrectinib brain accumulation and oral availability are substantially restricted by ABCB1 and ABCG2, and this can be reversed by pharmacological inhibition. Moreover, oral availability of selitrectinib is limited by CYP3A activity. These insights may be useful to optimize the clinical application of selitrectinib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-20-0705DOI Listing
March 2021

Development and validation of a combined liquid chromatography tandem-mass spectrometry assay for the quantification of aprepitant and dexamethasone in human plasma to support pharmacokinetic studies in pediatric patients.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Mar 9;1171:122639. Epub 2021 Mar 9.

Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.

A pharmacokinetic study was set up to investigate the pharmacokinetics of the anti-emetic agents aprepitant and dexamethasone and the drug-drug interaction between these drugs in children. In order to quantify aprepitant and dexamethasone, a liquid chromatography-tandem mass spectrometry assay was developed and validated for the simultaneous analysis of aprepitant and dexamethasone. Protein precipitation with acetonitrile-methanol (1:1, v/v) was used to extract the analytes from plasma. The assay was based on reversed-phase chromatography coupled with tandem mass spectrometry detection operating in the positive ion mode. The assay was validated based on the guidelines on bioanalytical methods by the US Food and Drug Administration and European Medicines Agency. The calibration model was linear and a weighting factor of 1/concentration was used over the range of 0.1-50 ng/mL for aprepitant and 1-500 ng/mL for dexamethasone. Intra-assay and inter-assay bias were within ±20% for all analytes at the lower limit of quantification and within ±15% at remaining concentrations. Dilution integrity tests showed that samples exceeding the upper limit of quantification can be diluted 100 times in control matrix. Stability experiments showed that the compounds are stable in the biomatrix for 25 h at room temperatures and 89 days at -20 °C. This assay is considered suitable for pharmacokinetic studies and will be used to study the drug-drug interaction between aprepitant and dexamethasone in pediatric patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchromb.2021.122639DOI Listing
March 2021

Pharmacokinetics of docetaxel and ritonavir after oral administration of ModraDoc006/r in patients with prostate cancer versus patients with other advanced solid tumours.

Cancer Chemother Pharmacol 2021 Mar 20. Epub 2021 Mar 20.

Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands.

Purpose: ModraDoc006 is a novel oral formulation of docetaxel. The clearance of intravenous docetaxel is higher in medically castrated prostate cancer patients as compared to patients with other types of solid tumours. Oral docetaxel requires co-administration ritonavir (r), which might further impact the pharmacokinetics (PK). We now compare the PK of docetaxel and ritonavir between patients with Hormone Sensitive Prostate Cancer (HSPC), metastatic Castration-Resistant Prostate Cancer (mCRPC) and other metastatic solid tumours, treated on the same dose and weekly schedule of ModraDoc006/r.

Methods: The docetaxel and ritonavir PK were compared between four patient groups from three clinical phase I trials, including eight male and eight female patients with different types of solid tumours (study 1), seven patients with HSPC (study 2) and five patients with mCRPC (study 3). All patients were treated with ModraDoc006 30 mg and ritonavir 100 mg in the morning, followed by ModraDoc006 20 mg and ritonavir 100 mg in the evening (ModraDoc006/r 30-20/100-100). For comparative purposes, the PK of six mCRPC patients that received 30-20/200-100 in study 3 were also evaluated.

Results: The maximum plasma concentration (C) was significantly lower for both docetaxel and ritonavir in the prostate cancer patients as compared to the patients with other types of solid tumours treated at ModraDoc006/r 30-20/100-100. The docetaxel area under the plasma concentration versus time curve (AUC) was significantly different at this dose, with a mean AUC of 1359 ± 374 ng/mL*h (N = 8) in female patients and 894 ± 223 ng/mL*h (N = 8) in male patients with different solid tumours (study 1), 321 ± 81 (N = 7) in HSPC (study 2) and 367 ± 182 ng/mL*h (N = 5) in mCRPC (study 3). A similar pattern was observed for ritonavir. ModraDoc006/r 30-20/200-100 in six mCRPC patients led to a comparable ritonavir exposure as compared to the patients at 30-20/100-100 in study 1 and increased the docetaxel AUC to 1266 ± 473 ng/mL*h (N = 6).

Conclusion: The exposure to docetaxel and ritonavir was significantly lower in prostate cancer patients as compared to patients with other types of solid tumours, treated on ModraDoc006/r 30-20/100-100. An increase of the ritonavir dose increased the docetaxel exposure in mCRPC patients. Therefore, a different RP2D of ModraDoc006/r is pursued in castrated prostate cancer patients as compared to patients with other types of solid tumours.

Trial Registration: Study 1: ClinicalTrials.gov Identifier NCT01173913, date of registration August 2, 2010. Study 2: ClinicalTrials.gov Identifier NCT03066154, date of registration February 28, 2017. Study 3: ClinicalTrials.gov Identifier NCT03136640, date of registration May 2, 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-021-04259-5DOI Listing
March 2021

Transtympanic Sodium Thiosulfate for Prevention of Cisplatin-Induced Ototoxicity: A Randomized Clinical Trial.

Otol Neurotol 2021 Mar 5. Epub 2021 Mar 5.

Department of Head and Neck Surgery and Oncology, the Netherlands Cancer Institute, Amsterdam Department of Otolaryngology, Leiden University Medical Centre, Leiden Division of Clinical Pharmacology Division of Pharmacology, the Netherlands Cancer Institute, Amsterdam Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar Department of Audiology, Amsterdam University Medical Centre Department of Pharmacy and Pharmacology Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands Institute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany Department of Maxillofacial Surgery, Amsterdam University Medical Centre Department of Medical Oncology Department of Thoracic Oncology, the Netherlands Cancer Institute, Amsterdam Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht Cell Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Objectives: To determine safety, feasibility, and preliminary activity of transtympanic injection of sodium thiosulfate (STS) against cisplatin-induced hearing loss (CIHL).DESIGN Randomized controlled trial.SETTING Tertiary cancer hospital.PATIENTS Adults to be treated with high-dose cisplatin (≥ 75 mg/m2).INTERVENTION Selected by randomization, 0.1 M STS gel on one side and placebo gel on the other side was transtympanically applied to the middle ear 3 hours before cisplatin administration. After amendment, the placebo ear was left untreated.

Main Outcome Measure: Primary outcome was safety and feasibility. Secondary outcomes included pharmacokinetic analysis of systemic cisplatin and preliminary activity of STS. Clinically relevant CIHL was defined as a ≥ 10 dB threshold shift at pure-tone average 8-10-12.5 kHz (PTA8-12.5). Response to STS was defined as a threshold shift at PTA8-12.5 in the STS-treated ear of ≥ 10 dB smaller than the untreated ear.

Results: Twelve patients were treated. Average CIHL at PTA8-12.5 was 12.7 dB in untreated ears and 8.8 dB SPL in STS-treated ears (p = 0.403). Four patients did not develop CIHL. Four out of eight patients with CIHL responded to STS: CIHL at PTA8-12.5 in STS-treated ears was 18.4 dB less compared to untreated ears (p = 0.068). Grade 1 adverse events were reported. Pharmacokinetic results were available for 11 patients.

Conclusion: Transtympanic application of STS was safe and feasible. Based on our pharmacokinetic analysis, we postulate that transtympanic STS does not interfere with the systemically available cisplatin. Our results provide a preliminary proof of concept for transtympanic application of STS in preventing CIHL and warrants further evaluation on a larger scale.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MAO.0000000000003069DOI Listing
March 2021

ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients: A phase Ib study.

Cancer Rep (Hoboken) 2021 Mar 12:e1367. Epub 2021 Mar 12.

Department of Medical Oncology and Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: ModraDoc006 is an oral formulation of docetaxel, which is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration-resistant prostate cancer (mCRPC).

Aim: We assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC.

Methods: mCRPC patients, treatment naïve or following abiraterone or enzalutamide treatment, were included. Dose-escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate-specific antigen (PSA) and radiological evaluation.

Results: Cohort 1 (n = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/100-100). The mean docetaxel area under the plasma concentration-time curve (mAUC0-inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (n = 6, ModraDoc006/r 30-20/200-200), the mAUC0-inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (n = 6, ModraDoc006/r 30-20/200-100), the mAUC0-inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B (n = 3, ModraDoc006/r 20-20/200-100), the mAUC0-inf was 558 ng/mL × h without DLTs. The mAUC0-inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of >50% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed.

Conclusion: The RP2D was established at weekly ModraDoc006/r 30-20/200-100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3-weekly IV docetaxel in patients with mCRPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cnr2.1367DOI Listing
March 2021

Low antileishmanial drug exposure in HIV-positive visceral leishmaniasis patients on antiretrovirals: an Ethiopian cohort study.

J Antimicrob Chemother 2020 Mar 2. Epub 2020 Mar 2.

Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Despite high HIV co-infection prevalence in Ethiopian visceral leishmaniasis (VL) patients, the adequacy of antileishmanial drug exposure in this population and effect of HIV-VL co-morbidity on pharmacokinetics of antileishmanial and antiretroviral (ARV) drugs is still unknown.

Methods: HIV-VL co-infected patients received the recommended liposomal amphotericin B (LAmB) monotherapy (total dose 40 mg/kg over 24 days) or combination therapy of LAmB (total dose 30 mg/kg over 11 days) plus 28 days 100 mg/day miltefosine, with possibility to extend treatment for another cycle. Miltefosine, total amphotericin B and ARV concentrations were determined in dried blood spots or plasma using LC-MS/MS.

Results: Median (IQR) amphotericin B Cmax on Day 1 was 24.6 μg/mL (17.0-34.9 μg/mL), which increased to 40.9 (25.4-53.1) and 33.2 (29.0-46.6) μg/mL on the last day of combination and monotherapy, respectively. Day 28 miltefosine concentration was 18.7 (15.4-22.5) μg/mL. Miltefosine exposure correlated with amphotericin B accumulation. ARV concentrations were generally stable during antileishmanial treatment, although efavirenz Cmin was below the 1 μg/mL therapeutic target for many patients.

Conclusions: This study demonstrates that antileishmanial drug exposure was low in this cohort of HIV co-infected VL patients. Amphotericin B Cmax was 2-fold lower than previously observed in non-VL patients. Miltefosine exposure in HIV-VL co-infected patients was 35% lower compared with adult VL patients in Eastern Africa, only partially explained by a 19% lower dose, possibly warranting a dose adjustment. Adequate drug exposure in these HIV-VL co-infected patients is especially important given the high proportion of relapses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jac/dkab013DOI Listing
March 2020

Investigating the influence of relevant pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of orally administered docetaxel combined with ritonavir.

Pharmacogenomics J 2021 Mar 1. Epub 2021 Mar 1.

Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.

The anticancer drug docetaxel exhibits large interpatient pharmacokinetic and pharmacodynamic variability. In this study, we aimed to assess the functional significance of 14 polymorphisms in the CYP3A, CYP1B1, ABCB1, ABCC2, and SLCO1B3 genes for the pharmacokinetics and pharmacodynamics of oral docetaxel, co-administered with ritonavir. None of the tested CYP3A, ABCB1, ABCC2, and SLCO1B3 genotypes and diplotypes showed a significant relation with an altered bioavailability or clearance of either docetaxel or ritonavir. Similarly, no clear effect of CYP1B1 genotype on clinical outcomes was observed in a subgroup of non-small cell lung cancer (NSCLC) patients. Our post hoc power analysis indicated that our pharmacogenetic-pharmacokinetic analysis was only powered for relatively high effect sizes, which were to be expected given the high interpatient variability. This makes it unlikely that future studies will explain the high observed interpatient variability in oral docetaxel pharmacokinetics as a result of any of these separate polymorphisms and diplotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41397-021-00213-zDOI Listing
March 2021

Diagnostic yield of colonoscopy surveillance in testicular cancer survivors treated with platinum-based chemotherapy: study protocol of a prospective cross-sectional cohort study.

BMC Gastroenterol 2021 Feb 12;21(1):67. Epub 2021 Feb 12.

Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Background: Testicular cancer (TC) survivors have an increased risk of various second primary malignancies. A recent cohort study detected an increased risk of colorectal cancer (CRC) in TC survivors treated with platinum-based chemotherapy with a hazard ratio of 3.9. CRC risk increased with higher cisplatin-dose. We know that colonoscopy surveillance in high-risk populations results in reduced incidence and mortality of CRC. TC survivors treated with platinum-based chemotherapy can potentially benefit from colonoscopy surveillance; however, to which extent is unknown. Furthermore, the pathogenesis of these secondary CRCs is unknown, and better insights into the carcinogenesis may affect surveillance decisions.

Methods: This prospective multicenter study will be performed in four Dutch hospitals. TC survivors are eligible if treated with ≥ 3 cycles of cisplatin before age 50. Colonoscopy will be performed ≥ 8 years after initial treatment (minimum and maximum ages at colonoscopy, 35 and 75 years, respectively). The primary aim of the study is the diagnostic yield of advanced neoplasia detected during colonoscopy. As secondary aim, we will evaluate the molecular profile of advanced colorectal neoplasia and will assess current platinum levels in blood and urine and correlate blood-platinum levels with prevalence of colorectal lesions. Furthermore, we will investigate effectiveness of fecal immunochemical testing (FIT) and burden of colonoscopy by two questionnaires. Demographic data, previous history, results of colonoscopy, hemoglobin level of FIT and results of molecular and platinum levels will be obtained. Yield of colonoscopy will be determined by detection rate of adenoma and serrated lesions, advanced adenoma detection rate and CRC detection rate. The MISCAN model will be used for cost-effectiveness analyses of CRC surveillance. With 234 participants undergoing colonoscopy, we can detect an absolute difference of 6% of advanced neoplasia with 80% power.

Discussion: TC survivors treated with cisplatin-based chemotherapy can benefit from CRC surveillance. Evaluation of the diagnostic performance and patient acceptance of CRC surveillance is of importance to develop surveillance recommendations. Insight into the carcinogenesis of cisplatin-related advanced colorectal lesions will contribute to CRC prevention in the increasing number of TC survivors. The results may also be important for the many other cancer survivors treated with platinum-based chemotherapy.

Trial Registration: Clinical Trials: NCT04180033, November 27, 2019, https://clinicaltrials.gov/ct2/show/NCT04180033 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12876-021-01639-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881638PMC
February 2021

Bioanalysis of erlotinib, its O-demethylated metabolites OSI-413 and OSI-420, and other metabolites by liquid chromatography-tandem mass spectrometry with additional ion mobility identification.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Mar 18;1166:122554. Epub 2021 Jan 18.

Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands. Electronic address:

Erlotinib is a first-generation epithelial growth factor receptor inhibitor used in the treatment of non-small cellular lung cancers. Our previously published method on a Thermo TSQ Quantum Ultra triple quadrupole mass spectrometer for the quantitation of erlotinib, OSI-420, and OSI-413 and some other kinase inhibitors was transferred to a more sensitive Sciex QTRAP5500 system. Both methods showed comparable performance in the previous range (5-5000 and 1-1000 ng/mL for erlotinib and OSI-420) with comparable accuracies and precisions (98.9-106.2 vs 98.7.0-104.0, and 3.7-13.4 vs 4.6-13.2), and a high level of agreement between the methods (R = 0.9984 and 0.9951) for the quality control samples. The new system however was also capable of quantifying lower concentrations of both erlotinib and OSI-420 (0.5 and 0.1 ng/mL) with sufficient accuracy and precision. Along with the increased sensitivity we included the semi-quantitative determination of additional erlotinib metabolites M2, M3, M5, M6, M7, M8, M9, M10, M11, M12, M16 (hydroxy-erlotinib), M17, M18, M19, M20, M21 in a 0.1-1000 ng/mL range to the method. With a simple crash, dilute, and shoot sample preparation with acetonitrile and a 4.5 min analytical run time the method outperformed most other published methods in speed and simplicity and was suitable for TDM. Further, enhancement of the understanding of the pharmacokinetics of erlotinib and its metabolites was demonstrated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchromb.2021.122554DOI Listing
March 2021

A Phase I dose-escalation study of two cycles carboplatin-olaparib followed by olaparib monotherapy in patients with advanced cancer.

Int J Cancer 2021 Feb 4. Epub 2021 Feb 4.

Department of Molecular Pathology, Antoni van Leeuwenhoek Hospital - Netherlands Cancer Institute, Amsterdam, The Netherlands.

Preclinical studies have shown synergistic effects when combining PARP1/2 inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. After a formulation change of olaparib from capsules to tablets, we initiated a dose finding study of olaparib tablets bidaily (BID) continuously with carboplatin to prepare comparative studies in this patient group. Patients were included in a 3 + 3 dose-escalation schedule: olaparib 25 mg BID and carboplatin area under the curve (AUC) 3 mg*min/mL d1/d22, olaparib 25 mg BID and carboplatin AUC 4 mg*min/mL d1/d22, followed by increasing dose-levels of olaparib from 50 mg BID, 75 mg BID, to 100 mg BID with carboplatin at AUC 4 mg*min/mL d1/d22. After two cycles, patients continued olaparib 300 mg BID as monotherapy. Primary objective was to assess the maximum tolerable dose (MTD). Twenty-four patients with a confirmed diagnosis of advanced cancer were included. Most common adverse events were nausea (46%), fatigue (33%) and platelet count decrease (33%). Dose-level 3 (olaparib 75 mg BID and carboplatin AUC 4 mg*min/mL; n = 6) was defined as MTD. Fourteen out of 24 patients (56%) had a partial response as best response (RECIST 1.1). Systemic exposure of the olaparib tablet formulation appeared comparable to the previous capsule formulation with olaparib tablet AUC of 16.3 μg/mL*h at MTD. Polymers of ADP-ribose levels in peripheral blood mononuclear cells were reduced by 98.7% ± 0.14% at Day 8 compared to Day 1 for dose-level 3. Olaparib tablets 75 mg BID and carboplatin AUC 4 mg*min/mL for two cycles preceding olaparib monotherapy 300 mg is a feasible and tolerable treatment schedule for patients with advanced cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33498DOI Listing
February 2021

The role of drug efflux and uptake transporters ABCB1 (P-gp), ABCG2 (BCRP) and OATP1A/1B and of CYP3A4 in the pharmacokinetics of the CDK inhibitor milciclib.

Eur J Pharm Sci 2021 Apr 30;159:105740. Epub 2021 Jan 30.

Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address:

The promising anticancer drug milciclib potently inhibits cyclin-dependent kinase (CDK) 2 and tropomyosin receptor kinase (TRK) A, and is currently in phase II clinical studies. To characterize factors affecting milciclib pharmacokinetics, we investigated whether milciclib is a substrate of the multidrug efflux and uptake transporters ABCB1 (P-gp), ABCG2 (BCRP), and OATP1A/1B, and the drug-metabolizing enzyme CYP3A, using genetically-modified mouse models and Madin-Darby Canine Kidney (MDCK-II) cells. In vitro, milciclib was transported by mAbcg2, and this was inhibited by the ABCG2 inhibitor Ko143. Upon oral administration of milciclib, its plasma exposure in Abcb1a/1b, Abcg2, and Abcb1a/1b;Abcg2 mice was similar to that found in wild-type mice. Milciclib showed good brain penetration even in wild-type mice (brain-to-plasma ratio of 1.2), but this was further increased by 5.2-fold when both Abcb1 and Abcg2 were ablated, and to a lesser extent in single Abcb1- or Abcg2-deficient mice. Oatp1a/1b deficiency had only a minor impact on the milciclib plasma AUC and C. The milciclib AUC increased 1.9-fold in Cyp3a mice but decreased only 1.3-fold upon overexpression of human CYP3A4. Thus, ABCB1 and ABCG2 cooperatively limit milciclib brain penetration. The low impact of OATP1 and CYP3A could be clinically favorable for milciclib, reducing the risks of unintended drug-drug interactions or interindividual variation in CYP3A4 activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2021.105740DOI Listing
April 2021

ATP-binding cassette transporters restrict drug delivery and efficacy against brain tumors even when blood-brain barrier integrity is lost.

Cell Rep Med 2021 Jan 19;2(1):100184. Epub 2021 Jan 19.

Division of Pharmacology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.

The impact of a compromised blood-brain barrier (BBB) on the drug treatment of intracranial tumors remains controversial. We characterize the BBB integrity in several intracranial tumor models using magnetic resonance imaging, distribution and efficacy of docetaxel in brain tumors grafted in Abcb1-proficient and Abcb1-deficient mice. Leakiness of the tumor vasculature varies from extensive to absent. Regardless of the extent of leakiness, tumor blood vessels express ATP-binding cassette transporters (Abcb1 and Abcg2). A leaky vasculature results in higher docetaxel tumor levels compared to normal brain. Nevertheless, Abcb1 can reduce drug distribution and efficacy even in leaky models. Thus, BBB leakiness does not ensure the unimpeded access of ATP-binding cassette transporter substrate drugs. Therapeutic responses may be observed, but the full potential of such therapeutics may still be attenuated. Consequently, BBB-penetrable drugs with little to no affinity for efflux transporters are preferred for the treatment of intracranial tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xcrm.2020.100184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817868PMC
January 2021

Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP).

Clin Pharmacokinet 2021 Jan 28. Epub 2021 Jan 28.

Department of Oncology, Catholic University of Leuven, Leuven, Belgium.

Background: Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy.

Objective: With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women.

Methods: PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates.

Results: Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients.

Conclusion: Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40262-020-00961-4DOI Listing
January 2021

Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours.

Drugs R D 2021 Mar 19;21(1):103-111. Epub 2021 Jan 19.

Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Introduction: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r.

Objectives: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir.

Methods: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03.

Results: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration-time curve (AUC), AUC and maximum concentration (C) were 1.11 (90% confidence interval [CI] 0.93-1.33), 1.19 (90% CI 1.00-1.41) and 1.07 (90% CI 0.81-1.42) in fed versus fasted conditions, respectively. For the ritonavir C, the GMR was 0.79 (90% CI 0.69-0.90), whereas the AUC and AUC were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity.

Conclusions: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir C. Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. CLINICALTRIALS.

Gov Identifier: NCT03147378, date of registration: May 10 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40268-020-00336-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937587PMC
March 2021

Cost-Effectiveness Assessment of Monitoring Abiraterone Levels in Metastatic Castration-Resistant Prostate Cancer Patients.

Value Health 2021 01 11;24(1):121-128. Epub 2020 Sep 11.

Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

Objectives: Abiraterone acetate is registered for the treatment of metastatic castration-sensitive and resistant prostate cancer (mCRPC). Treatment outcome is associated with plasma trough concentrations (C) of abiraterone. Patients with a plasma C below the target of 8.4 ng/mL may benefit from treatment optimization by dose increase or concomitant intake with food. This study aims to investigate the cost-effectiveness of monitoring abiraterone C in patients with mCRPC.

Methods: A Markov model was built with health states progression-free survival, progressed disease, and death. The benefits of monitoring abiraterone C followed by a dose increase or food intervention were modeled via a difference in the percentage of patients achieving adequate C taking a healthcare payer perspective. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainties and their impac to the incremental cost-effectiveness ratio (ICER).

Results: Monitoring abiraterone followed by a dose increase resulted in 0.149 incremental quality-adjusted life-years (QALYs) with €22 145 incremental costs and an ICER of €177 821/QALY. The food intervention assumed equal effects and estimated incremental costs of €7599, resulting in an ICER of €61 019/QALY. The likelihoods of therapeutic drug monitoring (TDM) with a dose increase or food intervention being cost-effective were 8.04%and 81.9%, respectively.

Conclusions: Monitoring abiraterone followed by a dose increase is not cost-effective in patients with mCRPC from a healthcare payer perspective. Monitoring in combination with a food intervention is likely to be cost-effective. This cost-effectiveness assessment may assist decision making in future integration of abiraterone TDM followed by a food intervention into standard abiraterone acetate treatment practices of mCRPC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jval.2020.04.1838DOI Listing
January 2021

Population Pharmacokinetics of Intracellular 5-Fluorouridine 5'-Triphosphate and its Relationship with Hand-and-Foot Syndrome in Patients Treated with Capecitabine.

AAPS J 2021 01 8;23(1):23. Epub 2021 Jan 8.

Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Capecitabine is an oral pro-drug of 5-fluorouracil. Patients with solid tumours who are treated with capecitabine may develop hand-and-foot syndrome (HFS) as side effect. This might be a result of accumulation of intracellular metabolites. We characterised the pharmacokinetics (PK) of 5-fluorouridine 5'-triphosphate (FUTP) in peripheral blood mononuclear cells (PBMCs) and assessed the relationship between exposure to capecitabine or its metabolites and the development of HFS. Plasma and intracellular capecitabine PK data and ordered categorical HFS data was available. A previously developed model describing the PK of capecitabine and metabolites was extended to describe the intracellular FUTP concentrations. Subsequently, a continuous-time Markov model was developed to describe the development of HFS during treatment with capecitabine. The influences of capecitabine and metabolite concentrations on the development of HFS were evaluated. The PK of intracellular FUTP was described by an one-compartment model with first-order elimination (k was 0.028 h (95% confidence interval 0.022-0.039)) where the FUTP influx rate was proportional to the 5-FU plasma concentrations. The predicted individual intracellular FUTP concentration was identified as a significant predictor for the development and severity of HFS. Simulations demonstrated a clear exposure-response relationship. The intracellular FUTP concentrations were successfully described and a significant relationship between these intracellular concentrations and the development and severity of HFS was identified. This model can be used to simulate future dosing regimens and thereby optimise treatment with capecitabine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1208/s12248-020-00533-1DOI Listing
January 2021

The intravenous to oral switch of taxanes: strategies and current clinical developments.

Future Oncol 2021 Apr 24;17(11):1379-1399. Epub 2020 Dec 24.

Department of Pharmacy & Pharmacology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands.

The taxanes paclitaxel, docetaxel and cabazitaxel are important anticancer agents that are widely used as intravenous treatment for several solid tumor types. Switching from intravenous to oral treatment can be more convenient for patients, improve cost-effectiveness and reduce the demands of chemotherapy treatment on hospital care. However, oral treatment with taxanes is challenging because of pharmaceutical and pharmacological factors that lead to low oral bioavailability. This review summarizes the current clinical developments in oral taxane treatment. Intravenous parent drugs, strategies in the oral switch, individual agents in clinical trials, challenges and further perspectives on treatment with oral taxanes are subsequently discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0876DOI Listing
April 2021

Chromatographic bioanalytical assays for targeted covalent kinase inhibitors and their metabolites.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jan 30;1162:122466. Epub 2020 Nov 30.

Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands. Electronic address:

Deriving from targeted kinase inhibitors (TKIs), targeted covalent kinase inhibitors (TCKIs) are a new class of TKIs that are covalently bound to their target residue of kinase receptors. Currently, there are many new TCKIs under clinical development besides afatinib, ibrutinib, osimertinib, neratinib, acalabrutinib, dacomitinib, and zanubrutinib that are already approved by the FDA. Subsequently, there is an increasing demand for bioanalytical methods to qualitatively and quantitively investigate those compounds, leading to a number of papers reporting the development, validation, and use of bioanalytical methods for TCKIs. Most publications describe the technological set up of analytical methods that allow quantification of TCKIs in various biomatrices such as plasma, cerebrospinal fluid, urine, tissue, and liver microsomes. In addition, the identification of metabolites and biotransformation pathways of new TCKIs has gained more interest in recent years. We provide an overview of bioanalytical methods of this new class of TCKIs. The included issues are sample pretreatment, chromatographic separation, detection, and method validation. In the scope of bioanalysis of TCKIs, protein precipitation is mostly applied to treat the biological matrices sample. Liquid chromatographic in reversed-phase mode (RPLC) and mass detection with triple quadrupole (QqQ) are the most often utilized separation and quantitative detection modes, respectively. There may be a possibility of increased use of the high-resolution mass spectrometry (HRMS) for qualitative investigation purposes in the future. We also found that US FDA and EMA guidelines are the most common guidelines employed as validation framework for the bioanalytical methods of TCKIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchromb.2020.122466DOI Listing
January 2021

Is Bodyweight-Based Dosing Truly Better Than Flat Dosing for Panitumumab? [Letter].

Clin Pharmacol 2020 30;12:177-178. Epub 2020 Oct 30.

Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/CPAA.S282866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610198PMC
October 2020

Toxicological analysis of azide and cyanide for azide intoxications using gas chromatography.

Basic Clin Pharmacol Toxicol 2021 Mar 3;128(3):534-541. Epub 2020 Nov 3.

Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Azide is a highly toxic chemical agent to human being. Accidental, but also intentional exposure to azide occurs. To be able to confirm azide ingestion, we developed a method to identify and quantify azide in biological matrices. Cyanide was included in the method to evaluate suggested in vivo production of cyanide after azide ingestion. Azide in biological matrices was first derivatized by propionic anhydride to form propionyl azide. Simultaneously, cyanide was converted into hydrogen cyanide. After thermal rearrangement of propionyl azide, ethyl isocyanate was formed, separated together with hydrogen cyanide by gas chromatography (GC) and detected using a nitrogen phosphorous detector (NPD). The method was linear from 1.0-100 µg/mL for both analytes, and azide was stable in human plasma at -20°C for at least 49 days. Azide was measured in the gastric content of two cases of suspected azide ingestion (case 1:1.2 mg/mL, case 2:1.5 mg/mL). Cyanide was only identified in the gastric content of case 1 (approximately 1.4 µg/mL). Furthermore, azide was quantified in plasma (19 µg/mL), serum (24 µg/mL), cell pellet (21 µg/mL) and urine (3.0 µg/mL) of case 2. This method can be used to confirm azide and cyanide exposure, and azide concentrations can be quantified in several biological matrices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcpt.13523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984282PMC
March 2021

Intracellular Pharmacokinetics of Pyrimidine Analogues used in Oncology and the Correlation with Drug Action.

Clin Pharmacokinet 2020 12;59(12):1521-1550

Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital-The Netherlands Cancer Institute, Louwesweg 6, 1066 EC , Amsterdam, The Netherlands.

Pyrimidine analogues can be considered as prodrugs, like their natural counterparts, they have to be activated within the cell. The intracellular activation involves several metabolic steps including sequential phosphorylation to its monophosphate, diphosphate and triphosphate. The intracellularly formed nucleotides are responsible for the pharmacological effects. This review provides a comprehensive overview of the clinical studies that measured the intracellular nucleotide concentrations of pyrimidine analogues in patients with cancer. The objective was to gain more insight into the parallels between the different pyrimidine analogues considering their intracellular pharmacokinetics. For cytarabine and gemcitabine, the intracellular pharmacokinetics have been extensively studied over the years. However, for 5-fluorouracil, capecitabine, azacitidine and decitabine, the intracellular pharmacokinetics was only very minimally investigated. This is probably owing to the fact that there were no suitable bioanalytical assays for a long time. Since the advent of suitable assays, the first exploratory studies indicate that the intracellular 5-fluorouracil, azacitidine and decitabine nucleotide concentrations are very low compared with the intracellular nucleotide concentrations obtained during treatment with cytarabine or gemcitabine. Based on their pharmacology, the intracellular accumulation of nucleotides appears critical to the cytotoxicity of pyrimidine analogues. However, not many clinical studies have actually investigated the relationship between the intracellular nucleotide concentrations in patients with cancer and the anti-tumour effect. Only for cytarabine, a relationship was demonstrated between the intracellular triphosphate concentrations in leukaemic cells and the response rate in patients with AML. Future clinical studies should show, for the other pyrimidine analogues, whether there is a relationship between the intracellular nucleotide concentrations and the clinical outcome of patients. Research that examined the intracellular pharmacokinetics of cytarabine and gemcitabine focused primarily on the saturation aspect of the intracellular triphosphate formation. Attempts to improve the dosing regimen of gemcitabine were aimed at maximising the intracellular gemcitabine triphosphate concentrations. However, this strategy does not make sense, as efficient administration also means that less gemcitabine can be administered before dose-limiting toxicities are achieved. For all pyrimidine analogues, a linear relationship was found between the dose and the plasma concentration. However, no correlation was found between the plasma concentration and the intracellular nucleotide concentration. The concentration-time curves for the intracellular nucleotides showed considerable inter-individual variation. Therefore, the question arises whether pyrimidine analogue therapy should be more individualised. Future research should show which intracellular nucleotide concentrations are worth pursuing and whether dose individualisation is useful to achieve these concentrations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40262-020-00934-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717039PMC
December 2020

Clinical Pharmacokinetics and Pharmacodynamics of the Cyclin-Dependent Kinase 4 and 6 Inhibitors Palbociclib, Ribociclib, and Abemaciclib.

Clin Pharmacokinet 2020 12;59(12):1501-1520

Division of Medical Oncology, Department of Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Palbociclib, ribociclib, and abemaciclib are inhibitors of the cyclin-dependent kinases 4 and 6 approved for the treatment of locally advanced or metastatic breast cancer. In this review, we provide an overview of the available clinical pharmacokinetic and pharmacodynamic characteristics of these novel drugs, summarize the results of food-effect and drug-drug interaction studies, and highlight exposure-response and exposure-toxicity relationships. All three drugs exhibit a large inter-individual variability in exposure (coefficient of variation range 40-95% for minimum plasma concentration), are extensively metabolized by cytochrome P450 3A4, and have their brain penetration limited by efflux transporters. Abemaciclib has three active metabolites with similar potency that are clinically relevant (i.e., M2, M20, M18), whereas the metabolites of palbociclib and ribociclib are not of clinical significance. Pharmacokinetic exposure increases in a dose-proportional manner for palbociclib, whereas exposure increases under- and over-proportionally with an increasing dose for abemaciclib and ribociclib, respectively. High exposure is associated with an increased risk of neutropenia, and for ribociclib also to corrected QT prolongation. For abemaciclib, a clear exposure-efficacy relationship has been described, while for palbociclib and ribociclib exposure-response analyses remain inconclusive. Future studies are needed to address exposure-efficacy relationships to further improve dosing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40262-020-00930-xDOI Listing
December 2020

A Phase 1 Dose-Escalation Study of Low-Dose Metronomic Treatment With Novel Oral Paclitaxel Formulations in Combination With Ritonavir in Patients With Advanced Solid Tumors.

Clin Pharmacol Drug Dev 2020 Oct 5. Epub 2020 Oct 5.

Division of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

ModraPac001 (MP1) and ModraPac005 (MP5) are novel oral paclitaxel formulations that are coadministered with the cytochrome P450 3A4 inhibitor ritonavir (r), enabling daily low-dose metronomic (LDM) treatment. The primary aim of this study was to determine the safety, pharmacokinetics and maximum tolerated dose (MTD) of MP1/r and MP5/r. The second aim was to establish the recommended phase 2 dose (RP2D) as LDM treatment. This was an open-label phase 1 trial. Patients with advanced solid tumors were enrolled according to a classical 3+3 design. After initial employment of the MP1 capsule, the MP5 tablet was introduced. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.02. Pharmacokinetic sampling was performed on days 1, 2, 8, and 22 for determination of paclitaxel and ritonavir plasma concentrations. In this study, 37 patients were treated with up to twice-daily 30-mg paclitaxel combined with twice-daily 100-mg ritonavir (MP5/r 30-30/100-100) in 9 dose levels. Dose-limiting toxicities were nausea, (febrile) neutropenia, dehydration and vomiting. At the MTD/RP2D of MP5/r 20-20/100-100, the maximum paclitaxel plasma concentration and area under the concentration-time curve until 24 hours were 34.6 ng/mL (coefficient of variation, 79%) and 255 ng • h/mL (coefficient of variation, 62%), respectively. Stable disease was observed as best response in 15 of 31 evaluable patients. Based on these results, LDM therapy with oral paclitaxel coadministrated with ritonavir was considered feasible and safe. The MTD and RP2D were determined as MP5/r 20-20/100-100. Further clinical development of MP5/r as an LDM concept, including potential combination treatment, is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.880DOI Listing
October 2020

Individualized Dosing of Fluoropyrimidine-Based Chemotherapy to Prevent Severe Fluoropyrimidine-Related Toxicity: What Are the Options?

Clin Pharmacol Ther 2021 Mar 12;109(3):591-604. Epub 2020 Nov 12.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Fluoropyrimidines are widely used in the treatment of several types of solid tumors. Although most often well tolerated, severe toxicity is encountered in ~ 20-30% of the patients. Individualized dosing for these patients can reduce the incidence of severe fluoropyrimidine-related toxicity. However, no consensus has been achieved on which dosing strategy is preferred. The most established strategy for individualized dosing of fluoropyrimidines is upfront genotyping of the DPYD gene. Prospective research has shown that DPYD-guided dose-individualization significantly reduces the incidence of severe toxicity and can be easily applied in routine daily practice. Furthermore, the measurement of the dihydropyrimidine dehydrogenase (DPD) enzyme activity has shown to accurately detect patients with a DPD deficiency. Yet, because this assay is time-consuming and expensive, it is not widely implemented in routine clinical care. Other methods include the measurement of pretreatment endogenous serum uracil concentrations, the uracil/dihydrouracil-ratio, and the 5-fluorouracil (5-FU) degradation rate. These methods have shown mixed results. Next to these methods to detect DPD deficiency, pharmacokinetically guided follow-up of 5-FU could potentially be used as an addition to dosing strategies to further improve the safety of fluoropyrimidines. Furthermore, baseline characteristics, such as sex, age, body composition, and renal function have shown to have a relationship with the development of severe toxicity. Therefore, these baseline characteristics should be considered as a dose-individualization strategy. We present an overview of the current dose-individualization strategies and provide perspectives for a future multiparametric approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.2069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983939PMC
March 2021

Skin tissue sample collection, sample homogenization, and analyte extraction strategies for liquid chromatographic mass spectrometry quantification of pharmaceutical compounds.

J Pharm Biomed Anal 2020 Nov 28;191:113590. Epub 2020 Aug 28.

Department of Pharmacy & Pharmacology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address:

Quantification of pharmaceutical compounds in skin tissue is challenging because of low expected concentrations, small typical sample volumes, and the hard nature of the skin structure itself. This review provides a comprehensive overview of sample collection, sample homogenization and analyte extraction methods that have been used to quantify pharmaceutical compounds in skin tissue, obtained from animals and humans, using liquid chromatography-mass spectrometry. For each step in the process of sample collection to sample extraction, methods are compared to discuss challenges and provide practical guidance. Furthermore, liquid chromatographic-mass spectrometry considerations regarding the quality and complexity of skin tissue sample measurements are discussed, with emphasis on analyte recovery and matrix effects. Given that the true recovery of analytes from skin tissue is difficult to assess, the extent of homogenization plays a crucial role in the accuracy of quantification. Chemical or enzymatic solubilization of skin tissue samples would therefore be preferable as homogenization method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpba.2020.113590DOI Listing
November 2020

Bottom-up sample preparation for the LC-MS/MS quantification of anti-cancer monoclonal antibodies in bio matrices.

Bioanalysis 2020 Oct 25;12(19):1405-1425. Epub 2020 Sep 25.

Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Therapeutic monoclonal antibodies (mAbs) are rapidly taking over the treatment of many malignancies, and an astonishing number of mAbs is in development. This causes a high demand for quantification of mAbs in biomatrices both for measuring therapeutic mAb concentrations and to support pharmacokinetics and pharmacodynamics studies. Conventionally, ligand-binding assays are used for these purposes, but LC-MS is gaining popularity. Although intact (top-down) and subunit (middle-down) mAb quantification is reported, signature peptide (bottom-up) quantification is currently most advantageous. This review provides an overview of the reported bottom-up mAb quantification methods in biomatrices as well as general recommendations regarding signature peptide and internal standard selection, reagent use and optimization of digestion in bottom-up quantification methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4155/bio-2020-0204DOI Listing
October 2020

PropAngio study protocol: a neoadjuvant trial on the efficacy of propranolol monotherapy in cutaneous angiosarcoma-a proof of principle study.

BMJ Open 2020 09 10;10(9):e039449. Epub 2020 Sep 10.

Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Introduction: Angiosarcoma is a rare and aggressive malignancy with a high metastatic potential and recurrence rate. Despite optimal treatment with surgery, with or without radiation, the prognosis remains poor and, therefore, new treatment strategies are warranted. Recently, propranolol has effectively been repurposed for the treatment of infantile haemangioma. Propranolol is a β3-sparing antagonist of the β-adrenergic receptor. In infantile haemangioma, the β1, β2 and β3 receptors are highly expressed. Angiosarcoma has several similarities with haemangioma, including its high β-adrenergic receptor expression and the supposedly important role of vascular endothelial growth factor in malignant growth. As a result, propranolol has been administered small scale in individual angiosarcoma cases with promising results. The precise effect of propranolol, however, is not yet established.

Methods And Analysis: The goal of this neoadjuvant window of opportunity study is to prospectively evaluate the activity of propranolol monotherapy in patients with cutaneous angiosarcoma. The neoadjuvant setting provides a good opportunity to rapidly evaluate both the clinical response and histological response, without a significant delay in standard anticancer treatment. Fourteen patients with primary, recurrent or metastatic cutaneous angiosarcoma will be included. Propranolol will be administered orally in an escalating dose during 3-6 weeks, before the initiation of standard treatment. The primary endpoint is clinical response according to Response Evaluation Criteria in Solid Tumours, as measured on consecutive coloured photographs or CT/MRI. The histological response will be determined as secondary endpoint, comparing the difference in proliferation index before and after propranolol by measuring the change in immunohistochemistry staining of Ki-67. The study will be considered positive when at least three patients have a response to propranolol.

Ethics And Dissemination: Ethical approval was obtained from the Medical Ethical Committee of the Netherlands Cancer Institute. Independent of the outcome, results of this study will be shared and submitted for publication in an international peer-reviewed journal.

Trial Registration Number: NL8118; registry through the Netherlands Trial Register.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-039449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485254PMC
September 2020

A cost analysis study of the implementation of fixed-dosing of monoclonal antibodies in the Netherlands Cancer Institute.

Int J Clin Pharm 2021 Feb 10;43(1):181-190. Epub 2020 Sep 10.

Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background There is a strong rationale for fixed-dosing of monoclonal antibodies in oncology. Although fixed-dosing of recently introduced monoclonal antibodies is well accepted, the rationale is also applicable for other monoclonal antibodies that already have been used for years, but are still body-size-based dosed in many hospitals. In the Netherlands Cancer Institute, Antoni van Leeuwenhoek (NKI-AVL), fixed-dosing has been implemented now for all monoclonal antibodies and, therefore, this site offers an ideal opportunity for a cost analysis study. Objective To investigate the financial impact of switching to fixed-dosing in the NKI-AVL. Setting The NKI-AVL. Method Information on the preparations of monoclonal antibodies was collected from August 2017 to February 2020. We compared the number of vials needed during preparation for fixed-dosing and body-size -based dosing strategies. The economic impact was calculated for 2 scenarios: scenario 1 assumed clustering of all preparations per day and scenario 2 assumed no clustering of preparations. Main outcome measure Number of saved vials and the correlating savings in health care costs. Results The implementation of fixed-dosing resulted in a substantial reduction in vials used for almost all monoclonal antibodies. The economic savings were calculated to be €0,8 and €3,1 million per year for scenario 1 and 2, respectively. Conclusion Fixed-dosing resulted in substantial savings in health care costs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11096-020-01131-zDOI Listing
February 2021

Quantitative LC-MS/MS analysis of 5-hydroxymethyl-2'-deoxyuridine to monitor the biological activity of J-binding protein.

Anal Biochem 2020 12 29;610:113930. Epub 2020 Aug 29.

Department of Pharmacy & Pharmacology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Science Faculty, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; Division of Pharmacology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands. Electronic address:

Base J replaces 1% of thymine in most kinetoplastid flagellates, and is implicated in transcription regulation. Base J is synthesized in two steps: first, a thymine base in DNA is converted to 5-hydroxymethyluracil by J-binding proteins (JBP1, JBP2); secondly, a glucosyl transferase glycosylates the 5-hydroxymethyluracil to form base J. Here, we present a highly sensitive and selective LC-MS/MS method to quantify the in vitro JBP1 activity on synthetic oligonucleotide substrates. The method demonstrated successful to support biochemical studies of JBPs and can be used as a template for additional JBP activity studies or for inhibitor screening in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ab.2020.113930DOI Listing
December 2020

Neoadjuvant Systemic Treatment of Primary Angiosarcoma.

Cancers (Basel) 2020 Aug 12;12(8). Epub 2020 Aug 12.

Department of Surgical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Angiosarcoma is an extremely rare and aggressive malignancy. Standard of care of localized tumors includes surgery ± radiation. Despite this multimodal treatment, >50% of the angiosarcoma patients develop local or distant recurrent disease. The role of neoadjuvant systemic therapy is still controversial and we therefore performed a systematic review of the literature to define the role of neoadjuvant systemic therapy based on available evidence. We focused on the effects of neoadjuvant systemic therapy on: 1. The success of surgical resection and 2. the long-term survival. All articles published before October 2019 on Ovid Medline, Ovid Embase, Cochrane library and Scopus were evaluated. Eighteen case reports and six retrospective cohort studies were included. There were no randomized controlled trials. This literature showed a beneficial role of neoadjuvant chemotherapy on downsizing of the tumor resulting in an improvement of the resection margins, especially in patients with cardiac or cutaneous angiosarcoma. However, no definitive conclusions on survival can be drawn based on the available literature lacking any prospective randomized studies in this setting. We advise that neoadjuvant chemotherapy should be considered, since this could lead to less mutilating resections and a higher rate of free resection margins. An international angiosarcoma registry could help to develop guidelines for this rare disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12082251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464310PMC
August 2020