30 research outputs found
Recent Clinical Developments of Nanomediated Drug Delivery Systems of Taxanes for the Treatment of Cancer
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
Quantification of afatinib, alectinib, crizotinib and osimertinib in human plasma by liquid chromatography/triple-quadrupole mass spectrometry; focusing on the stability of osimertinib
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%
Blood-based extracellular matrix biomarkers are correlated with clinical outcome after PD-1 inhibition in patients with metastatic melanoma
Background Immune checkpoint inhibitors that target
the programmed cell death protein 1 (PD-1) receptor
induce a response in only a subgroup of patients with
metastatic melanoma. Previous research suggests that
transforming growth factor beta signaling and a collagenrich peritumoral stroma (tumor fibrosis), may negatively
interfere with the interaction between T cells and tumor
cells and thereby contribute to resistance mechanisms by
immune-exclusion, while increased tumor infiltration of
M1-like macrophages enhances T cell activity. Hence, the
current study aimed to assess the relationship between
blood-based markers of collagen or vimentin turnover
(reflecting M1 macrophage activity) and clinical outcome in
patients with metastatic melanoma after PD-1 inhibition.
Methods Patients with metastatic melanoma who
were treated with anti-PD-1 monotherapy between May
2016 and March 2019 were included in a prospective
observational study. N-terminal pro-peptide of type III
collagen (PRO-C3) cross-linked N-terminal pro-peptides
of type III collagen (PC3X), matrix metalloprotease (MMP)-
degraded type III (C3M) and type IV collagen (C4M),
granzyme B-degraded type IV collagen and citrullinated
and MMP-degraded vimentin (VICM) were measured with
immunoassays in serum before (n=107), and 6weeks
after the first administration of immunotherapy (n=94). The
association between biomarker levels and overall survival
(OS) or progression-free survival (PFS) was assessed.
Results Multivariate Cox regression analysis identified
high baseline PRO-C3 (Q4) and PC3X (Q4) as independent
variables of worse PFS (PRO-C3: HR=1.81, 95% CI=1.06
to 3.10, p=0.030 and PC3X: HR=1.86, 95% CI=1.09
to 3.18, p=0.023). High baseline PRO-C3 was also
independently related to worse OS (HR=2.08, 95%
CI=1.06 to 4.09, p=0.035), whereas a high C3M/PRO-C3
ratio was related to improved OS (HR=0.42, 95% CI=0.20
to 0.90, p=0.025). An increase in VICM (p<0.0001; in 56%
of the patients) was observed after 6weeks of treatment,
and an increase in VICM was independently associated
with improved OS (HR=0.28, 95% CI=0.10 to 0.77,
p=0.014).
Conclusions Blood-based biomarkers reflecting
excessive type III collagen turnover were associated with
worse OS and PFS after PD-1 inhibition in metastatic
melanoma. Moreover, an increase in VICM levels after
6weeks of treatment was associated with improved OS These findings suggest that type III collagen and vimentin
turnover contribute to resistance/response mechanisms of
PD-1 inhibitors and hold promise of assessing extracellular
matrix-derived and stroma-derived components to predict
immunotherapy response
To quantify the small-molecule kinase inhibitors ceritinib, dacomitinib, lorlatinib, and nintedanib in human plasma by liquid chromatography/triple-quadrupole mass spectrometry
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
Feasibility of extrapolating randomly taken plasma samples to trough levels for therapeutic drug monitoring purposes of small molecule kinase inhibitors
Small molecule kinase inhibitors (SMKIs) are widely used in oncology. Therapeutic drug monitoring (TDM) for SMKIs could reduce underexposure or overexposure. However, logistical issues such as timing of blood withdrawals hamper its implementation into clinical practice. Extrapolating a random concentration to a trough concentration using the elimination half-life could be a simple and easy way to overcome this problem. In our study plasma concentrations observed during 24 h blood sampling were used for extrapolation to trough levels. The objective was to demonstrate that extrapolation of randomly taken blood samples will lead to equivalent estimated trough samples compared to measured Cmin values. In total 2241 blood samples were analyzed. The estimated Ctrough levels of afatinib and sunitinib fulfilled the equivalence criteria if the samples were drawn after Tmax . The calculated Ctrough levels of erlotinib, imatinib and sorafenib met the equivalence criteria if they were taken, respectively, 12 h, 3 h and 10 h after drug intake. For regorafenib extrapolation was not feasible. In conclusion, extrapolation of randomly taken drug concentrations to a trough concentration using the mean elimination half-life is feasible for multiple SMKIs. Therefore, this simple method could positively contribute to the implementation of TDM in oncology
Inhibiting CDK4/6 in Breast Cancer with Palbociclib, Ribociclib, and Abemaciclib: Similarities and Differences
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
A limited sampling schedule to estimate individual pharmacokinetics of pemetrexed in patients with varying renal functions
Purpose: Pemetrexed is a widely used cytostatic agent with an established exposure–response relationship. Although dosing is based on body surface area (BSA), large interindividual variability in pemetrexed plasma concentrations is observed. Therapeutic drug monitoring (TDM) can be a feasible strategy to reduce variability in specific cases leading to potentially optimized pemetrexed treatment. The aim of this study was to develop a limited sampling schedule (LSS) for the assessment of pemetrexed pharmacokinetics. Methods: Based on two real-life datasets, several limited sampling designs were evaluated on predicting clearance, using NONMEM, based on mean prediction error (MPE %) and normalized root mean squared error (NRMSE %). The predefined criteria for an acceptable LSS were: a maximum of four sampling time points within 8 h with an MPE and NRMSE ≤ 20%. Results: For an accurate estimation of clearance, only four samples in a convenient window of 8 h were required for accurate and precise prediction (MPE and NRMSE of 3.6% and 5.7% for dataset 1 and of 15.5% and 16.5% for dataset 2). A single sample at t = 24 h performed also within the criteria with MPE and NRMSE of 5.8% and 8.7% for dataset 1 and of 11.5% and 16.4% for dataset 2. Bias increased when patients had lower creatinine clearance. Conclusions: We presented two limited sampling designs for estimation of pemetrexed pharmacokinetics. Either one can be used based on preference and feasibility
Does Older Age Lead to Higher Risk for Neutropenia in Patients Treated with Paclitaxel?
Purpose: There is ongoing concern regarding increased toxicity from paclitaxel in elderly patients, particularly of severe neutropenia. Yet, data so far is controversial and this concern is not supported by a clinically relevant age-dependent difference in pharmacokinetics (PK) of paclitaxel. This study assessed whether age is associated with increased risk for paclitaxel-induced neutropenia. Methods: Paclitaxel plasma concentration-time data, pooled from multiple different studies, was combined with available respective neutrophil count data during the first treatment cycle. Paclitaxel pharmacokinetic-pharmacodynamic (PK-PD) d
Influence of genetic variation in COMT on cisplatin-induced nephrotoxicity in cancer patients
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
Influence of aprepitant and localization of the patch on fentanyl exposure in patients with cancer using transdermal fentanyl
__Background and Objectives:__ The cutaneous fentanyl patch is widely used to treat continuous pain in patients with cancer. Its use is hampered by a high inter- and intrapatient pharmacokinetic variability. Factors that influence this pharmacokinetic variability are largely unclear. The aim of these studies was to test if common patient variables, i) the use of the moderate CYP3A4 inhibitor aprepitant and ii) the localization of the fentanyl patch (upper arm versus thorax) influence systemic exposure to fentanyl in patients with cancer using a transdermal fentanyl patch.
__Results:__ The AUC0-6 h of fentanyl was 7.1% (95% CI: -28% to +19%) lower if patients concurrently used apre