188 research outputs found
Replacing Lu-177 with Tb-161 in DOTA-TATE and PSMA-617 therapy:potential dosimetric implications for activity selection
Aim: To explore the dosimetric effect of substituting Lu-177 with Tb-161 in targeted radionuclide therapy (TRT) using the registered tracers DOTA-TATE and PSMA-617. Methods: Using established kinetic data for [177Lu]Lu-DOTA-TATE and [177Lu]Lu-PSMA-617, radiation absorbed doses to typical tumour lesion as well as non-target tissues ([177Lu]Lu-DOTA-TATE: kidneys, spleen and liver, [177Lu]Lu-PSMA-617: kidneys, liver and salivary glands) were calculated for Lu-177 and Tb-161. Results: For both DOTA-TATE and PSMA-617, the substitution of Lu-177 with Tb-161 results in an increase in the delivered dose per unit of activity to tumour tissue by 40%. If an equivalent non-target delivered dose is strived for in order not to increase toxicity, based on kidney absorbed dose, 7400 MBq Lu-177 per cycle should be substituted with 5400 MBq Tb-161 for DOTA-TATE and 5300 MBq of Tb-161 for PSMA-617.Conclusion: When substituting Lu-177 with Tb-161, activity conversion is necessary in order not to exceed non-target dose limits.</p
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 (UPLCâMS/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 Âź BEH C18; 2.1 Ă 50 mm, 1.7 ÎŒm 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%
Pharmacokinetic profile of irinotecan in patients with chronic kidney disease:Two cases and literature review
Aims: There are limited pharmacokinetic data on the use of irinotecan in patients with reduced glomerular filtration rate (GFR) and no haemodialysis. In this case report, we present 2 cases and review the current literature. Methods: The dose of irinotecan in both patients was reduced pre-emptively due to reduced GFR. The first patient had her irinotecan dose reduced to 50%, but was nevertheless admitted to hospital because of irinotecan-induced toxicity, including gastrointestinal toxicity and neutropenic fever. The dose was reduced further to 40% for the second cycle; however, the patient was again admitted to the hospital, and irinotecan was stopped indefinitely. The second patient also had his irinotecan dose reduced to 50% and was admitted to the emergency department for gastrointestinal toxicity after the first cycle. However, irinotecan could be administered in the same dose in later cycles. Results: The area under the curve to infinity of irinotecan and SN-38 in the first patient were comparable to those of an individual receiving 100% dose intensity. The area under the curve to infinity of irinotecan and SN-38 in patient 2 in both cycles were slightly less than reference values. Furthermore, clearance values of irinotecan and SN-38 in our patients were comparable to those without renal impairment. Conclusion: Our case report suggests that reduced GFR may not significantly affect the clearance of irinotecan and SN-38, but can still result in clinical toxicity. Reduced initial dosing seems indicated in this patient population. Further research is needed to fully understand the relationship between reduced GFR, pharmacokinetics, and toxicity of irinotecan and SN-38.</p
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
Tamoxifen use and potential effects on liver parenchyma:A long-term prospective transient elastographic evaluation
Tamoxifen is a commonly prescribed drug in both early and metastatic breast cancer. Prospective studies in Asian populations demonstrated that tamoxifenârelated liver steatosis occurred in more than 30% of the patients within 2âyears after start of treatment. No wellâdesigned prospective studies on potential tamoxifenârelated liver steatosis have been conducted in Caucasian patients so far. Therefore, our prospective study aimed to assess the incidence of tamoxifenârelated liver steatosis for a period of 2âyears in a population of Caucasian breast cancer patients treated with tamoxifen. Patients with an indication for adjuvant treatment with tamoxifen were included in this study. Data were collected at 3 months (T1) and at 2âyears (T2) after start of tamoxifen treatment (followâup period of 21âmonths). For the quantification of liver steatosis, patients underwent liver stiffness measurement by transient elastography with simultaneous controlled attenuation parameter (CAP) determination using the FibroScan. A total of 95 Caucasian breast cancer patients were included in this evaluation. Liver steatosis was observed in 46 of 95 (48%) and 48 of 95 (51%) of the patients at T1 and T2, respectively. No clinically relevant increase in liver steatosis was observed during the treatment period of 2âyears with tamoxifen (median CAP = 243â±â49âdB/m (T1) and 253â±â55âdB/m (T2), respectively; p = 0.038). Conclusion: In this prospective longitudinal study in Caucasian breast cancer patients, no clinically relevant alterations in liver steatosis in terms of CAP values and liver/lipid parameters were observed after 2âyears of tamoxifen treatment. This study therefore demonstrates an absence of tamoxifenârelated adverse events such as steatosis and (early) development of fibrosis or cirrhosis during a treatment period of at least 2âyears
Integrated Data Analysis of Six Clinical Studies Points Toward Model-Informed Precision Dosing of Tamoxifen
Introduction: At tamoxifen standard dosing, âŒ20% of breast cancer patients do not reach proposed target endoxifen concentrations >5.97 ng/mL. Thus, better understanding the large interindividual variability in tamoxifen pharmacokinetics (PK) is crucial. By applying non-linear mixed-effects (NLME) modeling to a pooled âreal-worldâ clinical PK database, we aimed to (i) dissect several levels of variability and identify factors predictive for endoxifen exposure and (ii) assess different tamoxifen dosing strategies for their potential to increase the number of patients reaching target endoxifen concentrations.
Methods: Tamoxifen and endoxifen concentrations with genetic and demographic data of 468 breast cancer patients from six reported studies were used to develop a NLME parent-metabolite PK model. Different levels of variability on model parameters or measurements were investigated and the impact of covariates thereupon explored. The model was subsequently applied in a simulation-based comparison of three dosing strategies with increasing degree of dose individualization for a large virtual breast cancer population. Interindividual variability of endoxifen concentrations and the fraction of patients at risk for not reaching target concentrations were assessed for each dosing strategy.
Results and Conclusions: The integrated NLME model enabled to differentiate and quantify four levels of variability (interstudy, interindividual, interoccasion, and intraindividual). Strong influential factors, i.e., CYP2D6 activity score, drugâdrug interactions with CYP3A and CYP2D6 inducers/inhibitors and age, were reliably identified, reducing interoccasion variability to <20% CV. Yet, unexplained interindividual variability in endoxifen formation remained large (47.2% CV). Hence, therapeutic drug monitoring seems promising for achieving endoxifen target concentrations. Three tamoxifen dosing strategies [standard dosing (20 mg QD), CYP2D6-guided dosing (20, 40, and 60 mg QD) and individual model-informed precision dosing (MIPD)] using three therapeutic drug monitoring samples (5â120 mg QD) were compared, leveraging the model. The proportion of patients at risk for not reaching target concentrations was 22.2% in standard dosing, 16.0% in CYP2D6-guided dosing and 7.19% in MIPD. While in CYP2D6-guided- and standard dosing interindividual variability in endoxifen concentrations was high (64.0% CV and 68.1% CV, respectively), it was considerably reduced in MIPD (24.0% CV). Hence, MIPD demonstrated to be the most promising strategy for achieving target endoxifen concentrations
Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology
Although kinase inhibitors (KI) frequently portray large interpatient variability, a âone size fits allâ regimen is still often used. In the meantime, relationships between exposure-response and exposure-toxicity have been established for several KIs, so this regimen could lead to unnecessary toxicity and suboptimal efficacy. Dose adjustments based on measured systemic pharmacokinetic levelsâi.e., therapeutic drug monitoring (TDM)âcould therefore improve treatment efficacy and reduce the incidence of toxicities. Therefore, the aim of this comprehensive review is to give an overview of the available evidence for TDM for the 77 FDA/EMA kinase inhibitors currently approved (as of July 1st, 2023) used in hematology and oncology. We elaborate on exposure-response and exposure-toxicity relationships for these kinase inhibitors and provide practical recommendations for TDM and discuss corresponding pharmacokinetic targets when possible.</p
Clinical implications of food-drug interactions with small-molecule kinase inhibitors
During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food-drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food-drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food-drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food-drug interactions and herb-drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice
Development of [<sup>225</sup>ac]ac-psma-i&t for targeted alpha therapy according to gmp guidelines for treatment of mcrpc
Recently, promising results of the antitumor effects were observed in patients with metastatic castration-resistant prostate cancer treated with177Lu-labeled PSMA-ligands. Radionu-clide therapy efficacy may even be improved by using the alpha emitter Ac-225. Higher efficacy is claimed due to high linear energy transfer specifically towards PSMA positive cells, causing more double-strand breaks. This study aims to manufacture [225Ac]Ac-PSMA-I&T according to good manufacturing practice guidelines for the translation of [225Ac]Ac-PSMA-I&T into a clinical phase 1 dose escalation study. Quencher addition during labeling was investigated. Quality control of [225Ac]Ac-PSMA-I&T was based on measurement of Fr-221 (218 keV), in equilibrium with Ac-225 in approximately six half-lives of Fr-221 (T12 = 4.8 min). Radio-(i)TLC methods were utilized for identification of the different radiochemical forms, gamma counter for concentration determination, and HPGe-detector for the detection of the radiochemical yield. Radiochemical purity was determined by HPLC. The final patient dose was prepared and diluted with an optimized concentration of quenchers as during labeling, with an activity of 8â12 MBq (±5%), pH > 5.5, 100 ± 20 ”g/dose, PSMA-I&T, radiochemical yield >95%, radiochemical purity >90% (up to 3 h), endotoxin levels of <5 EU/mL, osmolarity of 2100 mOsmol, and is produced according to current guidelines. The start of the phase I dose escalation study is planned in the near future
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
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