61 research outputs found
Intravenous-to-oral switch in anticancer chemotherapy : focus on taxanes and gemcitabine
No full textMost anticancer chemotherapeutic drugs are given intravenously. However, there is a growing interest in developing anticancer drugs for oral application. Different classes of anticancer drugs are already orally available and widely applied such as the tyrosine kinase inhibitors (imatinib, erlotinib, gefitinib, sorafenib and sunitinib), alkylating agents (temozolamide and cyclophosphamide) and the 5FU prodrug, capecitabine, a drug for which the intravenous-to-oral switch has already been successfully implemented in clinical practice. One of the aims of this thesis was to investigate the oral application of docetaxel. Docetaxel has a low bioavailability due to affinity for drug transporters, especially ABCB1 (P-glycoprotein, P-gp), extensive first pass metabolism by cytochrome P450 3A4 (CYP3A4) and poor drug solubility. In previous studies it has been demonstrated that the low systemic exposure to docetaxel is primarily determined by CYP3A4 in gut and liver. Inhibition of CYP3A4 in mice using low-dose ritonavir was found to increase the systemic exposure in mice by 50-fold. In patients the apparent bioavailability of docetaxel increased to more than 100% after co-administration of ritonavir. The studies described in this thesis investigated the pharmacology of orally administered docetaxel more thoroughly in order to determine the optimal boosted oral docetaxel regimen. We demonstrated that the concept of boosting docetaxel is possible with any strong CYP3A4 inhibitor. We selected low-dose ritonavir for the further development of boosted orally administered docetaxel, since ritonavir resulted in high systemic exposure to docetaxel, had a good safety profile and since ritonavir is used as booster as standard practice in multiple anti-HIV regimens. Most studies described in this thesis were conducted with a novel solid docetaxel formulation, ModraDoc001 capsules. To improve the poor aqueous solubility, a solid dispersion formulation of docetaxel has been designed by the pharmacy of the Slotervaart Hospital. This formulation was investigated in 55 patients and resulted in high systemic exposure to docetaxel. The variability was modest and of the same order as after intravenous administration of docetaxel. This is an important finding since high variability may lead to unexpected severe toxicity or under-dosing. The safety of weekly oral docetaxel in combination with ritonavir was determined in a dose escalation study. The most observed adverse event was diarrhea with an overall incidence of 66%. Major treatment limiting adverse effects observed after intravenous therapy with docetaxel, e.g. fluid retention, hematological toxicity and infusion reactions were not observed. Consequently, high doses of dexamethason to prevent fluid retention and allergic reactions were not required. Furthermore, the anti-tumor activity observed at the two highest dose-levels strengthens the concept that oral administration of docetaxel is feasible and potentially active. Concluding, the oral application of the taxanes docetaxel and paclitaxel was found to be feasible. The presented pharmacokinetic data demonstrated that the systemic exposure to the taxanes was high and signs of antitumor activity were observed after treatment with ritonavir boosted ModraDoc001 capsules. Plans for phase II clinical testing of ritonavir boosted ModraDoc001 are made for maintenance or second line treatment of patients with non-small-cell-lung-cance
A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients
No full textFentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer-related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter- and intrapatient variability. This systematic review summarizes multiple studied factors that potentially influence fentanyl pharmacokinetics with a focus on implications for cancer patients. The use of CYP3A4 inhibitors and inducers, impaired liver function, and heating of the patch potentially influence fentanyl pharmacokinetics in a clinically relevant way. In elderly patients, current data suggest that we should carefully dose fentanyl due to alterations in absorption and metabolism. The influence of BMI and gender on fentanyl pharmacokinetics is questionable, most probably due to a large heterogeneity in the published studies. Pharmacogenetics, e.g. the CYP3A5*3 gene polymorphism, may influence fentanyl pharmacokinetics as well, although further study is warranted. Several other factors have been studied but did not show significant and clinically relevant effects on fentanyl pharmacokinetics. Unfortunately, most of the published papers that studied factors influencing fentanyl pharmacokinetics describe healthy volunteers instead of cancer patients. Results from the studies in volunteers may not be simply extrapolated to cancer patients because of multiple confounding factors. To handle fentanyl treatment in a population of cancer patients, it is essential that physicians recognize factors that influence fentanyl pharmacokinetics, thereby preventing potential side-effects and increasing its efficacy
Recent Clinical Developments of Nanomediated Drug Delivery Systems of Taxanes for the Treatment of Cancer
No full textConventional 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
No full textThe 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%
Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001)
No full textInhibiting CDK4/6 in Breast Cancer with Palbociclib, Ribociclib, and Abemaciclib: Similarities and Differences
No full textThe 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
Integrated Data Analysis of Six Clinical Studies Points Toward Model-Informed Precision Dosing of Tamoxifen
No full textIntroduction: At tamoxifen standard dosing, ∼20% 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 ‘realworld’ 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, drug–drug
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 (5–120 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
Blood-based extracellular matrix biomarkers are correlated with clinical outcome after PD-1 inhibition in patients with metastatic melanoma
No full textBackground 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
Feasibility of extrapolating randomly taken plasma samples to trough levels for therapeutic drug monitoring purposes of small molecule kinase inhibitors
No full textSmall 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
Pharmacokinetic boosting of olaparib to improve exposure, tolerance and cost-effectiveness part A
No full textItem does not contain fulltextBackground: Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose.Methods: This cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC0-12 h) within no-effect boundaries. These boundaries were set at 0.57-1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets.Results: Of 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC0-12 h was 1.45 (90% CI 1.27-1.65). No grade ≥3 adverse events were reported during the study.Conclusions: Boosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established.This collection contains the laboratory and pharmacokinetic data of the twelve participation subjects. This includes the olaparib and cobicistat plasma concentrations over one dosing interval with olaparib monotherapy and boosted therapy
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