Amina Haouala

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

Several cancer treatments are shifting from traditional, time-limited, nonspecific cytotoxic chemotherapy cycles to continuous oral treatment with specific protein-targeted therapies. In this line, imatinib mesylate, a selective tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia. It has opened the way to the development of additional TKIs against chronic myeloid leukemia, including nilotinib and dasatinib. TKIs are prescribed for prolonged periods, often in patients with comorbidities. Therefore, they are regularly co-administered along with treatments at risk of drug-drug interactions. This aspect has been partially addressed so far, calling for a comprehensive review of the published data. We review here the available evidence and pharmacologic mechanisms of interactions between imatinib, dasatinib, and nilotinib and widely prescribed co-medications, including known inhibitors or inducers of cytochromes P450 or drug transporters. Information is mostly available for imatinib mesylate, well introduced in clinical practice. Several pharmacokinetic aspects yet remain insufficiently investigated for these drugs. Regular updates will be mandatory and so is the prospective reporting of unexpected clinical observations.

Therapeutic Drug Monitoring of Imatinib

BackgroundThe imatinib trough plasma concentration (Cmin) correlates with clinical response in cancer patients. Therapeutic drug monitoring (TDM) of plasma Cmin is therefore suggested. In practice, however, blood sampling for TDM is often not performed at trough. The corresponding measurement is thus only remotely informative about Cmin exposure.ObjectivesThe objectives of this study were to improve the interpretation of randomly measured concentrations by using a Bayesian approach for the prediction of Cmin, incorporating correlation between pharmacokinetic parameters, and to compare the predictive performance of this method with alternative approaches, by comparing predictions with actual measured trough levels, and with predictions obtained by a reference method, respectively.MethodsA Bayesian maximum a posteriori (MAP) estimation method accounting for correlation (MAP-ρ) between pharmacokinetic parameters was developed on the basis of a population pharmacokinetic model, which was validated on external data. Thirty-one paired random and trough levels, observed in gastrointestinal stromal tumour patients, were then used for the evaluation of the Bayesian MAP-ρ method: individual Cmin predictions, derived from single random observations, were compared with actual measured trough levels for assessment of predictive performance (accuracy and precision). The method was also compared with alternative approaches: classical Bayesian MAP estimation assuming uncorrelated pharmacokinetic parameters, linear extrapolation along the typical elimination constant of imatinib, and non-linear mixed-effects modelling (NONMEM) first-order conditional estimation (FOCE) with interaction. Predictions of all methods were finally compared with ‘best-possible’ predictions obtained by a reference method (NONMEM FOCE, using both random and trough observations for individual Cmin prediction).ResultsThe developed Bayesian MAP-ρ method accounting for correlation between pharmacokinetic parameters allowed non-biased prediction of imatinib Cmin with a precision of ±30.7%. This predictive performance was similar for the alternative methods that were applied. The range of relative prediction errors was, however, smallest for the Bayesian MAP-ρ method and largest for the linear extrapolation method. When compared with the reference method, predictive performance was comparable for all methods. The time interval between random and trough sampling did not influence the precision of Bayesian MAP-ρ predictions.ConclusionClinical interpretation of randomly measured imatinib plasma concentrations can be assisted by Bayesian TDM. Classical Bayesian MAP estimation can be applied even without consideration of the correlation between pharmacokinetic parameters. Individual Cmin predictions are expected to vary less through Bayesian TDM than linear extrapolation. Bayesian TDM could be developed in the future for other targeted anticancer drugs and for the prediction of other pharmacokinetic parameters that have been correlated with clinical outcomes.

siRNA-Mediated Knock-Down of P-Glycoprotein Expression Reveals Distinct Cellular Disposition of Anticancer Tyrosine Kinases Inhibitors

Studies on the cellular disposition of targeted anticancer tyrosine kinases inhibitors (TKIs) have mostly focused on imatinib while the functional importance of P-glycoprotein (Pgp) the gene product of MDR1 remains controversial for more recent TKIs. By using RNA interference-mediated knockdown of MDR1, we have investigated and compared the specific functional consequence of Pgp on the cellular disposition of the major clinically in use TKIs imatinib, dasatinib, nilotinib, sunitinib and sorafenib. siRNA-mediated knockdown in K562/Dox cell lines provides a unique opportunity to dissect the specific contribution of Pgp to TKIs intracellular disposition. In these conditions, abrogating specifically Pgp-mediated efflux in vitro revealed the remarkable and statistically significant cellular accumulation of imatinib (difference in cellular levels between Pgp-expressing and silenced cells, at high and low incubation concentration, respectively: 6.1 and 6.6), dasatinib (4.9 and 5.6), sunitinib (3.7 and 7.3) and sorafenib (1.2 and 1.4), confirming that these TKIs are all substrates of Pgp. By contrast, no statistically significant difference in cellular disposition of nilotinib was observed as a result of MDR1 expression silencing (differences: 1.1 and 1.5), indicating that differential expression and/or function of Pgp is unlikely to affect nilotinib cellular disposition. This study enables for the first time a direct estimation of the specific contribution of one transporter among the various efflux and influx carriers involved in the cellular trafficking of these major TKIs in vitro. Knowledge on the distinct functional consequence of Pgp expression for these various TKIs cellular distribution is necessary to better appreciate the efficacy, toxicity, and potential drug-drug interactions of TKIs with other classes of therapeutic agents, at the systemic, tissular and cellular levels.

Photodynamic Therapy Selectively Enhances Liposomal Doxorubicin Uptake in Sarcoma Tumors to Rodent Lungs

In specific conditions, photodynamic therapy (PDT) can enhance the distribution of macromolecules across the endothelial barrier in solid tumors. It was recently postulated that tumor neovessels were more responsive to PDT than the normal vasculature. We hypothesized that Visudyne®‐mediated PDT could selectively increase liposomal doxorubicin (Liporubicin™) uptake in sarcoma tumors to rodent lungs while sparing the normal surrounding tissue.

Photodynamic induced uptake of liposomal doxorubicin to rat lung tumors parallels tumor vascular density

Visudyne®‐mediated photodynamic therapy (PDT) at low drug/light conditions has shown to selectively enhance the uptake of liposomal doxorubicin in subpleural localized sarcoma tumors grown on rodent lungs without causing morphological alterations of the lung. The present experiments explore the impact of low‐dose PDT on liposomal doxorubicin (Liporubicin™) uptake to different tumor types grown on rodent lungs.

Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours

AIM Total imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements. METHODS One hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1 -acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates. RESULTS A one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml(-1) , assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations. CONCLUSION Although free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice.

Drug uptake in a rodent sarcoma model after intravenous injection or isolated lung perfusion of free/liposomal doxorubicin

The distribution of free and liposomal doxorubicin (Liporubicin) administered by intravenous injection (IV) or isolated lung perfusion (ILP) was compared in normal and tumor tissues of sarcoma bearing rodent lungs. A single sarcomatous tumor was generated in the left lung of 35 Fischer rats, followed 10 days later by left-sided ILP (n=20) or IV drug administration (n=12), using 100 microg and 400 microg free or liposomal doxorubicin, respectively. The tumor and lung tissue drug concentration was measured by HPLC. Free doxorubicin administered by ILP resulted in a three-fold (100 microg) and 10-fold (400 microg) increase of the drug concentration in the tumor and normal lung tissue compared to IV administration. In contrast, ILP with Liporubicin resulted in a similar drug uptake in the tumor and lung tissue compared to IV injection. For both drug formulations and dosages, ILP resulted in a higher tumor to lung tissue drug ratio but also in a higher spatial heterogeneity of drug distribution within the lung compared to IV administration. ILP resulted in a higher tumor to lung tissue drug ratio and in a more heterogeneous drug distribution within the lung compared to IV drug administration.

Reverse pharmacology for developing an anti-malarial phytomedicine. The example of Argemone mexicana.

Graphical abstract

Photodynamic therapy enhances liposomal doxorubicin distribution in tumors during isolated perfusion of rodent lungs

Background: Photodynamic therapy (PDT) at low drug-light conditions can enhance the transport of intravenously injected macromolecular therapeutics through the tumor vasculature. Here we determined the impact of PDT on the distribution of liposomal doxorubicin (Liporubicin™) administered by isolated lung perfusion (ILP) in sarcomas grown on rodent lungs. Methods: A syngeneic methylcholanthrene-induced sarcoma cell line was implanted subpleurally in the left lung of Fischer rats. Treatment schemes consisted in ILP alone (400 µg of Liporubicin), low-dose (0.0625 mg/kg Visudyne®, 10 J/cm2 and 35 mW/cm2) and high-dose left lung PDT (0.125 mg/kg Visudyne, 10 J/cm2 and 35 mW/cm2) followed by ILP (400 µg of Liporubicin). The uptake and distribution of Liporubicin in tumor and lung tissues were determined by high-performance liquid chromatography and fluorescence microscopy in each group. Results: Low-dose PDT significantly improved the distribution of Liporubicin in tumors compared to high-dose PDT (p < 0.05) and ILP alone (p < 0.05). However, both PDT pretreatments did not result in a higher overall drug uptake in tumors or a higher tumor-to-lung drug ratio compared to ILP alone. Conclusions: Intraoperative low-dose Visudyne-mediated PDT enhances liposomal doxorubicin distribution administered by ILP in sarcomas grown on rodent lungs which is predicted to improve tumor control by ILP.

Therapeutic Drug Monitoring of Targeted Anticancer Therapy. Tyrosine Kinase Inhibitors and Selective Estrogen Receptor Modulators: A Clinical Pharmacology Laboratory Perspective

In the last decade, a new era of cancer therapy has emerged, and the treatment of several cancers has shifted from cytotoxic and nonspecific chemotherapy to chronic oral treatment with targeted molecular therapies. Most oral anticancer-targeted drugs approved at present are tyrosine kinase inhibitors (TKIs) and some of them are accompanied with diagnostic test aiming at preselecting patients who are more likely to respond to anticancer treatment, constituting vivid examples of the emerging field of personalized medicine. In that context, since most TKIs are also characterized by an important interindividual variability in their pharmacokinetics, renewed efforts for treatment optimization should be made for targeting adequate drug exposure in patients, increasing thereby the likelihood of optimal clinical response and tolerability of anticancer treatment. This can be done through the Therapeutic Drug Monitoring (TDM) approach, whereby the careful selection of TKI dosage is adapted to each patient according to individual plasma levels, contributing to minimize the risk of major adverse reactions and to increase the probability of efficient, long-lasting, therapeutic response. This chapter reviews the bioanalytical developments by chromatography and mass spectrometry in the field of targeted anticancer therapy, across the growing family of recent FDA-approved oral TKIs as well as for tamoxifen and its active metabolites, being in fact the most widely used targeted anticancer agent. The text also provides an introduction to existing pharmacokinetics–pharmacodynamics knowledge in the field of targeted anticancer therapy, and the rationale for a TDM program for TKIs.