ABSTRACT
A combination of tyrosine kinase inhibitors (TKIs) is likely to be a therapeutic option for numerous oncological situations due to high frequency of oncogenic addiction and progress in precision oncology. Non-small cell lung cancer (NSCLC) represents a subtype of tumors for which oncogenic drivers are frequently involved. To the best of our knowledge, we report the first case of a patient treated with three different TKIs. Osimertinib and crizotinib were administered concurrently for an epidermal growth factor receptor (EGFR)-mutated NSCLC developing a MET amplification as a resistance mechanism to osimertinib. Simultaneously, imatinib was administered for a metastatic gastrointestinal stromal tumor. The progression-free survival was 7 months for both tumors with this tritherapy. The use of therapeutic drug monitoring to assess plasma concentrations of each TKI was a powerful tool to manage the toxicity profile of this combination (creatine phosphokinase elevation) while preserving an optimal exposure to each TKI and treatment efficacy. We observed an imatinib over-exposition related to crizotinib introduction, probably explained by drug-drug interaction mediated by crizotinib enzymatic inhibition on cytochrome P-450 3A4. Posology adjustment due to therapeutic drug monitoring was probably involved in the good survival outcome of the patient. This tool should be used more routinely for patients treated by TKIs to prevent co-treatment interactions and, in particular, for patients receiving TKI combinations to obtain optimal therapeutic exposure and efficacy while reducing possible side-effects.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Crizotinib/therapeutic use , Crizotinib/pharmacology , Drug Monitoring , Imatinib Mesylate/pharmacology , Imatinib Mesylate/therapeutic use , Protein Kinase Inhibitors/adverse effects , Mutation , Precision Medicine , Drug Resistance, NeoplasmABSTRACT
WHAT IS KNOWN AND OBJECTIVE: Sunitinib pharmacokinetics can be influenced by the physio-pathological conditions of individual patients. Therapeutic drug monitoring (TDM) helps to optimize efficacy and reduce the risk of adverse effects. We report on the use of Bayesian analysis to optimize sunitinib blood levels. CASE SUMMARY: We describe two patients with risk of sunitinib pharmacokinetic variability due to gastrectomy and ongoing haemodialysis, respectively. TDM and Bayesian estimation allowed maintaining their sunitinib pharmacokinetic profiles within the usual limits. WHAT IS NEW AND CONCLUSION: Our analysis showed that Bayesian analysis can be successfully applied for real-time TDM to optimize sunitinib blood levels in patients with major comorbidities.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Drug Monitoring/methods , Kidney Neoplasms/drug therapy , Sunitinib/pharmacokinetics , Sunitinib/therapeutic use , Age Factors , Aged , Bayes Theorem , Comorbidity , Female , Gastrectomy , Humans , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Renal DialysisABSTRACT
High throughput confocal imaging poses challenges in the computational image analysis of complex subcellular structures such as the microtubule cytoskeleton. Here, we developed CellArchitect, an automated image analysis tool that quantifies changes to subcellular patterns illustrated by microtubule markers in plants. We screened microtubule-targeted herbicides and demonstrate that high throughput confocal imaging with integrated image analysis by CellArchitect can distinguish effects induced by the known herbicides indaziflam and trifluralin. The same platform was used to examine 6 other compounds with herbicidal activity, and at least 3 different effects induced by these compounds were profiled. We further show that CellArchitect can detect subcellular patterns tagged by actin and endoplasmic reticulum markers. Thus, the platform developed here can be used to automate image analysis of complex subcellular patterns for purposes such as herbicide discovery and mode of action characterisation. The capacity to use this tool to quantitatively characterize cellular responses lends itself to application across many areas of biology.
Subject(s)
Herbicides/pharmacology , High-Throughput Screening Assays/methods , Microtubules/drug effects , Optical Imaging/methods , Tubulin Modulators/pharmacology , Actins/metabolism , Arabidopsis/drug effects , Arabidopsis/metabolism , Arabidopsis Proteins/metabolism , Indenes/pharmacology , Microtubules/metabolism , Protein Binding , Triazines/pharmacology , Trifluralin/pharmacology , Tubulin/metabolismABSTRACT
The precision of a quantum sensor can overcome its classical counterpart when its constituents are entangled. In Gaussian squeezed states, quantum correlations lead to a reduction of the quantum projection noise below the shot noise limit. However, the most sensitive states involve complex non-Gaussian quantum fluctuations, making the required measurement protocol challenging. Here we measure the sensitivity of nonclassical states of the electronic spin J=8 of dysprosium atoms, created using light-induced nonlinear spin coupling. Magnetic sublevel resolution enables us to reach the optimal sensitivity of non-Gaussian (oversqueezed) states, well above the capability of squeezed states and about half the Heisenberg limit.
ABSTRACT
We report on an experimental study of the Lipkin-Meshkov-Glick model of quantum spins interacting at infinite range in a transverse magnetic field, which exhibits a ferromagnetic phase transition in the thermodynamic limit. We use dysprosium atoms of electronic spin J=8, subjected to a quadratic Zeeman light shift, to simulate 2J=16 interacting spins 1/2. We probe the system microscopically using single magnetic sublevel resolution, giving access to the spin projection parity, which is the collective observable characterizing the underlying Z_{2} symmetry. We measure the thermodynamic properties and dynamical response of the system, and we study the quantum critical behavior around the transition point. In the ferromagnetic phase, we achieve coherent tunneling between symmetry-broken states, and we test the link between symmetry breaking and the appearance of a finite order parameter.
ABSTRACT
Targeted therapies have revolutionized the treatment of many cancers. Widely developed over the last decade, this new concept of precision medicine relies on the use of genomic technologies to analyze tumor samples in order to identify actionable targets and biomarkers of resistance. The goal is to optimize treatment by identifying which therapeutic approach is best for each patient, i.e. the treatment that is effective, has minimal adverse effects, and avoids unnecessary intervention and cost. The purpose of this review is to highlight, using a few seminal examples of therapeutic targets, the important contribution of appropriate analysis of key oncogenes or driver genes in making clinical decisions. Cancer genomics is now an indispensable part of clinical management. Furthermore, the development of next generation sequencing (NGS) will enable exploration of more and more genes of interest, leading to new treatment options for personalized medicine.
Subject(s)
Molecular Targeted Therapy , Neoplasms/genetics , Neoplasms/therapy , Precision Medicine , High-Throughput Nucleotide Sequencing , Humans , PharmacogeneticsABSTRACT
OBJECTIVES: Low first-dose peak serum concentrations of amikacin and gentamicin are commonly reported in ICU patients. The present study aimed to assess whether 30 mg/kg amikacin or 8 mg/kg gentamicin achieved target concentrations in ICU patients with severe sepsis. PATIENTS AND METHODS: Sixty-three ICU patients (Simplified Acute Physiology Score IIâ=â43â±â16) with severe sepsis and an indication for intravenous amikacin (nâ=â47) or gentamicin (nâ=â16) were included. The first (30 mg/kg amikacin; 8 mg/kg gentamicin) and subsequent doses and corresponding peak concentrations (30 min after the completion of an infusion) were recorded. French guideline target concentrations were ≥60 and ≥30 mg/L for amikacin and gentamicin, respectively. A target pharmacokinetic/pharmacodynamic ratio of 10â×âMIC was also measured. RESULTS: Pulmonary, abdominal and urinary tract infections were diagnosed in 56 patients. Infection was confirmed in 37 patients (59%). The targeted first-dose peak concentration was achieved in 37/63 patients (59%) [amikacin 36/47 (77%) and gentamicin 1/16 (6%)], and 59/63 patients (94%) achieved the pharmacokinetic/pharmacodynamic ratio using the MIC data that were available from 21 patients. However, the second dose of aminoglycoside was withheld because of high trough concentrations in nearly half of patients who did not have renal dysfunction. CONCLUSIONS: In this study, 30 mg/kg amikacin and 8 mg/kg gentamicin led to target peak serum concentrations in 59% of patients.
Subject(s)
Amikacin/administration & dosage , Amikacin/pharmacokinetics , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Gentamicins/administration & dosage , Gentamicins/pharmacokinetics , Sepsis/drug therapy , Administration, Intravenous , Adult , Aged , Aged, 80 and over , Critical Illness , Female , France , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Serum/chemistry , Young AdultABSTRACT
The first layer of plant immunity is activated by cell surface receptor-like kinases (RLKs) and proteins (RLPs) that detect infectious pathogens. Constitutive interaction with the SUPPRESSOR OF BIR1 (SOBIR1) RLK contributes to RLP stability and kinase activity. As RLK activation requires transphosphorylation with a second associated RLK, it remains elusive how RLPs initiate downstream signaling. We employed live-cell imaging, gene silencing and coimmunoprecipitation to investigate the requirement of associated kinases for functioning and ligand-induced subcellular trafficking of Cf RLPs that mediate immunity of tomato against Cladosporium fulvum. Our research shows that after elicitation with matching effector ligands Avr4 and Avr9, BRI1-ASSOCIATED KINASE 1/SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3 (BAK1/SERK3) associates with Cf-4 and Cf-9. BAK1/SERK3 is required for the effector-triggered hypersensitive response and resistance of tomato against C. fulvum. Furthermore, Cf-4 interacts with SOBIR1 at the plasma membrane and is recruited to late endosomes upon Avr4 trigger, also depending on BAK1/SERK3. These observations indicate that RLP-mediated resistance and endocytosis require ligand-induced recruitment of BAK1/SERK3, reminiscent of BAK1/SERK3 interaction and subcellular fate of the FLAGELLIN SENSING 2 (FLS2) RLK. This reveals that diverse classes of cell surface immune receptors share common requirements for initiation of resistance and endocytosis.
Subject(s)
Arabidopsis Proteins/metabolism , Endocytosis , Fungal Proteins/metabolism , Plant Immunity , Protein Serine-Threonine Kinases/metabolism , Receptors, Cell Surface/metabolism , Cell Membrane/metabolism , Cladosporium , Endosomes/metabolism , Ligands , Solanum lycopersicum/immunology , Solanum lycopersicum/microbiology , Models, Biological , Plants, Genetically Modified , Protein Binding , Nicotiana/geneticsABSTRACT
BACKGROUND & AIMS: The nuclear Pregnane X Receptor (PXR, NR1I2) plays a pivotal role in xenobiotic metabolism. Here, we sought to characterize a new PXR isoform (hereafter called small PXR or sPXR) stemming from alternative transcription starting sites downstream of a CpG Island located near exon 3 of the human PXR gene. METHODS: Quantitative RT-PCR, western blot, methylation-specific PCR, luciferase reporter assays, electro-mobility shift assays, and stable sPXR overexpression were used to examine sPXR expression and function in hepatocellular cell lines, healthy human liver (n=99), hepatocellular adenomas (HCA, n=91) and hepatocellular carcinoma samples (HCC, n=213). RESULTS: Liver sPXR mRNA expression varied importantly among individuals and encodes a 37kDa nuclear protein consisting of the ligand-binding domain of PXR that behaves as a dominant-negative of PXR transactivation properties. In vitro methylation of the sPXR upstream promoter abolished its activity, while the demethylation agent 5-aza-2-deoxycytidine increased sPXR mRNA expression in several cell lines. Finally, we observed that sPXR mRNA expression displayed significant differences related to HCA or HCC biology. CONCLUSIONS: This novel PXR isoform, displaying a dominant-negative activity and regulated by DNA methylation, is associated with outcomes of patients with HCC treated by resection, suggesting that it represents a key modulator of PXR.
Subject(s)
Adenoma, Liver Cell/metabolism , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Liver/metabolism , Receptors, Steroid/metabolism , Adenoma, Liver Cell/pathology , Adenoma, Liver Cell/surgery , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/surgery , Cell Line, Tumor , Cells, Cultured , DNA Methylation , Hepatectomy , Humans , In Vitro Techniques , Liver/pathology , Liver Neoplasms/pathology , Liver Neoplasms/surgery , Pregnane X Receptor , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Steroid/genetics , Treatment OutcomeABSTRACT
PURPOSE: The combination of bevacizumab and FOLFIRINOX is used in patients with RAS-mutant metastatic colorectal cancer (RASm-mCRC). Regorafenib, an oral multi-tyrosine kinase inhibitor, has antiangiogenic properties, cytostatic effects and also true cytotoxic effects, unlike bevacizumab. The aim of this study was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the regorafenib-FOLFIRINOX combination in patients with RASm-mCRC. METHODS: The FOLFIRINOX-R trial was a phase 1/2 study where the dose-escalation part (3 + 3 design with three dose levels, DLs) was completed before its early termination. FOLFIRINOX (14-day cycle) included oxaliplatin (standard dose), folinic acid, fluorouracil and irinotecan (150 or 180 mg/m²). Regorafenib (120 or 160 mg daily) was given from day 4 to day 10 of each cycle. Dose-limiting toxicity (DLT) was studied in the first three cycles. Eligibility criteria included ECOG performance status ≤ 1 and not previously treated RASm-mCRC. RESULTS: Thirteen patients (median age: 65 years; min-max: 40-76) were enrolled. DLT could not be evaluated in one patient (DL3) due to poor observance. The median treatment duration and median follow-up were 6.2 (min-max: 2.3-10) and 13.4 (min-max: 3.8-18.0) months, respectively. Dose was modified in 12/13 (92%) patients. One grade 3 hypokalemia occurred at DL2. MTD was not reached at DL3. Grade 3 diarrhea was recorded in 7/13 patients (13 events) equally distributed in all DLs. CONCLUSION: The RP2D for this regorafenib-FFX combination could not be determined due to a high prevalence of grade 3 diarrhea related to treatment as advised by our Independent Data Monitoring Committee. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov : NCT03828799.
ABSTRACT
BACKGROUND: Letrozole, an aromatase inhibitor metabolised via CYP2A6 and CYP3A4/5 enzymes, is used as adjuvant therapy for women with hormone receptor (HR)-positive early breast cancer. The objective of this study was to quantify the impact of CYP2A6 genotype on letrozole pharmacokinetics (PK), to identify non-adherent patients using a population approach and explore the possibility of a relationship between non-adherence and early relapse. METHODS: Breast cancer patients enrolled in the prospective PHACS study (ClinicalTrials.gov NCT01127295) and treated with adjuvant letrozole 2.5 mg/day were included. Trough letrozole concentrations (Css,trough) were measured every 6 months for 3 years by a validated LC-MS/MS method. Concentration-time data were analysed using non-linear mixed effects modelling. Three methods were evaluated for identification of non-adherent subjects using the base PK model. RESULTS: 617 patients contributing 2534 plasma concentrations were included and led to a one-compartment PK model with linear absorption and elimination. Model-based methods identified 28 % of patients as non-adherent based on high fluctuations of their Css,trough compared to 3 % based on patient declarations. The covariate analysis performed in adherent subjects revealed that CYP2A6 intermediate (IM) and slow metabolisers (SM) had 21 % (CI95 % = 12 - 30 %) and 46 % (CI95 % = 41 - 51 %) lower apparent clearance, respectively, compared to normal and ultrarapid metabolisers (NM+UM). Early relapse (19 patients) was not associated with model-estimated, concentration-based or declared adherence in the total population (p = 0.41, p = 0.37 and p = 0.45, respectively). CONCLUSIONS: These findings will help future investigations focusing on the exposure-efficacy relationship for letrozole in adjuvant setting.
Subject(s)
Aromatase Inhibitors , Breast Neoplasms , Letrozole , Medication Adherence , Humans , Letrozole/pharmacokinetics , Letrozole/administration & dosage , Letrozole/therapeutic use , Letrozole/blood , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Middle Aged , Aged , Aromatase Inhibitors/pharmacokinetics , Aromatase Inhibitors/administration & dosage , Aromatase Inhibitors/therapeutic use , Aromatase Inhibitors/blood , Adult , Chemotherapy, Adjuvant/methods , Models, Biological , Prospective Studies , Receptors, Estrogen/metabolism , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/blood , Antineoplastic Agents/administration & dosage , Aged, 80 and overABSTRACT
With human genome mapping, the omics revolution and the empowering sequencing technologies developed at the turn of the century, the new goals in medicine are to switch from population medicine to individualized therapies, not only to cure diseases but also to prevent them. The purpose of this review by the pharmacogenetics and predictive medicine working group of the French clinical biology society (SFBC) is to situate in their correct context the notions of personalized medicine, pharmacogenetics, genetics and genomics, emphasizing their interactions and discussing their significance for researchers and clinicians.
Subject(s)
Precision Medicine , Biomarkers , Computational Biology , Genomics , Humans , Pharmacogenetics , Sequence Analysis, DNAABSTRACT
Despite the efficacy of targeted therapies in melanoma, the management of adverse events with BRAFi and MEKi (inhibitors) is one of the limits of these treatments. Close monitoring is required to ensure efficacy and patient safety. In this case study, we report a patient treated for metastatic melanoma with an unusual and innovative combination of dabrafenib (BRAFi) and cobimetinib (MEKi), to manage pyrexia, and lead to complete remission for 19 months. This is the first case ever reported of metastatic melanoma treated with this off-label combination and characterized by the use of therapeutic drug monitoring.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Proto-Oncogene Proteins B-raf/genetics , Melanoma/drug therapy , Melanoma/pathology , Protein Kinase Inhibitors/adverse effects , Mitogen-Activated Protein Kinase Kinases , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , MutationABSTRACT
Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, bicentric clinical trial, we evaluated the palbociclib exposure−toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug−drug interactions (DDI). We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies.
ABSTRACT
BACKGROUND: Preeclampsia is a frequent complication of pregnancy and a leading cause of perinatal mortality. Both genetic and environmental risk factors have been identified. Lipid metabolism, particularly cholesterol metabolism, is associated with this disease. Liver X receptors alpha (NR1H3, also known as LXRalpha) and beta (NR1H2, also known as LXRbeta) play a key role in lipid metabolism. They belong to the nuclear receptor superfamily and are activated by cholesterol derivatives. They have been implicated in preeclampsia because they modulate trophoblast invasion and regulate the expression of the endoglin (CD105) gene, a marker of preeclampsia. The aim of this study was to investigate associations between the NR1H3 and NR1H2 genes and preeclampsia. METHODS: We assessed associations between single nucleotide polymorphisms of NR1H3 (rs2279238 and rs7120118) and NR1H2 (rs35463555 and rs2695121) and the disease in 155 individuals with preeclampsia and 305 controls. Genotypes were determined by high-resolution melting analysis. We then used a logistic regression model to analyze the different alleles and genotypes for those polymorphisms as a function of case/control status. RESULTS: We found no association between NR1H3 SNPs and the disease, but the NR1H2 polymorphism rs2695121 was found to be strongly associated with preeclampsia (genotype C/C: adjusted odds ratio, 2.05; 95% CI, 1.04-4.05; p = 0.039 and genotype T/C: adjusted odds ratio, 1.85; 95% CI, 1.01-3.42; p = 0.049). CONCLUSIONS: This study provides the first evidence of an association between the NR1H2 gene and preeclampsia, adding to our understanding of the links between cholesterol metabolism and this disease.
Subject(s)
Orphan Nuclear Receptors/genetics , Polymorphism, Genetic , Pre-Eclampsia/genetics , Adult , Case-Control Studies , Female , Genetic Predisposition to Disease , Genotyping Techniques/methods , Humans , Liver X Receptors , Polymorphism, Single Nucleotide , Pregnancy , Young AdultABSTRACT
PURPOSE: The aim of the present study was to characterize the pharmacokinetics of irinotecan and its four main metabolites (SN-38, SN-38G, APC and NPC) in metastatic colorectal cancer patients treated with FOLFIRI and FOLFIRINOX regimens and to quantify and explain the inter-individual pharmacokinetic variability in this context. METHODS: A multicenter study including 109 metastatic colorectal cancer patients treated with FOLFIRI or FOLFIRINOX regimen, associated or not with a monoclonal antibody, was conducted. Concentrations of irinotecan and its four main metabolites were measured in 506 blood samples during the first cycle of treatment. Collected data were analyzed using the population approach. First, fixed and random effects models were selected using statistical and graphical methods; second, the impact of covariates on pharmacokinetic parameters was evaluated to explain the inter-individual variability in pharmacokinetic parameters. RESULTS: A seven-compartment model best described the pharmacokinetics of irinotecan and its four main metabolites. First-order rates were assigned to distribution, elimination, and metabolism processes, except for the transformation of irinotecan to NPC which was nonlinear. Addition of a direct conversion of NPC into SN-38 significantly improved the model. Co-administration of oxaliplatin significantly modified the distribution of SN-38. CONCLUSION: To our knowledge, the present model is the first to allow a simultaneous description of irinotecan pharmacokinetics and of its four main metabolites. Moreover, a direct conversion of NPC into SN-38 had never been described before in a population pharmacokinetic model of irinotecan. The model will be useful to develop pharmacokinetic-pharmacodynamic models relating SN-38 concentrations to efficacy and digestive toxicities. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT00559676.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Irinotecan/pharmacokinetics , Topoisomerase I Inhibitors/pharmacokinetics , Camptothecin/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Female , Fluorouracil/therapeutic use , Humans , Irinotecan/therapeutic use , Leucovorin/therapeutic use , Male , Oxaliplatin/therapeutic use , Topoisomerase I Inhibitors/therapeutic useABSTRACT
PURPOSE: Pharmacist consultation is unfrequently performed in oncology clinical trials that include patients who often have many co-treatments increasing the risk of drug-drug interactions (DDI). The aim of this study was to determine whether best possible medication history (BPMH) by hospital pharmacist at inclusion and therapeutic drug monitoring could be used for DDI risk evaluation and for current oral targeted therapy management. METHODS: A prospective clinical trial (ALCINA 2, NCT04025541) was carried out in metastatic breast cancer cohort treated by palbociclib to conduct pharmacokinetics-toxicity correlation study. BPMH was prospectively performed by the hospital pharmacist at each trial inclusion, followed by a contact to the patient's community pharmacy to complete the collected data. Pharmacokinetic analysis was performed on blood samples collected at day 15 of cycle 1 of palbociclib treatment. RESULTS: Pharmacist interventions indicated that at inclusion, current medications were incomplete for 63% of the enrolled patients (32/51). It allowed the real-time management of high-risk DDI detected in third of patients. The palbociclib Ctrough geometric median (min-max) was significantly higher in cohort with potential DDI [106 ng/mL (66.7-113)], than cohort without potential DDI [70.1 ng/mL (54.1-89.7)], p = 0.0284. CONCLUSION: This is the first prospective study evaluating the relevance of proactive BPMH by pharmacist with contact to the community pharmacy during the inclusion step of a clinical trial to ensure the efficacy and safety of the investigated drug. This investigation was thus able to highlight the statistically significant impact of these DDI on palbociclib plasma concentration variation during the clinical trial. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT04025541.
Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Pharmacists/organization & administration , Piperazines/administration & dosage , Pyridines/administration & dosage , Administration, Oral , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Drug Interactions , Drug Monitoring/methods , Female , Humans , Molecular Targeted Therapy , Pharmacy Service, Hospital/organization & administration , Piperazines/adverse effects , Piperazines/pharmacokinetics , Professional Role , Prospective Studies , Pyridines/adverse effects , Pyridines/pharmacokineticsABSTRACT
Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers.
ABSTRACT
Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration-time data for TAM and 6 metabolites come from a prospective, multicenter, 3-year follow-up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7-compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra-rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N-desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose-adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient's CYP2D6 phenotype for TAM dose adaptation.