Search

Introduction CDK4/6 inhibitors, such as palbociclib, are prescribed in association with hormonal therapy in metastatic breast cancer patients. In Phase II/III studies, high neutropenia occurred in more than one in two patients leading to significant dose reductions, palbociclib interruptions and additional hematological samplings. Like most oral targeted drug, therapeutic drug monitoring (TDM) may be of interest for monitoring plasma exposition and optimize their dosage. We evaluated the correlation of this toxicity with palbociclib pharmacokinetics (PK), and classical sources of PK variabilities. Materials and method This is an open-label biomarker study conducted in subjects with first-line ER+/HER2- metastatic breast cancer treated with a palbociclib-aromatase inhibitor association (NCT04025541). Primary endpoint was the correlation between palbociclib trough concentration (Ctrough) at day 15 of first cycle of treatment (D15C1) and incidence of grade 3/4 neutropenia, within the first two months of treatment. Secondary endpoints included the analysis of variables associated with grade 3/4 neutropenia, with D15C1 palbociclib Ctrough values, and correlations with genetic polymorphisms in selected genes involved in palbociclib PK. Co-medications were collected to assess drug-drug interactions (DDI) risk and the potential impact on palbociclib PK. Results 58 patients, with mean age of 62.9 years, were included and followed up for 1 year. Clinicopathological variables were classical for the setting. One third of the population was taking concurrently a CYP3A4 and/or Pgp inhibitor, and one fourth an anti-acid medication, drugs that may interact with palbociclib. High-grade neutropenia occurred in 67.2% of patients (70.7% all grade neutropenia). One third of patients required a dose reduction, mainly for hematological toxicity. The geometric median of palbociclib plasma Ctrough was 74.1 ng/ml (interquartile range 61.3 - 101.5). Other covariates influencing the PK of palbociclib were significant in the univariate analysis. Indeed, while age > 65.5 years old (median) and reduced renal function (< 88.5 ml/min, median) were correlated with increased palbociclib concentration (p=0.003 and p=0.017, respectively) in univariate analysis. In multivariate analysis, higher neutrophil counts at inclusion (HR=0.54 for each 109/L increase in neutrophils count, range 0.33 - 0.87, p=0.002) while higher (>74.1 ng/mL, HR 5.51, range 1.10 - 27.6, p=0.024) plasma concentration of palbociclib were the only 2 variables correlated with the incidence of neutropenia. PK of palbociclib is closely related to co-medications, with majored exposition in CYP3A4 inhibitor cohort (106 vs 71.3 ng/ml, p=0.031, HR 0.22) or reduced exposition in anti-acid cohort (72.2 vs 80 ng/ml, p= 0.016, HR -0.27). Lastly, the homozygote G/G allele of the NRI2 (PXR) variant (Rs10934498) was associated with reduced palbociclib concentration (p=0.031) in univariate analysis. Conclusion We have characterized PK/toxicity correlation of palbociclib, regarding high-grade neutropenia. D15C1 higher palbociclib Ctrough is associated with the occurrence of high-grade neutropenia. As drug-drug interaction appears to be the most relevant source of palbociclib Ctrough variability in our cohort, a special attention must be paid to comedications in this population of patients. This is the first prospective study which characterizes biomarkers of toxicity associated with palbociclib treatment. Therapeutic drug monitoring can be a tool to limit high grade toxicities under palbociclib. Citation Format: Fanny Leenhardt, Frédéric Fiteni, Ludovic Gauthier, Marie Alexandre, Séverine Guiu, Nelly Firmin, Stéphane Pouderoux, Chloé Gautier, Gerald Lossaint, Alexandre Payen, Celine Gongora, Litaty Mbatchi, Alexandre Evrard, William Jacot. Pharmacokinetic determinants of palbociclib hematological toxicity [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-23.

Background In the present study, the authors aimed to compare the pharmacokinetics (PK) of micafungin in critically ill patients receiving continuous veno-venous hemofiltration (CVVH, 30 mL/kg/h) with those of patients receiving equidoses of hemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h) and determine the optimal dosing regimen using the developed model. Methods Patients with septic shock undergoing continuous renal replacement therapy (CRRT) and receiving a conventional dose of 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations from eight CVVH sessions and eight CVVHDF sessions were subjected to a population PK analysis using Pmetrics. Validation of the model performance was reinforced by external validation. Monte Carlo simulations were performed considering the total ratio of free drug area under the curve (AUC) over 24 h to the minimum inhibitory concentration (MIC) (AUC0-24/MIC) in plasma. Results The median total body weight (min-max) was 94.8 (66-138) kg. Micafungin concentrations were best described by a two-compartmental PK model. No covariates, including CRRT modality (CVVH or CVVHDF), were retained in the final model. The mean parameter estimates (standard deviation) were 0.96 (0.32) L/h for clearance and 14.8 (5.3) L for the central compartment volume. External validation confirmed the performance of the developed PK model. Dosing simulations did not support the use of standard 100 mg daily dosing, except for Candida albicans on the second day of therapy. A loading dose of 150 mg followed by 100 mg daily reached the probability of target attainment for all C. albicans and C. glabrata, but not for C. krusei and C. parapsilosis. Conclusions No difference was observed in micafungin PK between equidoses of CVVH and CVVHDF. A loading dose of 150 mg is required to achieve the PK/PD target for less susceptible Candida species from the first day of therapy.

OBJECTIVES To describe micafungin pharmacokinetic (PK) alterations of sepsis induced in piglets and to determine whether the porcine septic model is able to predict the PK of micafungin in septic patients at the plasma and peritoneal sites. METHODS From healthy (n = 8) and septic piglet group (n = 16), total micafungin concentrations were subject to a population PK analysis using Monolix®. Data from 16 septic humans patients from others studies was used to compare micafungin PK between septic piglets and septic patients. RESULTS Sepsis induced in piglets slightly alters the total clearance and the volume of distribution, while inter-compartment clearance is increased (from 3.88 to 5.74 L/h) as well as the penetration into peritoneal cavity (from 61 to 90%). In septic human patients, PK parameters are similar except for the Vd, which is corrected by an allometric factor based on the body weight of each species. Micafungin penetration into peritoneal cavity of humans is lower than in septic piglets (40 versus 90%). CONCLUSIONS The sepsis induced in the porcine model alters the PK of micafungin comparable to that in humans. In addition, micafungin PK is similar between these two species at the plasma level taking into account the allometric relationship of the body weight of these species on the central volume of distribution. The porcine septic plasma model would be able to predict the micafungin PK in the septic patients. However, further studies on peritoneal penetration are necessary to characterize this inter-species difference.

International audience; PurposeThe 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.MethodsA 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.ResultsA 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.ConclusionTo 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.

Background: The CDK4/6 inhibitors palbociclib is prescribed in association with hormonal therapy for the management of metastatic breast cancer patients. Like most oral targeted drug, therapeutic drug monitoring may be used for personalize their dosage. Using a recently published dosing technique (LC-MS/MS), we aimed at evaluating the correlation between first-cycle palbociclib plasma exposition and co-medications in order to evaluate drug-drug interaction (DDI) impact under palbociclib treatment.Methods: This is an open-label phase 4 study conducted in female subjects with first-line metastatic breast cancer (NCT04025541) treated with a palbociclib-aromatase inhibitor association. Plasma concentration of palbociclib was assessed at 24 hours postdose (plasma trough concentration Ctrough) at day 15 of first cycle of treatment. A dedicated pharmacist consultation allowed the determination of clinical covariates of interest, such as weight, body surface area, ethnicity, food intake, co-medications use and DDI before Palbociclib initiation and retrospectively at the end of clinical trial. Patients were classified then according to their risk of DDI potentially leading to inhibition of CYP3A4 and/or P-glycoprotein and gastric pH increase by gastric acid-suppressive (GAS) agents (such as proton pump inhibitors, histamine H2-receptor blockers or alginic acid). Relevant drug known to have an inhibition of CYP3A4 and/or P-glycoprotein or pH-modification activity were checked in databases (e.g. DDI predictor®, Drugs.com®, Pubmed®). Results: To date, after Ctrough analysis of the 35 first cases, the geometric mean (± standard deviation [min-max]) of palbociclib plasma Ctrough was 79.5 ng/ml (± 26.1% [43.6 ng/mL - 133 ng/mL]) at day 15, similar to what reported in the PALOMA trials. No correlation between plasma concentration and body weight, body area or also age of the patients was found in our cohort. Regarding ethnicity, all the included patients were from Caucasian origin. 31% of patients (11/35) were identified of taking drugs that could cause DDI CYP3A4 and P-glycoprotein inhibition mediated (amlodipine n=3, simvastatin n=3, losartan n=2, fluconazole n=1, atorvastatin n=1, ivabradine n=1). These potential DDI interactions were associated with a significantly higher palbociclib concentration DDI subgroup (102 ng/mL vs 69 ng/mL) (p=0.000272) (Table 1). No CYP3A4 and/or P-glycoprotein inductor were reported in cohort. 1.4% of patients (5/35) were identified of taking GAS agents (pantoprazole n=2, ranitidine n=2, alginic acid n=1). We found a significantly reduction of palbociclib concentration (59.2 ng/mL vs 79.8 ng/mL) (p=0.048) in patients taking GAS medications (Table 1). Conclusion : These preliminary results, in real-life settings, obtained with our recently-published HPLC-MS/MS method, give important information on palbociclib monitoring and pharmacokinetic variability. DDI appear to have a significant impact on palbociclib plasma exposure, GAS agents are already know to modified palbociclib absorption. Additional studies are needed to characterize palbociclib plasma concentration variations between patients, and their clinical impact on efficacy and safety. The study is ongoing and will evaluate additional potential clinical and biological impact of DDI on neutropenia occurrence, on a larger population of patients. Table 1: Patients’ plasma palbociclib concentration (day 15 of cycle 1 of treatment).Plasma palbociclib concentrations (ng/ml), global cohort (n=35)Geometric mean (CV%) (min;max)79.5 (26.1%) (43.6;133)Plasma palbociclib concentrations (ng/ml), cohort with DDI CYP3A4 and P-gp mediated (n=11)Geometric mean (CV%)102 (24.3%)Plasma palbociclib concentrations (ng/ml), cohort without DDI CYP3A4 and P-gp mediated (n=24)Geometric mean (CV%)69 (19.8%)Plasma palbociclib concentrations (ng/ml), cohort with GAS treatment (n=5)Geometric mean (CV%)59.2 (15.9%)Plasma palbociclib concentrations (ng/ml), cohort without GAS treatment (n=30)Geometric mean (CV%)82.9 (26.1%) Citation Format: Fanny Leenhardt, Matthieu Gracia, Catherine Perrin, Claudia Muracciole-Bich, Bénédicte Marion, Celine Roques, Marie Alexandre, Nelly Firmin, Stephane Pouderoux, Litaty Mbatchi, Celine Gongora, William Jacot, Alexandre Evrard. Impact of drug-drug interaction on palbociclib serum levels: Interest of therapeutic drug monitoring [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-16.

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.

Simple Summary Many kinase inhibitors have been tested as potential alternatives for the treatment of castration-resistant prostate cancers. However, none of these clinical trials led to drug approval despite interesting responses. Our study reveals that genes involved in drug metabolism and their master regulator PXR (Pregnane X Receptor) could be responsible, at least in part, for these disappointing results as they can modulate tumor cell response to specific kinase inhibitors. We found that stable expression of PXR sensitized prostate cancer cells to erlotinib, dabrafenib, and afatinib, while it rendered cells resistant to dasatinib and had no effect for other inhibitors tested. We also report for the first time that sensitization to afatinib is due to an alteration in drug transport that involves the SLC16A1 monocarboxylate transporter. Together, our results further indicate that PXR might be considered as a biomarker of response to kinase inhibitors in castration-resistant prostate cancers. Abstract 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.

International audience; A 53-year-old woman with papillary thyroid cancer treated with 800 mg sorafenib therapy rapidly experienced grade 3 toxicities. Dosing was reduced in a step-wise manner with several treatment discontinuations down to 200 mg every 2 days but severe toxicities continued. Plasma drug monitoring showed high exposure, even at low dose. Dosing was then further reduced at 200 mg every 3 days and tolerance was finally acceptable (i.e., grade 1 toxicity) with stable disease upon RECIST imaging. Pharmacogenetic investigations showed polymorphisms affecting both UGT1A9 ( UGT1A9-rs3832043) and nuclear receptor PXR ( NR1I2-rs3814055 , NR1I2-rs2472677 and NR1I2-rs10934498), possibly resulting in downregulation of liver metabolizing enzymes of sorafenib (i.e., CYP and UGT). Patient's clearance (0.48 l/h) estimated by Bayesian approach was consistently lower than usually described. This is the first time that, in addition to mutations affecting UGT1A9, genetic polymorphisms of NR1I2 have possibly been associated with both plasma overexposure and severe toxicities upon sorafenib intake.

Supported by a PHRC grant (#09-18-005) Background: Recent literature has suggested that germline genetic variants of drug-metabolizing enzymes or CYP19A1 (coding for aromatase) may be involved in the systemic aromatase inhibitors (AI) concentrations or the occurrence of side effects (Hertz et al. Pharmacogenomics 2017). A prospective multicentre 3-year follow-up study was carried out to investigate the relationships between pharmacogenetics (PG), pharmacokinetics (PK) and toxicity in breast cancer patients treated with adjuvant AI (n=1098) or tamoxifen (n=879). The clinical results and the tamoxifen PG/PK analyses are described elsewhere (abstracts #851544 and #850248). Methods: SNP genotyping of 95 SNPs was performed on the Biomark (Fluidigm) with Taqman assays and was available for 373, 515 and 151 patients treated with anastrozole (ANA), letrozole (LETRO) and exemestane (EXE) respectively. CYP2A6 metaboliser status (MS) (poor, intermediate or normal) was determined based on alleles function (*1, *9, *2) and number of CYP2A6 copies. Trough plasma concentrations of each drug were determined 6 months after the start of the study by UPLC-MS/MS and were available for 342, 463 and 130 patients of the ANA, LETRO and EXE arms. Patients with AI concentrations below the limit of quantification were excluded for non-compliance (9 patients for ANA, 8 patients for LETRO and 7 patients for EXE). Toxicity was measured as a binary outcome (occurrence or worsening of hot flushes, fatigue, pain, arthralgia, vaginal dryness). All genetic associations were adjusted for multiple testing. Results: ANA concentration was significantly higher in patients experiencing pain (p=0.025) and was associated with rs28365063 (UGT2B7 g.372A>G). LETRO concentrations were strongly associated with CYP2A6 metabolizer status (p=0.0001) but did not differ in patients with or without toxicity. In the EXE arm, patients with hot flushes or arthralgia had a significantly lower level of exemestane (p= 0.0002 and p=0.023 respectively) but since the metabolism of EXE leads to active 17-hydroexemestane, we can hypothesize that the lower EXE concentration is an indirect reflection of the metabolite formation. A SNP (rs2307424) in NR1I3 gene (coding for the constitutive androstane receptor CAR) was associated with EXE concentrations. CAR has been shown to regulate CYP2B6, which is involved in the formation of 6-hydroxy-methyl-exemestane (inactive metabolite). Regarding the relationships between PG and toxicity, in the ANA arm, 3 SNPs of CYP19A1 gene tended to be associated with hot flushes worsening (rs934635) and arthralgia (rs10046 and rs2304463) but did not remain significant after multiple tests correction. In the EXE arm, several SNPs in NR1I3 gene were associated with fatigue. In the LETRO arm, patients with a poor CYP2A6 MS had a higher risk of experiencing depression. Conclusions: Our study confirms the predominant role of CYP2A6 in LETRO PK. To our knowledge, this is the first study to report on the role of UGT2B7 rs28365063 in ANA and NR1I3 in EXE PK and side effects. These relationships need to be re-evaluated with the drug concentrations obtained during the 3-year follow-up. Citation Format: Thomas F, Marquet P, Pinguet F, White-Koning M, Robert J, Tafzi N, Solassol I, Despax R, Levasseur N, Ellis S, Massoubre A, Mbatchi L, Le Morvan V, Roché H, Chatelut E, Evrard A. Pharmacogenetic determinants of aromatase inhibitors pharmacokinetics and side effects: 6-month results of the adjuvant breast cancer longitudinal PHACS study (NCT01127295) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-07.

The CDK4/6 inhibitors palbociclib and ribociclib are kinase inhibitors used in association with hormonal therapy for the management of patients with metastatic breast cancer. Like most kinase inhibitors, therapeutic drug monitoring may be used for personalize their dosage. To this aim, we developed and validated a sensitive and specific HPLC-MS/MS method for palbociclib and ribociclib quantification in blood samples. We then quantified exposure to palbociclib (plasma trough concentration; Ctrough) in a real-life cohort of patients with locally invasive or metastatic breast cancer (n = 18) at day 15 of the first cycle of palbociclib treatment to characterize palbociclib concentration at steady state (Clinicaltrials.gov identifier NCT04025541, IdRCB n° 2018-A00064-51, 03/07/2018). The geometric mean (± standard deviation [min-max]) of palbociclib plasma Ctrough was 88.58 ng/mL (± 26.4 [46.5 ng/mL - 133 ng/mL]) at day 15. Some covariates, such as drug-drug interactions, could explain the concentration variations observed in our Caucasian cohort. These first results in real-life settings obtained with our HPLC-MS/MS method give important information on palbociclib monitoring and pharmacokinetic variability.

International audience; NR1I2 (PXR) and NR1I3 (CAR) are nuclear receptors that are classified as xenoreceptors. Upon activation by various xenobiotics, including marketed drugs, they regulate the transcription level of major drug-metabolizing enzymes and transporters and facilitate the elimination of xenobiotics from the body. The modulation of the activity of these two xenoreceptors by various ligands is a major source of pharmacokinetic variability of environmental origin. NR1I2 and NR1I3 genetic polymorphisms can affect the pharmacokinetics and therapeutic response to many drugs, such as irinotecan, tacrolimus and atazanavir. This review provides an overview of NR1I2 and NR1I3 pharmacogenetic studies in various therapeutic fields (oncology, immunomodulation and infectiology) and discusses the implementation of NR1I2 and NR1I3 genetic polymorphism testing in the clinical routine.

International audience; PURPOSE:Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor that exhibits antitumor activity in renal cell carcinoma and mantle cell lymphoma. The metabolism of temsirolimus and its active metabolite sirolimus mainly depends on cytochrome P450 3A4/5 (CYP3A4/A5) and the ABCB1 transporter. Differently from sirolimus, no pharmacogenetic study on temsirolimus has been conducted. Therefore, the aim of this pilot study was to identify genetic determinants of the inter-individual variability in temsirolimus pharmacokinetics and toxicity.METHODS:Pharmacokinetic profiles were obtained for 16 patients with bladder cancer after intravenous infusion of 25 mg temsirolimus. Non-compartmental analysis was performed to calculate the pharmacokinetic parameters of temsirolimus and sirolimus, its main metabolite. The presence of single nucleotide polymorphisms (SNPs) in CYP3A5, ABCB1 and in their transcriptional regulator NR1I2 (PXR) was assessed by genotyping. Non-parametric statistical tests were used to assess associations between candidate SNPs and temsirolimus pharmacokinetics and toxicity.RESULTS:The ratio between sirolimus AUC and temsirolimus AUC was 1.6-fold higher in patients who experienced serious toxic events (p = 0.034). The frequency of adverse events was significantly higher in patients homozygous for the NR1I2-rs6785049 A allele (OR = 0.065, p = 0.04) or NR1I2-rs3814055 C allele (OR = 0.032, p = 0.006). These NR1I2 SNPs were also predictive of temsirolimus half-life and global exposure to temsirolimus and sirolimus. Finally, the effect of the ABCB1-rs1128503, ABCB1-rs2032582 and CYP3A5*3 SNPs on sirolimus pharmacokinetics was confirmed.CONCLUSIONS:Our findings suggest that SNPs of NR1I2 and its target genes CYP3A5 and ABCB1 are genetic determinants of temsirolimus pharmacokinetics and toxicity in patients with bladder cancer.

International audience; Background: Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine.Methods: Two-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3’UTR and 5’UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement.Results: Among the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3–4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR.Conclusions: Exploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3–4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V.

International audience; BACKGROUND AND OBJECTIVES:Nuclear receptors PXR (pregnane X receptor, NR1I2) and CAR (constitutive androstane receptor, NR1I3) are key regulators of irinotecan metabolism, and ligand-dependent modulation of their activity leads to significant drug-drug interactions. Because genetic polymorphisms can also affect the activity of these xenobiotic-sensing receptors, we hypothesized that they could contribute to the interpatient variability of irinotecan pharmacokinetics and to the toxicity of irinotecan-based regimens.PATIENTS AND METHODS:In a cohort of 109 metastatic colorectal cancer patients treated with irinotecan (180 mg/m(2)) in combination with other drugs, associations were assessed between 21 selected single nucleotide polymorphisms of NR1I2 or NR1I3 and pharmacokinetic parameters or toxicity of irinotecan and its metabolites.RESULTS:After adjustment of the tests by the UGT1A1*28 genotype and correction for multiple testing, the A allele of NR1I2-rs10934498 was associated with a decreased exposition and an increased degradation of SN-38, the active metabolite (p = 0.009 and p = 0.017, respectively). The risk of hematological toxicity was associated with NR1I2-rs10934498 and NR1I2-rs2472677 (p = 0.009 and p = 0.003, respectively).CONCLUSION:Our results reveal for the first time the involvement of NR1I2 in the pharmacogenetics of irinotecan and suggest that it may help to predict the toxicity of low-dose irinotecan.

Aim: The goal of our study was to assess the impact of patients’ genetic background on their sensitivity to carboplatin/paclitaxel hematotoxicity. Patients & methods: Parameters describing sensitivity to neutropenia and to thrombocytopenia of 201 patients were extracted from a previous pharmacokinetic/pharmacodynamics analysis, in order to assess their association with 52 candidates SNPs in 18 genes. Results: Carriers of a T allele of SLCO1B3-rs4149117 were 19% less sensitive to thrombocytopenia than the homozygotes for the G allele (p = 0.00279). Carriers of two copies of the ATG haplotypes of NR1I2-rs1523130, rs3814055 and rs1523127 were 19% less sensitive to thrombocytopenia than those harboring other haplotypes (p = 0.025). Conclusion: Our results revealed the importance of SLCO1B3 and NR1I2 in the sensitivity to carboplatin/paclitaxel thrombocytopenia.

Pharmacogenetics has progressively become a major concern in personalized medicine. The development of modern technologies in genetic testing and cost-effectiveness have rendered genotyping strategies easy to perform comparing to time-consuming phenotyping methods. In oncology, canonical markers such TPMT, DPYD or UGT1A1 are routinely included in clinical practice but their use is still controversial partly because of insufficient genotype to phenotype correlation. The next challenge is to accurately translate genotype-phenotype correlations into clinically useful diagnostics, and clinically useful leads concerning new therapeutic targets. Besides, recent studies have focused on emerging genetic variants of ADME genes such cytidine deaminase (CDA) or pregnane X receptor (PXR) that could be of interest for predicting anticancer drug response or toxicity. The candidate gene approach "metabolism guided" now evolves towards more global strategies thanks to genome resequencing projects such HapMap that have considerably increased our knowledge of genetics variations in humans. Multiplexed genotyping methods make possible the set-up of panels of candidate or tag SNPs for subsequent haplotypic analysis. Last, genome-wide association studies (GWAS) are feasible when large cohort of patients is available to identify new loci associated with drug response or adverse drug reactions or to definitively confirm the role of candidate genetic variations.

International audience

From the promising results we previously obtained in quinazoline series and to complete the evaluation of the in vitro antiplasmodial activity of original 2-trichloromethylquinazolines, we synthesized new quinazolines possessing a variously substituted phenoxy group at position 4 through a simple and efficient two-step-synthesis approach. The studies of their activity toward the multi-resistant W2 Plasmodium falciparum strain and of their cytotoxicity on the human hepatocyte HepG2 cell line highlighted a hit compound (molecule 7) displaying a W2 IC(50) value of 1.1 μM and a HepG2 CC(50) value of 50 μM, comparable to chloroquine and doxycycline. Structure-activity- and toxicity relationships indicate that the trichloromethyl group plays a key role in the antiplasmodial activity of such chemical scaffold and also that the phenoxy group substitution as a direct influence on the molecules selectivity. Moreover, molecule 7 displays significant specific activity against the Plasmodium genus in comparison with Toxoplasma and does not show any mutagenic property at the Ames test.