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Cystic fibrosis is one of the most common genetic diseases among caucasian population. This disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding for the CFTR protein. Lumacaftor, elexacaftor, tezacaftor, and ivacaftor were currently used as the treatment to Cystic fibrosis. In this study, we describe a new method for the simultaneous quantification of four molecules: lumacaftor, elexacaftor, tezacaftor, and ivacaftor, alongside two metabolites of ivacaftor, specifically hexyl-methyl ivacaftor and ivacaftor carboxylate by liquid chromatography-tandem mass spectrometry. This method holds significant utility for therapeutic drug monitoring and the optimization of treatments related to CFTR modulators. Molecules were extracted from 100 µL of plasma by a simple method of protein precipitation using acetonitrile. Following extraction, chromatographic separation was carried out by reverse chromatography on a C18 analytical column, using a gradient elution of water (0.05 % formic acid, V/V) and acetonitrile (0.05 % formic acid, V/V). The run time was 7 minutes at a flow rate of 0.5 mL/min. After separation, molecules were detected by electrospray ionization on a Xevo TQD triple-quadrupole-mass-spectrometer (Waters®, Milford, USA). The calibration range were: 0.053-20.000 mg/L for elexacaftor, tezacaftor and lumacaftor, 0.075-14.000 mg/L for ivacaftor, and 0.024-6.500 mg/L for hexyl-methyl ivacaftor and ivacaftor carboxylate. The proposed method underwent throughout validation demonstrating satisfactory precision (inter- and intra-day coefficients of variation less than 14.3 %) and a good accuracy (inter- and intra-day bias ranging between -13.7 % and 14.7 %) for all the analytes. The presented method for the simultaneous quantification of CFTR modulators and their metabolites in human plasma has undergone rigorous validation process yielding good results including strong precision and accuracy for all analytes. This method has been effectively used in routine analytical analysis and clinical investigations within our laboratory., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Reducing nivolumab dose intensity could increase patients' life quality and decrease the financial burden while maintaining efficacy. The aims of this study were to develop a population PK model of nivolumab based on data from unselected metastatic cancer patients and to simulate extended-interval regimens allowing to maintain minimal effective plasma concentrations (MEPC)., Methods: Concentration-time data (992 plasma nivolumab concentrations, 364 patients) were modeled using a two-compartment model with linear elimination clearance in Monolix software. Extended-interval regimens allowing to maintain steady-state trough concentrations (C min,ss ) above the MEPC of 2.5 mg/L or 1.5 mg/L in >90% of patients were simulated., Results: Increasing 3-times the dosing interval from 240 mg every two weeks (Q2W) to Q6W and 2-times from 480 mg Q4W to Q8W resulted in C min,ss above 2.5 mg/L in 95.8% and 95.4% of patients, respectively. 240 mg Q8W and 480 mg Q10W resulted in C min,ss above 1.5 mg/L in 91.0% and 91.8% of patients, respectively. Selection of a 240 mg Q6W regimen would decrease by 3-fold the annual treatment costs compared to standard regimen of 240 mg Q2W (from 78,744€ to 26,248€ in France)., Conclusions: Clinical trials are warranted to confirm the non-inferiority of extended-interval compared to standard regimen., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: BRAF and MEK inhibitors are cornerstones of the redifferentiation strategy in metastatic radioactive iodine (RAI)-resistant mutant thyroid cancers. We explored the exposure-toxicity relationship for dose-limiting toxicity (DLT) onset in patients treated with dabrafenib and/or trametinib and investigated whether plasma exposure was associated with RAI reuptake. Methods: We conducted a retrospective monocentric study in which we reviewed the electronic medical records of patients treated in our institution with a tumor redifferentiation strategy, for whom plasma concentration of dabrafenib, its active metabolite hydroxy-dabrafenib, and trametinib was measured. Trough concentrations (C minpred ) and total plasma drug exposure (area under the curve, AUC) of dabrafenib (AUC DAB ), hydroxy-dabrafenib (AUC OHD ), and trametinib (AUC TRA ) were estimated. Results: Of the 22 patients treated in a redifferentiation strategy between March 2014 and December 2021, 15 were included in this study. A dabrafenib- or trametinib-related DLT was experienced by 8 (62%) and 9 (64%) patients, respectively. Patients who experienced a trametinib-related DLT exhibited a significantly higher last AUC TRA than the average AUC TRA of patients who had no DLT (390, IQR: 67 vs. 215, IQR: 91 ng/mL·h -1 , respectively; p  = 0.008). Patients who experienced a dabrafenib-related DLT had a higher AUC DAB than observed in other patients (9265 ng/mL·h -1 vs. 6953 ng/mL·h -1 , respectively; p  = 0.09). No clinical and demographical characteristic was associated with the DLT onset. Overall, 9 of 15 (60%) patients demonstrated tumor redifferentiation. Patients in whom RAI reuptake was achieved had significant lower AUC DAB (6990 ng/mL·h -1 vs. 9764 ng/mL·h -1 , p  = 0.014; respectively) compared with patients who did not. Moreover, the relative exposure ratio of AUC OHD/DAB was significantly higher in patients who achieved RAI reuptake (1.11 vs. 0.71, respectively; p  = 0.0047). Conclusions: Our data suggest a relationship between DLT onset and trametinib plasma exposure, as well as an association between achievement of RAI reuptake and dabrafenib plasma exposure (AUC and ratio of AUC OHD/DAB ). These data imply that the use of plasma drug monitoring could be helpful in guiding clinical practice in redifferentiation treatment.

Background: Lipin-1 deficiency is a life-threatening disease that causes severe rhabdomyolysis (RM) and chronic symptoms associated with oxidative stress. In the absence of treatment, Hydroxychloroquine sulfate (HCQ) was administered to patients off label use on a compassionate basis in order to improve their physical conditions., Methods: Eleven patients with LPIN1 mutations were treated with HCQ. Clinical and biological efficacy and tolerance were assessed, including pain and quality of life, physical capacities, cardiopulmonary parameters, creatine kinase levels and plasma proinflammatory cytokines. To explore a dose-dependent effect of HCQ, primary myoblasts from 4 patients were incubated with various HCQ concentrations in growth medium (GM) or during starvation (EBSS medium) to investigate autophagy and oxidative stress., Findings: Under HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM. We hypothesized that HCQ exerts deleterious effects at high concentrations by blocking autophagy, and beneficial effects on oxidative stress at low concentrations. We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation in myoblasts during starvation., Interpretation: HCQ improves the condition of patients with lipin-1 deficiency, but at low concentrations. In vitro, 1 µM HCQ decreases oxidative stress in myoblasts whereas higher concentrations have a deleterious effect by blocking autophagy., Competing Interests: Declaration of Competing Interest PVE and PDL have filed PCT (WO/2017/085115; EP3377095; PCT/EP2016/077843) and US patent applications (US20180325890). PVE and PDL have filed PCT (WO/2019/020732; PCT/EP2018/070256) patent applications. The remaining authors have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Steroidogenesis inhibitors such as metyrapone (MTP) and osilodrostat (ODT) have a key role in the medical treatment of endogenous Cushing's Syndrome (ECS). Both drugs are characterized by a high inter-individual variability of response and require a dose-titration period to achieve optimal control of cortisol excess. However, PK/PD data remain scarce for both molecules and a pharmacokinetically guided approach could help reaching eucortisolism more rapidly. We aimed to develop and validate a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of ODT and MTP in human plasma. After addition of isotopically labeled internal standard (IS), plasma pretreatment consisted in protein precipitation with acetonitrile including 1% formic acid (v/v). Chromatographic separation was performed on Kinetex® HILIC (4.6 × 50 mm; 2.6 µm) analytical column with an isocratic elution during the 2.0-min run time. The method was linear from 0.5 to 250 ng/mL for ODT and from 2.5 to 1250 ng/mL for MTP. Intra- and inter-assay precisions were < 7.2%, with an accuracy ranging from 95.9% to 114.9%. The IS-normalized matrix effect ranged from 106.0% to 123.0% (ODT) and from 107.0% to 123.0% (MTP) and the range of the IS-normalized extraction recovery was 84.0-101.0% for ODT and 87.0-101.0% for MTP. The LC-MS/MS method was successfully applied in patients' plasma samples (n = 36), trough concentration of ODT and MTP ranged from 2.7 ng/mL to 8.2 ng/mL and from 10.8 ng/mL to 27.8 ng/mL, respectively. Incurred sample reanalysis exhibits less than 14% difference between the first and the second analysis for both drugs. This accurate and precise method, meeting all validation criteria, can therefore be used for plasma drug monitoring of ODT and MTP within the dose-titration period., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fideline Bonnet-Serrano reports a relationship with Ricordati that includes: speaking and lecture fees. Jerome Bertherat reports a relationship with Novartis, HRA Pharma, Recordati that includes: consulting or advisory, funding grants, and speaking and lecture fees. FBS participated in a symposium organized by Ricordati as a speaker. JB has received grants to his institution from Novartis, HRA Pharma, and Recordati, and personal honoraria for consulting, lectures, and/or meeting attendance from Novartis, HRA Pharma, Ipsen, Corcept and Recordati. BB has received consulting and speaking fees (BMS, Clovis Oncology, Pierre Fabre, Pfizer, Promise)., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Patients treated with dabrafenib and trametinib for BRAF V600 -mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib ( p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters.

High interindividual variability (IIV) of the clinical response to epidermal growth factor receptor (EGFR) inhibitors such as osimertinib in non-small-cell lung cancer (NSCLC) might be related to the IIV in plasma exposure. The aim of this study was to evaluate the exposure−response relationship for toxicity and efficacy of osimertinib in unselected patients with advanced EGFR-mutant NSCLC. This retrospective analysis included 87 patients treated with osimertinib. Exposure−toxicity analysis was performed in the entire cohort and survival analysis only in second-line patients (n = 45). No significant relationship between occurrence of dose-limiting toxicity and plasma exposure was observed in the entire cohort (p = 0.23, n = 86). The median overall survival (OS) was approximately two-fold shorter in the 4th quartile (Q4) of osimertinib trough plasma concentration (>235 ng/mL) than in the Q1−Q3 group (12.2 months [CI95% = 8.0−not reached (NR)] vs. 22.7 months [CI95% = 17.1−34.1]), but the difference was not statistically significant (p = 0.15). To refine this result, the exposure−survival relationship was explored in a cohort of 41 NSCLC patients treated with erlotinib. The Q4 erlotinib exposure group (>1728 ng/mL) exhibited a six-fold shorter median OS than the Q1−Q3 group (4.8 months [CI95% = 3.3-NR] vs. 22.8 months (CI95% = 10.6−37.4), p = 0.00011). These results suggest that high exposure to EGFR inhibitors might be related to worse survival in NSCLC patients.

Background: Pazopanib (PAZ) is an oral angiogenesis inhibitor approved to treat soft tissue sarcoma (STS) but associated with a large interpatient pharmacokinetic (PK) variability and narrow therapeutic index. We aimed to define the specific threshold of PAZ trough concentration (Cmin) associated with better progression-free survival (PFS) in STS patients. Methods: In this observational study, PAZ Cmin was monitored over the treatment course. For the primary endpoint, the 3-month PFS in STS was analyzed with logistic regression. Second, we performed exposure−overall survival (OS) (Cox model plus Kaplan−Meier analysis/log-rank test) and exposure−toxicity analyses. Results: Ninety-five STS patients were eligible for pharmacokinetic/pharmacodynamic (PK/PD) assessment. In the multivariable analysis, PAZ Cmin < 27 mg/L was independently associated with a risk of progression at 3 months (odds ratio (OR) 4.21, 95% confidence interval (CI) (1.47−12.12), p = 0.008). A higher average of PAZ Cmin over the first 3 months was associated with a higher risk of grade 3−4 toxicities according to the NCI-CTCAE version 5.0 (OR 1.07 per 1 mg/L increase, CI95 (1.02−1.13), p = 0.007). Conclusion: PAZ Cmin ≥ 27 mg/L was independently associated with improved 3-month PFS in STS patients. Pharmacokinetically-guided dosing could be helpful to optimize the clinical management of STS patients in daily clinical practice.

Background: The risk of drug-drug interactions (DDI) has become a major issue in cancer patients. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency and the factors associated with DDI with antitumor treatments, and to evaluate the impact of a pharmacist evaluation before anticancer treatment., Patients and Methods: We performed a retrospective review of consecutive sarcoma patients starting chemotherapy (CT) or Tyrosine kinase inhibitor (TKI). A pharmacist performed medication reconciliation and established an early toxicity risk assessment. Potential DDI with antitumor drugs were identified using Micromedex electronic software., Results: One hundred and twenty-two soft-tissue and 80 bone sarcoma patients (103 males, median age 50 years,) were included before CT (86%) or TKI (14%). The median number of medications was 3; 34 patients (22% of patients with medication reconciliation) reported complementary medicine use. 37 potential DDI classified as major, were identified (12% of the 243 pre-therapeutic assessments). In multivariate analysis, TKI (p < 0.0001), proton pump inhibitor (p = 0.026) and antidepressant (p < 0.001) were identified as risk factors of DDI (p < 0.02). Only marital status (p = 0.003) was associated with complementary medicine use. A pharmacist performed 157 medication reconciliations and made 71 interventions among 59 patients (37%). In multivariate analysis, factors associated with pharmacist intervention were: complementary medicines (p = 0.004), drugs number (p = 0.005) and treatment with TKI (p = 0.0002) CONCLUSIONS: Clinical interventions on DDI are more frequently required among sarcoma patients treated with TKI than CT. Multidisciplinary risk assessment including a medication reconciliation by a pharmacist could be crucial to prevent DDI with TKI., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from "real life" data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of dabrafenib (DAB), its main metabolite hydroxy-dabrafenib (OHD) and trametinib (TRA) in human plasma has been developed and validated. After addition of internal standard (dabrafenib-d9), extraction was achieved after protein precipitation with acetonitrile containing 1 % (v/v) formic acid. Chromatographic separation was performed on an Accucore® C18 (2.1 × 50 mm; 2.6 μm) column using a gradient elution of water acidified with 0.1 % (v/v) formic acid (A) and acetonitrile containing 0.1 % (v/v) formic acid (B) at a flow rate of 500 μL/min. The calibration ranged from 10 to 2000 ng/mL for DAB and OHD and from 5 to 50 ng/mL for TRA. This method was validated with satisfactory results including good precision (intra- and inter-assay coefficient of variation from 2.0 %-14.9 %) and good accuracy (inter- and intra-day bias between -1.2 % and 10.9 %), as well as long term stability in unprocessed plasma at -20 °C. This newly proposed method is useful for clinical research purposes as well as therapeutic drug monitoring for patients with a Rapidly Accelerated Fibrosarcoma kinase B (BRAF)-mutated cancer., Competing Interests: Declaration of Competing Interest Benoit Blanchet has served on advisory boards and received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Leo Pharma, and Pfizer. Francois Goldwasser has received a travel, accommodation, and research grant from Bristol-Myers Squibb. Nicolas Dupin reports personal fees, travel, accommodations, and expenses from Roche. Selim Aractingi has been a speaker for Pierre Fabre, Novartis, Janssen, and Abbvie and a member of boards of meetings for BMS and Sanofi. Other authors have declared no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure-response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances ( p < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively, p < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUC OHD /AUC DAB ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29-33.56); p = 0.023 and 10.61 (2.34-48.15), p = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11-9.50); p = 0.032 and HR = 1.23 (1.35-10.39), p = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUC OHD /AUC DAB deserves more investigation in a larger cohort of MM patients.

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p<0.05). No association was found between CYP3A4 or CYP3A5 genotypes and TAC whole blood or intracellular concentrations. Finally, intra-PBMC calcineurin activity appeared incompletely inhibited by TAC and less than 50% of patients were expected to achieve intracellular IC50 concentration (100 pg/millions of cells) at therapeutic whole blood concentration (i.e.: 4-10 ng/mL). Together, these data suggest that personalized medicine regarding TAC therapy might be optimized by ABCB1 pharmacogenetic biomarkers and by monitoring intracellular concentration whereas the relationship between intracellular TAC exposure and pharmacodynamics biomarkers more specific than calcineurin activity should be further investigated., Competing Interests: The authors have declared that no competing interests exist.