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Abstract: Tyrosine kinase inhibitors efficacy in central nervous system (CNS) disease remains uncertain. Ponatinib was studied for CNS distribution in 16 patients with Philadelphia-positive acute lymphoblastic leukemia. Cerebrospinal fluid concentrations fell below the 40 nM threshold, suggesting suboptimal CNS exposure., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB)., Methods: In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1∗G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models., Findings: Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ± 32 μg/g vs. 0.16 ± 0.008 μg/g, p < 0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p = 0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs. untreated mice (178.5 vs. 166.5 days, p = 0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation., Interpretation: These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells., Funding: Fondation pour la Recherche Médicale (FRM). Investissements d'avenirANR-10-IAIHU-06, Société Française de Neurochirurgie (SFNC), Fond d'étude et de Recherche du Corps Medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA)., Competing Interests: Declaration of interests Michael Canney is an employee of Carthera and has ownership interest in the company as well as patents related to this technology. Alexandre Carpentier is a consultant to Carthera, has ownership interest in the company, and has filed patents pertaining to the results presented in the paper. Gaelle Bruneteau: Grants from the French association for ALS (ARSLA) and the French association for Myopathies (AFM), National Hospital Clinical Research Programs (PHRC-N)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In a cohort of 72 consecutive virologically-suppressed patients with HIV-1 switching to long-acting cabotegravir and rilpivirine, we observed low cabotegravir trough concentrations 1 and 3 months after the first injection, with a significant association with no oral lead-in at 1 month [odds ratio (OR) = 6.3 [95% confidence interval (CI) 1.7-29.5], P = 0.01] and three months (OR = 5.6 [95% CI 1.3-29.7], P = 0.03), and with high BMI at 1 month (OR = 1.3 [95% CI 1.1-1.6], P = 0.007)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Increased rates of sexually transmitted infections (STIs) are reported among men who have sex with men (MSM) and new interventions are needed. We aimed to assess whether post-exposure prophylaxis (PEP) with doxycycline could reduce the incidence of chlamydia or syphilis (or both) and whether the meningococcal group B vaccine (4CMenB) could reduce the incidence of gonorrhoea in this population., Methods: ANRS 174 DOXYVAC is a multicentre, open-label, randomised trial with a 2 × 2 factorial design conducted at ten hospital sites in Paris, France. Eligible participants were MSM aged 18 years or older, HIV negative, had a history of bacterial STIs within the 12 months before enrolment, and who were already included in the ANRS PREVENIR study (a cohort of MSM using pre-exposure prophylaxis with tenofovir and emtricitabine for HIV prevention). Participants were randomly assigned (2:1) to doxycycline PEP (two pills of 100 mg each orally within 72 h after condomless sex, with no more than three doses of 200 mg per week) or no PEP groups and were also randomly assigned (1:1) to the 4CMenB vaccine (GlaxoSmithKline, Paris, France; two intramuscular injections at enrolment and at 2 months) or no vaccine groups, using a computer-generated randomisation list with a permuted fixed block size of four. Follow-up occurred for at least 12 months (with visits every 3 months) up to 24 months. The coprimary outcomes were the risk of a first episode of chlamydia or syphilis (or both) after the enrolment visit at baseline for the doxycycline intervention and the risk of a first episode of gonorrhoea starting at month 3 (ie, 1 month after the second vaccine dose) for the vaccine intervention, analysed in the modified intention-to-treat population (defined as all randomly assigned participants who had at least one follow-up visit). This trial is registered with ClinicalTrials.gov, NCT04597424 (ongoing)., Findings: Between Jan 19, 2021, and Sept 19, 2022, 556 participants were randomly assigned. 545 (98%) participants were included in the modified intention-to-treat analysis for the doxycycline PEP and no PEP groups and 544 (98%) were included for the 4CMenB vaccine and no vaccine groups. The median follow-up was 14 months (IQR 9-18). The median age was 40 years (34-48) and all 545 participants were male. There was no interaction between the two interventions (p≥0·1) for the primary outcome. The incidence of a first episode of chlamydia or syphilis (or both) was 8·8 per 100 person-years (35 events in 362 participants) in the doxycycline PEP group and 53·2 per 100 person-years (80 events in 183 participants) in the no PEP group (adjusted hazard ratio [aHR] 0·17 [95% CI 0·12-0·26]; p<0·0001). The incidence of a first episode of gonorrhoea, starting from month 3 was 58·3 per 100 person-years (103 events in 274 participants) in the 4CmenB vaccine group and 77·1 per 100 person-years (122 events in 270 participants) in the no vaccine group (aHR 0·78 [95% CI 0·60-1·01]; p=0·061). There were no deaths during the study. One drug-related serious adverse event (fixed-drug eruption) occurred in the doxycycline PEP group. Six (2%) participants in the doxycycline group discontinued doxycycline PEP because of gastrointestinal adverse events., Interpretation: Doxycycline PEP strongly reduced the incidence of chlamydia and syphilis in MSM, but we did not show efficacy of the 4CmenB vaccine for gonorrhoea. Doxycycline PEP should be assessed in other populations, such as heterosexual men and women, and its effect on antimicrobial resistance carefully monitored., Funding: ANRS Maladies Infectieuses Emergentes., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests J-MM received support as an adviser for Gilead Sciences, Merck, Abbott, and ViiV; consulting fees from Aelix; and research grants from Gilead Sciences and Merck. GP received consulting fees from AstraZeneca, Gilead Sciences, Merck, and ViiV. JG received consulting fees from Gilead Sciences and ViiV. DC received personal fees from Pfizer for a lecture outside of the submitted work. CD, CK, and LSl received consulting fees from Gilead Sciences, Merck, and ViiV. LG received support from Novartis and consulting fees from AbbVie, Promise, Ipsen, and Takeda. All other authors declare no competing interests., (2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: We wished to assess time to protection from HIV-1 infection following oral tenofovir disoproxil and emtricitabine (TDF/FTC) as preexposure prophylaxis (PrEP), using ex-vivo rectal tissue infections and drug concentration measures in blood and rectal tissue., Design/methods: Participants from the ANRS PREVENIR study (NCT03113123) were offered this sub-study after a 14-day wash-out. We used an ex-vivo model to evaluate rectal tissue HIV-1 susceptibility before and after PrEP, 2 h after two pills or 7 days of a daily pill of TDF/FTC. PrEP efficacy was expressed by the difference (after-before) of 14-day cumulative p24 antigen levels. TFV-DP and FTC-TP levels were measured in rectal tissue and PBMCs and correlated with HIV-1 infection., Results: Twelve and 11 men were analyzed in the 2 h-double dose and 7 days-single dose groups, respectively. Cumulative p24 differences after-before PrEP were -144 pg/ml/mg (IQR[-259;-108]) for the 2 h-double dose group ( P  = 0.0005) and -179 pg/ml/mg (IQR [-253;-86]) for the 7 days-single dose group ( P  = 0.001), with no differences between groups ( P  = 0.93). Rectal TFV-DP was below quantification after a double dose, but FTC-TP levels were similar to levels at 7 days. There was a significant correlation between rectal FTC-TP levels and p24 changes after a double dose ( R  = -0.84; P  = 0.0001)., Conclusion: Oral TDF/FTC provided similar protection against HIV-1 infection of rectal tissue 2 h after a double dose or 7 days of a daily dose. At 2 h, this protection seems driven by high FTC-TP concentrations in rectal tissue. This confirms the importance of combining TDF and FTC to achieve early protection., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

The treatment of chronic myeloid leukemia relies on orally available tyrosine kinase inhibitors targeting the BCR::ABL1 oncoprotein. Bosutinib is a second generation adenosine triphosphate-competitive inhibitor approved for use in frontline adult chronic phase-chronic myeloid leukemia and all phases-chronic myeloid leukemia in the second line setting or beyond. Its efficacy was demonstrated in several pivotal clinical trials at 400mg once daily in the first line context and at 500mg once daily beyond first line. Bosutinib-related adverse events frequently occur early after treatment initiation and include gastro-intestinal symptoms and cytolytic hepatitis. These drug-related adverse events must be properly managed in order to preserve safety, efficacy and treatment acceptability. The French chronic myeloid leukemia study group gathered a panel of experts in hematology, pharmacology and hepatology in order to elaborate practical recommendations on the management of bosutinib treatment. These recommendations aim at optimizing the short and long-term tolerance and benefit/risk balance of bosutinib, mainly focusing at gastro-intestinal and liver toxicities., (Copyright © 2023 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery., (© 2023. The Author(s).)

Objectives: To assess the impact on the estimated glomerular filtration rate (eGFR) of different tenofovir disoproxil/emtricitabine dosing regimens for HIV pre-exposure prophylaxis (PrEP)., Patients and Methods: We included in the study individuals with baseline eGFR > 50 mL/min/1.73 m2 who initiated PrEP in the ongoing ANRS-PREVENIR PrEP cohort. We retrospectively classified PrEP users in three groups: 'on-demand' (reported at ≥75% of study visits), 'daily' (≥75% of study visits) or 'switches'. We compared the area under curve (AUC) of the eGFR variation from baseline (ΔeGFR) between groups using analysis of covariance, and assessed factors associated with a negative AUC of ΔeGFR., Results: From May 2017 to October 2020, 1253 PrEP-naïve participants (98% of MSM) were included in the study with a median follow-up of 22 months. 499 (40%), 494 (39%) and 260 (21%) users were in the group daily, on-demand and switches, respectively, for a median number of pills taken per week of 6, 1.7 and 4. The mean AUC of the ΔeGFR was -1.09 mL/min/1.73 m2 in the daily PrEP group, -0.69 mL/min/1.73 m2 in the switches group and +0.18 mL/min/1.73 m2 with on-demand PrEP. In a model adjusted on baseline age and eGFR, the AUC of the ΔeGFR was significantly higher with on-demand PrEP compared to daily PrEP (P = 0.037). Independent factors associated with a negative AUC of ΔeGFR were a daily PrEP regimen, a switches regimen, an age > 40 years and a baseline eGFR≥90 mL/min/1.73 m²., Conclusions: On-demand PrEP dosing had a smaller impact on eGFR evolution than daily PrEP, but the difference was not clinically relevant., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (6-MP) are used extensively in pediatric and adult patients with inflammatory and neoplastic diseases. They are metabolized to 6-thioguanine nucleotides (6-TGN) or to 6-methyl-mercaptopurine nucleotides (6-MMPN). The balance between 6-TGN and 6-MMPN is highly variable and monitoring is recommended, but its benefit in outcome gives rise to conflicting results, potentially increased by differences in quantifying 6-MP metabolism. Our aim was to report (1) the HPLC-UV procedure used in our laboratory to quantify red blood cells (RBCs) with 6-TGN and 6-MMPN (as its derivate: 6-MMP(d)) in patients treated with thiopurines and (2) additional tests, sometimes confirmatory, to improve method standardization. The comparison of two methods to count RBCs shows that metabolite concentrations were slightly lower in the washed and resuspended RBCs than in whole blood. Perchloric acid (0.7 M), dithiothreitol (DTT, final 0.013 M sample concentration) and 60 min hydrolysis were selected for acid hydrolysis. (3) Monitoring data from 83 patients receiving AZA or 6-MP showed that at steady state, only 53/183 (29%) had 6-TGN and 6-MMPN in the recommended therapeutic range. Our method is discussed in light of the technical conditions and sample stability data from 17 publications identified since the first analytical report in 1987. Monitoring data demonstrate, if required, that inter-patient variability in 6-TGN and 6-MMPN concentrations is high in samples from treated patients.

Background: There are few data available regarding the use of on-demand pre-exposure prophylaxis (PrEP) for HIV prevention. We aimed to assess PrEP effectiveness, adherence, and safety in adults using daily or on-demand PrEP., Methods: We conducted a prospective observational cohort study (ANRS PREVENIR) at 26 sites in the Paris region, France. We enrolled HIV-negative adults (aged ≥18 years) at high risk of HIV infection who were starting or continuing PrEP. PrEP was prescribed as a fixed-dose combination of tenofovir disoproxil and emtricitabine (245 mg and 200 mg, respectively, per pill). PrEP could be prescribed as a daily regimen with one pill per day or, in men who have sex with men (MSM) or in transgender women who have sex with men, as an on-demand regimen following the IPERGAY dosing recommendation. At enrolment and every 3 months thereafter, participants were tested for HIV and provided information regarding the PrEP dosing regimen used. Adherence to PrEP was assessed by self-report and by tenofovir diphosphate concentrations in dried blood spots. The primary outcome of HIV-1 incidence was assessed using Poisson regression among participants who started PrEP. This study is registered with ClinicalTrials.gov, NCT03113123, and EudraCT, 2016A0157744., Findings: Between May 3, 2017, and May 2, 2019, 3082 people were assessed for eligibility and 3065 participants were enrolled. 3056 (99·7%) of 3065 participants reported using PrEP and were included in the analyses. The median age was 36 years (IQR 29-43), 1344 (44·0%) of 3056 participants were PrEP-naive, and 3016 (98·7%) were MSM. At enrolment, 1540 (50·5%) of 3049 participants opted for daily PrEP dosing and 1509 (49·5%) opted for on-demand PrEP dosing; these proportions remained stable during follow-up. Median follow-up was 22·1 months (IQR 15·9-29·7) and incidence of study discontinuation was 17·6 participants (95% CI 16·5-18·7) per 100 person-years. At the data cutoff on Sept 30, 2020, there had been six HIV-1 seroconversions (three participants using daily PrEP and three using on-demand PrEP; all were MSM) over 5623 person-years. Overall HIV-1 incidence was 1·1 cases (95% CI 0·4-2·3) per 1000 person-years, and did not differ between participants using daily PrEP and those using on-demand PrEP (incidence rate ratio 1·00, 95% CI 0·13-7·49; p=0·99). Four participants (two using daily PrEP and two using on-demand PrEP) discontinued PrEP due to treatment-related adverse events (nausea [n=2], vomiting and diarrhoea [n=1], and lumbar pain [n=1])., Interpretation: In this study, which enrolled mainly MSM, HIV-1 incidence on PrEP was low and did not differ between participants using daily PrEP and those using on-demand PrEP. On-demand PrEP therefore represents a valid alternative to daily PrEP for MSM, providing greater choice in HIV prevention., Funding: ANRS/Maladies Infectieuses Emergentes, Gilead Sciences, SIDACTION, and Région Ile de France., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests J-MM reports receiving support as an advisor for Gilead Sciences, Merck, Janssen, and ViiV; and research grants from Gilead Sciences. JG reports receiving support as an advisor for Gilead Sciences, Merck, Janssen, Roche, AstraZeneca, Theratechnologies, and ViiV; and research grants from Gilead Sciences and ViiV. CK reports research grants from Merck; and personal fees from Gilead Sciences, Merck, and ViiV. GP reports consulting fees from Gilead, Merck, and ViiV; and research grants from AbbVie and Gilead Sciences. CD reports support as an advisor for Gilead Sciences, Merck, and ViiV; and research grants from Merck, ViiV, and Gilead Sciences. DC reports a research grant from Janssen; and personal fees from Gilead for lectures. MB-M reports a research grant from Gilead Sciences. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This work’s objective was to evaluate the safety of isavuconazole (ISA) as a treatment or prophylaxis for invasive fungal infections (IFIs) in immunocompromised children. IFI was reported as proven or probable according to international definitions. Therapeutic drug monitoring was performed using mass tandem spectrometry to quantify trough plasma concentrations. Targeted ISA levels were 2−4 mg/L, as reported in adult series. Nine patients received ISA as a curative treatment, and six received ISA as prophylaxis. IFIs were proven in four cases and probable in five. The median ISA trough plasma concentration in curative use was 3.19 mg/L [0.88;5.00], and it was 2.94 mg/L [2.77;3.29] in the prophylactic use. The median durations of treatment were 81 days [15;276] and 95 days [15;253], respectively. Three patients had elevated aspartate aminotransferase and alanine aminotransferase, and three patients had elevated creatinine serum. The IFI response was satisfactory in all cases at day 90. No side effects were reported. No patients developed an IFI. Our data underline the safety of an ISA 100 mg dosing regimen in children of <30 kg, which we recommend in this fragile population. We suggest that ISA plasma levels are monitored 10 days after ISA initiation and then every two weeks, alongside guided therapeutic drug monitoring (TDM) administration.

The discovery of molecular alterations involved in oncogenesis is evolving rapidly and has led to the development of new innovative targeted therapies in oncology. High-throughput sequencing techniques help to identify genomic targets and to provide predictive molecular biomarkers of response to guide alternative therapeutic strategies. Besides the emergence of these theranostic markers for the new targeted treatments, pharmacogenetic markers (corresponding to genetic variants existing in the constitutional DNA, i.e., the host genome) can help to optimize the use of chemotherapy. In this review, we present the current clinical applications of constitutional PG and the recent concepts and advances in pharmacogenomics, a rapidly evolving field that focuses on various molecular alterations identified on constitutional or somatic (tumor) genome., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is a reliable pharmacokinetics biomarker of adherence to tenofovir disoproxil fumarate (TDF). We aimed to use DBSs to estimate pill intake among participants using on-demand pre-exposure prophylaxis (PrEP) and to identify predictive factors associated with higher TFV-DP concentrations., Methods: DBSs were collected at the last study visit of the open-label phase of the ANRS IPERGAY study, assessing on-demand oral TDF/emtricitabine for PrEP among MSM and transgender female participants. We quantified TFV-DP in DBSs centrally. We assessed correlation between pill count and TFV-DP concentration by Spearman correlation and explored associations between participant demographics, sexual behaviour and PrEP use during sexual intercourse (SI) with TFV-DP concentrations by univariate and multivariate logistic regression models., Results: The median age of the 245 participants included in this study was 40 years, with a median body weight of 73 kg. Median (IQR) TFV-DP concentration reached 517 (128-868) fmol/punch, corresponding to an estimated intake of 8-12 tablets per month (2-3 doses per week). Only 39% of participants had a TFV-DP concentration above 700 fmol/punch. TFV-DP concentrations were moderately correlated with pill count (r: 0.59; P < 0.001). In multivariate analysis, only systematic use of PrEP during SI and more frequent episodes of SI in the past 4 weeks were significantly associated with higher TFV-DP levels [OR (95% CI): 11.30 (3.62-35.33) and 1.46 (1.19-1.79), respectively; P < 0.001]., Conclusions: Among participants using on-demand PrEP, estimated pill intake reached 8-12 tablets per month and was correlated with frequency and systematic use of PrEP for SI., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Dabrafenib plus trametinib combination has greatly improved survival in BRAFV600 mut metastatic melanoma patients. However, data regarding the influence of pharmacokinetic markers in real-life patients are lacking. In this study, we aimed to explore dabrafenib and trametinib pharmacokinetic impact on progression-free survival (PFS), duration of response (DOR) or all grades treatment-related adverse events (ARAE) occurrence in routine care patients., Methods: BRAFV600 mut metastatic melanoma patients initiating standard doses of dabrafenib 150 mg BID plus trametinib 2 mg QD were included. Clinical data were collected via the French biobank MelBase, prospectively enrolling unresectable stage III or IV melanoma. Clinical response evaluation, ARAE reporting and dabrafenib and trametinib plasma quantification were performed. Association of individual Bayesian-estimated pharmacokinetic markers (AUC 0-τ and C trough ) and baseline clinical variables with DOR, PFS, clinical response, and ARAE was then assessed., Results: Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3 n = 10, G4 n = 0). In univariate analysis, median dabrafenib C trough within intermediate range was associated with a significantly higher PFS (HR [95% CI] = 0.41 [0.18; 0.91], p = 0.029) and DOR (HR [95% CI] = 0.39 [0.16; 0.94], p = 0.024), and association with DOR remained significant in multivariate analysis (HR [95% CI] = 0.34 [0.12; 0.95], p = 0.040). Trametinib pharmacokinetic markers were significantly higher in patients experiencing ARAE compared to patients without ARAE., Conclusion: In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in BRAFV600 mut metastatic melanoma patients based on trough concentrations of dabrafenib and trametinib., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The therapeutic management of cancers has undergone considerable changes due to the emergence of genomics tools and tumor molecular deciphering. In this context, a dual pharmacological approach based on pharmacogenomic analyses and therapeutic drug monitoring is now part of the routine care in cancer management for personalized therapies. First, molecular and immune profiling of tumors allows the emergence of new pharmacological targets in common as well as in rare cancers. Second, pharmacogenomic analyses coupled to therapeutic drug monitoring guide the prescription by adjusting regimen and managing drug resistance., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Rationale: Cytotoxic drug preparation in hospital pharmacies is associated with chronic occupational exposure leading to a risk of adverse effects. The objective was to develop and validate a quantification method for the following cytotoxic drugs in environmental wipe samples: cyclophosphamide, ifosfamide, cytarabine, dacarbazine, docetaxel, paclitaxel, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, methotrexate and pemetrexed., Methods: The quantification method was developed using liquid chromatography coupled to tandem mass spectrometry and a wiping technique using viscose swabs. Linearity, accuracy, precision, limit of quantification, specificity and stability were assessed, from swab desorbed solution, to validate the analytical method, with respect to ICH guidelines. Environmental samples were collected by wiping five work surfaces of 225 cm 2 with viscose swabs, during three days., Results: The quantification method was linear over the calibration range with a lower limit of quantification ranging from 0.5 to 5.0 ng mL -1 depending on the cytotoxic drug. The intra-day and inter-day relative biases were below 1.5% and 13.5%, respectively. This method was successfully applied to surface-wipe sampling and environmental contaminations ranged from 0.7 to 1840.0 ng cm -2 for the most contaminated areas., Conclusions: This quantification method for 14 cytotoxic drugs was successfully applied to environmental contamination monitoring and could therefore be a useful tool for monitoring and toxicological studies., (© 2019 John Wiley & Sons, Ltd.)

The development of BRAF and MEK inhibitors (BRAFi/MEKi) has led to major advances in melanoma treatment. However, the emergence of resistance mechanisms limits the benefit duration and a complete response occurs in less than 20% of patients receiving BRAFi ± MEKi. In this study, we evaluated the impact of an intermittent versus continuous dosing schedule of BRAF/MEK inhibition in a melanoma model mildly sensitive to a BRAF inhibitor. The combination of a BRAFi with three different MEKi was studied with a continuous or intermittent dosing schedule in vivo, in a xenografted melanoma model and ex vivo using histoculture drug response assays (HDRAs) of patient-derived xenografts (PDX). To further understand the underlying molecular mechanisms of therapeutic efficacy, a biomarker pharmacodynamic readout was evaluated. An equal impact on tumor growth was observed in monotherapy or bitherapy regimens whether we used continuous and intermittent dosing schedules, with no significant differences in biomarkers expression between the treatments. The antitumoral effect was mostly due to modulations of expression of cell cycle and apoptotic mediators. Moreover, ex vivo studies did not show significant differences between the dosing schedules. In this context, our preclinical and pharmacodynamic results converged to show the similarity between intermittent and continuous treatments with either BRAFi or MEKi alone or with the combination of both., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Direct-acting antiviral agents have demonstrated their efficacy in treating HCV recurrence after liver transplantation and particularly the sofosbuvir/daclatasvir combination. Pharmacokinetic data on both calcineurin inhibitors and direct-acting antiviral exposure in liver transplant recipients remain sparse., Methods: Patients were enrolled from the ANRS CO23 CUPILT cohort. All patients treated with sofosbuvir/daclatasvir with or without ribavirin were included in this study when blood samples were available to estimate the clearance of immunosuppressive therapy before direct-acting antiviral initiation and during follow-up. Apparent tacrolimus and cyclosporine clearances were estimated from trough concentrations measured using validated quality control assays., Results: Sixty-seven mainly male patients (79%) were included, with a mean age of 57 years and mean MELD score of 8.2; 50 were on tacrolimus, 17 on cyclosporine. Ribavirin was combined with sofosbuvir/daclatasvir in 52% of patients. Cyclosporine clearance remained unchanged as well as tacrolimus clearance under the ribavirin-free regimen. Tacrolimus clearance increased 4 weeks after direct-acting antivirals and ribavirin initiation versus baseline (geometric mean ratio 1.81; 90% CI 1.30-2.52). Patients under ribavirin had a significantly higher fibrosis stage (> 2) (p = 0.02) and lower haemoglobin during direct-acting antiviral treatment (p = 0.02) which impacted tacrolimus measurements. Direct-acting antiviral exposure was within the expected range., Conclusion: Our study demonstrated that liver transplant patients with a recurrence of hepatitis C who are initiating ribavirin combined with a sofosbuvir-daclatasvir direct-acting antiviral regimen may be at risk of lower tacrolimus concentrations because of probable ribavirin-induced anaemia and higher fibrosis score, although there are no effects on cyclosporine levels., Trial Registration: NCT01944527.

Posaconazole diffusion has been documented in various organs, which contrasts with the scarce data available for the human central nervous system (CNS). We analyzed posaconazole concentrations in plasma and multiple CNS specimens taken from a patient who received posaconazole because of cerebral phaeohyphomycosis. Low posaconazole concentrations were obtained in CNS specimens, with sample-to-plasma ratios between 5% and 22%. This case highlights the role of neurosurgery during cerebral phaeohyphomycoses, even those caused by posaconazole-susceptible black fungi., (Copyright © 2019 American Society for Microbiology.)

We report the cases of a 39-year-old woman with chronic lymphocytic leukemia and a 21-year-old man with chronic granulomatous disease treated for cerebral aspergillosis. The patients required radical surgery for infection progression despite adequate isavuconazole plasma concentration or neurological complication. We thus decided to measure the brain isavuconazole concentration. These results suggest that the concentrations of isavuconazole obtained in the infected brain tissue clearly differ from those obtained in the normal brain tissue and the cerebrospinal fluid., (Copyright © 2019 American Society for Microbiology.)

The blood-spinal cord barrier (BSCB) considerably limits the delivery and efficacy of treatments for spinal cord diseases. The blood-brain barrier can be safely opened with low-intensity pulsed ultrasound when microbubbles are simultaneously administered intravenously. This technique was tested on the BSCB in a rabbit model in this work. Twenty-three segments of spinal cord were sonicated with a 1-MHz unfocused pulsed ultrasound device and compared with non-sonicated segments. BSCB disruption was assessed using Evan's blue dye (EBD) extravasation. Tolerance was assessed by histologic analysis. An increased EBD concentration indicating BSCB disruption was clearly observed in sonicated segments compared with controls (p = 0.004). On one animal, which received 10 sonications, repetitive BSCB disruptions revealed no evidence of cumulative toxicity. BSCB can be disrupted using an unfocused pulsed ultrasound device in combination with microbubbles without neurotoxicity even in case of repeated sonications., (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Introduction: Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. Few cytotoxic chemotherapies have been shown to be effective against GBM, due in part to the presence of the blood-brain barrier (BBB), which reduces the penetration of chemotherapies from the blood to the brain. Ultrasound-induced BBB opening (US-BBB) has been shown to increase the penetration of multiple chemotherapeutic agents in the brain in animal models. In the current study, the anti-tumor activity of carboplatin chemotherapy with and without US-BBB was investigated in several GBM mouse models., Methods: First, the IC50 of two commercial (U87 and U251) and six patient-derived GBM cell lines (PDCL) to carboplatin was measured. Next, U87 was subcutaneously grafted to a nude mouse model to test the in vivo response of the tumor to carboplatin in the absence of the BBB. Lastly, nude mice bearing orthotopically xenografted GBM cell lines (U87 or a PDCL) were randomized to four experimental groups: (i) untreated, (ii) US-BBB alone, (iii) carboplatin alone and, (iv) carboplatin + US-BBB. Mice were treated once weekly for 4 weeks and monitored for toxicity, tumor growth, and survival., Results: Carboplatin plus US-BBB enhanced survival (p = 0.03) and delayed tumor growth (p < 0.05) of GBM-bearing mice compared to carboplatin alone, with a 4.2-fold increase of carboplatin penetration in the brain, without evidence of significant neurological or systemic toxicity., Conclusions: Carboplatin efficacy was enhanced in GBM mouse models with US-BBB and appears to be a promising chemotherapy for this approach.

Background: A simple, rapid, and sensitive liquid chromatography coupled with tandem mass spectrometry method has been developed and validated for the quantification of ruxolitinib, olaparib, vismodegib, and pazopanib in human plasma., Methods: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using an ultraperformance liquid chromatography system coupled with mass tandem spectrometry in a positive ionization mode. The mobile phase consisted of a gradient elution of 10-mmol/L formate ammonium buffer containing 0.1% (vol/vol) formic acid (phase A) and acetonitrile with 0.1% (vol/vol) formic acid (phase B) at a flow rate at 300 µL/min., Results: Analysis time was 5.0 minutes per run, and all analytes and internal standards eluted within 1.5-1.73 minutes. The calibration curves were linear over the range from 10 to 2500 ng/mL for ruxolitinib and from 100 to 100,000 ng/mL for olaparib, vismodegib, and pazopanib with coefficients of correlation above 0.99 for all analytes. The intraday and interday coefficients of variation were below 14.26% and 14.81%, respectively, for lower concentration and below 9.94% and 6.37%, respectively, for higher concentration., Conclusions: Using liquid chromatography coupled with tandem mass spectrometry, we have developed and validated a simple and rapid assay for the simultaneous quantification of olaparib, vismodegib, pazopanib, and ruxolitinib in human plasma. This method is now part of our therapeutic drug monitoring service provision and is currently used clinically to manage patients prescribed these drugs.

Background: Idelalisib is the first orally active selective phosphatidylinositol 3-kinase delta inhibitor approved by Food and Drug Administration and European Medicines Agency in 2014 for the treatment of several types of blood cancer. Idelalisib is widely used as a monotherapy or in combination with rituximab, bendamustine, or ofatumumab with a significant efficacy. However, idelalisib has shown increased risk of infection and a higher frequency of serious adverse events. It may be useful to determine idelalisib concentration in human plasma to adjust dose and to manage adverse effects in clinical practice., Methods: After a single-step protein precipitation of plasma samples, the chromatographic separation was performed using an ultra-high performance liquid chromatography system coupled with mass tandem spectrometry in a negative ionization mode using isotope-labeled internal standard. This method was validated by studies of its linearity, accuracy, imprecision, limit of quantification, recovery, matrix effect, selectivity, and stability., Results: The quantification method was linear from 10 to 2500 ng/mL with a 5 ng/mL lower limit of quantification that encompasses the clinical range of drug concentration. The intraday and interday imprecisions were below 8.1% and 11.4%, respectively. The recoveries and matrix effect of idelalisib were 85.6% ± 1.2% and 95.7% ± 3.0%, respectively, which are consistent, precise, and reproducible (coefficient of variation % < 15%). Peak plasma concentration and trough plasma concentration ranges of idelalisib reached 1591-1937 ng/mL and 256.3-303.3 ng/mL, respectively, in 3 follicular lymphoma patients treated with idelalisib 150 mg twice a day., Conclusions: A robust and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated to quantify idelalisib concentration in human plasma. This method was effectively applied to 3 follicular lymphoma patients.

Purpose: Central nervous system (CNS) dissemination occurs in 4.1% of mantle cell lymphoma (MCL) patients and clinically significant CNS involvement in chronic lymphocytic leukemia (CLL) patients reaches 4%. Ibrutinib, an orally administered Bruton's tyrosine kinase (BTK) inhibitor, has shown substantial activity in CLL or MCL patients with CNS localization, and in primary central nervous system lymphoma (PCNSL). The drug efficacy to treat primary or secondary CNS impairments relies on its brain distribution through the blood-brain barrier (BBB), the aim of the present work was to study the brain distribution of ibrutinib using an in vivo mice model., Methods: Brain and plasma pharmacokinetics of ibrutinib were assessed in a healthy Swiss mice model. Brain accumulation of ibrutinib was evaluated through an escalation single-dose study and a multiple-dose study in whole brain and in its specific anatomic structures. Ibrutinib plasma and brain quantification was performed using a validated liquid-chromatography mass tandem spectrometry method., Results: Maximal concentration of ibrutinib in plasma and brain were close thus showing that ibrutinib rapidly crosses the BBB in 0.29 h (0.2-0.32 h) [median (min-max)]. Ibrutinib brain exposure was also correlated to the dose, and correlated to plasma exposure. AUC 0-t brain to AUC 0-t plasma ratio average for ibrutinib was found to reach 0.7 and ibrutinib accumulates in the ventricle area., Conclusion: The high level of ibrutinib brain distribution supports the clinical efficacy of this drug in CNS localization of MCL, CLL or PCNSL.

In situ carmustine wafers containing 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) are commonly used for the treatment of recurrent glioblastoma to overcome the brain-blood barrier. In theory, this chemotherapy diffuses into the adjacent parenchyma and the excipient degrades in maximum 8 weeks but no clinical data confirms this evolution, because patients are rarely operated again. A 75-year-old patient was operated twice for recurrent glioblastoma, and a carmustine wafer was implanted during the second surgery. Eleven months later, a third surgery was performed, revealing unexpected incomplete degradation of the wafer. 1H-Nuclear Magnetic Resonance was performed to compare this wafer to pure BCNU and to an unused copolymer wafer. In the used wafer, peaks corresponding to hydrophobic units of the excipient were no longer noticeable, whereas peaks of the hydrophilic units and traces of BCNU were still present. These surprising results could be related to the formation of a hydrophobic membrane around the wafer, thus interfering with the expected diffusion and degradation processes. The clinical benefit of carmustine wafers in addition to the standard radio-chemotherapy remains limited, and in vivo behavior of this treatment is not completely elucidated yet. We found that the wafer may remain after several months. Alternative strategies to deal with the blood-brain barrier, such as drug-loaded liposomes or ultrasound-opening, must be explored to offer larger drug diffusion or allow repetitive delivery.