Synthetic cathinones in drug-facilitated sexual assault: A case report involving the novel generation substituted cathinone N-ethylpentedrone and a review of the literature.

The use of 3,4-methylenedioxymethamphetamine (MDMA) in drug-facilitated sexual assault (DFSA) is not uncommon. Indeed, the effects associated with the use of this substance may lead to disinhibition. Several synthetic cathinones, such as mephedrone or methylone, also possess marked entactogenic properties. This manuscript aims to (i) report a DFSA case involving a novel cathinone derivative, namely N-ethyl-pentedrone (NEPD) and (ii) review previously reported DFSA cases involving synthetic cathinones. Using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), NEPD was detected in both plasma and urine collected from a 36-year-old male who had been victim of DFSA. Furthermore, an exhaustive, non-period-specific English-language literature search was performed using several different electronic databases to identify DFSA cases involving synthetic cathinones. Overall, five synthetic cathinones have been associated with DFSA:methylenedioxypyrovalerone, 4-methylethcathinone, α -pyrrolidinopentiophenone, mephedrone, α -pyrrolidinohexiophenone, and methylone, which appears to be the most frequently reported. Methylone is the ß-keto analog of MDMA, with which it shares substantial pharmacological similarities. Indeed, the pharmacological effects of methylone are similar to those associated with MDMA. By contrast, little is known regarding NEPD's pharmacological effects in humans. Based on subjective reports, NEPD can produce both positive and negative effects in human. Unlike what is reported in the case of methylone or mephedrone, only a small minority of NEPD users report slightly entactogenics effects. Such properties theoretically make NEPD more suitable for use in a chemsex context than in DFSA context; even though, the boundary between these two specific forms of sexualized drug use can sometimes appear tenuous.

The interest of using vitreous humor for γ-hydroxybutyrate (GHB) quantification in related fatalities: Stability evaluation, case report and literature review.

Analysis and interpretation of the findings for γ-hydroxybutyrate (GHB) in related fatalities remains problematic. Indeed, GHB is a naturally occurring compound present in both the mammalian central nervous system and peripheral tissue. Moreover, a postmortem increase in endogenous GHB concentration has been observed, especially in blood. Facing this issue, the use of an alternative matrix such as vitreous humor (VH) can thus be particularly interesting for GHB testing and quantification. VH is considered to be less prone to postmortem redistribution, is easy to collect, and has relatively few interfering compounds for the analytical process. In this context, the authors report the case of a GHB-related fatality involving 22-year-old male. In this case, GHB femoral blood (FB) (790 mg/L) and vitreous (750 mg/L) concentrations appeared similar with a FB to VH (FB/VH) ratio of 1.05. In addition, other similar cases with both GHB blood and vitreous concentrations were reviewed. Five cases were identified. The blood to VH ratios ranging from 0.13 to 2.58. Finally, GHB stability was documented in postmortem blood and VH, in order to address the reliability of VH as an alternative matrix for GHB quantitation at postmortem. GHB appeared relatively stable in postmortem blood specimens (at 50 mg/L) over a period of 28 days when stored at +4 °C or -20 °C. The same results were observed in VH specimens.

Pharmacobezoar-Related Fatalities: A Case Report and a Review of the Literature.

ABSTRACT: Pharmacobezoars develop after an acute overdose or during routine drug administration. Here, the authors present a case of fatal multidrug overdose involving a 62-year-old woman. Her usual treatment included tramadol extended-release, citalopram, and mirtazapine. Furthermore, she self-medicated and misused her husband's medications. The autopsy revealed the presence of a voluminous medication bezoar in the stomach. No mechanical complication was noted. Toxicologic analyses were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection, gas chromatography with mass spectrometry detection, and liquid chromatography coupled to tandem mass spectrometry. Tramadol (34,000 mcg/L), O-desmethyltramadol (2200 mcg/L), propranolol (6000 mcg/L), bromazepam (2500 mcg/L), zopiclone (1200 mcg/L), and citalopram (700 mcg/L) were identified in femoral blood at toxic concentrations. Interestingly, the femoral blood and vitreous humor concentration ratio was approximately 0.7. Furthermore, an English exhaustive literature search was performed using several different electronic databases without any limiting period to identify published pharmacobezoar-related fatalities. Seventeen publications were identified reporting a total of 19 cases. Decedents' mean age was 47.6 years [0.8-79] and a clear female predominance emerged. Several drugs were involved in pharmacobezoar formation. Death was attributed to drug toxicity in 13 cases, and to mechanical complications and/or sepsis in 4 cases. A mixed cause of death was reported in 2 cases. Although rare, pharmacobezoars remain potentially lethal and raise challenges in therapeutic management.

3-Methylmethcathinone Intoxication: Discrepancies Between Blood Concentrations and Clinical Outcomes-A Short Communication.

BACKGROUND: The absence of a correlation between the blood concentration of 3-methylmethcathinone (3-MMC) and clinical outcomes in intoxication cases has been attributed to stability issues. Indeed, a loss of more than 50%, 70%, and even 95% of 3-MMC in whole blood after 2 weeks of storage at 20°C, 4°C, and room temperature, respectively, has been reported in the past. Here, the authors report the case of a 43-year-old man who was hospitalized with generalized convulsive status epilepticus related to 3-MMC use with a plasma concentration of 9600 ng/mL (delay between sampling and analysis <72 hours). The stability of 3-MMC was evaluated in several biological specimens. METHODS: Three quality control samples (human plasma, whole blood, and postmortem blood) spiked with 3-MMC were stored at -20°C and 4°C for 14 days. The initial analysis was performed on day 1 to establish the initial concentration of 3-MMC in each specimen type, and the samples were divided into 2 aliquots for storage under both conditions. Further analyses were performed on days 7 and 14 for each specimen, and the results were compared with those obtained on day 1. RESULTS: 3-MMC appeared relatively stable in whole and postmortem blood when stored at -20°C for 1 week, with losses of <3% in both matrices (0% and 2.5%, respectively). At +4°C, 3-MMC losses ranged from 25% to 53%. CONCLUSIONS: These results differ from others reported in the literature. Hence, it may be hypothesized that other elements should be considered to explain the discrepancy between the concentration and toxicity pointed out by the Toxicology community, especially the development of tolerance.

Renal Safety Profile of BCR-ABL Tyrosine Kinase Inhibitors in a Real-Life Setting: A Study Based on Vigibase®, the WHO Pharmacovigilance Database.

BACKGROUND: Alongside their BCR-ABL specificity, TKIs used in chronic myeloid leukemia also target other tyrosine kinases expressed in the kidney such as PDGFR, c-KIT, SRC, and VEGFR, which may result in specific renal adverse drug reaction (ADR). To evaluate the renal safety profile in real-life conditions, a case/non-case study was performed on VigiBase®, the WHO global safety database. METHODS: From 7 November 2001 to 2 June 2021, all cases in which the involvement of imatinib, dasatinib, nilotinib, bosutinib, and ponatinib was suspected in the occurrence of renal ADR were extracted from VigiBase®. Disproportionality analyses were assessed using the reporting odds ratio. RESULTS: A total of 1409 cases were included. Imatinib accounts for half of the reported cases. A signal of disproportionate reporting (SDR) of renal failure and fluid retention was found for the five TKIs. Only dasatinib and nilotinib were related to an SDR for nephrotic syndrome. Nilotinib and ponatinib were related to an SDR for renal artery stenosis, while dasatinib was related to an SDR for thrombotic microangiopathy. No SDR for tubulointerstitial nephritis was observed. CONCLUSION: This study identified a new safety signal, nephrotic syndrome, for nilotinib and highlights the importance of post-marketing safety surveillance.

Designer Benzodiazepines: Effects, Toxicity, and Interactions.

PURPOSE: Although designer benzodiazepines (DBZDs) constitute a minor part of new psychoactive substances, they deserve the greatest attention because of their popularity among drug users and increasing number and availability. This review covers the effects of different DBZDs, available pharmacological evaluation tools, and their reported toxicity and potential pharmacodynamic and pharmacokinetic interactions with other drugs commonly co-abused with DBZDs. METHODS: For this narrative review, a nonsystematic search was performed on PubMed, EMBASE, Google Scholar, and PubMed Central databases between June and July 2021. RESULTS: The current consensus hypothesis suggests that DBZDs mediate their effects through interactions with the GABA A receptor, producing similar effects to benzodiazepines used in therapy, including sedation, hypnosis, anxiolysis, muscle relaxation, euphoria, amnesia, and addiction. Owing to the complexity of their action mechanism and the numerous GABA A subtype receptors, the pharmacodynamic metrics of DBZDs are very difficult to establish. The pharmacological effects of DBZD are related to their structure, influencing their binding to GABA A receptor subunits. Quantitative structure-activity relationship studies successfully predicted the biological activity and relative potency of DBZD but could not predict the main pharmacological effect of a given DBZD. Exploring the effects by netnographic studies is one of the available alternatives, despite its limitations. DBZDs are usually identified in the context of polysubstance use. Pharmacodynamic interactions between DBZDS and other CNS depressants, such as opioids, have been extensively reported. However, pharmacokinetic interactions between DBZDs and opioids are considered less important, and contradictory conclusions about their clinical significance have been reported. CONCLUSIONS: Understanding the mechanism of action and other pharmacological metrics is highly important in the clinical management of DBZDs.

Acute Sodium Oxybate Intoxication: A Case Report and Review of the Literature.

PURPOSE: Despite a better safety profile than illicit γ-hydroxybutyric acid (GHB) and other GHB analogs, sodium oxybate continues to raise serious concerns regarding clinical safety. In this study, the authors report the case of near-fatal intoxication involving sodium oxybate-alcohol combination in a 40-year-old woman. In addition, a review of the literature on published cases of intoxication involving this pharmaceutical form of GHB was conducted. A 40-year-old woman was admitted to the intensive care unit in a coma after voluntary ingestion of 18 g of sodium oxybate and alcohol. METHODS: The GHB plasma concentration was quantified to be 146 mg/L using liquid chromatography coupled with tandem mass spectrometry. An English literature search was performed using PubMed without any limiting period to identify all available scientific publications involving cases of sodium oxybate intoxication. RESULTS: Six cases were identified. Five involved fatal intoxication cases, with GHB postmortem blood concentrations ranging from 11.5 to 3500 mg/L. One involved a nonfatal intoxication case with a GHB serum concentration of 569 mg/L 7 hours postingestion. CONCLUSIONS: In the present case, the estimated elimination half-life was 154 minutes. The risk of acute poisoning seems to be high considering the pharmacokinetic properties of sodium oxybate. Physicians and toxicologists must take such properties into account.

Toxicity of designer benzodiazepines: A case of etizolam and cocaine intoxication.

During the last decade, only few cases of acute etizolam intoxication have been detailed. Little is known about the toxic effects of etizolam overdose. Here, the authors report the case of a 42-year-old man who was admitted to the emergency department for intense agitation following etizolam and cocaine consumption. Detection and determination of etizolam and cocaine (including metabolites) were achieved using liquid chromatography tandem mass spectrometry. Etizolam and benzoylecgonine (BZE) were detected in plasma at 64 and 10 ng/mL, respectively. The level of cocaine was below the limit of quantification (< 5 ng/mL). To the authors' knowledge, the only report detailing an etizolam overdose was provided by O'Connell et al. and was characterized by the presence of central nervous system (CNS) depression signs. Interestingly, here, there were no signs of CNS depression but only signs of CNS excitation. With regard to cocaine and BZE plasma concentrations, the clinical presentation cannot be only explained by the co-consumption of cocaine. It may be hypothesized that the clinical presentation was related to a paradoxical reaction to etizolam overdose. To date, no case of paradoxical excitation related to etizolam use has been reported in adults. The case presented here appears particularly interesting, given the limited data relating to high-dose etizolam toxicity.

Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial.

Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optimal population PK study design. Fourteen patients were enrolled in the PK ancillary study of the BIG-1 trial and 6-8 samples were taken up to 24 h after administration of the first dose of daunorubicin (90 mg/m2/day). Daunorubicin and daunorubicinol quantifications were assessed using a validated liquid chromatography technique coupled with a fluorescence detector method. Data were analysed using a non-compartmental approach and non-linear mixed effects modelling. Optimal sampling strategy was proposed using the R function PFIM. The median daunorubicin and daunorubicinol AUC0-tlast were 577 ng/mL·hr (Range: 375-1167) and 2200 ng/mL·hr (range: 933-4683), respectively. The median metabolic ratio was 0.32 (range: 0.1-0.44). Daunorubicin PK was best described by a three-compartment parent, two-compartment metabolite model, with a double first-order transformation of daunorubicin to metabolite. Body surface area and plasma creatinine had a significant impact on the daunorubicin and daunorubicinol PK. A practical optimal population design has been derived from this model with five sampling times per subject (0.5, 0.75, 2, 9, 24 h) and this can be used for a future population PK study.

Lethal self-administration of propofol and atracurium.

Acute propofol intoxications appear rare and remain primarily related to the acquisition of the material from the hospital. In this study, two cases of suicide following self-administration of a propofol-atracurium combination are presented as well as other propofol-related fatalities, in order to investigate propofol postmortem blood concentrations and circumstances surrounding death. The two case studies involved a 48-years-old male and a 61-year-old female, both anesthesiologists, who were found unresponsive with drugs (propofol, atracurium for both, and cisatracurium for one of them) discovered at the scene. Toxicological analyses were performed using validated chromatographic methods and highlighted the presence of propofol (1.0 µg/ml), laudanosine (0.2 µg/ml), paroxetine (3.4 µg/ml), and ethanol (12 mg/dl) for the first case and propofol (1.9 µg/ml), laudanosine (1.2 µg/ml), and hydroxyzine (0.03 µg/ml) for the second case. In the literature, 14 publications describing 27 cases of propofol-related lethal intoxications were identified. Except for two cases, all these fatalities involved healthcare professionals. Accidental overdose was the most frequently reported manner of death and the reported propofol blood concentrations ranged from 0.026 to 223.8 µg/ml. These cases, in agreement with other reported cases, highlight the concerns related to the misuse of hospital-based medicines, especially by health-care professionals, and so, the need for a much more stringent internal control of such drugs.

Renal Safety Profile of EGFR Targeted Therapies: A Study from VigiBase® the WHO Global Database of Individual Case Safety Reports.

Kidney EGFR expression together with reported cases of glomerular diseases in the context of anti-EGFR drug administration raise concerns about the renal safety profile of these drugs. This issue is addressed in a case/non-case study carried out on VigiBase®, the WHO global database of individual case safety reports (ICRS). Disproportionality analysis of renal adverse effects related to the selected anti-EGFR drugs, erlotinib, gefitinib, afatinib, osimertinib, cetuximab and panitumumab, was assessed using the reporting odds ratio (ROR). Nine hundred and eighty-nine ICRSs were included. A signal of disproportionate reporting (SDR) was found for afatinib (ROR = 2.70; 95% CI [2.22-3.29]) and erlotinib (ROR = 1.73; 95% CI [1.46-2.04]) with acute kidney injury, and for afatinib (ROR = 2.41; 95% CI [1.78-3.27]), cetuximab (ROR = 1.42; 95% CI [1.14-1.78]) and erlotinib (ROR = 2.23; 95% CI [1.80-2.77]) with renal failure. The preferred term "diarrhoea" was frequently reported in the included cases. An SDR was found for erlotinib with haemolytic and uremic syndrome (ROR = 4.01; 95% CI [1.80-8.94]) and thrombotic microangiopathy (ROR = 4.94; 95% CI [2.80-8.72]). No SDR was seen for glomerular or tubule-interstitial diseases. This study showed that the anti-EGFR drug renal toxicity is mainly related to renal failure in the context of digestive toxicity.

New In Vitro Coculture Model for Evaluating Intestinal Absorption of Different Lipid Nanocapsules.

Standard models used for evaluating the absorption of nanoparticles like Caco-2 ignore the presence of vascular endothelium, which is a part of the intestinal multi-layered barrier structure. Therefore, a coculture between the Caco-2 epithelium and HMEC-1 (Human Microvascular Endothelial Cell type 1) on a Transwell® insert has been developed. The model has been validated for (a) membrane morphology by transmission electron microscope (TEM); (b) ZO-1 and ß-catenin expression by immunoassay; (c) membrane integrity by trans-epithelial electrical resistance (TEER) measurement; and (d) apparent permeability of drugs from different biopharmaceutical classification system (BCS) classes. Lipid nanocapsules (LNCs) were formulated with different sizes (55 and 85 nm) and surface modifications (DSPE-mPEG (2000) and stearylamine). Nanocapsule integrity and particle concentration were monitored using the Förster resonance energy transfer (FRET) technique. The result showed that surface modification by DSPE-mPEG (2000) increased the absorption of 55-nm LNCs in the coculture model but not in the Caco-2. Summarily, the coculture model was validated as a tool for evaluating the intestinal absorption of drugs and nanoparticles. The new coculture model has a different LNCs absorption mechanism suggesting the importance of intestinal endothelium and reveals that the surface modification of LNCs can modify the in vitro oral absorption.

Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.

OBJECTIVES: To determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk of worsening. METHODS: We conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: need for supplemental oxygen, age ≥75 years, age between 60 and 74 years and presence of at least one co-morbidity. Severely ill patients requiring oxygen therapy >3 L/min or intensive care were excluded. Eligible patients were randomized in a 1:1 ratio to receive either 800 mg hydroxychloroquine on day 0 followed by 400 mg per day for 8 days or a placebo. The primary end point was a composite of death or start of invasive mechanical ventilation within 14 days following randomization. Secondary end points included mortality and clinical evolution at days 14 and 28, and viral shedding at days 5 and 10. RESULTS: The trial was stopped after 250 patients were included because of a slowing down of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years (interquartile range 58-86 years) and 151/250 (60.4%) patients required oxygen therapy. The primary end point occurred in 9/124 (7.3%) patients in the hydroxychloroquine group and 8/123 (6.5%) patients in the placebo group (relative risk 1.12; 95% CI 0.45-2.80). The rates of positive SARS-CoV-2 RT-PCR tests at days 5 and 10 were 72.8% (75/103) and 57.1% (52/91) in the hydroxychloroquine group, versus 73.0% (73/100) and 56.6% (47/83) in the placebo group, respectively. No difference was observed between the two groups in any of the other secondary end points. CONCLUSION: In this underpowered trial involving mainly older patients with mild to moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04325893 (https://clinicaltrials.gov/ct2/show/NCT04325893).

Chemsex/slamsex-related intoxications: A case report involving gamma-hydroxybutyrate (GHB) and 3-methylmethcathinone (3-MMC) and a review of the literature.

Chemsex and slamsex represent a serious public health concern that has to be considered by both clinical and forensic toxicologists. Indeed, such practices appear to carry a significant degree of risk, including acute intoxication. Here we report the case of the intoxication of a 31-year-old male involving 3-methylmethcathinone (3-MMC) and gamma-hydroxybutyrate (GHB) during a slamsex session. In addition, we conducted a review of further cases. The 31-year-old man was admitted to the emergency department for severe impaired consciousness following the administration of psychoactive substances during a chemsex party. The detection and determination of 3-MMC and GHB concentrations were achieved using liquid chromatography-tandem mass spectrometry. 3-MMC and GHB blood concentrations were 177 ng/mL and 131 mg/L, respectively. Further, an English and French exhaustive literature search was performed using several different electronic databases without any limiting period in order to identify all published case reports detailing chemsex/slamsex-related (fatal and nonfatal) intoxications. Nine publications detailing chemsex/slamsex-related intoxication cases have been published (between 2016 and 2020). These articles reported an overall of 13 cases, all involving men with a mean age of 39.1±9.8 years. The outcome was fatal in only 6 cases. 4-MEC and GHB were the two predominant drugs identified. However, given the rapid emergence of novel NPSs in the global market as well as the ease with which they can be accessed through the Internet, toxicological laboratories have to be ready to face new patterns of intoxications resulting from chemsex/slamsex.

Slower degradation rate of cytarabine in blood samples from acute myeloid leukemia by comparison with control samples.

PURPOSE: Cytarabine, a key chemotherapy agent for acute myeloid leukemia (AML) treatment, is deaminated into inactive uracil-arabinoside by cytidine deaminase. This deamination leads to samples stability issues with respect to clinical pharmacokinetic trials. The aim of our study was to study in vitro cytarabine stability in blood samples obtained from AML patients. METHODS: Cytarabine quantification was performed using a fully validated LC/MS/MS method. In vitro cytarabine stability was assessed at room temperature over 24 h in samples coming from 14 AML patients and 7 control patients (CTRL) with no hematological malignancy. In vitro concentrations versus time data were analyzed using a noncompartmental approach. RESULTS: Cytarabine in vitro area under the curve (AUCIVlast) was 22-fold higher in AML samples as compared to CTRL samples (AML mean (standard deviation (SD)), 51,829 (27,004) h ng/mL; CTRL mean (SD), 2356 (1250) h ng/mL, p = 0.00019). This increase was associated with a prolonged in vitro degradation half-life (t1/2IVdeg AML mean (SD), 15 (11.8) h; CTRL mean (SD), 0.36 (0.37) h, p = 0.0033). Multiple linear regression analysis showed that AML diagnosis significantly influenced t1/2IVdeg and AUCIVlas relationship. CONCLUSION: Cytarabine stability is higher in AML than in CTRL samples. The absence of correlation between t1/2IVdeg and AUCIVlast in AML samples suggests that in vitro cytarabine degradation in AML is complex. These results open perspectives including the evaluation of the clinical relevance and the involved molecular mechanisms.

CYP450 activities before and after Roux-en-Y gastric bypass: correlation with their intestinal and liver content.

BACKGROUND: Several anatomic and physiologic changes occur after Roux-en-Y gastric bypass (RYGB) and its associated weight loss. At present, no single unified model can predict changes in drug metabolism associated with either RYGB surgery or weight loss. OBJECTIVE: The aim of this longitudinal human study was to measure the activity of the 5 most important Cytochrome P450 (CYP) involved in drug metabolism in patients with obesity before and after RYGB. Jejunal and liver biopsies obtained during bariatric surgery were used to measure CYP amount, and correlation between jejunal and hepatic content was estimated. SETTING: French university hospital. METHODS: Eleven volunteers with a mean body mass index of 44.1 (39.4-50.0) kg/m2 participated in the study. CYP1 A2, CYP2 C9, CYP2 C19, CYP2 D6, and CYP3 A4/A5 activities were measured with a cocktail approach before surgery (visit 1), 5 to 8 weeks after surgery (visit 2), and 25 to 30 weeks after surgery (visit 3). RESULTS: CYP3 A4/A5 and CYP2 C9 metabolic ratios were transitorily and significantly increased immediately after surgery (visit 2 versus 1). RYGB procedure does not lead to significant change in CYP activity 25 to 30 weeks after surgery (visit 3 versus 1). Samples obtained during surgery showed significant correlation between intestinal and liver contents of CYP2 C9 and CYP3 A4/A5. Except for liver CYP1 A2 content, CYP metabolic activities were not correlated to their intestinal or liver contents. CONCLUSIONS: This study showed that RYGB does not lead to a significant change in CYP activity 25 to 30 weeks after surgery. However, CYP3 A4/A5 and CYP2 C9 activities were transitorily and significantly increased in the immediate postoperative context (<1 mo), representing a situation at risk of reduced drug exposure for several drugs that have a narrow therapeutic window. In addition, considering high interindividual variability in liver contents and activity of CYP3 A4 and CYP2 C9, patients receiving drugs highly metabolized by these 2 CYPs should be closely monitored in the immediate postoperative period.

Enzalutamide and analytical interferences in digoxin assays.

Objective: We report two cases of elevated digoxin plasma levels in patients receiving enzalutamide. Cases reported: The first patient, an 84-year-old male treated with enzalutamide, was hospitalized due to deterioration in his general state. Atrial fibrillation was discovered and treatment with digoxin was initiated. Supratherapeutic digoxin concentrations (4 µg/L and 3.5 µg/L 3 days later) led to treatment being stopped despite the lack of clinical or biological signs of overdose. The second patient, an 84-year-old male treated with digoxin and enzalutamide, was hospitalized for the same reasons. Digoxin concentration upon admission was 2.8 µg/L. Despite stopping treatment, digoxin blood levels were observed to have increased on D3 and D7 following admission (3 and 3.6 µg/L, respectively). However, no clinical or biological findings indicated an overdose. Blood samples were sent to the Pharmacology and Toxicology Laboratory for analysis. Methods: The second patient's digoxin plasma level was determined using the chemiluminescent microparticle immunoassay (CMIA®, Abbott, Illinois) method. Enzalutamide levels were determined using HPLC-UV/DAD method. An interference study was performed using different assay methods by adding enzalutamide to control plasma at various concentrations from a Xtandi® (40mg) capsule. Results: Plasma concentration of digoxin at D7 for patient 2 was identical in both laboratories (3.5 vs. 3.6 µg/L). Enzalutamide was found in the patient's plasma (12,5 mg/L). Adding 4, 10, 20, and 40 mg/L of enzalutamide to the untreated plasma showed that the plasma concentration of digoxin was positive (from 0.35 to 3.69 µg/L) using the CMIA method. Conclusions: Our results highlight the analytical interferences of enzalutamide with digoxin assays using the CMIA method.

Cetuximab increases concentrations of irinotecan and of its active metabolite SN-38 in plasma and tumour of human colorectal carcinoma-bearing mice.

In a previous study, we showed that cetuximab, a monoclonal antibody directed towards epidermal growth factor receptor, could inhibit P-glycoprotein (P-gp), an efflux protein of ATP-binding cassette family, and lead to an increased P-gp substrate intracellular concentration. Cetuximab is given with irinotecan to patients with metastasis colorectal cancer who did not respond to irinotecan-based therapy. The mechanism of this successful clinical reversion remains unknown. As irinotecan is a P-gp substrate, we tested here whether cetuximab could modify irinotecan concentration in mice. Therefore, concentrations of irinotecan and of its active metabolite SN-38 were measured by HPLC in plasma and tumour of mice bearing a human colorectal carcinoma xenograft when irinotecan is given orally alone or after a pretreatment with cetuximab. Pharmacokinetic analysis showed no significant modification of irinotecan concentrations but a significant increase (1.7-fold) in SN-38 AUCs in plasma and in tumour after a pretreatment with cetuximab. Those results suggest that cetuximab influence irinotecan distribution into tissues probably due to inhibition of P-gp. As SN-38 is 200-fold more potent than irinotecan, cetuximab could reverse irinotecan resistance by an effect on its active metabolite. Inhibiting SN-38 efflux by P-gp drug transporters in biliary system and tumour can lead to pharmacokinetic modification and a higher anticancer efficacy.