Effect of Coffee and Chocolate Ingestion on Clozapine Dose and on Plasma Clozapine and Norclozapine Concentrations in Clinical Practice.

BACKGROUND: Some reports point to dietary caffeine intake as a cause of increased plasma clozapine concentrations in certain patients. METHODS: We compared clozapine dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in male and female smokers and nonsmokers in relation to reported (i) coffee (caffeine) and (ii) chocolate (caffeine and theobromine) intake in samples submitted for clozapine therapeutic drug monitoring, 1993-2017. RESULTS: There was information on coffee ingestion for 16,558 samples (8833 patients) from males and 5886 samples (3433 patients) from females and on chocolate ingestion for 12,616 samples (7568 patients) from males and 4677 samples (2939 patients) from females. When smoking was considered, there was no discernible effect of either coffee or chocolate ingestion either on the median dose of clozapine or on the median plasma clozapine and norclozapine concentrations in men and in women. However, cigarette smoking was associated with higher coffee and chocolate consumption. Although male nonsmokers who reported drinking 3 or more cups of coffee daily had significantly higher median plasma clozapine and norclozapine concentrations than those who drank less coffee, they were also prescribed a significantly higher clozapine dose. There was no clear effect of coffee ingestion on plasma clozapine and norclozapine in female nonsmokers. IMPLICATIONS: Inhibition of clozapine metabolism by caffeine at the doses of caffeine normally encountered in those treated with clozapine is unlikely even in male nonsmokers. Measurement of plasma caffeine in an appropriate sample should be considered in any future investigation into a presumed clozapine-caffeine interaction.

A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status.

AIMS: Guidance on clozapine dosing in treatment-resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and N-desmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status and body weight. METHODS: A population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993-2017. RESULTS: There were 17 787 measurements from 5960 patients (4315 male) aged 18-86 years. The estimated clozapine plasma clearance was reduced from 20.2 to 12.0 L h-1 between 20 and 80 years. Model-based dose predictions to attain a predose plasma clozapine concentration of 0.35 mg L-1 was 275 (90% prediction interval 125, 625) mg day-1 in nonsmoking, White males weighing 70 kg and aged 40 years. The corresponding predicted dose was increased by 30% in smokers, decreased by 18% in females, and was 10% higher and 14% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. Overall, the predicted dose decreased by 56% between 20 and 80 years. CONCLUSION: The large sample size and wide age range of the patients studied allowed precise estimation of dose requirements to attain predose clozapine concentration of 0.35 mg L-1 . The analysis was, however, limited by the absence of data on clinical outcome and future studies are required to determine optimal predose concentrations specifically in those aged over 65 years.

Effect of Cigarette Smoking on Clozapine Dose and on Plasma Clozapine and N-Desmethylclozapine (Norclozapine) Concentrations in Clinical Practice.

BACKGROUND: Cigarette smoking enhances plasma clozapine clearance and thus affects the clozapine dose requirement. METHODS: We compared clozapine daily dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in male and female smokers and nonsmokers in samples submitted for clozapine therapeutic drug monitoring (1996-2017). RESULTS: There were 105,316/60,792 and 34,290/31,309 samples with dose information from male and female smokers/nonsmokers, respectively. There was information on the number of cigarettes smoked daily for 12,842 samples (8409 patients) and 3948 samples (2753 patients) from men and women, respectively. Of these, 574 and 253 samples were from men and women, respectively, who reported smoking 1-9 cigarettes daily.In both sexes, the median clozapine doses in the nonsmokers were 75%-80% of those in the smokers, but the median plasma clozapine and norclozapine concentrations were 136% higher. The effect of smoking on the dose and on median plasma clozapine and norclozapine concentrations seemed maximal after 2-3, perhaps fewer, cigarettes daily in males. In females, the effect of smoking seemed to be near maximal after some 4-5 cigarettes per day. IMPLICATIONS: The optimum target range for predose plasma clozapine may be different in smokers (0.35-0.45 mg L-1) as opposed to nonsmokers (0.50-0.60 mg L-1). That changes in clozapine clearance are likely near maximal with cigarette smoking as low as 2-3 d-1 in males, perhaps slightly more in females, emphasizes that covert or passive smoking may be an important factor in seemingly random changes in plasma clozapine concentration at constant dose.

Assessing Adherence to Clozapine: Practical Considerations.

BACKGROUND: The clinical assessment of adherence to clozapine may prove difficult. METHOD: We studied the incidence of nonadherence (plasma clozapine <0.01 mg L -1 ) in samples submitted to a clozapine therapeutic drug monitoring (TDM) service, 1993-2017. RESULTS: Clozapine was not detected in 2865 samples from men (2214 patients, 1.1% of all samples from men) and 1068 samples from women (822 patients, 1.0% of all samples from women). Information on the prescribed dose was supplied for 1623 of these samples from men and 492 of these samples from women. Prescribed doses ranged up to 1200 mg d -1 , although most were in the range 100 to 600 mg d -1 . Norclozapine was detected in 260 (9.1%) and 67 (6.3%) of the samples from men and from women, respectively, that did not contain clozapine. While an assay was requested to confirm either a patient history of nonadherence, or to establish that clozapine had been cleared from the circulation after overdosage, for example, in at least 38 instances, in the vast majority of cases the absence of clozapine from the sample was unexpected. IMPLICATIONS: While adherence to clozapine may be good in general, tolerance to its potentially fatal cardiovascular effects is easily lost. Moreover, in treatment-resistant schizophrenia, the risk of self-harm increases if the drug is not taken regularly. In addition to presently available TDM services, the advent of a clozapine immunoassay for laboratory use should make it easy to institute at least monthly clozapine TDM at minimal extra cost.

A Ceratopteris EXCESS MICROSPOROCYTES1 suppresses reproductive transition in the fern vegetative leaves.

Land plant sexual reproduction involves the transition of cells from somatic to reproductive identity during post-embryonic development. In Arabidopsis, the leucine-rich repeat receptor-like kinase EXCESS MICROSPOROCYTES1 (EXS/EMS1) restricts the number of sporogenous cells during the transition from diploid tissue to haploid spore production by promoting the formation of the tapetum cell layer within the anther. Although all land plants studied contain EMS1 genes, its function is unknown beyond a few angiosperms. In the model fern Ceratopteris (Ceratopteris richardii), we discovered an EMS1 homolog (CrEMS1) that functions to suppress formation of reproductive structures on vegetative leaves of the fern sporophyte, a role not found in angiosperms. Suppression of CrEMS1 by RNAi did not affect sporogenesis on reproductive leaves but did affect antheridium production of the fern gametophyte. Expression patterns of CrEMS1 across developmental stages suggest threshold levels of CrEMS1 control the specification of reproductive organs during both generations of the fern. Additional EMS1 homologs present in the fern genome suggest a dynamic role of EMS1 receptors in the evolution of reproductive development in vascular plants.

Clozapine: Dose, Sex, Ethnicity, Smoking Habit, Age, Body Weight, and Plasma Clozapine and N -Desmethylclozapine (Norclozapine) Concentrations in Clinical Practice.

BACKGROUND: Guidance on clozapine dosing in treatment refractory schizophrenia is based largely on data from young adult male White patients. AIM: This study aimed to audit the plasma clozapine and N -desmethylclozapine (norclozapine) concentrations attained in male and female patients of different ethnicity and smoking habit. METHOD: The effect of dose, sex, ethnicity, age, body weight, and smoking habit on plasma clozapine and norclozapine concentrations were studied using data from a therapeutic drug monitoring service, 1993 to 2017. RESULTS: There were 371,610 samples (48,098 patients, 32,855 male). Ethnicity was recorded for 763 Afro-Caribbean, 536 Asian, and 7940 White patients. Males were prescribed significantly higher median doses than females but attained significantly lower median plasma clozapine and norclozapine concentrations. Asian and Afro-Caribbean males were prescribed significantly lower and higher median doses, respectively, than White males but attained significantly higher and lower median plasma clozapine and norclozapine concentrations, respectively. Data from 78,431 samples (23,516 patients) were analyzed using a linear mixed model. The predicted dose to attain a predose plasma clozapine concentration of 0.35 mg/L in a nonsmoking White male aged 40 years, with weight of 70 kg, and plasma clozapine-norclozapine ratio of 1.32 was 344 mg/d (95% confidence interval, 227-526 mg/d). The predicted dose was 33% higher and 20% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. In all cases, the predicted dose was increased by 36% in smokers and decreased by 22% in females. CONCLUSIONS: Research is needed to further investigate the complex relationships between dose, sex, ethnicity, plasma clozapine and norclozapine concentrations, and clinical outcome such as weight gain.

Plasma Clozapine and Norclozapine After Use of Either Crushed Tablets or Suspension Compared With Tablets.

BACKGROUND: With clozapine, either crushed tablets suspended in an aqueous medium or proprietary suspension is sometimes prescribed as an alternative to tablets, but bioequivalence data are scant. METHODS: We compared clozapine dose, and plasma clozapine and N -desmethylclozapine (norclozapine) concentrations after use of either tablets or crushed tablets/suspension in samples submitted for clozapine therapeutic drug monitoring, 1993 to 2017. RESULTS: There were 846 patients (1646 samples) given crushed tablets/suspension and 6065 patients (10,779 samples) given tablets. The median dose (mg d -1 ) was significantly higher in men (500 vs 450) and women (500 vs 400) given crushed tablets/suspension, but the median plasma clozapine and norclozapine concentrations (mg L -1 ) were significantly lower (men: 0.29 and 0.22 vs 0.39 and 0.28; women: 0.35 and 0.26 vs 0.50 and 0.32, respectively). A subgroup of 480 patients was prescribed either crushed tablets/suspension (1016 samples) or tablets (1259 samples) at different times. The median dose was again significantly higher in men (500 vs 500) and women (500 vs 450), but the median plasma clozapine and norclozapine concentrations were significantly lower (men: 0.29 and 0.22 vs 0.32 and 0.24; women: 0.30 and 0.24 vs 0.38 and 0.29, respectively). IMPLICATIONS: Poor adherence, sedimentation of suspension before use, and incomplete dosage are potential contributors to the lower median plasma clozapine and norclozapine concentrations observed after use of either crushed clozapine tablets or suspension as compared with tablets. Those administering crushed tablets/suspension should be aware of these factors.

Fatal Unintentional Non-Fire Related Carbon Monoxide Poisoning: Data from Narrative Verdicts in England and Wales, 1998-2019.

Unintentional non-fire related (UNFR) carbon monoxide (CO) poisoning continues to cause fatalities. The narrative verdicts from coroners concerning fatal UNFR CO poisoning in England and Wales, 1998-2019, were collated by the Office for National Statistics. Search terms related to CO exposure were used to obtain information regarding the circumstances of death. Findings were grouped by the location of death, the source of CO, and the reason or behaviour underlying the exposure. There were 750 deaths (77% male). The annual number of deaths decreased over the period studied. Two thirds (68%) of the deaths occurred in the autumn or winter. From the records with information, 59% of deaths occurred within a dwelling (67% male). Males also predominated deaths within vehicles (91%) and garages or outbuildings (95%). From the deaths with information, domestic piped gas was the most common source of CO (36%) and the most frequent underlying factor was inadequate ventilation of exhaust gases (39%, 91% male). Despite the decrease in the annual number of deaths over the study period, there remains a clear need for measures that raise awareness of the dangers of CO poisoning, especially amongst men working alone in garages or outbuildings. Education campaigns and fitting and maintaining CO alarms in high-risk areas should be encouraged.

Antipsychotic-Related Fatal Poisoning, England and Wales, 1993-2019: The Impact of Second-Generation Antipsychotics.

BACKGROUND: Deaths from antipsychotic (AP) poisoning have increased in England and Wales despite restriction of the use of thioridazine in 2000. METHODS: We analyzed data from the Office for National Statistics drug-related death database, England and Wales, 1993-2019, to investigate fatal AP poisoning. RESULTS: There were 2286 deaths (62% male patients). Annual numbers of intentional AP-related fatal poisonings (suicides) were relatively stable (1993, 35; 2019, 44; median, 44; range, 30-60). Intentional overdose deaths involving clozapine (96 male, 25 female) increased from 1 in 1994 to 5 in 2003 and have since remained relatively constant (median, 6; range, 3-10 per annum). Unintentional second-generation AP-related fatal poisonings have increased steadily since 1998, featuring in 828 (74%) of all unintentional, AP-related fatal poisonings in the period studied (2019, 89%). There were 181 unintentional clozapine-related deaths, (107 [59%] alone without other drugs ± alcohol) as compared with 291 quetiapine-related deaths (86 [30%] alone without other drugs ± alcohol) and 314 unintentional olanzapine-related deaths (77 [25%] alone without other drugs ± alcohol). Some 75% of all unintentional clozapine- and olanzapine-related deaths were of male patients (78% and 73%, respectively) as compared with 58% of unintentional quetiapine-related fatal poisonings. Clozapine now features prominently in intentional and in unintentional AP-related fatal poisoning in England and Wales. Deaths of male patients predominate in both categories. There were also 77 and 86 deaths attributed to unintentional poisoning with olanzapine and with quetiapine, respectively, in the absence of other drugs. CONCLUSIONS: More effort is needed to prevent unintentional deaths not only from clozapine but also from olanzapine and quetiapine.

Detecting Nuclear Materials in Urban Environments Using Mobile Sensor Networks.

Radiation detectors installed at major ports of entry are a key component of the overall strategy to protect countries from nuclear terrorism. While the goal of deploying these systems is to intercept special nuclear material as it enters the country, no detector system is foolproof. Mobile, distributed sensors have been proposed to detect nuclear materials in transit should portal monitors fail to prevent their entry in the first place. In large metropolitan areas, a mobile distributed sensor network could be deployed using vehicle platforms such as taxis, Ubers, and Lyfts, which are already connected to communications infrastructure. However, performance and coverage that could be achieved using a network of sensors mounted on commercial passenger vehicles has not been established. Here, we evaluate how a mobile sensor network could perform in New York City using a combination of radiation transport and geographic information systems. The geographic information system is used in conjunction with OpenStreetMap data to isolate roads and construct a grid over the streets. Vehicle paths are built using pickup and drop off data from Uber, and from the New York State Department of Transportation. The results show that the time to first detection increases with source velocity, decreases with the number of mobile detectors, and reaches a plateau that depends on the strength of the source.

Analytical Detection of Novel Stimulants by Immunoassay and Liquid Chromatography-High Resolution Mass Spectrometry: Case Studies on Ethylphenidate and Mephedrone.

The advent of hundreds of new compounds aimed at the substance misuse market has posed new analytical challenges. A semi-quantitative liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method has been developed to detect exposure to two novel stimulants, mephedrone and ethylphenidate, and selected metabolites. Centrifuged urine (50 µL) was diluted with LC eluent containing internal standards (mephedrone-d3, methylphenidate-d9 and ritalinic acid-d10; all 0.02 mg/L) (450 µL). Intra- and inter-assay accuracy and precision were within ±15% and <6%, respectively, for all analytes. The limit of detection was 0.01 mg/L for all analytes. Urine samples from mephedrone and ethylphenidate users were analyzed using immunoassay (amphetamine-group cloned enzyme donor immunoassay [CEDIA]) and LC-HRMS. Ethylphenidate, mephedrone and selected metabolites all had low cross-reactivity (<1%) with the immunoassay. The median (range) amphetamine-group CEDIA concentration in urine samples from mephedrone users (n = 11) was 0.30 (<0.041-3.04) mg/L, with only 1 sample giving a positive CEDIA result. The amphetamine-group CEDIA concentration in the urine sample from an ethylphenidate user was <0.041 mg/L. Improving the detection of novel compounds is of increasing importance to enable accurate diagnosis and treatment. Immunoassay methods used for drug screening may be inappropriate and lead to false-negative results. Conversely, detection of these compounds is possible through use of LC-HRMS and can provide information on the metabolites present after exposure to these drugs.

Changes in smoking status, mental state and plasma clozapine concentration: retrospective cohort evaluation.

AIMS AND METHOD: To investigate the percentage of patients who commenced smoking after transferring out of a non-smoking forensic psychiatric unit, the corresponding clozapine dose adjustments, the effects on plasma clozapine/norclozapine concentrations and observed changes in mental state. We reviewed the notes and plasma clozapine/norclozapine concentrations of 46 patients transferred to medium secure units between July 2008 and December 2013. RESULTS: Thirty-five patients commenced smoking. Their median clozapine dose was increased by 50 mg/d. In the non-smokers, the median clozapine dose remained unchanged. Plasma clozapine/norclozapine concentrations were significantly reduced in smokers despite dosage adjustment. Eighteen patients experienced deterioration in mental state after transfer; almost all these patients were smokers. CLINICAL IMPLICATIONS: Approximately three-quarters of patients who were non-smokers by virtue of being in a secure non-smoking environment commenced smoking after transfer. Monitoring of clozapine serum levels and assessment of mental state in the immediate period after a change in smoking status is indicated.

Detection of fentanyl and fentanyl analogues in biological samples using liquid chromatography-high resolution mass spectrometry.

BACKGROUND: Fentanyl and analogues such as butyrylfentanyl, carfentanil, 4-fluorobutyrylfentanyl, and furanylfentanyl may be either added to, or sold as, heroin. Fentanyl and carfentanil have approximately 100 and 10,000 times the potency of morphine, respectively, and there is thus a high risk of death with the use of these drugs. METHODS: We looked for fentanyl/fentanyl analogues using liquid chromatography-high resolution mass spectrometry (LC-HRMS) in selected biological samples obtained post-mortem February 2017-end January 2018. Suspicion of fentanyl poisoning arose from the circumstances of death, a history of heroin use, and the geographical area in which the deceased was discovered, supplemented by drugs intelligence data. RESULTS: Of the 84 deaths investigated, fentanyl and/or a fentanyl analogue were detected in 40 (48%). The fentanyls encountered were carfentanil (N = 17), fentanyl (9), carfentanil and fentanyl together (12), and fentanyl, carfentanil, 4-fluorobutyrylfentanyl, and butyrylfentanyl together (2). The median (range) post-mortem blood fentanyl concentration was 2.66 (0.21-107) µg/L and the median (range) carfentanil concentration was 0.24 (0.03-1.66) µg/L. The most prevalent compounds present together with fentanyls were ethanol [N = 28, median (range) post-mortem blood concentration: 44 (<10-249) mg/dL)], benzoylecgonine [N = 22, 0.64 (<0.05-3.17) mg/L] and free morphine [N = 20, 0.05 (<0.05-0.34) mg/L]. Deaths in hospital excluded, median blood free morphine, and ethanol concentrations were significantly lower in deaths where fentanyl/fentanyl analogues were present, but there was much overlap with the blood concentrations of these analytes in the non-fentanyl related deaths. A routine drugs of abuse assay using LC-HRMS identified fentanyl with 100% sensitivity and carfentanil with 89% sensitivity. CONCLUSIONS: Given their potency, misuse of fentanyl and its analogues is likely to cause severe toxicity. A simple LC-HRMS method detected all cases in which fentanyl was identified post-mortem and most of the cases in which carfentanil was detected.

Ultra-fast LC-MS/MS in therapeutic drug monitoring: Quantification of clozapine and norclozapine in human plasma.

A novel approach to high-throughput, targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis has been developed. A single chromatographic system can be used for the analysis of a range of 20 drugs and metabolites with a total analysis time of 36 s (one 96-well plate of prepared samples per hour). To demonstrate the applicability of this approach to quantitative analysis, a method has been validated for the therapeutic drug monitoring of clozapine and norclozapine following automated extraction from human plasma. Chromatographic retention times were 11.4 and 12.4 s for norclozapine and clozapine, respectively (for both analytes the chromatographic peak width was less than 1 s). Comparison with a conventional LC-MS/MS method (5 min analysis time) showed excellent agreement. This new approach offers analysis times more akin to flow-injection analysis, but is likely to be more widely applicable because of chromatographic resolution from residual matrix components and isobaric interferences.

The interpretation of hair analysis for drugs and drug metabolites.

INTRODUCTION: Head hair analysis for drugs and drug metabolites has been used widely with the aim of detecting exposure in the weeks or months prior to sample collection. However, inappropriate interpretation of results has likely led to serious miscarriages of justice, especially in child custody cases. OBJECTIVE: The aim of this review is to assess critically what can, and perhaps more importantly, what cannot be claimed as regards the interpretation of hair test results in a given set of circumstances in order to inform future testing. METHODS: We searched the PubMed database for papers published 2010-2016 using the terms "hair" and "drug" and "decontamination", the terms "hair" and "drug" and "contamination", the terms "hair" and "drug-facilitated crime", the terms "hair" and "ethyl glucuronide", and the terms "hair", "drug testing" and "analysis". Study of the reference lists of the 46 relevant papers identified 25 further relevant citations, giving a total of 71 citations. Hair samples: Drugs, drug metabolites and/or decomposition products may arise not only from deliberate drug administration, but also via deposition from a contaminated atmosphere if drug(s) have been smoked or otherwise vaporized in a confined area, transfer from contaminated surfaces via food/fingers, etc., and transfer from sweat and other secretions after a single large exposure, which could include anesthesia. Excretion in sweat of endogenous analytes such as γ-hydroxybutyric acid is a potential confounder if its use is to be investigated. Cosmetic procedures such as bleaching or heat treatment of hair may remove analytes prior to sample collection. Hair color and texture, the area of the head the sample is taken from, the growth rate of individual hairs, and how the sample has been stored, may also affect the interpretation of results. Toxicological analysis: Immunoassay results alone do not provide reliable evidence on which to base judicial decisions. Gas or liquid chromatography with mass spectrometric detection (GC- or LC-MS), if used with due caution, can give accurate analyte identification and high sensitivity, but many problems remain. Firstly, it is not possible to prepare assay calibrators or quality control material except by soaking "blank" hair in solutions of appropriate analytes, drying, and then subjecting the dried material to an analysis. The fact that solvents can be used to add analytes to hair points to the fact that analytes can arrive not only on, but also in hair from exogenous sources. A range of solvent-washing procedures have been advocated to "decontaminate" hair by removing adsorbed analytes, but these carry the risk of transporting adsorbed analytes into the medulla of the hair therefore confounding the whole procedure. This is especially true if segmental analysis is being undertaken in order to provide a "time course" of drug exposure. Proposed clinical applications of hair analysis: There have been a number of reports where drugs seemingly administered during the perpetration of a crime have been detected in head hair. However, detailed evaluation of these reports is difficult without full understanding of the possible effects of any "decontamination" procedures used and of other variables such as hair color or cosmetic hair treatment. Similarly, in child custody cases and where the aim is to demonstrate abstinence from drug or alcohol use, the issues of possible exogenous sources of analyte, and of the large variations in analyte concentrations reported in known users, continue to confound the interpretation of results in individual cases. CONCLUSIONS: Interpretation of results of head hair analysis must take into account all the available circumstantial and other evidence especially as regards the methodology employed and the possibility of surface contamination of the hair prior to collection.

Sodium valproate and clozapine induced neutropenia: A case control study using register data.

BACKGROUND: The use of clozapine is limited due to the occurrence of neutropenia, and the rare but life threatening adverse event of agranulocytosis. There is little epidemiological research into clinical factors that may impact on this risk. We conducted a case control study examining the clinical risk factors for neutropenia patients treated with clozapine. METHOD: A case-control study was conducted within a database of anonymised electronic clinical records. All patients who discontinued clozapine due to a neutropenic event were included as cases. Matched controls were selected from patients with a documented clozapine exposure at the time of the clozapine neutropenic event of the case patient, matched by duration of clozapine treatment. RESULTS: 136 cases and 136 controls were included. In multivariable analysis, the concurrent use of sodium valproate was associated with neutropenia (Odds Raito (OR) 2.28, 95%CI: 1.27-4.11, p=0.006). There was a dose-response effect, with greater associations for higher doses. Patients who discontinued clozapine due to neutropenia were more likely to be of black ethnicity (OR 2.99, p<0.001), were younger (t=5.86, df=267, p<0.001), and received lower doses of clozapine (t=-2.587, p=0.01) than those who did not develop neutropenia. CONCLUSION: We identified an association between the concurrent use of sodium valproate and an increased risk of clozapine associated neutropenia. These results, taken in combination with the results from previous case series, suggest that the risk of clozapine associated neutropenia could be reduced by avoiding concurrent valproate treatment.

The Use of Granulocyte Colony-Stimulating Factor in Clozapine Rechallenge: A Systematic Review.

PURPOSE/BACKGROUND: Clozapine is associated with hematological abnormalities, with neutropenia and agranulocytosis of most concern. Granulocyte colony-stimulating factor (G-CSF) has been used to support clozapine rechallenge after neutropenia with the aim of maintaining the neutrophil count. This study aims to explore the practice, use, safety, and efficacy of G-CSF in this context. METHODS/PROCEDURES: We conducted a systematic review to identify all studies investigating or describing G-CSF as a prophylaxis to enable continued clozapine treatment during a rechallenge. FINDINGS/RESULTS: We identified 32 reports of patients who received G-CSF either regularly (n = 23) or as required (n = 9) to support clozapine rechallenge after an episode of neutropenia necessitating discontinuation of clozapine. Seventy-five percent (n = 24) of published cases remained on clozapine with the use of continual prophylactic G-CSF or after single G-CSF administrations (n = 8). Seventy percent (n = 16) of patients in receipt of continual prophylactic G-CSF were successfully maintained on clozapine. However, 1 of the 3 episodes of rechallenge in those with a history of severe agranulocytosis (absolute neutrophil count <0.1 × 10/L) had a recurrence of agranulocytosis at week 9. IMPLICATIONS/CONCLUSIONS: Our findings suggest that G-CSF can sometimes be safely used to support the maintenance of normal neutrophil counts and clozapine use after neutropenia. Publication bias is an important limitation, however. Also, few reports clearly documented the presence or absence of an independent nonclozapine cause of the index neutropenia, which may have increased success rates. Furthermore, adverse events were not systematically recorded. Prospective studies are needed to determine safety because if agranulocytosis occurs on clozapine while supported by G-CSF, there is no obvious alternate rescue therapy to promote granulopoiesis. From the available data, it is not possible to recommend this course of action for someone with a true clozapine agranulocytosis.

Women Administered Standard Dose Imatinib for Chronic Myeloid Leukemia Have Higher Dose-Adjusted Plasma Imatinib and Norimatinib Concentrations Than Men.

BACKGROUND: The standard dose of imatinib for the treatment of chronic-phase chronic myeloid leukemia (CML) is 400 mg·d. A predose plasma imatinib concentration of >1 mg·L is associated with improved clinical response. This study aimed to assess the plasma imatinib and norimatinib concentrations attained in patients with chronic myeloid leukemia administered standard doses of imatinib adjusted for dose, age, sex, body weight, and response. METHODS: We evaluated data from a cohort of patients treated between 2008 and 2014 with respect to dose, age, sex, body weight, and response. RESULTS: The study comprised 438 samples from 93 patients (54 male, 39 female). The median imatinib dose was 400 mg·d in men and in women. The plasma imatinib concentration ranged 0.1-5.0 mg·L and was below 1 mg·L in 20% and 16% of samples from men and women, respectively. The mean dose normalized plasma imatinib and norimatinib concentrations were significantly higher in women in comparison with men. This was partially related to body weight. Mixed effects ordinal logistic regression showed no evidence of an association between sex and plasma imatinib (P = 0.13). However, there was evidence of an association between sex and plasma norimatinib, with higher norimatinib concentrations more likely in women than in men (P = 0.02). CONCLUSIONS: Imatinib therapeutic drug monitoring only provides information on dosage adequacy and on short-term adherence; longer-term adherence cannot be assessed. However, this analysis revealed that approximately 1 in 5 samples had a plasma imatinib concentration <1 mg·L, which was suggestive of inadequate dosage and/or poor adherence and posed a risk of treatment failure. Higher imatinib exposure in women may be a factor in the increased rate of long-term, stable, deep molecular response (undetectable breakpoint cluster-Abelson (BCR-ABL) transcript levels with a PCR sensitivity of 4.5 log, MR4.5) reported in women.