Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP2C19 and non-SSRI/non-TCA antidepressants.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy based on pharmacogenetic test results. The current guideline describes the gene-drug interaction between CYP2D6 and venlafaxine, mirtazapine and duloxetine. In addition, the interaction between CYP2C19 and mirtazapine and moclobemide is presented. The DPWG identified a gene-drug interaction that requires therapy adjustment for CYP2D6 and venlafaxine. However, as the side effects do not appear to be related to plasma concentrations, it is not possible to offer a substantiated advice for dose reduction. Therefore, the DPWG recommends avoiding venlafaxine for CYP2D6 poor and intermediate metabolisers. Instead, an alternative antidepressant, which is not, or to a lesser extent, metabolized by CYP2D6 is recommended. When it is not possible to avoid venlafaxine and side effects occur, it is recommended to reduce the dose and monitor the effect and side effects or plasma concentrations. No action is required for ultra-rapid metabolisers as kinetic effects are minimal and no clinical effect has been demonstrated. In addition, a gene-drug interaction was identified for CYP2D6 and mirtazapine and CYP2C19 and moclobemide, but no therapy adjustment is required as no effect regarding effectiveness or side effects has been demonstrated for these gene-drug interactions. Finally, no gene-drug interaction and need for therapy adjustment between CYP2C19 and mirtazapine and CYP2D6 and duloxetine were identified. The DPWG classifies CYP2D6 genotyping as being "potentially beneficial" for venlafaxine, indicating that genotyping prior to treatment can be considered on an individual patient basis.

Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology - an analysis of the closed cohorts of a multicentre prospective study.

BACKGROUND: Therapeutic drug monitoring (TDM) - performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets - could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible. METHODS: We evaluated drug cohorts from the Dutch Pharmacology Oncology Group - TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed. RESULTS: For 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort. CONCLUSIONS: Although TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.

Sertraline, citalopram and paroxetine in lactation: passage into breastmilk and infant exposure.

Objectives: This study aimed to investigate the plasma and breastmilk concentrations for sertraline, citalopram and paroxetine for assessment of the Milk/Plasma (M/P) ratio and Absolute Infant Dose (AID), and to determine actual infant drug exposure through breastfeeding. Subsequently, informed recommendations will be formulated regarding the advisability of breastfeeding in women undergoing treatment with the three most widely used antidepressants. Methods: A pharmacokinetic study in lactating women and their infants using sertraline, citalopram or paroxetine was performed. Paired breastmilk and plasma samples and single point infant plasma samples were collected to determine antidepressant concentrations. An Area Under the Curve (AUC) based approach with the trapezoidal rule was used to calculate M/P ratios and AID for all three antidepressants by combining all measured concentrations for the same dose. Results: Thirty-seven lactating women and their infants participated in this study. 111 paired breastmilk and plasma samples and 37 single point infant plasma samples were collected. Detectable concentrations of sertraline, citalopram and paroxetine were present in all breastmilk samples. For sertraline and citalopram M/P ratio is above one, indicating higher breastmilk than plasma concentrations, however, drug exposure by breastmilk did not lead to detectable plasma drug levels in any of the 15 infants for sertraline, for nine (out of 13) infants for citalopram and for eight (out of nine) infants for paroxetine. Conclusion: Given the well-known benefits of breastfeeding, our findings support breastfeeding of infants by mothers who are taking sertraline, citalopram or paroxetine is safe. Sertraline and paroxetine are the preferred antidepressants during breastfeeding, reaching mostly undetectable infant drug levels.

Infliximab in paediatric inflammatory bowel disease: External evaluation of population pharmacokinetic models.

AIMS: Use of infliximab (IFX) has improved outcomes in children with inflammatory bowel disease (IBD). However, a proportion of patients does not respond to IFX or loses response over time. Population pharmacokinetic (PopPK) modelling is a promising approach for IFX dose optimization, but with the increasing number of PopPK models in literature, model evaluation is essential. The aims of this study are: (i) to validate the predictive performance of existing IFX PopPK models using a cohort of children with IBD; and (ii) to perform a Bayesian estimation of the most suitable model to predict the next IFX concentrations. METHODS: PubMed was searched for IFX PopPK models in children. Selected models were rebuilt and analysed using R. Model performance was assessed through goodness-of-fit-plots, residuals against time, prediction error and prediction-corrected visual predictive checks. The validation cohort consisted of 73 children with IBD who were treated with IFX in our centre between 2017 and 2023 (340 IFX measurements). RESULTS: We identified 9 PopPK models. Model bias for individual predicted values ranged from -9.29% to 8.01% compared to bias for population predicted values. The model by Vande Casteele et al. demonstrated superior performance (individual predicted bias 2.13, population predicted bias -6.11); upon Bayesian estimation, it predicted induction trough levels with median error of 12.95% but had a median error of -69% predicting maintenance concentrations. CONCLUSION: The model by Vande Casteele et al. displayed superior performance in initial evaluations but had a high error in estimating next IFX levels and can only be used in practice to predict induction levels.

Paralytic ileus in a patient on clozapine therapy showing an inverted clozapine/norclozapine ratio after switching valproic acid to carbamazepine: a case report.

This case report examines the possible correlation between the clozapine/norclozapine ratio and the occurrence of constipation and paralytic ileus. We present the case of a 42-year-old patient diagnosed with schizoaffective disorder undergoing clozapine therapy. Despite intensive treatment with clozapine, haloperidol, valproic acid and biweekly electroconvulsive therapy sessions for over a year, florid psychotic symptoms and fluctuating mood swings persisted. Therefore, valproic acid was replaced by carbamazepine, a potent inducer of several CYP450-enzymes. To maintain clozapine plasma levels, fluvoxamine, a CYP1A2-inhibitor, was introduced at a dose of 25 mg before this switch. After addition of carbamazepine, there was a significant decline in clozapine levels, necessitating an increase in fluvoxamine dosage to 50 mg. Five weeks later the patient was admitted to a general hospital with a diagnosis of paralytic ileus. Treatment with enemas proved effective. Drug concentration analysis revealed a 2.5-fold increase in norclozapine levels in the weeks preceding hospital admission, resulting in an inverted clozapine/norclozapine ratio. Treatment with clozapine, carbamazepine and fluvoxamine was continued as the patient demonstrated clinical improvement on carbamazepine. Concurrently, an intensive laxative regimen was initiated. Two weeks later, the patient was readmitted to the general hospital due to suspected paralytic ileus and faecal vomiting, once again displaying an inverted clozapine/norclozapine ratio. We discuss potential mechanisms contributing to the occurrence of the paralytic ileus in this patient, including the antagonism of muscarinic M3 receptors by both clozapine and norclozapine, as well as the agonism of delta-opioid receptors by norclozapine. This case highlights the potential significance of both the clozapine/norclozapine ratio and absolute norclozapine levels as risk factors for constipation and paralytic ileus in patients on clozapine therapy.

Impact of obesity and roux-en-Y gastric bypass on the pharmacokinetics of (R)- and (S)-omeprazole and intragastric pH.

This study employed physiologically-based pharmacokinetic-pharmacodynamics (PBPK/PD) modeling to predict the effect of obesity and gastric bypass surgery on the pharmacokinetics and intragastric pH following omeprazole treatment. The simulated plasma concentrations closely matched the observed data from non-obese, morbidly obese, and post-gastric bypass populations. Obesity significantly reduces CYP3A4 and CYP2C19 activities, as reflected by the metabolic ratio [omeprazole sulphone]/[omeprazole] and [5-hydroxy-omeprazole]/[omeprazole]. The morbidly obese model accounted for the down-regulation of CYP2C19 and CYP3A4 to recapitulate the observed data. Sensitivity analysis showed that intestinal CYP3A4, gastric pH, small intestine bypass, and the delay in bile release do not have a major influence on omeprazole exposure. Hepatic CYP3A4 had a significant impact on the AUC of (S)-omeprazole, while hepatic CYP2C19 affected both (R)- and (S)-omeprazole AUC. After gastric bypass surgery, the activity of CYP3A4 and CYP2C19 is restored. The PBPK model was linked to a mechanism-based PD model to assess the effect of omeprazole on intragastric pH. Following 40 mg omeprazole, the mean intragastric pH was 4.3, 4.6, and 6.6 in non-obese, obese, and post-gastric bypass populations, and the daily time with pH >4 was 14.7, 16.4, and 24 h. Our PBPK/PD approach provides a comprehensive understating of the impact of obesity and weight loss on CYP3A4 and CYP2C19 activity and omeprazole pharmacokinetics. Given that simulated intragastric pH is relatively high in post-RYGB patients, irrespective of the dose of omeprazole, additional clinical outcomes are imperative to assess the effect of proton pump inhibitor in preventing marginal ulcers in this population.

Systematic Evaluation of Osimertinib Population Pharmacokinetic Models in a Cohort of Dutch Adults with Non-Small Cell Lung Cancer.

BACKGROUND AND OBJECTIVE: Several population pharmacokinetic (popPK) studies have been reported that can guide the prediction of osimertinib plasma concentrations in individual patients. It is currently unclear which popPK model offers the best predictive performance and which popPK models are most suitable for nonadherence management and model-informed precision dosing. Therefore, the objective of this study was to externally validate all osimertinib popPK models available in the current literature. METHODS: Published popPK models for osimertinib were constructed using NONMEM version 7.4.4. The predictive quality of the identified models was assessed with goodness-of-fit (GoF) plots, conditional weighted residuals (CWRES) plots and a prediction-corrected visual predictive check (pcVPC) for osimertinib and its active metabolite AZ5104. A subset from the Dutch OSIBOOST trial, where 11 patients with low osimertinib exposure were included, was used as evaluation cohort. RESULTS: The population GoF plots for all four models poorly followed the line of identity. For the individual GoF plots, all models performed comparable and were closely distributed among the line of identity. CWRES of the four models were skewed. The pcVPCs of all four models showed a similar trend, where all observed concentrations fell in the simulated shaded areas, but in the lower region of the simulated areas. CONCLUSION: All four popPK models can be used to individually predict osimertinib concentrations in patients with low osimertinib exposure. For population predictions, all four popPK models performed poorly in patients with low osimertinib exposure. A novel popPK model with good predictive performance should be developed for patients with low osimertinib exposure. Ideally, the cause for the relatively low osimertinib exposure in our evaluation cohort should be known. CLINICAL TRIALS REGISTRATION: NCT03858491.

Effects of Plasmapheresis on Serum Lithium Levels in an ICU Patient with Bipolar Disorder: A Case Study.

ABSTRACT: This is a case description of a patient with bipolar disorder undergoing lithium therapy who received plasmapheresis for neuromyelitis optica spectrum disorder. Plasmapheresis resulted in lower and subtherapeutic serum lithium levels. Using therapeutic drug monitoring, a dose escalation of 80% was necessary to maintain therapeutic serum lithium levels. This underscores the importance of individualized therapy through therapeutic drug monitoring.

Self-reported smoking, urine cotinine, and risk of type 2 diabetes: Findings from the PREVEND prospective cohort study.

BACKGROUND: Smoking is a major risk factor for type 2 diabetes (T2D), but the evidence has mostly relied on self-reports. We aimed to compare the associations of smoking exposure as assessed by self-reports and urine cotinine with T2D. METHODS: Using the PREVEND prospective study, smoking status was assessed at baseline by self-reports and urine cotinine in 4708 participants (mean age, 53 years) without a history of diabetes. Participants were classified as never, former, light current and heavy current smokers according to self-reports and analogous cut-offs for urine cotinine. Hazard ratios (HRs) with 95% CIs were estimated for T2D. RESULTS: During a median follow-up of 7.3 years, 259 participants developed T2D. Compared with self-reported never smokers, the multivariable adjusted HRs (95% CI) of T2D for former, light current, and heavy current smokers were 1.02 (0.75-1.4), 1.41 (0.89-2.22), and 1.30 (0.88-1.93), respectively. The corresponding adjusted HRs (95% CI) were 0.84 (0.43-1.67), 1.61 (1.12-2.31), and 1.58 (1.08-2.32), respectively, as assessed by urine cotinine. Urine cotinine-assessed but not self-reported smoking status improved T2D risk prediction beyond established risk factors. CONCLUSION: Urine cotinine assessed smoking status may be a stronger risk indicator and predictor of T2D compared to self-reported smoking status.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.

By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin "essential" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine "beneficial", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.

Safety, tolerability and toxicokinetics of the novel mitochondrial drug SUL-138 administered orally to rat and minipig.

Noncommunicable Chronic Diseases (NCD) are a socioeconomic burden and considered one of the major health challenges for coming decades. Mitochondrial dysfunction has been implicated mechanistically in their pathophysiology. Therefore, targeting mitochondria holds great promise to improve clinical outcomes in NCDs. SUL-138, an orally bioavailable small molecule efficacious from 0.5 mg/kg, improves mitochondrial function during disease in several preclinical animal models. As preparation for a First-in-Human (FIH) trial, SUL-138 was investigated in 30-day GLP repeated dose toxicity studies in rat and minipig, selected based on their comparability with human metabolism, to determine toxicokinetics, potential toxicity and its reversibility. Rats were allocated to either vehicle, 27, 136 or 682 mg/kg SUL-138 dose groups and minipigs were allocated to either vehicle, 16, 82 or 409 mg/kg. Treatment occurred orally for 30 days followed by a recovery period of 14 days. During these studies clinical observations, toxicokinetic, clinical pathology, necropsy and histopathology evaluations were performed. There was significant systemic exposure to SUL-138 and toxicokinetics was characterized by a rapid absorption and elimination. In the rat, toxicokinetics was dose-proportional and AUC0-tlast ratios in both species indicated that SUL-138 does not accumulate in vivo. No treatment-related adverse effects were observed for dose levels up to 136 and 82 mg/kg/day in rat and minipig respectively. In conclusion, these preclinical studies demonstrate that SUL-138 is well tolerated after repeated administration in rat and minipig, with NOAELs of 136 and 82 mg/kg/day, respectively.

Everolimus decreases [U-13C]glucose utilization by pyruvate carboxylase in breast cancer cells in vitro and in vivo.

Reprogrammed metabolism is a hallmark of cancer, but notoriously difficult to target due to metabolic plasticity, especially in response to single metabolic interventions. Combining mTOR inhibitor everolimus and mitochondrial complex 1 inhibitor metformin results in metabolic synergy in in vitro models of triple-negative breast cancer. Here, we investigated whether the effect of this drug combination on tumor size is reflected in changes in tumor metabolism using [U-13C]glucose labeling in an MDA-MB-231 triple negative breast cancer xenograft model. The in vitro effects of everolimus and metformin treatment on oxidative phosphorylation and glycolysis reflected changes in 13C-labeling of metabolites in MDA-MB-231 cells. Treatment of MDA-MB-231 xenografts in SCID/Beige mice with everolimus resulted in slower tumor growth and reduced tumor size and tumor viability by 35%. Metformin treatment moderately inhibited tumor growth but did not enhance everolimus-induced effects. High serum levels of everolimus were reached, whereas levels of metformin were relatively low. Everolimus decreased TCA cycle metabolite labeling and inhibited pyruvate carboxylase activity. Metformin only caused a mild reduction in glycolytic metabolite labeling and did not affect pyruvate carboxylase activity or TCA cycle metabolite labeling. In conclusion, treatment with everolimus, but not metformin, decreased tumor size and viability. Furthermore, the efficacy of everolimus was reflected in reduced 13C-labeling of TCA cycle intermediates and reduced pyruvate carboxylase activity. By using in-depth analysis of drug-induced changes in glucose metabolism in combination with measurement of drug levels in tumor and plasma, effects of metabolically targeted drugs can be explained, and novel targets can be identified.

GC-MS analysis of 4-hydroxyproline: elevated proline hydroxylation in metformin-associated lactic acidosis and metformin-treated Becker muscular dystrophy patients.

Metformin (N,N-dimethylbiguanide), an inhibitor of gluconeogenesis and insulin sensitizer, is widely used for the treatment of type 2 diabetes. In some patients with renal insufficiency, metformin can accumulate and cause lactic acidosis, known as metformin-associated lactic acidosis (MALA, defined as lactate ≥ 5 mM, pH < 7.35, and metformin concentration > 38.7 µM). Here, we report on the post-translational modification (PTM) of proline (Pro) to 4-hydroxyproline (OH-Pro) in metformin-associated lactic acidosis and in metformin-treated patients with Becker muscular dystrophy (BMD). Pro and OH-Pro were measured simultaneously by gas chromatography-mass spectrometry before, during, and after renal replacement therapy in a patient admitted to the intensive care unit (ICU) because of MALA. At admission to the ICU, plasma metformin concentration was 175 µM, with a corresponding lactate concentration of 20 mM and a blood pH of 7.1. Throughout ICU admission, the Pro concentration was lower compared to healthy controls. Renal excretion of OH-Pro was initially high and decreased over time. Moreover, during the first 12 h of ICU admission, OH-Pro seems to be renally secreted while thereafter, it was reabsorbed. Our results suggest that MALA is associated with hyper-hydroxyprolinuria due to elevated PTM of Pro to OH-Pro by prolyl-hydroxylase and/or inhibition of OH-Pro metabolism in the kidneys. In BMD patients, metformin, at the therapeutic dose of 3 × 500 mg per day for 6 weeks, increased the urinary excretion of OH-Pro suggesting elevation of Pro hydroxylation to OH-Pro. Our study suggests that metformin induces specifically the expression/activity of prolyl-hydroxylase in metformin intoxication and BMD.

Unexpected Amanita phalloides-Induced Hematotoxicity-Results from a Retrospective Study.

INTRODUCTION: Amanita phalloides poisoning is a serious health problem with a mortality rate of 10-40%. Poisonings are characterized by severe liver and kidney toxicity. The effect of Amanita phalloides poisonings on hematological parameters has not been systematically evaluated thus far. METHODS: Patients with suspected Amanita phalloides poisonings were retrospectively selected from the hospital database of the University Medical Center Groningen (UMCG). Medical data-including demographics; liver, kidney, and blood parameters; treatment; and outcomes-were collected. The severity of the poisoning was scored using the poison severity score. RESULTS: Twenty-eight patients were identified who were admitted to the UMCG with suspected Amanita phalloides poisoning between 1994 and 2022. A time-dependent decrease was observed for hemoglobin and hematocrit concentrations, leukocytes, and platelets. Six out of twenty-eight patients developed acute liver failure (ALF). Patients with ALF showed a higher increase in liver enzymes, international normalized ratios, and PSS compared to patients without ALF. Conversely, hemoglobin and platelet numbers were decreased even further in these patients. Three out of six patients with ALF died and one patient received a liver transplant. CONCLUSION: Our study shows that Amanita phalloides poisonings may be associated with hematotoxicity in patients. The quantification of hematological parameters is of relevance in intoxicated patients, especially in those with ALF.

Urine cotinine versus self-reported smoking and the risk of chronic kidney disease.

BACKGROUND AND HYPOTHESIS: Evidence on the role of smoking in the development of chronic kidney disease (CKD) has mostly relied on self-reported smoking status. We aimed to compare the associations of smoking status as assessed by self-reports and urine cotinine with CKD risk. METHODS: Using the PREVEND prospective study, smoking status was assessed at baseline using self-reports and urine cotinine in 4333 participants (mean age, 52 years) without a history of CKD at baseline. Participants were classified as never, former, light current and heavy current smokers according to self-reports and comparable cut-offs for urine cotinine. Hazard ratios (HRs) with 95% CIs were estimated for CKD. RESULTS: The percentages of self-reported and cotinine-assessed current smokers were 27.5% and 24.0%, respectively. During a median follow-up of 7.0 years, 593 cases of CKD were recorded. In analyses adjusted for established risk factors, the HRs (95% CI) of CKD for self-reported former, light current, and heavy current smokers compared with never smokers were 1.17 (0.95-1.44), 1.48 (1.10-2.00), and 1.48 (1.14-1.93), respectively. On further adjustment for urinary albumin excretion (UAE), the HRs (95% CI) were 1.07 (0.87-1.32), 1.26 (0.93-1.70), and 1.20 (0.93-1.57), respectively. For urine cotinine-assessed smoking status, the corresponding HRs (95% CI) were 0.81 (0.52-1.25), 1.17 (0.92-1.49), and 1.32 (1.02-1.71), respectively, in analyses adjusted for established risk factors plus UAE. CONCLUSION: Self-reported current smoking is associated with increased CKD risk, but dependent on UAE. The association between urine cotinine-assessed current smoking and increased CKD risk is independent of UAE. Urine cotinine-assessed smoking status may be a more reliable risk indicator for CKD incidence than self-reported smoking status.

Effects of interrupting the enterohepatic circulation in amatoxin intoxications.

BACKGROUND: Interruption of the enterohepatic circulation is regarded as an effective way to treat patients with amatoxin poisoning. Nonetheless, its effectiveness has not yet been systematically evaluated. Therefore, we performed a systematic review to investigate the role of enterohepatic circulation on patient outcome and clinical laboratory values. We specifically sought to evaluate the effect of activated charcoal, which absorbs drugs and toxins in the gastrointestinal tract. METHODS: A previously established database with data extracted from case reports and series from literature, supplemented with recent publications, was used. Patient characteristics, outcome, and laboratory values were evaluated. RESULTS: We included 133 publications describing a total of 1,119 unique cases. Survival was 75 per cent in the control group (n = 452), whereas in the group treated with single or multiple doses of activated charcoal (n = 667) survival was 83 per cent (P < 0.001, odds ratio 1.89 [95 per cent confidence interval 1.40-2.56]). Furthermore, no difference in peak values of alanine aminotransferase and aspartate aminotransferase activities were observed, whereas peak values of total serum bilirubin concentration and international normalized ratio were statistically significantly reduced in patients treated with activated charcoal. DISCUSSION: The ability of activated charcoal to enhance the elimination of amatoxin through interruption of the enterohepatic circulation offers a potentially safe and inexpensive therapy for patients in the post-absorptive phase. LIMITATIONS: Limitations include the potential for publication bias, the lack of universal confirmation of amatoxin concentrations, and the inability to directly measure enterohepatic circulation of amatoxin. CONCLUSION: Treatment with activated charcoal in patients with amatoxin poisoning was associated with a greater chance of a successful outcome. Additionally, activated charcoal was associated with a reduction in markers of liver function, but not markers of liver injury.