Drug Level Monitoring Research Articles

POS-713 TACROLIMUS INDUCED HEPATIC VENO OCCLUSIVE DISEASE IN RENAL TRANSPLANT PATIENT

Tacrolimus is widely used immunosuppressive agent used in solid organ transplant recipients to prevent rejection. It is a calcineurin inhibitor which results in reduced transcription of IL-2 levels thereby mediating the process of preventing rejection. It is extensively metabolized by cytochrome P-450 CYP3A enzymes in the liver and its drug level monitoring is very crucial in managing such patients as it is associated with wide array of adverse effects and multiple drug-drug interactions. Hepatic veno occlusive disease a non thrombotic veno occlusion of hepatic vein is a rare and reversible adverse effect of tacrolimus is being discussed. A 39 year old male with native kidney disease of IgA nephropathy presented 10 months post transplant with fever and cough. He was triple immunosuppression with tac level of 5.8 ng/ml on Tacrolimus 2mg twice daily. He was diagnosed with Aspergillus fumigatus pneumonia for which he was started on Voriconazole. On third day of antifungal he developed acute onset abdominal distension with ascites. Ascitic fluid analysis was suggestive of high SAAG, high protein fluid and contrast enhanced CT abdomen showed significant stenosis of hepatic vein at its confluence of IVC. Concomitantly checked Tacrolimus trough level was greater than 40ng/ml. Gradually tacrolimus dose was reduced and Tacrolimus trough levels were maintained between 2-5 ng/ml. With reduction of tacrolimus dose his ascites reduced and repeat CT abdomen showed opening of hepatic veins.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Hepatic veno occlusive disease is more common in patients with stem cell transplant recipients rather than solid organ transplant patients. HVOD in SOT recipients has been mostly related to the use of Azathioprine and has been rarely reported with pancreas and lung transplant patients. Herewith reporting an rare case of Tacrolimus induced hepatic veno occlusive disease in a renal transplant patient associated with raised tacrolimus trough levels > 40ng/ml due to the concomitant usage of Voriconazole (Known to inhibit metabolism of Tacrolimus). This patient had a complete recovery of symptoms following reduction in dosage of Tacrolimus. In summary, tacrolimus (especially in the event of an overdose), alone or in combination with drugs known to cause VOD (like Azathioprine, valaciclovir) or known to inhibit the metabolism of CNIs may give rise to VOD. It is therefore necessary to monitor tacrolimus levels and liver parameters throughout treatment. In the event of clinical or biochemical abnormalities, appropriate monitoring of drug levels, reduction in dosage of tacrolimus may completely reverse this dreadful life threatening complication.

POS-748 TUBERCULOSIS IN PAEDIATRIC KIDNEY TRANSPLANT RECIPIENTS – A SINGLE CENTRE EXPERIENCE.

Tuberculosis (TB) remains a major challenge in transplant patients particularly in endemic countries with frequent loss of transplanted kidneys. Importantly, many of the features for TB, specifically in the paediatric post-kidney transplant population, have not yet been adequately defined. The aim of the study was to describe the incidence, clinical presentation and outcomes in our paediatric kidney transplant recipients. This was a retrospective descriptive study of 212 paediatric kidney transplant recipients at Red Cross War Memorial Children`s Hospital from 1995 to 2019. Among the 212 kidney transplant patients, 20 (9%) were diagnosed with tuberculosis (TB) of which two thirds (n=13) were diagnosed during the first two years post-transplant. TB was confirmed bacteriologically in 12 (60%) children, and the remaining 8(40%) were clinically diagnosed. The main presenting symptoms were fever (n=13, 65%), weight loss (n=12, 60%) and cough (n=10, 50%). Acute rejection of the transplanted kidney was confirmed at diagnosis in nine children. Immunosuppression had been intensified with pulsed intravenous steroids for a rejection episode within the 3 months before the diagnosis of tuberculosis in 8 (40%) children. Tuberculin skin test was done in all children and was positive in 4 (20%) whilst chest radiography showed abnormalities suggestive of TB in 16 (80%) children. Among the children with TB, 15 (75%) were pulmonary, five (25%) extra-pulmonary among whom three with the TB foci in the allograft. A coinfection with Ebstein Barr virus was found in three cases, Cytomegalovirus in two children and Staphylococcus in another two children. Due to drug interactions, up to three fold increase in cyclosporine or tacrolimus dose was required to maintain therapeutic blood levels which was regularly monitored in the weeks after commencing TB treatment. Isoniazid (INH) prophylaxis appeared protective against development of TB (p=0.04). Other factors such as gender (p=0.25), age group above 15 years (p=0.59) ,10-14 years(p= 0.76), 5-9 years (p=0.81), and type of allograft (p= 0.73) were not significant risk factors for developing TB post kidney transplantation. All the TB infections were successfully treated with a graft and patient survival of 100%. Kidney transplant recipients have a high risk of TB. Chest radiography is a sensitive TB screening tool. A high index of suspicion is required due to its atypical presentation in these patients and frequent association with other infections. Frequent and meticulous monitoring of immunosuppression drug levels during treatment of TB is required to avoid loss of patient or graft. Isoniazid prophylaxis protects against development of TB in this population.

Cell-Free DNA to Monitor Immunosuppression Adequacy in Lung Transplantation

<h3>Purpose</h3> Tacrolimus is a primary immunosuppressive drug used in lung transplantation (LTx). Unfortunately, significant variability in drug level monitoring and dosing makes it challenging to determine immunosuppression adequacy. Furthermore, the relationship between drug levels and allograft injury remain poorly defined. This study examines the relationship between tacrolimus blood and donor-derived cell-free DNA (ddcfDNA), a biomarker of allograft injury. <h3>Methods</h3> 96 LTx from a multicenter cohort were included. Periodic tacrolimus blood levels (n= 4,204) were obtained. Serial plasma samples (n=2,122) were assayed for %ddcfDNA by shotgun sequencing. %ddcfDNA was log-transformed to adjust for skewness. Tacrolimus trough levels were dichotomized to "therapeutic" and "non-therapeutic" based on clinically desirable trough ranges. Tacrolimus trough and %ddcfDNA trends were analyzed. Separate analysis was performed in patients with and without ACR (> Grade 1 per ISHLT criteria). <h3>Results</h3> Over a 24-month follow up period, %ddcfDNA showed an inverse relationship to tacrolimus tough levels (Figure 1a); patients showed higher %ddcfDNA with non-therapeutic tacrolimus trough levels than with therapeutic levels (p<0.0001) (Figure 1b). 27% of patients experienced at least one episode of ACR. During the study follow-up, their %ddcfDNA levels were higher (p=0.049) and their percentage of non-therapeutic trough levels was higher (p=0.006) compared to patients with no ACR. However, even when tacrolimus trough levels were therapeutic, patients with ACR showed higher %ddcfDNA levels compared to patients without ACR (p=0.020). <h3>Conclusion</h3> %ddcfDNA levels vary inversely with tacrolimus blood trough levels in LTx. Even in patients with therapeutic trough levels, those with ACR demonstrate higher %ddcfDNA levels. Further studies should examine whether sensitive biomarkers such as ddcfDNA can be used to augment immunosuppression monitoring in LTx rather than trough levels alone.

Impact of infliximab therapeutic drug level monitoring on outcomes of patients with inflammatory bowel disease: A real-world experience from a Middle Eastern cohort

Background and study aimTherapeutic drug monitoring (TDM) through measurement of infliximab (IFX) trough levels and antibodies to infliximab (ATI) is performed to guide IFX intensification strategies and improve its efficacy. We conducted this study to explore the relationship between clinical and endoscopic/radiological remission and IFX and ATI levels in patients with inflammatory bowel disease (IBD) treated with IFX and to evaluate the appropriateness of treatment decision post TDM. Patients and methodsThis was a cross-sectional study of a cohort of adult patients with IBD. Serum IFX trough concentrations and ATI were measured. ResultsA total of 129 patients [104] with ulcerative colitis (UC) and 25 with Crohn’s disease (CD)] were included in this study, of whom 61.2% were men. The mean disease duration was 6.7 years, and 72% of patients with UC had extensive colitis. The mean serum IFX trough level was 4.1 µg/mL; the IFX trough levels were subtherapeutic in 75 patients (58%), therapeutic in 37 patients (29%), and supratherapeutic in 17 patients (13%). Positivity to ATI was found in 16 patients (12.4%). Only 43 patients (33.3%) underwent an appropriate change in therapy after TDM, patients with penetrating CD disease had low IFX levels and higher C-reactive protein levels at 12 months before TDM. ConclusionsPatients with IBD with therapeutic IFX levels tend to have increased endoscopic/radiological remission rates. However, an appropriate change in management based on TDM was absent in the majority of patients, potentially reflecting the need to have a dashboard to support and guide clinicians in decision-making.

Teicoplanin Therapeutic Drug Monitoring and Treatment Outcomes in Children With Gram-Positive Infections.

This is a retrospective audit of teicoplanin dosing, drug-level monitoring, and outcomes in 29 children who received 31 courses of teicoplanin. Our study of noncritically ill children showed that the majority (35/43, 81%) of trough concentrations were within the therapeutic range (10-30 mg/L) contrasting previous studies in children. Overall, 21 of the 24 (88%) children with Gram-positive infections achieved cure.

Monitoring New Long-Lasting Intravitreal Formulation for Glaucoma with Vitreous Images Using Optical Coherence Tomography.

Intravitreal injection is the gold standard therapeutic option for posterior segment pathologies, and long-lasting release is necessary to avoid reinjections. There is no effective intravitreal treatment for glaucoma or other optic neuropathies in daily practice, nor is there a non-invasive method to monitor drug levels in the vitreous. Here we show that a glaucoma treatment combining a hypotensive and neuroprotective intravitreal formulation (IF) of brimonidine–Laponite (BRI/LAP) can be monitored non-invasively using vitreoretinal interface imaging captured with optical coherence tomography (OCT) over 24 weeks of follow-up. Qualitative and quantitative characterisation was achieved by analysing the changes in vitreous (VIT) signal intensity, expressed as a ratio of retinal pigment epithelium (RPE) intensity. Vitreous hyperreflective aggregates mixed in the vitreous and tended to settle on the retinal surface. Relative intensity and aggregate size progressively decreased over 24 weeks in treated rat eyes as the BRI/LAP IF degraded. VIT/RPE relative intensity and total aggregate area correlated with brimonidine levels measured in the eye. The OCT-derived VIT/RPE relative intensity may be a useful and objective marker for non-invasive monitoring of BRI/LAP IF.

Real-Time Monitoring and Point-of-Care Testing: A Review of the Current Landscape of PrEP Adherence Monitoring.

BackgroundDespite pre-exposure prophylaxis (PrEP) being highly effective at preventing HIV, HIV infections among individuals prescribed PrEP continue to occur. The vast majority of these new infections occur among individuals with sub-optimal adherence. One factor that is likely to decrease HIV incidence among PrEP users is a real-time, objective measurement of adherence. Monitoring adherence to PrEP can identify those at risk of becoming lost to follow-up and therefore at greater risk of HIV infection, those in need of additional layers of support to overcome barriers to PrEP, and individuals who need enhanced adherence support.ObjectiveThis paper reviews subjective and objective methods for monitoring PrEP including self-report, drug level monitoring (including serum, plasma, peripheral blood mononuclear cells [PBMC], red blood cell dried blood spots [DBS], hair, and urine) and by measuring participant interaction with the study drug (pill counts, medication event monitoring systems [MEMS] caps).Clinical UseA multitude of methods exist for monitoring and supporting adherence. Objective monitoring using DBS and urine will provide a more accurate picture of adherence compared to subjective and non-biomarker objective methods. Preliminary data show that detection of non-adherence using biomarkers, followed by augmented adherence support and counseling, is associated with improved adherence, although more research is needed. PrEP providers will need knowledge of and access to these various strategies, which will require investment and resource allocation from clinics and other PrEP care sites to provide these tools.

ISPD guidelines for peritoneal dialysis in acute kidney injury: 2020 Update (paediatrics).

1.1 Peritoneal dialysis is a suitable renal replacement therapy modality for treatment of acute kidney injury in children. (1C)2. Access and fluid delivery for acute PD in children.2.1 We recommend a Tenckhoff catheter inserted by a surgeon in the operating theatre as the optimal choice for PD access. (1B) (optimal)2.2 Insertion of a PD catheter with an insertion kit and using Seldinger technique is an acceptable alternative. (1C) (optimal)2.3 Interventional radiological placement of PD catheters combining ultrasound and fluoroscopy is an acceptable alternative. (1D) (optimal)2.4 Rigid catheters placed using a stylet should only be used when soft Seldinger catheters are not available, with the duration of use limited to <3 days to minimize the risk of complications. (1C) (minimum standard)2.5 Improvised PD catheters should only be used when no standard PD access is available. (practice point) (minimum standard)2.6 We recommend the use of prophylactic antibiotics prior to PD catheter insertion. (1B) (optimal)2.7 A closed delivery system with a Y connection should be used. (1A) (optimal) A system utilizing buretrols to measure fill and drainage volumes should be used when performing manual PD in small children. (practice point) (optimal)2.8 In resource limited settings, an open system with spiking of bags may be used; however, this should be designed to limit the number of potential sites for contamination and ensure precise measurement of fill and drainage volumes. (practice point) (minimum standard)2.9 Automated peritoneal dialysis is suitable for the management of paediatric AKI, except in neonates for whom fill volumes are too small for currently available machines. (1D)3. Peritoneal dialysis solutions for acute PD in children3.1 The composition of the acute peritoneal dialysis solution should include dextrose in a concentration designed to achieve the target ultrafiltration. (practice point)3.2 Once potassium levels in the serum fall below 4 mmol/l, potassium should be added to dialysate using sterile technique. (practice point) (optimal) If no facilities exist to measure the serum potassium, consideration should be given for the empiric addition of potassium to the dialysis solution after 12 h of continuous PD to achieve a dialysate concentration of 3-4 mmol/l. (practice point) (minimum standard)3.3 Serum concentrations of electrolytes should be measured 12 hourly for the first 24 h and daily once stable. (practice point) (optimal) In resource poor settings, sodium and potassium should be measured daily, if practical. (practice point) (minimum standard)3.4 In the setting of hepatic dysfunction, hemodynamic instability and persistent/worsening metabolic acidosis, it is preferable to use bicarbonate containing solutions. (1D) (optimal) Where these solutions are not available, the use of lactate containing solutions is an alternative. (2D) (minimum standard)3.5 Commercially prepared dialysis solutions should be used. (1C) (optimal) However, where resources do not permit this, locally prepared fluids may be used with careful observation of sterile preparation procedures and patient outcomes (e.g. rate of peritonitis). (1C) (minimum standard)4. Prescription of acute PD in paediatric patients4.1 The initial fill volume should be limited to 10-20 ml/kg to minimize the risk of dialysate leakage; a gradual increase in the volume to approximately 30-40 ml/kg (800-1100 ml/m2) may occur as tolerated by the patient. (practice point)4.2 The initial exchange duration, including inflow, dwell and drain times, should generally be every 60-90 min; gradual prolongation of the dwell time can occur as fluid and solute removal targets are achieved. In neonates and small infants, the cycle duration may need to be reduced to achieve adequate ultrafiltration. (practice point)4.3 Close monitoring of total fluid intake and output is mandatory with a goal to achieve and maintain normotension and euvolemia. (1B)4.4 Acute PD should be continuous throughout the full 24-h period for the initial 1-3 days of therapy. (1C)4.5 Close monitoring of drug dosages and levels, where available, should be conducted when providing acute PD. (practice point)5. Continuous flow peritoneal dialysis (CFPD)5.1 Continuous flow peritoneal dialysis can be considered as a PD treatment option when an increase in solute clearance and ultrafiltration is desired but cannot be achieved with standard acute PD. Therapy with this technique should be considered experimental since experience with the therapy is limited. (practice point) 5.2 Continuous flow peritoneal dialysis can be considered for dialysis therapy in children with AKI when the use of only very small fill volumes is preferred (e.g. children with high ventilator pressures). (practice point).

Treatment results of modified BFM protocol in pediatric high-risk Burkitt lymphoma.

Chemotherapy with high dose methotrexate is the mainstay of treatment for Burkitt lymphoma (BL), especially to manage central nervous system (CNS) disease. However, methotrexate administration requires close drug level monitoring for appropriate folinic acid rescue, which might not be readily available in all centers. In this study, we assessed the long-term treatment outcomes of a modified Non-Hodgkin lymphoma (NHL)-Berlin-Frankfurt-Munster (BFM) 90 regimen in pediatric high-risk BL without CNS involvement. Between 1999 and 2011, 42 patients (median age: 7 years) with advanced-stage BL were treated with modified NHL-BFM 90 regimen (methotrexate at a dose of 1 g/m2). Demographic data, stage, lactate dehydrogenase (LDH) and treatment results were retrospectively evaluated. The patients were assessed for toxicity, survival and CNS recurrence. Thirty-six patients had Stage III and six had Stage IV disease, respectively. The median LDH level was 1,432 IU/L. Four patients died of infectious and metabolic complications. One patient had local recurrence at the 48 < sup > th < /sup > month of the follow-up and he is in the second remission for 72 months. In Kaplan-Meier analysis, the overall survival and event-free survival rates at 10 years were found as 90 % and 88 %, respectively. None of our patients died of treatment failure. The administration of the reduced dose of methotrexate seems to not compromise treatment success nor increase the risk of CNS recurrence in high-risk BL without CNS involvement. The limitation of the study is that it is not randomized. Our treatment scheme might be considered for centers without methotrexate measurement facility.

Drug-Based Gold Nanoparticles Overgrowth for Enhanced SPR Biosensing of Doxycycline.

In clinical chemistry, frequent monitoring of drug levels in patients has gained considerable importance because of the benefits of drug monitoring on human health, such as the avoidance of high risk of over dosage or increased therapeutic efficacy. In this work, we demonstrate that the drug doxycycline can act as an Au nanoparticle (doxy-AuNP) growth and capping agent to enhance the response of a surface plasmon resonance (SPR) biosensor for this drug. SPR analysis revealed the high sensitivity of doxy-AuNPs towards the detection of free doxycycline. More specifically, doxy-AuNPs bound with protease-activated receptor-1 (PAR-1) immobilized on the SPR sensing surface yield the response in SPR, which was enhanced following the addition of free doxy (analyte) to the solution of doxy-AuNPs. This biosensor allowed for doxycycline detection at concentrations as low as 7 pM. The study also examined the role of colloidal stability and growth of doxy-AuNPs in relation to the response-enhancement strategy based on doxy-AuNPs. Thus, the doxy-AuNPs-based SPR biosensor is an excellent platform for the detection of doxycycline and demonstrates a new biosensing scheme where the analyte can provide enhancement.

Neuroactive drugs and other pharmaceuticals found in blood plasma of wild European fish

To gain a better understanding of which pharmaceuticals could pose a risk to fish, 94 pharmaceuticals representing 23 classes were analyzed in blood plasma from wild bream, chub, and roach captured at 18 sites in Germany, the Czech Republic and the UK, respectively. Based on read across from humans, we evaluated the risks of pharmacological effects occurring in the fish for each measured pharmaceutical. Twenty-three compounds were found in fish plasma, with the highest levels measured in chub from the Czech Republic. None of the German bream had detectable levels of pharmaceuticals, whereas roach from the Thames had mostly low concentrations. For two pharmaceuticals, four individual Czech fish had plasma concentrations higher than the concentrations reached in the blood of human patients taking the corresponding medication. For nine additional compounds, determined concentrations exceeded 10% of the corresponding human therapeutic plasma concentration in 12 fish. The majority of the pharmaceuticals where a clear risk for pharmacological effects was identified targets the central nervous system. These include e.g. flupentixol, haloperidol, and risperidone, all of which have the potential to affect fish behavior. In addition to identifying pharmaceuticals of environmental concern, the results emphasize the value of environmental monitoring of internal drug levels in aquatic wildlife, as well as the need for more research to establish concentration-response relationships.

First-Time Use of Clinical Pharmacists to Improve Appropriate Antibiotic Prescribing in a Medical ICU in Viet Nam

Background: Antibiotic overuse has led to increasing rates of antibiotic resistant infections and unnecessary antibiotic costs. Clinical pharmacists can play a key role in optimizing appropriate use of antimicrobials and reducing antimicrobial resistance. However, the role of clinical pharmacists in antimicrobial stewardship is new and not well established in Viet Nam. Objective: We evaluated the use of clinical pharmacists for improved antimicrobial prescribing. Methods: We assembled an antibiotic stewardship program (ASP) team consisting of a clinical pharmacist and a specialist in infection prevention and control in a 60-bed medical intensive care unit (MICU) at Hue Central Hospital in central Viet Nam. During January–September 2018, the ASP team collected baseline antibiotic prescribing days of therapy (DOT) for all antibiotics administered in the MICU. Then, from October 2018 through June 2019, the ASP team reviewed daily positive clinical bacterial cultures and susceptibility results for all patients present in the MICU. They reviewed medical charts, including antimicrobial prescriptions, during week days and only if patient was still in the ICU at the time of ASP rounds. The team recommended changes to antibiotic therapy verbally to physicians and left the decision to change antibiotic therapy to their discretion. The ASP team documented whether their recommendations were accepted or rejected. Statistical significance was determined using the Student t test. Results: The ASP team reviewed 160 medical charts and made 169 ASP recommendations: 122 (72%) to continue current treatment; 24 (14%) to monitor drug levels or obtain diagnostic tests; 10 (6%) to discontinue therapy; 6 (4%) to de-escalate therapy; 5 (3%) to adjust doses; and 2 (1%) to broaden therapy. Only 8 of the recommended changes (5%) were declined by the clinicians. The average monthly DOT for all types of antibiotics declined significantly from 2,213 to 1,681 (24% decrease; P = .04). Reductions in DOT for the most common broad-spectrum antibiotics included colistin from 303 to 276 (P = .75); imipenem-cilastatin 434 to 248 (P = .06); doripenem 150 to 144 (P = .85). Piperacillin-tazobactam increased from 122 to 142 (P = 0.75). Conclusions: We demonstrated that daily review of cultures and antibiotic use decreased overall antibiotic prescribing. Given that few recommendations included discontinuation of therapy, ASP rounds likely raised awareness for clinicians to optimize antibiotic use.Funding: NoneDisclosures: None

Securing the future of kidney transplantation by addressing the challenges of transplant nephrology.

Kidney transplant is a life-changing procedure, and transplant nephrologists, as part of a larger transplant team, play an important role in the field by managing the complex medical needs of transplant patients. The subspecialty of transplant nephrology, however, faces structural challenges related to its workforce, reporting structures, compensation, research and innovation, and health care information technology. The position of transplant nephrology at the academic and operational intersection of medicine and surgery may limit its access to critical resources, hinder academic promotion, and contribute to physician burnout. The authors provide an overview of the subspecialty transplant nephrology and propose solutions. Collaborative efforts that fortify the subspecialty of transplant nephrology will ultimately improve the lives of patients suffering from kidney disease.

Solid phase microextraction chemical biopsy tool for monitoring of doxorubicin residue during in vivo lung chemo-perfusion

Development of a novel in vivo lung perfusion (IVLP) procedure allows localized delivery of high-dose doxorubicin (DOX) for targeting residual micrometastatic disease in the lungs. However, DOX delivery via IVLP requires careful monitoring of drug level to ensure tissue concentrations of this agent remain in the therapeutic window. A small dimension nitinol wire coated with a sorbent of biocompatible morphology (Bio-SPME) has been clinically evaluated for in vivo lung tissue extraction and determination of DOX and its key metabolites. The in vivo Bio-SPME-IVLP experiments were performed on pig model over various (150 and 225 mg/m2) drug doses, and during human clinical trial. Two patients with metastatic osteosarcoma were treated with a single 5 and 7 μg/mL (respectively) dose of DOX during a 3-h IVLP. In both pig and human cases, DOX tissue levels presented similar trends during IVLP. Human lung tissue concentrations of drug ranged between 15 and 293 μg/g over the course of the IVLP procedure. In addition to DOX levels, Bio-SPME followed by liquid chromatography-mass spectrometry analysis generated 64 metabolic features during endogenous metabolite screening, providing information about lung status during drug administration. Real-time monitoring of DOX levels in the lungs can be performed effectively throughout the IVLP procedure by in vivo Bio-SPME chemical biopsy approach. Bio-SPME also extracted various endogenous molecules, thus providing a real-time snapshot of the physiology of the cells, which might assist in the tailoring of personalized treatment strategy.

Safe administration of high-dose methotrexate with minimal drug level monitoring: Experience from a center in north India.

High-dose methotrexate (HDMTX) is recommended to be administered with serial monitoring of methotrexate (MTX) levels, which may not be universally feasible in resource-limited settings. In this study, we evaluated the overall experience of administration of HDMTX at our center by monitoring a single drug level at 54h from the start of MTX infusion. This retrospective study was performed at a tertiary level hospital in north India, over a 5-year period (2011-2015). All patients <18years of age with newly diagnosed acute lymphoblastic leukemia (ALL) and T-non-Hodgkin lymphoma (T-NHL) were enrolled in the study. Details of HDMTX and all significant toxicities requiring prolonged or repeat hospitalization were retrieved from the medical records. All eligible patients received HDMTX as per the recommendations followed by at least three doses of leucovorin rescue, before drug levels were sent at 54h. Subsequent leucovorin doses were adjusted accordingly. The records of 598 cycles of HDMTX in 184 patients were reviewed. A total of 531 of 598 cycles (88.7%) were managed with monitoring only a single plasma drug level at 54h from the beginning of infusion. Delayed MTX clearance was seen in 260 of 598 cycles (43.5%). Only three episodes (0.5%) were associated with significant toxicity. There were no deaths. The strategy of monitoring MTX concentration at 54h was safe in our cohort. Although recommended, dynamic monitoring of plasma drug levels may not always predict toxicity.

Global Survey of Guidelines for the Management of Epilepsy in Pregnancy: A report from the International League Against Epilepsy Task Force on Women and Pregnancy.

The ILAE Task Force on Women and Pregnancy conducted a survey among ILAE Chapters of their use of guidelines or recommendations for the management of women with epilepsy during pregnancy. A web‐based questionnaire including 10 questions was sent to the 118 ILAE Chapters in December 2017 with repeated reminders until the end of February 2018. In total, 77 chapters (65%) responded, although not to all questions. Out of those responding, 68% reported having guidelines or recommendations, 34% of which were from 2014 or earlier. At least 20% of the guidelines did not include information on possible risk to cognitive development, information regarding specific risks with specific antiepileptic drugs, nor recommendations regarding selection of antiepileptic drugs. Among those responding to the question, 91% reported that recommendations were made regarding folate supplementation, but the recommended dose ranged from 0.4 mg/d to 4 mg/d or more; 34% did not include recommendations regarding drug level monitoring during pregnancy, and 19% did not include guidelines on breastfeeding. Our survey demonstrates that there is a need for the development of up‐to‐date, globally applicable recommendations for the management of epilepsy during pregnancy.

On precision dosing of oral small molecule drugs in oncology.

Personalization of oral small molecule anticancer drug doses based on individual patient blood drug levels, also known as therapeutic drug monitoring (TDM), has the potential to significantly improve the effectiveness of treatment by maximizing drug efficacy and minimize toxicity. However, this option has not yet been widely embraced by the oncology community. Some reasons for this include increased logistical complexity of dose individualization, the lack of clinical laboratories that measure small molecule drug concentrations in support of patient care, and the lack of reimbursement of costs. However, the main obstacle may be the lack of studies clearly demonstrating that monitoring of oral small molecule anticancer drug levels actually improves clinical outcomes. Without unequivocal evidence in support of TDM-guided dose individualization, especially demonstration of improved survival with TDM in randomized controlled trials, wide acceptance of this approach by oncologists and reimbursement by insurance companies is unlikely, and patients may continue to suffer as a result of receiving incorrect drug doses. This article reviews the current status of TDM of oral small molecule drugs in oncology and intends to provide strategic insights into the design of studies for evaluating the utility of TDM in this clinical context.

Tacrolimus dose modification in patients receiving concomitant isavuconazole after hematopoietic stem cell transplantation.

Isavuconazole is increasingly being used for antifungal prophylaxis during stem cell transplantation. Isavuconazole is a moderate inhibitor of Cytochrome P4503A4, and tacrolimus levels are anticipated to be elevated when given concomitantly with isavuconazole. We developed and validated a dose-modified tacrolimus regimen to better achieve and maintain target tacrolimus levels.Methods: Allogeneic stem cell transplantation recipients who received concomitant tacrolimus and isavuconazole from September 2017 to September 2018 were included. Tacrolimus was adjusted to achieve a target range 8-12ng/ml. Intravenous tacrolimus was first initiated at 0.02 mg/kg/day on day 1, and transitioned to oral therapy using a 2:1 conversion ratio (n = 48). Clinical observations showed high interpatient variability. The intravenous dose was then reduced to 0.017 mg/kg/day, and oral:intravenous conversion changed to 3.1:1 (n = 24). Interpatient variability was high (lower in the 0.017 mg/kg/day group; P < 0.0217). Patients in the 0.017 mg/kg/day group required fewer dose changes (P < 0.023) and had fewer levels >15ng/ml (P < 0.021). Median tacrolimus dose declined over time; 0.016, 0.012 and 0.011 on days 1, 7 and 10 for patients receiving 0.02 mg/kg/day and 0.017, 0.014 and 0.013 in the 0.017 mg/kg group. Day 10 tacrolimus accumulation factor was 1.42 Rac(Cmax) in the 0.02 mg/kg/day cohort compared to 1.23 Rac(Cmax) in the 0.017 mg/kg/day cohort (P < 0.015). When transitioned to oral therapy, a oral:intravenous conversion ratio >3.1:1 was shown to improve chances for achieving target levels (P > 0.0744). We recommend initiating intravenous tacrolimus dose at 0.017 mg/kg/day and using a 3.1:1 oral:intravenous conversion to reduce interpatient variability, drug accumulation and the number of suboptimal tacrolimus levels. Tacrolimus requires frequent drug level monitoring.

Rapid Capture and Extraction of Sweat for Regional Rate and Cytokine Composition Analysis Using a Wearable Soft Microfluidic System

Rapid Capture and Extraction of Sweat for Regional Rate and Cytokine Composition Analysis Using a Wearable Soft Microfluidic System

Proactive Drug Monitoring Is Associated With Higher Persistence to Infliximab and Adalimumab Treatment and Lower Healthcare Utilization Compared With Reactive and Clinical Monitoring.

BackgroundSerum drug-level assays for infliximab (IFX) and adalimumab (ADA) are widely available and are most often obtained reactively, to determine the next steps in patients with loss of response. Studies done thus far on the use of these assays proactively, or during symptom remission, have had mixed results. Here we investigate persistence on therapy and healthcare utilization in patients on 3 drug-level monitoring strategies.MethodsWe conducted a retrospective chart review of 235 patients treated for both Crohn disease and ulcerative colitis on either IFX or ADA. Monitoring strategy was defined as proactive if patients underwent testing at predefined time points regardless of symptoms or signs of disease, reactive if done during relapse, or control if no drug levels were obtained. Groups were compared on persistence on original therapeutic at 1 and 2 years as well as on various measures of healthcare utilization during the 2-year follow-up period.ResultsProactive drug monitoring was associated with a higher likelihood of persistence on therapy at 1 year when compared with the control (odds ratio [OR] = 4.76, 95% confidence interval [CI] = 1.65, 13.67) and reactive groups (OR = 6.10, CI = 2.19, 17.02). Similarly, at 2 years, proactive monitoring was superior to the control (OR = 5.41, CI = 2.26, 12.94) and reactive groups (OR = 4.51, CI = 1.88, 10.80). Proactive monitoring was also associated with lower healthcare utilization across almost all measures related to inflammatory bowel disease.ConclusionsProactive drug monitoring increases persistence on IFX and ADA in patients with ulcerative colitis or Crohn disease and decreases overall healthcare utilization in these patients.