Need For Therapeutic Drug Monitoring Research Articles

Pharmacokinetics of Mycophenolate Mofetil Metabolites in Older Patients on the Seventh Day After Renal Transplantation

Currently, immunosuppression schemes are age-independent; however, physiological changes may alter drugs' pharmacokinetics in the older population. We compared mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) pharmacokinetics among patients aged <60 and >60 years on the seventh day after renal transplantation. We included 7 and 10 renal transplant recipients, aged >60 and <60 years, respectively, treated with mycophenolate mofetil. MPA and MPAG concentrations were determined using the high-performance liquid chromatography method with ultraviolet detection (HPLC-UV). Noncompartmental pharmacokinetic analysis was performed. In patients aged >60 years, mean MPA and MPAG concentrations before the next dose and ratio of MPAG area under the concentration-time curve (AUC0-12) to MPA AUC0-12 were higher by 1.6-fold, 1.4-fold, and 1.9-fold, respectively. Other MPAG concentrations appeared to be slightly higher (1.2- to 1.5-fold) in older patients. MPA apparent clearance was similar in both groups, whereas volume of distribution at steady state was slightly higher (1.6-fold) in patients aged >60 years. The variability of most MPA and some MPAG pharmacokinetics was greater in patients aged >60 years. The MPA AUC0-12 target was achieved in 40% and 14% of patients aged <60 and >60 years, respectively. The highest MPAG concentrations and AUC0-12 were observed for patients with the lowest glomerular filtration rate. Higher variability of MPA and MPAG pharmacokinetic parameters, MPA AUC0-12 above the reference range, higher values of MPAG pharmacokinetics in patients with lower glomerular filtration rates, as well as lower proportion of patients achieving MPA targets all indicate the need for therapeutic drug monitoring in renal transplant recipients aged >60 years and to verify target MPA AUC0-12 for this population.

FC 035VOCLOSPORIN INCREASES RENAL RESPONSE AT COMMONLY USED UPCR THRESHOLDS IN PATIENTS WITH LUPUS NEPHRITIS

Abstract Background and Aims Voclosporin is a novel calcineurin inhibitor with a favorable metabolic profile and a consistent dose-concentration relationship, potentially eliminating the need for therapeutic drug monitoring. We have previously reported the primary endpoint of the Phase 3 AURORA trial showing the addition of voclosporin to mycophenolate mofetil (MMF) and a low-dose glucocorticoid regimen results in significantly higher renal response (RR) rates at one year of treatment compared to MMF and low-dose glucocorticoids alone in patients with lupus nephritis (LN). For the primary endpoint, RR was defined as ≤0.5 mg/mg UPCR with stable renal function in the presence of low-dose glucocorticoids and no use of rescue medication. Several studies have demonstrated that proteinuria represents the best single predictor for long-term renal outcomes.1,2 Given the efficacy of voclosporin in terms of proteinuria reduction, we conducted a sensitivity analysis evaluating RR with additional UPCR targets. Method A total of 179 participants in the voclosporin (23.7 mg BID) arm and 178 participants in the control arm from the AURORA trial were included in this analysis. All participants received MMF (target 1 g BID) and low-dose oral glucocorticoids (initiated at 20-25 mg/day and tapered to 2.5 mg/day at 16 weeks). For this post hoc analysis, the UPCR component of RR was revised to include UPCR targets at 0.2 mg/mg intervals above and below the original ≤0.5 target used for the primary endpoint in AURORA (i.e., ≤0.7 mg/mg or ≤0.3 mg/mg, respectively). Odds ratios for RR at six months and one year of treatment were analyzed using a logistic regression model with terms for treatment, baseline UPCR, biopsy class, and MMF use at baseline and region. Results RR with UPCR ≤0.7 mg/mg was achieved by 46.9% of participants in the voclosporin arm vs 32.0% of participants in the control arm at one year of treatment (OR 2.07, p&amp;lt;0.0014) and 39.1% of participants in the voclosporin arm vs 24.7% of participants in the control arm at six months of treatment (OR 2.10, p=0.0020). RR with UPCR ≤0.3 mg/mg was achieved by 28.5% of participants in the voclosporin arm vs 15.7% of participants in the control arm at one year (OR 2.27, p=0.0023 and 22.9% of participants in the voclosporin arm vs 14.0% of participants in the control arm at six months of treatment (OR 1.90, p=0.0238; Table 1). Conclusion Participants treated with voclosporin in addition to MMF and low-dose glucocorticoids achieved statistically significantly increased renal response rates regardless of the level of UPCR used, including at an even more stringent ≤0.3 mg/mg target. This analysis further supports the efficacy observed with voclosporin in the Phase 3 AURORA and the prior Phase 2 AURA-LV global trials.

Optimisation du traitement par β-Lactamines chez le patient de réanimation en hyperclairance rénale

L'optimisation du traitement par β-Lactamines représente toujours un défi complexe chez le patient de soins critiques, compte tenu de la large variabilité des concentrations d'antibiotiques en relation avec d’importantes interactions pharmacocinétiques et pharmacodynamiques (PK/PD). D’une part, il est communément admis que les patients présentant une insuffisance rénale justifient une diminution des posologies afin de limiter le risque de toxicité. D’autre part, certains patients peuvent également présenter une hyperclairance rénale (HCR), désormais reconnue comme un des principaux facteurs de risque de sous-dosage et d’échec thérapeutique des agents anti-infectieux à élimination urinaire. L’hyperclairance est une entité fréquente en réanimation chirurgicale, probablement sous-diagnostiquée en l’absence de mesure de clairance urinaire de la créatinine (CLCR). Pour certaines β-lactamines prescrites en probabiliste, plusieurs études de pharmacocinétique suggèrent une augmentation des posologies recommandées afin d’atteindre les objectifs PK/PD chez les patients atteints d'HCR. En cas d’impossibilité de monitorer les concentrations plasmatiques dans des délais brefs, l'optimisation des posologies de β-lactamines selon le monitorage quotidien de la CLCR est une stratégie sûre et efficace pour améliorer les taux de succès thérapeutique. L’HCR étant un phénomène fluctuant, cette stratégie impose un monitorage quotidien de la CLCR afin d’adapter les posologies et limiter le risque de surdosage.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Pediatric Venous Thromboembolism Treatment and Thromboprophylaxis: A Systematic Review of the Literature.

Venous thromboembolism (VTE) in children can lead to significant morbidity and mortality. Traditionally, treatment for thrombotic events in pediatric patients has been limited mainly to unfractionated heparin, low-molecular-weight heparin (LMWH), or vitamin K antagonists. Since the first non-vitamin K antagonist oral anticoagulant (NOAC) was approved for adult use, these agents have gained popularity for a variety of indications. This is largely due to their ease of administration, favorable pharmacokinetic and pharmacodynamic profile, decreased food interactions, and decreased need for therapeutic drug monitoring. Treating and preventing VTE with traditional anticoagulants in pediatric patients presents many challenges. This systematic review evaluated the current literature regarding pediatric NOAC trials. Additionally, based on an up-to-date query of clinicaltrials.gov, we detail current ongoing and as-yet unpublished clinical trials, study outcomes, and projected completion dates. Published pediatric NOAC trials have included 1,007 total children to date and have ranged from phase 1 to 4, with "indications" including both thromboembolism prophylaxis and VTE treatment. Three recent phase 3 trials, specifically involving rivaroxaban and dabigatran, have shown the agents to be at least as effective as traditional anticoagulants for acute and/or extended VTE treatment, with low frequency of recurrent thrombosis and clinically significant bleeding rates. Additionally, specially developed and tested pediatric formulations have allowed for accurate and reliable dosing, oral administration, stable pharmacokinetics and pharmacodynamics, and fewer drug or food interactions. Ongoing trials, anticipated for completion in the next few years, will reveal important information with regard to thromboembolism prophylaxis in special pediatric subpopulations and settings.

Plasma drug concentrations of 4-drug fixed-dose combination regimen and its efficacy for treatment of pulmonary tuberculosis under National Tuberculosis Elimination Programme: A prospective pilot study

BackgroundThe thrice weekly dosing regimen of DOTS has shown low rifampicin plasma concentrations as an independent risk factor for unfavourable tuberculosis (TB) outcome. With introduction of daily regimen using fixed dose combinations (FDC) under National Tuberculosis Elimination Programme (NTEP) the existence of suboptimal plasma levels of first-line antitubercular drugs and its clinical significance remain poorly understood. MethodWe included a prospective cohort of newly diagnosed pulmonary tuberculosis (PTB) patients receiving 4-FDC daily regimen under NTEP. Plasma concentration at 2 hours (C2h) of each drug was determined after two weeks of treatment using liquid chromatography (LCMS/MS) developed by us. TB card and laboratory reports were reviewed for baseline characteristics and clinical status at 2, 4 and 6 months after the initiation of treatment. At a 1 year follow-up, therapy failure was defined as death or a relapse of tuberculosis. ResultsAmong 40 PTB patients, the C2h post dose plasma concentrations of H, R and E were suboptimal in 25%, 60% and 10% respectively. The C2h of H, R, Z and E were respectively 4.2 ± 2.0, 7.3 ± 2.8, 39.2 ± 8.8 and 3.5 ± 1.2 μg/ml; 60% of the patients had suboptimal plasma concentrations and commonly it was observed with H and R. C2h were lower than expected for at least two drugs i.e. H and R in 25% (10/40) of the patients. Plasma concentration of isoniazid and rifampicin has always been considered important for microbiological response and treatment outcome and low concentrations has been associated with poor treatment response. These patients may require a two year follow up and critical evaluation for prevention of MDR-TB. However, all the TB patients were cured and none of them had recurrence within one year follow up. ConclusionsAll the pulmonary TB patients administering 4-FDC daily regimen under programmatic settings were cured despite the suboptimal levels of isoniaizd and rifampicin. All the patients achieved pyrazinamide plasma levels and probably this could be the reason behind favourable outcome. Further study is required on large sample size with various subset of population to understand the need of therapeutic drug monitoring.

Model-Optimized Fluconazole Dose Selection for Critically Ill Patients Improves Early Pharmacodynamic Target Attainment without the Need for Therapeutic Drug Monitoring.

Fluconazole has been associated with higher mortality compared with the echinocandins in patients treated for invasive candida infections. Underexposure from current fluconazole dosing regimens may contribute to these worse outcomes, so alternative dosing strategies require study. The objective of this study was to evaluate fluconazole drug exposure in critically ill patients comparing a novel model-optimized dose selection method with established approaches over a standard 14-day (336-h) treatment course. Target attainment was evaluated in a representative population of 1,000 critically ill adult patients for (i) guideline dosing (800-mg loading and 400-mg maintenance dosing adjusted to renal function), (ii) guideline dosing followed by therapeutic drug monitoring (TDM)-guided dose adjustment, and (iii) model-optimized dose selection based on patient factors (without TDM). Assuming a MIC of 2 mg/liter, free fluconazole 24-h area under the curve (fAUC24) targets of ≥200 mg · h/liter and <800 mg · h/liter were used for assessment of target attainment. Guideline dosing resulted in underexposure in 21% of patients at 48 h and in 23% of patients at 336 h. The TDM-guided strategy did not influence 0- to 48-h target attainment due to inherent procedural delays but resulted in 37% of patients being underexposed at 336 h. Model-optimized dosing resulted in ≥98% of patients meeting efficacy targets throughout the treatment course, while resulting in less overexposure compared with guideline dosing (7% versus 14%) at 336 h. Model-optimized dose selection enables fluconazole dose individualization in critical illness from the outset of therapy and should enable reevaluation of the comparative effectiveness of this drug in patients with severe fungal infections.

Only Modest Effect of Lipids and Albumin on Apparent Mycophenolic Acid Clearance in Pediatric Transplant Recipients – a Retrospective Cohort Study

Background: There is growing evidence for the need of therapeutic drug monitoring (TDM) of the active compound Mycophenolic Acid (MPA) of mycophenolate mofetil therapy for the management of antirejection therapy after pediatric renal transplantation. While there is substantial inter- and intra-patient variability of MPA exposure, the factors affecting its apparent clearance (CL/F) are understudied. The objective of this study was to determine the relationship between MPA CL/F, eGFR, creatinine, Cystatin C, triglycerides, cholesterol and albumin. Material and Methods: We calculated 1004 estimated mass-spectrometry-determined MPA CL/F using trough concentrations from 35 pediatric renal transplant patients. Results: Mean age was 8.7±4.6 years at transplant with a median follow-up of 5.8 years. Each patient had a median of 30 MPA trough concentrations. The median MPA AUC was 53.21 mg*h/L, the median CL/F was 8.66 L/h. Univariate and multivariate analysis revealed significant correlations of CL/F with creatinine, triglycerides, cholesterol and albumin, and very weakly with hemoglobin, whereas cystatin C was unrelated. Especially higher lipid levels and weekly, but significantly, lower albumin augmented CL/F. However, the correlations were not strong enough to predict CL/F. Conclusion: The data presented indicate the necessity for MPA TDM and suggest that dose modifications may apply in the face of low serum albumin and hyperlipidemia.

Mucormycosis: Literature review and retrospective report of 15 cases from Portugal.

Background and Purpose: Prevalence of mucormycosis is growing with the increase of the population at risk. Current recommendations for its management are mostly based on retrospective studies. 3 study aimed to present the cumulative experience of an Infectious Diseases Department from a Portuguese hospital in the management of mucormycosis and discuss the potential gaps in the diagnostic and therapeutic approaches of this infection. Materials and Methods: For the purposes of the study, the electronic hospital database was searched for adult patients with mucormycosis from 1996 to 2019 based on the definition provided by the Consensus Definitions of Invasive Fungal Disease. Demographic, clinical, treatment, and outcome data were collected and compared to what had been described in the related literature. Results: In total, 15 cases of mucormycosis were found, including 11 cases with sinus involvement (10 with central nervous system involvement), two pulmonary, and two gastrointestinal infections. Diabetes mellitus (n=7) and corticosteroid therapy (n=7) were frequent risk factors. Median duration of symptoms before the suspicion of diagnosis was 26 days (3-158). The diagnosis was confirmed in 12 patients mostly by histopathology (n=9); the culture was positive only once. Systemic antifungals and surgical debridement were the backbones of treatment; however, side effects, the need for therapeutic drug monitoring, and the anatomical location of lesions added complexity to management. Overall, seven patients died, two of them before the consideration of clinical suspicion. Conclusion: More medications are becoming available for the treatment of mucormycosis. Nevertheless, we believe that its prognosis will only significantly change through the increase of awareness and reduction of the time to diagnosis. An effective multidisciplinary approach among surgeons, infectious diseases specialists, radiologists, microbiologists, and anatomopathologists is critical to the achievement of this goal.

Dermatologists on the medical need for therapeutic drug monitoring of biologics in psoriasis: results of a structured survey

Background Therapeutic drug monitoring (TDM) may lead to more rational use of biologics. Still, TDM is largely underexplored in psoriasis. Little is known about the dosing behavior of biologics by dermatologists, and their attitude toward TDM. Objective Exploration of the awareness and need for the concept of TDM in psoriasis amongst (inter)national dermatologists. Method A survey was distributed at the Belgian Dermatology Days 2019 and Skin Inflammation & Psoriasis International Network (SPIN) Congress 2019. Next, an online survey version was launched amongst the SPIN Scientific Committee members. We collected physician’s characteristics, prescription behavior of biologics, data regarding clinical response to biologics and attitude toward TDM. Results A total of 107 surveys were included for analysis. Most dermatologists were Belgium-based (54.2%), others from European (23.4%) or non-European countries (19.6%). Seventy percent performed either dose increase (64.8%), time interval shortening (74.6%), dose lowering (16.9%) or time interval extension (33.8%). The majority who performed dose adaptations acknowledged the need for TDM. Conclusion This study showed most dermatologists perform dose adaptations empirically. The need for TDM was indicated by the majority, implying the need for effective communication regarding availability, utility and implementation of TDM assays in daily dermatology practice.

Clinical efficacy and pharmacokinetics of colistimethate sodium and colistin in critically ill patients in an Indian hospital with high endemic rates of multidrug-resistant Gram-negative bacterial infections: A prospective observational study

BackgroundSafe and effective use of colistin requires robust pharmacokinetic (PK) and pharmacodynamic (PD) data to guide dosing. AimTo evaluate the pharmacokinetics of colistimethate sodium and colistin in critically ill patients and correlate with clinical efficacy and renal function. Materials and MethodsTwenty critically ill adult patients with colistin-susceptible multidrug-resistant (MDR) infections and normal renal function treated with intravenous colistimethate sodium – at a 9 million units (270 mg CBA) loading dose followed by maintenance (MD) of 3 million units t.i.d, 24 hours later – were evaluated for clinical cure (CC) at the end of therapy. Patient characteristics and plasma colistin levels at 0, 0.5, 1, 2, 4, 8 and 12 hours after the loading dose and at 1, 2 and 8 hours after the eighth and ninth infusion of MD were evaluated. Colistimethate sodium and colistin levels were measured by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS). ResultsAmong the 20 patients who were evaluated, 60% had pneumonia. Predominant pathogens were Klebsiella pneumoniae and Acinetobacter spp. Clinical cure was 50% (10/20). Mean peak loading dose concentrations were 3 ± 1.1 mg/L (1.75–5.14) and 2.37 ± 1.2 mg/L (1.52–5.54) for ‘cure’ and ‘failure’ groups, respectively (p = 0.13), while mean steady-state (Cssavg) concentrations were 2.25 ± 1.3 mg/L and 1.78 ± 1.1 mg/L in ‘cure’ and ‘failure’ groups, respectively (p = 0.19). Nephrotoxicity was 5% on day 7 of therapy. However, bacteriological cure could not be correlated with PK/PD. ConclusionsSubtherapeutic Cssavg with clinical failure and lower efficacy without significant nephrotoxicity highlights the need for therapeutic drug monitoring to guide colistin dosing.

MO019AURORA PHASE 3 TRIAL DEMONSTRATES VOCLOSPORIN STATISTICAL SUPERIORITY OVER STANDARD OF CARE IN LUPUS NEPHRITIS (LN)

Abstract Background and Aims Voclosporin (VCS) is a novel high potency calcineurin inhibitor (CNI) with a favorable metabolic profile and a consistent predictable dose response potentially eliminating the need for therapeutic drug monitoring. The Aurinia Renal Response in Active Lupus with Voclosporin (AURORA) study, involving 357 patients with active LN, was a Phase 3 global, double-blind, placebo-controlled RCT designed to evaluate the efficacy and safety of VCS (23.7mg BID) vs placebo in combination with mycophenolate (MMF, 2 g/day) and rapidly tapered low dose oral steroids. Method The primary endpoint was renal response (RR) at 52 weeks. RR was defined as UPCR of ≤ 0.5 mg/mg, eGFR ≥ 60 mL/min, or no confirmed decrease from baseline in eGFR of &amp;gt; 20%, presence of sustained, low dose steroids and no administration of rescue medication. Results AURORA met its primary endpoint, achieving statistically superior RR rates of 40.8% for voclosporin vs. 22.5% for the control (OR 2.65, 95% CI; p &amp;lt; 0.001). The benefits of VCS were also seen for all predetermined secondary endpoints, achieving statistical significance in favor of VCS for RR at 24 weeks, partial renal response (PRR) at 24 and 52 weeks, time to achieve UPCR ≤ 0.5, and time to 50% reduction in UPCR. Prespecified confirmed eGFR decreases &amp;gt;30% were similar in both groups, with 10.1% reported in the VCS group and 10.2% in the control arm (p= 0.971). No significant differences were seen at any timepoints in the study. Furthermore, all pre-specified subgroup analyses (age, sex, race, biopsy class, region, and prior MMF use) also favored VCS. VCS was well tolerated with no unexpected safety signals. Similar SAEs were reported in the VCS group (20.8%) and in the control arm (21.3%). Infection was the most commonly reported SAE with 10.1% of VCS patients versus 11.2% of patients in the control arm. Overall mortality in the trial was low, with 6 deaths observed; 1 in the VCS arm and 5 in the control group. Additionally, the VCS arm showed no significant decrease at week 52 in eGFR or increase in BP, lipids or glucose. Conclusion While maintaining a comparable safety profile, VCS plus standard therapy achieved a statistically superior RR over one year compared to placebo plus standard therapy in adults with active LN.

Therapeutic Drug Monitoring of Cyclosporine Using Single Sampling Strategy

Cyclosporine is mainly used as Immunosuppressant after different kinds of transplantation including bone marrow, lungs, kidneys, liver, heart, and other types of organ transplantations. Immunosuppressants diminish organ rejection and elongate the survival of the transplanted organs. Due to the narrow therapeutic ranges and significantly&#x0D; high interindividual and intraindividual variability in blood levels of cyclosporine, there is essential and vital need of therapeutic drug monitoring (TDM) of this drug in order to maintain the patient within the required therapeutic concentrations, which consequently lead to optimizing the clinical outcome and decrease the hazard of toxicity or rejection following organ transplantations. The current review article was aimed to present data for using a single or possibly two blood sampling strategy to be used for TDM of cyclosporine in order to assess the optimal blood levels of cyclosporine used in organ transplant recipients. The results showed that steady state blood concentration of cyclosporine obtained after 2 hours (C2) and possibly after 3 hours (C3) of drug administration are the best sampling time points which reflect total drug exposure (area under blood concentration versus time curve=AUC) and consequently reflecting the effect and the adverse effect(s) of cyclosporine. On the other hand, blood samples obtained at other time points particularly steady state trough concentration obtained before the next dose (C0) demonstrated poor correlation with total drug exposure and consequently the clinical outcome of the drug. Moreover, this study also demonstrated that for organs transplantations TDM of cyclosporine and assessing the clinical conditions of the patients should be routinely performed in order to adjust the dose to get optimal effect and to diminish the adverse effects of the drug. This review article focused on the findings which indicated that monitoring steady-state blood levels of cyclosporine after 2 hours (C2) and likely after 3 hours (C3) of drug intake may be used as ideal surrogate index in TDM of cyclosporine and for predicting the clinical outcome of the drug in all and different types of organs transplantations.

OP0277 AURORA PHASE 3 STUDY DEMONSTRATES VOCLOSPORIN STATISTICAL SUPERIORITY OVER STANDARD OF CARE IN LUPUS NEPHRITIS (LN)

Background:Voclosporin (VCS) is a novel high potency calcineurin inhibitor (CNI) with a favorable metabolic profile and a consistent predictable dose response potentially eliminating the need for therapeutic drug monitoring. LN occurs more frequently and is more severe in Hispanic/Latino ethnicity SLE patients. The recently completed phase 3 AURORA study builds on the favorable efficacy seen in the Phase IIb AURA-LV study in patients with active LN.Objectives:Document efficacy and safety of VCS vs placebo over one year when used with 2 grams of MMF daily and a rapid steroid taper in patients with active LN.Methods:AURORA is a Phase III multicenter, randomized, double-blind, placebo-controlled 52-week study of active LN patients. Patients were randomized 1:1 to VCS (23.7 mg BID) or placebo in combination with mycophenolate (MMF, 1 g BID) and rapidly tapered oral steroids. The primary endpoint was renal response (RR) at 52 weeks, defined as UPCR of ≤ 0.5 mg/mg, eGFR ≥ 60 mL/min, or no confirmed decrease from baseline in eGFR of &gt; 20%, presence of sustained, low dose steroids and no administration of rescue medication. Ethnicity subgroup analyses of RR was also undertaken given the higher severity of disease in the Hispanic/Latino LN patients.Results:There were 357 patients enrolled, 88% female, median age of 31 and 33% of Hispanic/Latino ethnicity. Renal response by intention to treat analysis at 52 weeks was 40.8% for the voclosporin arm and 22.5% for the control arm (OR: 2.65; 95% CI: 1.64, 4.27; p&lt; 0.001); therefore, AURORA met its primary endpoint. These findings were consistent with those observed in the previously completed pivotal AURA-LV study. Ethnicity subgroup analysis of RR at 52 weeks noted benefit of VCS in both Hispanic/Latino (VCS 38.6% and control 18.6%, p=0.0062, OR 3.45) and non-Hispanic/Latino patients (VCS 41.8% and control 24.6%, p=0.0045, OR 2.29). The benefits of VCS were also seen for all pre-specified hierarchical secondary endpoints: RR at 24 weeks, partial renal response (PRR) at 24 and 52 weeks, time to achieve UPCR ≤ 0.5, and time to 50% reduction in UPCR. Furthermore, all pre-specified subgroup analyses (age, sex, race, biopsy class, region, and prior MMF use) favored VCS. VCS was well tolerated with no unexpected safety signals. The overall incidence of SAEs were similar in both groups (VCS 20.8% and control 21.3%); with infection most commonly reported (VCS 10.1% and control 11.2%). Overall mortality in the trial was low, with one death in the voclosporin arm and five in the control arm. Additionally, the VCS arm showed no significant decrease at week 52 in eGFR or increase in BP, lipids, or glucose.Conclusion:The AURORA study met its primary endpoint and VCS was efficacious in Hispanic/Latino ethnicity patients, a difficult to treat group.Disclosure of Interests:Cristina Arriens Grant/research support from: - BMS: Investigator Initiated Trial Research Funding, GSK: Investigator Initiated Trial Research Funding, Exagen: Research Grant, Consultant of: AstraZeneca (Sci Ad Board Dec 2017), GSK (Sci Ad Board Oct 2018), BMS (Sci Ad Board April 2019), Svetlana Polyakova: None declared, Igor Adzerikho: None declared, Simrat Randhawa Shareholder of: Aurinia Pharmaceuticals, Inc. stock, Employee of: Aurinia Pharmaceuticals, Inc., Neil Solomons Shareholder of: Aurinia Pharmaceuticals, Inc. stock, Employee of: Aurinia Pharmaceuticals.

Therapeutic Drug Monitoring of Cyclosporine Using Single Sampling Strategy

Cyclosporine is mainly used as Immunosuppressant after different kinds of transplantation including bone marrow, lungs, kidneys, liver, heart, and other types of organ transplantations. Immunosuppressants diminish organ rejection and elongate the survival of the transplanted organs. Due to the narrow therapeutic ranges and significantly high interindividual and intraindividual variability in blood levels of cyclosporine, there is essential and vital need of therapeutic drug monitoring (TDM) of this drug in order to maintain the patient within the required therapeutic concentrations, which consequently lead to optimizing the clinical outcome and decrease the hazard of toxicity or rejection following organ transplantations. The current review article was aimed to present data for using a single or possibly two blood sampling strategy to be used for TDM of cyclosporine in order to assess the optimal blood levels of cyclosporine used in organ transplant recipients. The results showed that steady state blood concentration of cyclosporine obtained after 2 hours (C2) and possibly after 3 hours (C3) of drug administration are the best sampling time points which reflect total drug exposure (area under blood concentration versus time curve=AUC) and consequently reflecting the effect and the adverse effect(s) of cyclosporine. On the other hand, blood samples obtained at other time points particularly steady state trough concentration obtained before the next dose (C0) demonstrated poor correlation with total drug exposure and consequently the clinical outcome of the drug. Moreover, this study also demonstrated that for organs transplantations TDM of cyclosporine and assessing the clinical conditions of the patients should be routinely performed in order to adjust the dose to get optimal effect and to diminish the adverse effects of the drug. This review article focused on the findings which indicated that monitoring steady-state blood levels of cyclosporine after 2 hours (C2) and likely after 3 hours (C3) of drug intake may be used as ideal surrogate index in TDM of cyclosporine and for predicting the clinical outcome of the drug in all and different types of organs transplantations.

Population pharmacokinetics and target attainment of ciprofloxacin in critically ill patients

PurposeTo develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens.MethodsNon-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an ƒAUC0–24/MIC ≥ 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens.ResultsA total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400–1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m2, and eGFR of 58.5 mL/min/1.73 m2. The median ƒAUC0–24 and ƒCmax were 29.9 mg•h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target ƒAUC0–24/MIC ≥ 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of ≥ 1200 mg/day is needed to achieve sufficient ƒAUC0–24/MIC ratios.ConclusionsThe model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure.

Is Therapeutic Drug Monitoring of Lacosamide Needed in Patients with Seizures and Epilepsy?

Lacosamide is an antiepileptic drug (AED) that has linear pharmacokinetics, predictable blood concentrations, and few drug interactions, setting it apart from other AEDs that require vigorous therapeutic drug monitoring (TDM) such as phenytoin and carbamazepine. However, there have been reports of altered lacosamide pharmacokinetics in some populations. The purpose of this review is to determine whether lacosamide pharmacokinetics are altered in certain patient populations, suggesting the need for TDM. A literature search of Medline, Scopus, Embase, and Cochrane trials was conducted on January 3, 2019 (and then updated on September 2, 2019) to search for articles relevant to the TDM or pharmacokinetics of lacosamide. A total of 56 relevant articles were found and included in this review. Dose of lacosamide is linearly correlated with plasma concentrations and efficacy. However, currentlythere is no well-established reference range. Overall, the recommended reference ranges varied from 2.2 to 20mg/L. Lacosamide has very few clinically relevant drug-drug interactions; however, there seems to be a significant drug interaction between lacosamide and enzyme-inducer AEDs. Based on available literature, it appears that lacosamide pharmacokinetics may be altered in severe renal dysfunction, in patients on dialysisand with extremes of age. More evidence is currently needed on lacosamide pharmacokinetics in pregnancy and critical illness. While it is not practical to utilize TDM for all patients, TDM may be useful in patients taking enzyme-inducer AEDs, in patients with decreased renal function or on dialysis, and older adults.

Therapeutic drug monitoring of levetiracetam in newborns

Neonatal seizures in full-term and preterm infants represent a common neurological syndrome. Levetiracetam (LEV) is one of the new and widely prescribed second- or third-line antiepileptic drug for the treatment of seizures. Routine therapeutic drug monitoring of LEV was not recommended due to its almost ideal pharmacokinetic profile: linear pharmacokinetics, predictable dose-concentration relationship, wide therapeutic index, favourable safety profile, and unlikely clinically significant drug-drug pharmacokinetic interactions. In newborns, drug pharmacokinetics may be under the influence of maturation process. LEV pharmacokinetics in newborns appears to be age (gestational, postnatal) dependent and highly variable within the age ranges. These aspects make therapeutic drug monitoring a useful procedure for therapy optimization in this specific patient population. In population modeling based on therapeutic drug monitoring and nonlinear mixed effects models, covariates were found that should significantly affect the LEV clearance and volume of distribution in newborns — creatinine clearance and total body weight. Using of these regression equations can help to adjust the LEV doses without the patient's measured concentration data. But the significant magnitudes of the interindividual variability remaining in these final regression models justify the need for therapeutic drug monitoring and Bayesian adaptive control for personalization of LEV dosage regimens in neonates.

1733. Voriconazole Prophylaxis Following Allogeneic Hematopoietic Stem Cell Transplant: How Much Is Enough, Are Low Voriconazole Levels Associated With Opportunistic Infections, and What Are the Reasons for Discontinuation?

BackgroundPatients who undergo allogeneic hematopoietic stem cell transplantation (alloHSCT) are at increased risk for invasive fungal infections with associated high morbidity and mortality that necessitates the use of prophylactic antifungals. Voriconazole is commonly used for prophylaxis, but there are no recommendations for therapeutic drug monitoring. The purpose of this study was to characterize voriconazole therapeutic drug monitoring and associated outcomes in this patient population.MethodsAlloHSCT patients receiving voriconazole prophylaxis at the University of Alabama at Birmingham Hospital between March 2015 and March 2018 were included in the analysis. Serum voriconazole levels (SVL) were evaluated to determine what percentage of patients achieved prophylactic or therapeutic concentrations. Incidence of invasive fungal infections (IFI) and voriconazole discontinuation was also assessed.ResultsVoriconazole prophylaxis was used in 151 of 162 alloHSCT patients, and 120 patients (79%) had SVL drawn correctly (≥4 days after initiation of course). We found that 35 (29%) patients achieved a subtherapeutic level (<0.5 μg/mL), 17 (14%) prophylactic level (0.5 to 1 μg/mL), 68 (57%) therapeutic level (1 to 5.5 μg/mL), and no patients achieved a supratherapeutic level (level ≥5.5 μg/mL). Voriconazole prophylaxis was discontinued early in 60 of 151 patients. Most common etiologies for discontinuation included liver function test abnormalities (44%) and encephalopathy (21%). The average SVL was 1.2 μg/mL in those requiring discontinuation. Four patients (3%) developed an IFI while receiving prophylactic voriconazole, of which only 1 had subtherapeutic level.ConclusionEven though approximately one-third of patients achieved a subtherapeutic SVL, there was no correlation with breakthrough IFI. There was also no linear correlation between SVL and risk of adverse effects requiring discontinuation. Our observational data do not support a need for therapeutic drug monitoring in alloHSCT patients receiving prophylactic voriconazole. Disclosures All authors: No reported disclosures.

2121. Isavuconazole (ISAV) as Primary Anti-Fungal Prophylaxis (PAP) in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS): An Open-Label, Prospective Study

BackgroundMold-active antifungal prophylaxis (ppx) is recommended in neutropenic patients with newly diagnosed AML or MDS. ISAV is an extended spectrum triazole with superior tolerability, reliability of absorption, fewer drug–drug interactions, lack of QTc prolongation or need for therapeutic drug monitoring, approved for the treatment of invasive aspergillosis (IA) and mucormycosis. NCT03019939 is an investigator-initiated, phase 2 trial of PAP with ISAV in patients with AML/MDS.MethodsTreatment-naïve adult patients with AML or MDS initiating remission-induction chemotherapy (RIC) received ISAV per the dosing recommendations in the United States label until recovery from neutropenia (neutrophils (ANC) ≥ 0.5 × 109/L) and attainment of complete remission (CR), occurrence of proven or probable invasive fungal infection (IFI, EORTC/MSG criteria), or for a maximum of 12 weeks. The primary endpoint was incidence of proven/probable IFI during the study period (up to 30 days from the last dose of ISAV).Results67 patients were enrolled (April 28, 2017 to February 14, 2019) and 60 patients were eligible for assessment (median age 67 years, 57 patients with AML, median ANC on enrollment was 660). Reasons for study completion were achievement of CR with ANC recovery (n = 35), completion of 12 weeks of PAP (n = 9), possible IFI (n = 7), investigator decision (n = 3), death (n = 2, 1 disease progression, 1 cardiac arrest), proven/probable IFI (n = 3), and mild transaminitis, possibly ISAV-related (n = 2). The median durations of neutropenia and ISAV ppx were 33 (7–86) and 31 (7–86) days, respectively. One microbiologically-proven (gluteal abscess due to Candida glabrata) and 2 cases of probable breakthrough IFIs (probable IA with positive galactomannan) occurred (IFI incidence 5%). ISAV trough serum concentrations were available in 31 patients on both day 8 (median 3.74 µg/mL, 2.03–7.65) and day 15 (median 4.10 µg/mL, 2.17–9.25), and were not significantly different.ConclusionISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC, with a breakthrough (proven/probable) IFI rate of 5%. ISAV serum levels were adequate in patients with AML/MDS undergoing RIC. Pharmacological features make ISAV attractive for PAP in the era of recently approved or emerging small-molecule AML therapies.Disclosures All authors: No reported disclosures.

Burden of Inappropriate Prescription of Direct Oral Anticoagulants at Hospital Admission and Discharge in the Elderly: A Prospective Observational Multicenter Study.

Direct oral anticoagulants (DOACs) were developed to overcome some of the limitations associated with vitamin K antagonists (VKAs), such as interindividual variability or the need for therapeutic drug monitoring. However, the complexity of DOAC dose regimens can still lead to dosing errors and potential bleeding-related or thromboembolic adverse events, especially in the elderly. Our objective was to evaluate the rate of inappropriate preadmission DOAC prescriptions at hospital and to evaluate the ability of hospitals to correct them. An observational prospective study was conducted in elderly patients (aged ≥ 65years) hospitalized in six acute units of three Parisian university hospitals between February and July 2018. DOAC prescriptions prior to admission and at discharge were analyzed according to the guidelines in the summaries of product characteristics. A total of 157 patients were included in the study, with a median age of 84years (interquartile range [IQR] 77-89). The median glomerular filtration rate, determined with the Cockcroft-Gault equation, was 48mL/min (IQR 35-61). Apixaban was the most frequently prescribed drug, mainly for atrial fibrillation. Overall, 48 (30.6%) and 34 (22.4%) prescriptions were inappropriate prior to admission and at discharge, respectively, showing a significant decrease (p < 0.001). Hospitals significantly corrected more inappropriate prescriptions (37.5%) than they generated (4.6%) (p < 0.05). The nature of the inappropriate prescribing was underdosing (68.8% and 76.5% prior to admission and at discharge, respectively), followed by overdosing (stable rate at almost 20%) and indication errors. No risk factors for inappropriate use were identified by our analysis. One-third of DOAC preadmission prescriptions for elderly patients were inappropriate, indicating that a need remains to strengthen DOAC prescribing guidelines in ambulatory clinical practice. However, the rate of inappropriate prescriptions decreased at patient discharge. Future studies are needed to test actions to promote the proper use of DOACs.