Target Therapeutic Range Research Articles

P-1046. Isavuconazonium Utilization in Pediatric Patients at a Free-Standing Children’s Hospital

Abstract Background Isavuconazonium sulfate is a newer triazole antifungal used for the treatment of invasive aspergillosis and mucormycosis. In December 2023, the FDA expanded approval for isavuconazonium sulfate (Cresemba) to include pediatric patients 1 year and older. The most common adverse effect requiring monitoring is hepatotoxicity. Routine therapeutic drug monitoring is not recommended for most patients but may be considered if there is a concern for toxicity, therapeutic failure, or impaired drug absorption. With limited published data in pediatric patients, our aim is to evaluate the use of isavuconazonium at Children's Hospital Los Angeles (CHLA) and assess safety and tolerability in our patient population. Methods A retrospective chart review was performed to evaluate utilization of isavuconazonium from 01/01/2023 – 12/31/2023 at CHLA. Demographic data, Infectious Diseases consultation, indication for therapy, liver function before and during treatment, and serum drug level results were collected and analyzed. Results A total of 54 patient encounters included an isavuconazonium order during the review period. All study patients had a primary diagnosis of leukemia or stem cell transplant (SCT), the most common (45%) being Acute Lymphoblastic Leukemia (ALL). 3 patients had mildly elevated liver function tests (LFTs) at baseline, and 6 total patients developed grade 3 or 4 liver toxicity during therapy. The most common indication for treatment was empiric or definitive treatment of invasive fungal infection, with 15 (28%) and 20 (37%) patients, respectively. 19 patients (35%) received off-label prophylaxis for invasive fungal infection due to contraindications to alternative antifungal agents. 33 of 54 patients had at least one serum trough level measured at steady state. Although a therapeutic target range is not well established, 26 patients (79%) achieved levels within typical expected range of 1-5 mg/L. Of 3 patients with trough level < 1 mg/L, 2 were determined to be due to non-adherent to outpatient therapy. Conclusion Based on serum drug levels and LFT results collected for routine therapeutic monitoring, isavuconazonium appears well-tolerated for treatment or prophylaxis of invasive fungal infection in our immunocompromised pediatric population. Disclosures All Authors: No reported disclosures

Origanum vulgare and hemorrhagic risk, about a case

The use of medicinal plants in Algeria is an ancestral practice that remains relevant today. The population relies on plants to treat various diseases and everyday ailments, which can be dangerous, especially when taking medication [1,2]. The interaction between plants and medication can lead to a modification of the plasma concentrations of the latter, which can impact its therapeutic effectiveness and be responsible for toxicity or therapeutic failure [1,2]. The interaction can also be pharmacodynamic, resulting in the potentiation of the effect or its antagonism. The risk is even higher when the medication has a narrow therapeutic range or presents high inter- or intra-individual variability, such as with vitamin K antagonist anticoagulants. We report the case of patient B.Z., aged 77, who is suffering from complete atrial fibrillation (ACFA). The patient has been under antivitamin K (AVK) treatment with acenocoumarol for 8 years and has been followed at the central laboratory of Didouche Mourad Hospital since August 2019. The patient has been stable with an INR within the therapeutic target range of 2-3 for 4 years. She is compliant and adheres to the dietary regimen. The dosage of acenocoumarol is alternated between 1/2 tablet and 1/4 tablet. On September 6, 2023, during a routine check-up, the patient's INR was 6.42, and the PT was 17.9%. The recommendation was to stop AVK and perform a control the following day. The interview revealed that the patient had started taking an infusion of oregano (Origanum vulgare), and occasionally verbena, at a rate of one 200 ml cup per day for a week. On September 7, 2023, the INR decreased to 3.80 and the PT to 26.9%, so the recommendation was to resume AVK at a dosage of 1/4 tablet to 1/2 tablet, with discontinuation of the herbal tea intake and an INR check after 72 hours. On the fourth day after resuming the anticoagulant, the INR was 2.5. Despite being informed of the risk of interaction, the patient resumed taking the freshly picked oregano herbal tea from her garden. Given the patient's determination to continue her infusion, the recommendation was made to limit her intake, to prepare much more diluted infusions, and to reduce the dose of acenocoumarol to 1/4 tablet; this allowed the stabilization of the patient's INR. The last check-up was performed on April 7, 2024, with an INR value of 2.3. Oregano, a plant from the Lamiaceae family, is used in herbal tea to treat a wide range of diseases, including joint pain, respiratory conditions, and digestive disorders. Similarly, verbena is also used to combat sleep disorders [2-4]. Origanum and verbena are both plants rich in polyphenols, as well as tannins and flavonoids. These substances are inhibitors of CYP 450, particularly CYP 2C9 and CYP 3A4, which are responsible for the metabolism of many drugs, including painkillers, antihypertensives, central nervous system drugs, and anticoagulants such as acenocoumarol. Origanum also exhibits anticoagulant activity due to its high content of carvacrol and thymol [4-6]. These two modes of interaction lead to an increase in the pharmacodynamic effect of acenocoumarol and, therefore, an increased risk of bleeding. This was the case for our patient, who saw her INR increase to more than twice the normal level, coinciding with the intake of oregano and verbena infusions, which normalized after their discontinuation. Oregano is an endemic plant widely used in Algeria, whose anti-inflammatory properties are well established. However, its side effects, toxicity, and risk of interaction when combined with medications are less known. The interaction between oregano and AVK (acenocoumarol) exists and deserves to be recognized and monitored, especially in a population with a traditional culture where the use of plants is common. This practice should be accompanied by national phytovigilance.

Bemiparin in neonatal thrombosis: therapeutic dosing and safety.

To evaluate the therapeutic dose and safety of bemiparin in neonatal thrombosis treatment. A retrospective review was conducted on infants treated with bemiparin between 2018 and 2023 at a tertiary hospital. 72 neonates with a mean gestational age of 37 weeks were included. Twenty were preterm, with a median gestational age of 33.5 weeks and a median birth weight of 1847.5 grams. The mean (SD) initial and therapeutic bemiparin doses were 170.5 (31) and 200 (37.2) IU/kg/day, respectively. Only 32% of patients reached the therapeutic target range (TTR) with the initial dose. Preterm infants required higher doses to reach TTR (215 vs 194.7 IU/kg/day, p = 0.05). Adverse events were minimal (1.4%) and unrelated to the starting dose or prematurity. Bemiparin appears to be a potential therapeutic option for anticoagulation in neonates; however, targeted anti-Xa levels were rarely achieved with the initial dose and most patients required uptitration.

B-302 Therapeutic Drug Monitoring (TDM) of Hydroxychloroquine in Whole Blood: Analysis of Over 10,000 Patient Results

Abstract Background Hydroxychloroquine (HCQ), a mainstay of systemic lupus erythematosus (SLE) therapy, improves survival and reduces flares. Therapeutic drug monitoring (TDM) may be useful in 1) identifying and improving adherence issues, 2) titrating daily dose to achieve therapeutic benefits while 3) minimizing retinopathy due to longterm cumulative exposure. Whole blood (WB) is the correct specimen for HCQ TDM because WB HCQ levels are higher than serum or plasma levels, more stable and reflective of the last month of HCQ ingestion, and are better correlated to efficacy and retinopathy risk. Here, we report WB HCQ concentrations in 10,463 clinical patient samples and their distribution. Methods HCQ concentrations in whole blood are measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and reported in nanograms per milliliters whole blood. Recommended sample collection is ∼ 3 - 6 months into regular stable dosing to reach pharmacokinetic steady state and correlate with clinical efficacy. Results Here, we report the analysis of 10,463 patient samples for whole blood hydroxychloroquine (WB HCQ) concentrations. More than one-third (3752, 35.9%) were within the target range of > 1000 and < 2000 ng/mL. About one-quarter (2568, 24.5%) were within a tighter therapeutic target window, 1000 to 1500 ng/mL. The vast majority (9852, 94.2%,) of all WB HCQ were < 2000 ng/mL with a small percentage >2000 ng/mL (611, 5.8% between 2000 - 9502 ng/mL). About one-third (31.3%) were higher than 1177 ng/mL which corresponds to higher retinopathy risk. Adherence issues were evident in 10.5% (1102) with undetectable (483, 4.6%) and very low (<200 ng/mL) drug (619, 5.9%) (yellow). Depending upon the target threshold, levels < 500 ng/mL or <1000 ng/mL may be considered subtherapeutic as seen in 2498 (23.9%) and 4263 (40.7%) samples, respectively. Conclusions Due to wide pharmacokinetic variability and adherence issues, a given prescribed dose of HCQ does not correspond to WB HCQ, e.g. following 4, 5 or 6 mg/kg/day, levels are known to vary widely from subtherapeutic <500 to >2000 ng/mL. Here, our clinical database reiterates this wide range in WB HCQ levels from undetectable (<25) to 9502 ng/mL in 10,463 patient samples. One-quarter or one-third were within the therapeutic target range of 1000-1500 or 1000-200 ng/mL where >1000 has been associated with better disease control and survival. At the same time, levels less than 1177 avoid higher retinopathy risk. A small percentage of samples, 5.8%, were higher than 2000 ng/mL, suggesting the usefulness in TDM to fine-tune daily dose. In 10%, there was evidence of poor adherence, with very low or no detectable drug, and one quarter to 40% were subtherapeutic (<500 or <1000). The potential benefits of HCQ are many and include reduced flares and improved lupus nephritis, thrombosis risk, and long-term survival. At the same time, prescribed dose does not predict therapeutic levels. TDM-based counseling and dose adjustment may be instrumental in optimizing HCQ benefits while minimizing retinopathy risk. In conclusion, our analysis demonstrates the growing use of whole blood HCQ TDM to facilitate dose titration to safe and most effective target levels.

Influence of CYP2C9 phenotypes on phenytoin plasma concentration in neurosurgical Brazilian patients.

To investigate the association of CYP2C9 metabolic phenotypes with phenytoin plasma concentration ([PTH]) in neurosurgical patients from the Brazilian Public Health System. Patients (n = 170) were treated with phenytoin (300 mg/day) perioperatively as prophylaxis for postoperative seizures. Two to 10 days after surgery, a blood sample was collected for quantification of [PTH] and genotyping of CYP2C9*2 and *3 alleles. CYP2C9 metabolic phenotypes, NM (normal), IM (intermediate), and PM (poor) metabolizer, were inferred from CYP2C9 diplotypes. Linear regression modeling was applied to identify predictors of [PTH]. Wide (22-fold) interindividual variation in [PTH] was observed (2.2-47.5 mg/l). [PTH] associated significantly (Kruskal-Wallis P < 0.005) with CYP2C9 phenotypes and there was a significant trend (Jonckheere-Terpstra test, P < 0.0001) for [PTH] increase in the order NM < IM < PM. [PTH] was within the target therapeutic range (10-20 mg/l) in 34.7% of patients, while 39.4% and 25.9% had [PTH] below and above the range, respectively. CYP2C9 phenotypes associated significantly (chi-square P = 0.004) with the distribution of patients in [PHT] therapeutic categories and the Cramér's V test pointed to moderate magnitude of the effect of CYP2C9 phenotypes (V = 0.211). Diplotype-predicted CYP2C9 metabolic phenotypes are associated significantly with [PTH] in neurosurgical Brazilian patients receiving phenytoin for postsurgery seizure prophylaxis. [PHT] increased progressively in the phenotype order NM < IM < PM, and all PM patients had [PHT] above the target therapeutic range, consistent with the CPIC guideline 'strong' recommendation for phenytoin dosing adjustments in PMs.

Time in Therapeutic Range of Unfractionated Heparin-Based Therapy in Critically Ill Patients with COVID-19 Pneumonia.

Anticoagulation therapy aims to improve the outcome of critically ill patients with severe COVID-19-associated pneumonia. Activated partial thromboplastin time (aPTT) is commonly used to maintain the target therapeutic range of continuous infusion of unfractionated heparin (UFH). The UFH infusion efficacy can be evaluated by determining the time in therapeutic range (TTR) using a modified Rosendaal method. The present study's primary aim was to evaluate TTR based on the aPTT in critically ill patients with severe forms of COVID-19 pneumonia and its influence on survival. The secondary aim was to evaluate the time spent above (TATR) and below the therapeutic range (TBTR). We performed a retrospective analysis of critically ill patients with COVID-19-associated pneumonia. All patients received a continuous infusion of UFH from the 2nd to 8th day since admission to the ICU. TTR, TATR, and TBTR were calculated using the modified Rosendaal method, and survival days were analyzed by regression (censored after 60 days). Of 103 patients, the median TTR was 49% (IQR 38-63%), TATR 11% (IQR 5-20%), and TBTR 33% (IQR 22-51%). The regression analysis indicated a positive impact of higher TTR and TATR on the number of survival days [β=0.598 (p=0.0367) and β=1.032 (p=0.0208), respectively] and a negative impact of higher TBTR [β=-0.681 (p=0.0033)] on the number of survival days. Higher TTR and TATR were associated with better survival of critically ill patients with a severe course of COVID-19-associated pneumonia. Higher TBTR was associated with worse survival in these patients.

Unlocking Potential: Personalized Lifestyle Therapy for Type 2 Diabetes Through a Predictive Algorithm-Driven Digital Therapeutic.

We present a digital therapeutic (DTx) using continuous glucose monitoring (CGM) and an advanced artificial intelligence (AI) algorithm to digitally personalize lifestyle interventions for people with type 2 diabetes (T2D). A study of 118 participants with non-insulin-treated T2D (HbA1c ≥ 6.5%) who were already receiving standard care and had a mean baseline (BL) HbA1c of 7.46% (0.93) used the DTx for three months to evaluate clinical endpoints, such as HbA1c, body weight, quality of life and app usage, for a pre-post comparison. The study also included an assessment of initial long-term data from a second use of the DTx. After three months of using the DTx, there was an improvement of 0.67% HbA1c in the complete cohort and -1.08% HbA1c in patients with poorly controlled diabetes (BL-HbA1c ≥ 7.0%) compared with standard of care (P < .001). The number of patients within the therapeutic target range (< 7.0%) increased from 38% to 60%, and 33% were on the way to remission (< 6.5%). Patients who used the DTx a second time experienced a reduction of -0.76% in their HbA1c levels and a mean weight loss of -6.84 kg after six months (P < .001) compared with BL. These results indicate that the DTx has clinically relevant effects on glycemic control and weight reduction for patients with both well and poorly controlled diabetes, whether through single or repeated usage. It is a noteworthy improvement in T2D management, offering a non-pharmacological, fully digital solution that integrates biofeedback through CGM and an advanced AI algorithm.

Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients.

In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability, necessitating therapeutic drug monitoring of whole-blood concentrations. Pharmacogenetic research, although not representative of SA population groups, suggests that single-nucleotide polymorphisms within the cytochrome P450 3A5 (CYP3A5) gene contribute to the variability in tacrolimus dosing requirements. The rs776746 polymorphism, CYP3A5*3, results in a splice defect and a non-functional enzyme. Clinically, to reach the same tacrolimus concentration-to-dose ratio (CDR), expressors (CYP3A5*1/*1 and *1/*3) require a higher tacrolimus dose than non-expressors (*3/*3). To compare the pharmacokinetics of tacrolimus in paediatric liver transplant recipients with their donors' CYP3A5 genotypes, considering both donor and recipient characteristics. Blood samples from 46 living liver donors were collected, their genomic DNA was extracted, and their CYP3A5 genotype was established (polymerase chain reaction and restriction fragment length polymorphism analysis, validated by Sanger sequencing). The relationship of donor and recipient characteristics with the mean tacrolimus CDR was analysed using a general linear model. Non- confounding significant variables were included in a multiple regression model. The study showed that all expressor donors genotyped as CYP3A5*1/*1 were of black African self-reported race and ethnicity. During the first 15 days post-transplant, we found that children who received grafts from donor CYP3A5 expressors (CYP3A5*1/*1 and *1/*3) had significantly lower mean tacrolimus CDRs compared with those who received grafts from donor CYP3A5 non-expressors (*3/*3); the recipients of CYP3A5 expressor grafts therefore require higher doses of oral tacrolimus to achieve the same therapeutic target range. In addition, graft-to-recipient weight ratio and the CYP3A5 donor genotypes were independent factors that significantly (p<0.05) affected mean tacrolimus CDRs in recipients. In this study, we showed that all CYP3A5*1 homozygote donors were of black African self-reported race and ethnicity, and tacrolimus CDRs in paediatric living-donor liver transplant recipients were significantly affected by donor graft size and donor CYP3A5 genotypes. Information from this study may inform the development of an Afrocentric tacrolimus precision-medicine algorithm to optimise recipient safety and graft outcomes.

Pilot study examining anti-factor Xa levels for heparin monitoring and outcomes in patients with cerebral venous thrombosis.

There are no studies to date that examine the association between anti-factor-Xa (AFXa)-based heparin monitoring and clinical outcomes in the setting of cerebral venous thrombosis (CVT). This pilot study included adults aged ≥18 admitted with CVT between 1 January 2018 and 1 January 2021, who were treated with unfractionated heparin (UFH) and were monitored via AFXa-based nomogram within 24 h of arrival. Comparisons were made between patients with AFXa levels within the target therapeutic range (0.25-0.5 IU/mL) and patients whose levels were not within the therapeutic range within 24 h of arrival; the time (hours) from arrival to reach the therapeutic range was also examined. Outcomes were length of stay (LOS) in the hospital, major (actionable) bleeding events, and discharge home (vs. higher acuity location). Continuous data are reported in the form of the median (interquartile range). Among 45 patients, treatment with UFH was initiated 2 (1-11) h after arrival, and the majority (84%) of UFH infusions did not need dose adjustment. AFXa assays were conducted every 6 (5.5-7) h. Thirty patients (67%) fell within the therapeutic range. Outcomes were similar for patients with levels within the therapeutic range vs. not: major bleeding events, 10% vs. 0% (p = 0.54); discharge home, 77% vs. 80% (p = 1.0); LOS, 5 days in each group (p = 0.95). There was also no association between outcomes and time to reach the therapeutic range. Our findings demonstrate the practicability of monitoring UFH based on AFXa values in this population of patients with CVT, but reaching target AFXa levels within 24 h of arrival may not necessarily be prognostic.

Factors influencing vancomycin trough concentration in burn patients: a single center retrospective study.

To analyze factors influencing the vancomycin trough concentration in burn patients to provide a basis for the more rational use of vancomycin in these patients. We collected the clinical data of adult burn patients treated with vancomycin in a Chinese hospital. Vancomycin was administered at a dosing regimen of 1.0g q12h. Patients were divided into a therapeutic group with vancomycin trough concentration in the target therapeutic range (10-20μg/mL) and a subtherapeutic group with vancomycin trough concentration in the subtherapeutic range (<10μg/mL). The therapeutic group included 14 patients (17.5%), with an average trough concentration of 14.36 ± 2.82μg/mL; the subtherapeutic group included 66 patients (82.5%), with an average trough concentration of 5.18 ± 2.77μg/mL. The serum creatinine level was significantly higher in the therapeutic group (84.93 ± 47.26μmol/L) than that in the subtherapeutic group (62.44 ± 14.49μmol/L) (p < 0.01). Serum albumin levels were significantly lower in the therapeutic group (30.50 ± 2.28g/L) than those in the subtherapeutic group (34.00 ± 6.22g/L) (p < 0.05). Using receiver operating characteristic (ROC) curve analysis, for serum albumin, the area under the ROC curve (AUC) (95% confidence interval [CI]) was 0.67 (0.553, 0.788); the optimal cut-off point was 34.50g/L (p = 0.046), the sensitivity was 0.379, and the specificity was 1.0. For creatinine clearance, the AUC (95% CI) was 0.72 (0.537, 0.902); the optimal cut-off point was 76.64mL/min (p = 0.01), the sensitivity was 0.985, and the specificity was 0.5. The linear stepwise regression equation was as follows: trough concentration = 0.14 × age + 0.071 × serum creatinine -4.196. In this study, a high proportion of burn patients had a vancomycin trough concentration below the standard range. Serum creatinine clearance and albumin levels are important indicators for predicting whether the vancomycin trough concentration is within the standard range. Using a linear stepwise regression equation, the vancomycin trough concentration can be estimated using the patient's age and serum creatinine level.

A single centre experience with clinical use of Neria™ Guard as mode of pain and distress management in the administration of emicizumab in children

Abstract Background The introduction of emicizumab as prophylactic subcutaneous (SC) administered treatment for people with haemophilia A has revolutionised its treatment and care; SC injection and the infrequent treatment intervals that can be achieved with emicizumab reduces treatment burden and interference in daily life. The efficacy and safety of emicizumab have been investigated in the Haven 1-7 trials. In contrast to the 4% of enrolled patients experiencing pain at the injection site across all seven trials, 11 out of 16 families at our treatment centre reported pain-related distress in administering emicizumab to their children, despite the application of local analgesia. Aim The study aimed to retrospectively evaluate whether using the Neria™ Guard infusion set, a single-use medical device for SC drug delivery that allows for slow infusion, reduced pain and distress in children receiving emicizumab. Methods This single-centre retrospective study included 11 paediatric patients whose families were introduced to the Neria™ Guard infusion set with the intent of reducing pain and distress. Plasma emicizumab values were tested after the introduction in relation to routine clinical check-ups in all patients. Data was collected retrospectively from patient files. According to local regulations ethical approval and consent was not necessary. Results Parents/caregivers had no difficulty learning how to use the system; a single demonstration was sufficient in all cases. All families reported a reduction or complete resolution of pain and distress in relation to emicizumab injection after the introduction of Neria™ Guard, and all families have continued using the device. Plasma levels of emicizumab were sustained within the target therapeutic range. Conclusion There is a need for more recognition of and research into the prevalence of pain and distress among children receiving treatment with emicizumab, and a need for a validated and stability tested solution to alleviate this. Neria™ Guard has proven to be effective in the reduction of pain and distress in our clinic.

How enoxaparin underdosing and sex contribute to achieving therapeutic anti-Xa levels.

Anti-Xa serves as a clinical surrogate for assessing the efficacy and bleeding risk in patients treated with enoxaparin for thromboembolic events. Evidence from the literature and empirical observations suggest that patients are underdosed in clinical practice to avoid bleeding complications. This study aimed to investigate such underdosing of enoxaparin and its potential impact on achieving therapeutic anti-Xa levels. This multicentric, retrospective, observational study included patients with acute ischemic stroke due to atrial fibrillation. All patients received enoxaparin in the therapeutic setting with subsequent anti-Xa measurements. The one-sample, one-tailed Wilcoxon signed-rank test was used to identify a significant difference between the doses administered and the recommended daily dose. Logistic regression model analysis was performed to identify additional predictors affecting achievement of the therapeutic anti-Xa target range. Stepwise forward-backward selection with Akaike's information criterion as metric was applied to refine the logistic regression model. A total of 145 patients from the university hospitals of St. Pölten and Tulln in Lower Austria were included. The median daily enoxaparin dose administered was 1.23mg/kg, resulting in an overall target range achievement rate of 66%. As compared to recommended therapeutic doses, significant underdosing of enoxaparin was evident in both participating centers (p < 0.001). The calculated threshold dose to achieve the therapeutic target range with a 90% probability was 1.5mg/kg enoxaparin daily. Female sex was found to be a strong independent predictor of achieving a therapeutic target range (OR 9.44; 95% CI 3.40-30.05, p < 0.001). Despite the underdosing observed in both centers, therapeutic anti-Xa levels were achieved with lower than recommended doses of enoxaparin, and women required even lower doses than men. These findings warrant further confirmation by prospective studies.

Skin temperature of the knee was effectively reduced when using a new continuous cold-flow cryocompression device: a randomised controlled crossover trial

ObjectiveTo determine which temperature settings on a new continuous cold-flow cryocompression device effectively reduce knee skin temperature to 10–15 °C, where pain and swelling are expected to be attenuated. DesignRandomised controlled crossover trial. SettingUniversity laboratory. Participants32 healthy adult participants recruited (1 dropout) with no contraindications to cryocompressive therapy. InterventionA k-type thermocouple was used to record skin temperature at baseline and every five minutes during a 30-minute cryocompression treatment in a control condition and when using four different device temperature settings (6 °C, 8 °C, 10 °C, and 12 °C) on a continuous cold-flow cryocompression device. Conditions were labelled Control, Con-6, Con-8, Con-10, and Con-12, respectively. Main outcome measuresSkin temperature change (°C) throughout cryocompression; time taken (mins) to achieve skin temperature < 15 °C; and the difference between final skin temperature and device temperature setting (°C). ResultsMedian (IQR) skin temperature after cryocompression was 32.1 °C (29.3–33.4), 12.8 °C (12.1–14.6), 14.3 °C (13.8–15.7), 16.1 °C (15.2–17.3), and 17.7 °C (16.9–18.9) for the Control condition and Con-6, Con-8, Con-10 and Con-12, respectively. It took 20 min (Con-6) and 25 min (Con-8) for skin temperature to reach < 15 °C. A median (IQR) difference of 6.8 °C (6.1–8.6), 6.3 °C (5.8–7.7), 6.1 °C (5.2–7.3), and 5.7 °C (4.9–6.9) for Con-6, Con-8, Con-10, and Con-12, respectively was observed between device temperature setting and final skin temperature. ConclusionsThe device is recommended as it reduced skin temperature to the therapeutic range of 10–15 °C during a 30-minute treatment when using the 6 °C or 8 °C device temperature settings. Future research should determine optimal treatment lengths for cryocompression. Contribution of the Paper•The Physiolab S1 cryocompression device allows users to determine precise temperatures of the ice-water that is circulated around the knee during a treatment.•This paper demonstrates the ability of each temperature setting to reduce skin temperature around the knee to within the target therapeutic range of 10–15 °C.•There is a significant discrepancy between the temperature setting of the device and the skin temperature achieved during a treatment.•Clinicians should not assume that all temperature settings on this and similar devices sufficiently reduce skin temperature of the knee to confer a therapeutic benefit.

B-329 Comparison Between Trough and AUC Monitoring of MPA in Patients With and Without Organ Transplantation. Influence of the Co-administered Immunosuppressant

Abstract Background Monitoring of mycophenolic acid (MPA) could be performed by measurement of trough concentrations with target therapeutic range of 1.3 to 3.5 mg/L, or by calculation of area under the drug concentration vs time curve (AUC) utilizing 3 or 4 samples within a dosing interval, with a target range of 30 to 60 mg*h/L. AUC is considered more reliable compared to trough levels, and MPA kinetics are dependent on the type of the co-administered calcineurine inhibitor. This study compares trough vs AUC MPA monitoring received alone or in co-administration with Cyclosporine (CsA) or with Tacrolimus (TAC). Methods 77 transplanted patients receiving MPA, 25 of them on CsA, 49 on TAC, and 20 non-transplanted patients on MPA alone, were evaluated more than once, yielding 260 monitoring consults included for assessment: 45 for MPA alone, 108 for MPA combined with CsA, and 117 consults for the MPA combined with TAC. MPA, CsA, and TAC levels were measured by validated LC/MS/MS methods. Validated pharmacokinetic programs for the calculation of MPA AUC were used, adapted to the type of calcineurine inhibitor. Assessment was made by comparison of the distribution and coincidence between trough levels and AUC with respect to the above therapeutic ranges. Results Transplanted patents: when combined with CsA, MPA AUC was in the target range in 61% of cases, under it—in 31%, and in 8%—over it, while trough levels were 52% under, 42.5% within, and 5.5% over the therapeutic range; agreement between trough MPA and MPA AUC was poor—there was coincidence in 37.5% of sub-therapeutic, 63% of therapeutic and 0% of supra-therapeutic ranges, 3 cases were identified with sub-therapeutic trough and supra-therapeutic AUC; when combined with TAC, MPA AUC was in the target range in 63% of cases, under it—in 13%, and in 24%—over it; trough levels being 23% under, 60% within and 17% over the therapeutic range; agreement between trough MPA and MPA AUC was much better, compared to the combination with CsA: there was coincidence in 56% of sub-therapeutic, 84% of therapeutic and 80% of supra-therapeutic ranges. Nevertheless, 1 case was found with sub-therapeutic trough and supra-therapeutic AUC. In non-transplanted patients MPA AUC was in the target range in 47% of cases, under it—in 13%, and in 40%—over it; trough levels being 18% under, 53% within and 29% over the therapeutic range; agreement between trough MPA and MPA AUC showed coincidence in 75% of sub-therapeutic, 75% of therapeutic and 92% of supra-therapeutic ranges. Conclusion This study confirms that MPA AUC is more relevant than trough monitoring for dose individualization. It also shows that MPA trough levels are much more concordant with MPA AUC in non-transplanted patients and in transplanted patients on TAC, while in combination with CsA, discordance remains significant.

Therapeutic Drug Monitoring of Voriconazole in Patients with End-Stage Liver Disease.

This study aimed to identify the factors that influence voriconazole (VCZ) plasma concentrations and optimize the doses of VCZ in patients with end-stage liver disease (ESLD). Patients with ESLD who received a VCZ maintenance dose of 100 mg twice daily (group A, n = 57) or the VCZ maintenance dose of 50 mg twice daily (group B, n = 37), orally or intravenously, were enrolled in this study. Trough plasma concentrations (Cmin) of VCZ between 1 and 5 mg/L were considered within the therapeutic target range. The VCZ Cmin was determined in 94 patients with ESLD. The VCZ Cmin of patients in group A was remarkably higher than those in group B (4.85 ± 2.53 mg/L vs 2.75 ± 1.40 mg/L; P < 0.001). Compared with group A, fewer patients in group B had VCZ Cmin outside the therapeutic target (23/57 vs. 6/37, P = 0.021). Univariate and multivariate analyses suggested that both body weight and Model for End-Stage Liver Disease scores were closely associated with the VCZ Cmin in group B. These data indicate that dose optimization based on body weight and Model for End-Stage Liver Disease scores is required to strike an efficacy-safety balance during VCZ treatment in patients with ESLD.

Evaluation of a New Glycomacropeptide-Based Protein Substitute in Powdered and Liquid Format in Patients with PKU.

(1) Background: Good adherence to a Phe-restricted diet supplemented with an adequate amount of a protein substitute (PS) is important for good clinical outcomes in PKU. Glycomacropeptide (cGMP)-PSs are innovative, palatable alternatives to amino acid-based PSs (AA-PS). This study aimed to evaluate a new cGMP-PS in liquid and powder formats in PKU. (2) Methods: Children and adults with PKU recruited from eight centres were prescribed at least one serving/day of cGMP-PS for 7-28 days. Adherence, acceptability, and gastrointestinal tolerance were recorded at baseline and the end of the intervention. The blood Phe levels reported as part of routine care during the intervention were recorded. (3) Results: In total, 23 patients (powder group, n = 13; liquid group, n = 10) completed the study. The majority assessed the products to be palatable (77% of powder group; 100% of liquid group) and well tolerated; the adherence to the product prescription was good. A total of 14 patients provided blood Phe results during the intervention, which were within the target therapeutic range for most patients (n = 11) at baseline and during the intervention. (4) Conclusions: These new cGMP-PSs were well accepted and tolerated, and their use did not adversely affect blood Phe control.

Phenylalanine Tolerance over Time in Phenylketonuria: A Systematic Review and Meta-Analysis.

In phenylketonuria (PKU), natural protein tolerance is defined as the maximum natural protein intake maintaining a blood phenylalanine (Phe) concentration within a target therapeutic range. Tolerance is affected by several factors, and it may differ throughout a person's lifespan. Data on lifelong Phe/natural protein tolerance are limited and mostly reported in studies with low subject numbers. This systematic review aimed to investigate how Phe/natural protein tolerance changes from birth to adulthood in well-controlled patients with PKU on a Phe-restricted diet. Five electronic databases were searched for articles published until July 2020. From a total of 1334 results, 37 articles met the eligibility criteria (n = 2464 patients), and 18 were included in the meta-analysis. The mean Phe (mg/day) and natural protein (g/day) intake gradually increased from birth until 6 y (at the age of 6 months, the mean Phe intake was 267 mg/day, and natural protein intake was 5.4 g/day; at the age of 5 y, the mean Phe intake was 377 mg/day, and the natural protein intake was 8.9 g/day). However, an increase in Phe/natural protein tolerance was more apparent at the beginning of late childhood and was >1.5-fold that of the Phe tolerance in early childhood. During the pubertal growth spurt, the mean natural protein/Phe tolerance was approximately three times higher than in the first year of life, reaching a mean Phe intake of 709 mg/day and a mean natural protein intake of 18 g/day. Post adolescence, a pooled analysis could only be performed for natural protein intake. The mean natural protein tolerance reached its highest (32.4 g/day) point at the age of 17 y and remained consistent (31.6 g/day) in adulthood, but limited data were available. The results of the meta-analysis showed that Phe/natural protein tolerance (expressed as mg or g per day) increases with age, particularly at the beginning of puberty, and reaches its highest level at the end of adolescence. This needs to be interpreted with caution as limited data were available in adult patients. There was also a high degree of heterogeneity between studies due to differences in sample size, the severity of PKU, and target therapeutic levels for blood Phe control.

Successful management of aortic root thrombosis in a patient with Heartmate 3.

A 74-year-old female with ischemic cardiomyopathy underwent Heartmate 3 (HM 3) implantation for advanced heart failure as destination therapy. Anticoagulation with unfractionated heparin was started within 24 h after implantation. Warfarin and aspirin were started on post-operative Day 3. The patient was mostly in the therapeutic range of the international normalized ratio and activated partial thromboplastin time. On a post-operative Day 11, the patient took a chest computed tomography (CT) for the evaluation of new-onset dyspnea. The CT demonstrated a large aortic root thrombosis (ART) measuring 2.9 cm in maximum diameter covering all three cusps of the aortic valve (AV) (Panel A) and showed a close location with the left coronary ostium (Panel B, arrow: left coronary ostium). After a multidisciplinary discussion with heart failure physicians, cardiac surgeons, and cardiac imaging specialists, we decided to intensify anticoagulation and withhold thrombectomy. We also increased the pump speed in an effort to minimize the AV motion for the prevention of systemic embolization or myocardial infarction. After 3 weeks, follow-up CT showed regression of the ART (Panel C). Accordingly, we lowered the left ventricular assist device (LVAD) pump speed for adequate AV opening to prevent recurrent ART. Three-dimensional (3D) CT reconstruction of the LVAD (Panel D) and follow-up chest x-ray (Panel E) showed well positioned LVAD. The patient was discharged and has been doing well for more than a year with a good therapeutic target range of anticoagulation.

Design and initial testing of a novel disposable oscillating positive expiratory pressure device.

Oscillating positive expiratory pressure (OPEP) devices play a key role in airway clearance, particularly in patients with cystic fibrosis. These devices, however, have the potential to become reservoirs for pathogenic organisms and require daily, or even more frequent, cleaning. This places a large burden on patients and their carers. The objective of this work was to develop a disposable OPEP device, with comparable mechanical performance to commercial devices, that negates the need for cleaning after use thus reducing microbiological risks. 3D printing was used to iterate and develop a prototype disposable device (The University of Limerick OPEP, abbreviated to the UL-OPEP) that was compared with a selection of commercially available devices for mean pressure and oscillation amplitude (cmH2O), as well as oscillation frequency (Hz). All devices were tested using a healthy volunteer at a target expiratory flow of ~ 20 L/min. The target therapeutic range was 10-20 cmH2O at a flow rate of 10-20 L/min as is reported widely in the literature. The prototype disposable device achieved a mean pressure of 14.82 cmH2O at a mean flow rate of 18.82 L/min, and generated an oscillation frequency of 26Hz with an amplitude of 1.28 cmH2O. These characteristics compare favourably with existing, more complex, reusable OPEP devices. The UL-OPEP device is a small, disposable OPEP device, that generates pressure and oscillation amplitudes for clinically effective airway clearance. The device negates the need for cleaning and disinfecting, removing the risk of devices acting as a potential reservoir for pathogenic organisms while maintaining mucus-clearing benefits.

Development of a Quantitative Systems Pharmacology Model to Explore Hemostatic Equivalency of Antithrombin Lowering

Fitusiran is an investigational siRNA therapeutic that targets antithrombin (AT) to rebalance hemostasis in people with hemophilia A (PwHA) or B (PwHB), irrespective of inhibitor status. Phase 3 clinical studies have demonstrated that fitusiran prophylaxis significantly reduced bleeding events compared to on-demand or prophylaxis treatment with factor concentrates or bypassing agents (Srivastava et al. Blood 2021; Young et al. Blood 2021; Kenet et al. ISTH 2022). To better understand the hemostatic equivalency of fitusiran prophylaxis (i.e., AT lowering), a quantitative systems pharmacology (QSP) model was developed to investigate thrombin generation in PwHA and PwHB in the context of AT lowering. QSP modeling is a mechanistic approach that integrates clinical and nonclinical data of the coagulation pathway to simulate the results of multiple in vitro coagulation assays, including the thrombin generation assay (TGA) and to mechanistically understand the readouts of these assays. The QSP model builds on prior published models of the coagulation cascade (Attarwala et al. ISTH 2017; Sridharan et al. Blood 2017), updated to represent reported steady-state levels of coagulation factors and accessory proteins in the plasma of healthy individuals and PwHA and PwHB (Figure 1). In addition, the model was extended to describe the impact of α-2-macroglobulin, a key regulator of thrombin, with increased influence at reduced AT levels that is critical to understand the impact of fitusiran on thrombin generation (Kattula et al. Blood 2020). After representing coagulation dynamics from plasma from healthy individuals, PwHA, and PwHB, the QSP model was applied to simulate TGA and relevant metrics, including thrombin peak height (Figure 1). TGA simulations were performed across different percentages of AT and FVIII. These simulations reproduced experimental TGA data from AT- and FVIII-double depleted plasma that was spiked with different levels of AT and/or FVIII. For these in vitro experiments, Factor VIII (FVIII) and AT-double depleted plasma was generated from congenital FVIII-deficient plasma by immunodepleting AT using an anti-AT antibody and recombinant AT protein was spiked back in to achieve different levels of AT. The QSP simulations also reproduced the reported formation of α-2-macroglobulin complexes with thrombin in each condition. Subsequently, the model was validated using both internal and published TGA and activated partial thromboplastin time (aPTT) datasets that were not used during model development. Next, a large (n=1000) virtual population (VP) of severe PwHA (<1% FVIII) was generated based on calibration of the model to individual patient data from completed fitusiran clinical studies. This analysis considered individual patient pharmacokinetic and AT time courses to describe thrombin peak height associated with different levels of AT reduction from fitusiran prophylaxis within a representative population of severe PwHA. The target therapeutic AT range of fitusiran prophylaxis treatment at steady state is 15-35%. Based on this model, the peak thrombin generated at 15-35% AT was similar to peak thrombin observed at 10-20 IU/kg FVIII in PwHA. In summary, by considering the impact of α-2-macroglobulin, the QSP model provides a mechanistic representation of thrombin generation under conditions of AT lowering, consistent with internal TGA data from donor-derived spiked plasma and clinical TGA data from both PwHA and PwHB. The VP analysis of fitusiran prophylaxis provided hemostatic equivalency with FVIII in a representative population of severe PwHA, with a targeted therapeutic range of AT of 15-35% resulting in a thrombin peak profile which was comparable to 10-20 IU/kg FVIII. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal