Target Trough Research Articles

First Report of Immunoglobulin G4-related Hepatic Inflammatory Pseudotumor in Transplanted Liver.

Immunoglobulin (Ig)G4–related hepatic inflammatory pseudotumor (IgG4-HIPT) is a rare subset of IgG4-related disease characterized by IgG4-positive plasma cell infiltration and fibrosis.1 Only 28 cases have been reported, all occurring in native livers.1-3 We report herein the first case of IgG4-HIPT developing in a transplanted liver. All ethical approval and consent procedures were approved by the Medical Ethical Committee of Icahn School of Medicine at Mount Sinai. According to the institutional guidelines, the patient’s signed privacy consent is not necessary for a single case report with deidentified patient-specific information. Our patient, who is a 62-y-old women who underwent liver transplantation for primary biliary cholangitis 14 y prior, presented with bacteremia. Laboratory tests showed normal white blood cell count, elevated gamma-glutamyl transferase 101 U/L (normal, 8–35), normal alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin. Blood culture was positive for methicillin-resistant Staphylococcus aureus and Klebsiella oxytoca. Serological tests for hepatitis A, B, C, and E; cytomegalovirus; and Epstein-Barr virus were negative. Serum total IgG 1654 mg/dL (normal, 586–1602) and IgG4 171 mg/dL (normal, 2–96) were elevated. Computed tomography (Figure 1A) and magnetic resonance imaging (Figure 1C–E) of the abdomen revealed a 6-cm infiltrative mass in segment 8 of the liver. A biopsy of the lesion demonstrated parenchymal collapse replaced with fibrosis and sheets of plasma cells (Figure 1F). Immunohistochemical stains showed up to 150 IgG4-positive plasma cells per high power field and an IgG4:IgG ratio of 60% (Figure 1G and H). There was no evidence of malignancy, recurrent primary biliary cholangitis, acute cellular rejection, or chronic rejection, and a diagnosis of IgG4-HIPT was rendered. Given the patient’s bacteremia, she was started on intravenous daptomycin and ertapenem. Prednisone was deferred because she was asymptomatic from the lesion. The patient was restarted on mycophenolate mofetil 1 mo postdischarge. Repeat computed tomography of the abdomen 7 mo later demonstrated the decreased size of the lesion to 2.3 cm (Figure 1B).FIGURE 1.: Radiology features (A–E). A, Contrast-enhanced computed tomography images demonstrate an infiltrative enhancing mass in segment 8 measuring 6 cm (arrow). B, Follow-up postcontrast computed tomography after 7 mo demonstrates the decreased conspicuity and size of the lesion (measuring 2.3 cm, arrow). Contrast-enhanced MRI obtained during the (C) arterial, (D) portal venous, and (E) delayed venous phases demonstrates an ill-defined lobulated infiltrative progressively enhancing mass (arrow). Microscopic and immunohistochemical features (F–H). F, The inflammatory cells consist predominantly of lymphocytes and plasma cells (arrow) (hematoxylin and eosin stain ×200). The inflammatory cells demonstrated diffuse reactivity for (G) cluster of differentiation 138 and (H) immunoglobulin G4. MRI, magnetic resonance imaging.IgG4-related disease is generally described as an autoimmune disease because the oligoclonal expansions of both activated B cells and cytotoxic CD4+ T cells were considered central to the process.4 In our case, the IgG4-HIPT developed in a liver allograft in a patient on immunosuppression (tacrolimus target trough level 2–6 ng/dL, mycophenolate mofetil 500 mg twice daily). It may seem counterintuitive that an autoimmune process may develop in such a setting. On the other hand, infections such as Escherichia coli and Klebsiella may also incite an IgG4-predominant inflammatory response.3 In our case, the patient developed bacteremia with methicillin-resistant Staphylococcus aureus and Klebsiella at the time the liver mass was noted. Bacterial translocation from the gut to the portal circulation may have provoked an intrahepatic inflammatory response. This theory was further supported by partial or complete treatment response observed in the current and prior reported cases2 upon administration of antibiotics. Diagnosing IgG4-HIPT is challenging because of its rarity and overlapping clinical and radiological features with malignancy. Because IgG4-HIPT is clinically benign, the recognition of this entity is important to avoid unnecessary treatment.

Drug-drug interaction: decreased posaconazole trough concentrations during concomitant flucloxacillin treatment.

Posaconazole is used as prophylaxis of invasive fungal disease in immune-compromised haematological patients with prolonged neutropenia after intensive chemotherapy. During routine therapeutic drug monitoring of posaconazole, we repeatedly observed low posaconazole serum concentrations in patients that were concomitantly treated with flucloxacillin. A possible interaction between flucloxacillin and posaconazole was explored in this case series. Posaconazole trough serum concentrations during and before/after flucloxacillin treatment were collected from 10 patients. With a median concentration of 0.5 mg/L (IQR 0.3-0.6), the posaconazole trough serum concentration decreased by 47% during flucloxacillin treatment compared with the concentration before/after flucloxacillin treatment (0.9 mg/L, IQR 0.6-1.3). As a result, the posaconazole target trough concentration of ≥0.7 mg/L was only achieved in five out of nine patients during flucloxacillin treatment. Careful monitoring of posaconazole serum trough concentrations is recommended when concomitant use of flucloxacillin cannot be avoided.

British Society for Haematology guideline for anticoagulantmanagement of pregnant individuals with mechanical heart valves.

British Society for Haematology guideline for anticoagulantmanagement of pregnant individuals with mechanical heart valves.

Correlation of Calculated Vancomycin Trough Concentrations and Exposure: A Monte Carlo Simulation.

Current recommendations are to dose vancomycin to target 24-hour area under the curve (AUC) of 400-600 mg·h/L to optimize efficacy and safety. Limited data support AUC monitoring, and some centers continue to use trough concentrations. A target of 10-20 mg/L has been proposed to reduce nephrotoxicity risk. To use previously published pharmacokinetic equations in a Monte Carlo simulation relating AUC exposure to trough concentrations when targeting an AUC between 400 and 600 mg·h/L. Previously published pharmacokinetic data were used as input parameters for a Monte Carlo simulation using previously published formulae to correlate AUC to simulated trough concentrations. Pharmacokinetic parameters were assumed to occur in a normal distribution pattern. We excluded irrelevant simulated cases. Maintenance doses of 15 mg/kg were rounded to the nearest 250 mg. Calculated trough concentrations for AUCs of both 400 and 600 mg·h/L were evaluated in each simulation. A total of 10 000 Monte Carlo simulations were performed. Targeting an AUC of 400 mg·h/L resulted in a mean trough concentration of 10.3 ± 0.8 mg/L. Targeting an AUC of 600 mg·h/L resulted in a mean trough concentration of 15.4 ± 1.2 mg/L. We demonstrate that a lower trough concentration range may be supported by an AUC of 400-600 mg·h/L, which may reduce risk and rates of nephrotoxicity without compromising previously established efficacious target trough concentrations.

A HPLC-DAD method to facilitate large-scale therapeutic drug monitoring of dalbavancin

Dalbavancin, a long-acting lipoglycopeptide antibiotic targeting susceptible Gram-positive bacteria, is WHO critically important antibiotic, increasingly used in critical situations such as osteoarticular infections. To ensure its effectiveness and its safety, the therapeutic drug monitoring (TDM) of dalbavancin is strongly recommended. In the absence of an available minimum inhibitory concentration (MIC), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommends a breakpoint of 0.125 mg/L for Staphylococcus aureus, corresponding to a trough target concentration of 25 mg/L. Nowadays, the TDM is usually performed using a high-performance liquid chromatography (HPLC) method coupled with a tandem mass spectrometry. However, this expensive and specialized equipment and reagents may be difficult to acquire for non-specialized laboratories. The use of HPLC coupled with diode array detector (DAD) facilitates TDM with a lower cost, while preserving the reliability of the results. Our aim was to provide a sensitive and specific method, relying on HPLC-DAD for extending the TDM of dalbavancin beyond non-specialized labs, therefore maximizing its efficiency and Benefit/risk ratio. Our method complied with the European Medicines Agency guidelines of bioanalytical validation. Irrespective of the concentrations of dalbavancin, the coefficient of variation < 10% confirmed the reliability of this analytical method, with a calibration curve ranging from 5 to 100 mg/L. No interferences nor carryover was observed. Our HPLC-DAD method, combined with a simple extraction, provides a widely usable, inexpensive and easy-to-implement new asset for the TDM of Dalbavancin.

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis.

Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 1012/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 1012/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 1012/L and 4.9 × 1012/L. RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses.

Isavuconazole is a triazole antifungal agent recently recommended as first-line therapy for invasive pulmonary aspergillosis. With the COVID-19 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been described with a prevalence ranging from 5 to 30%. We developed and validated a population pharmacokinetic (PKpop) model of isavuconazole plasma concentrations in intensive care unit patients with CAPA. Nonlinear mixed-effect modeling Monolix software were used for PK analysis of 65 plasma trough concentrations from 18 patients. PK parameters were best estimated with a one-compartment model. The mean of ISA plasma concentrations was 1.87 [1.29-2.25] mg/L despite prolonged loading dose (72 h for one-third) and a mean maintenance dose of 300 mg per day. Pharmacokinetics (PK) modeling showed that renal replacement therapy (RRT) was significantly associated with under exposure, explaining a part of clearance variability. The Monte Carlo simulations suggested that the recommended dosing regimen did not achieve the trough target of 2 mg/L in a timely manner (72 h). This is the first isavuconazole PKpop model developed for CAPA critical care patients underlying the need of therapeutic drug monitoring, especially for patients under RRT.

P502 Application of an algorithm-based precision-dosing model to a real-world cohort of patients on infliximab maintenance therapy: implications for drug usage and cost

Abstract Background Infliximab is registered for use in patients with inflammatory bowel disease (IBD) at an intravenous maintenance dose of 5 mg/kg eight-weekly. Secondary loss of response during maintenance therapy occurs in up to 50% of patients. New precision dosing models, which forecast infliximab doses to achieve targeted trough levels, reduce non-response and improve patient outcomes. Aim: To compare standard 5 mg/kg eight-weekly infliximab dosing to the infliximab doses theoretically required to achieve predefined infliximab trough target levels, as determined by the iDOSE® precision dosing dashboard model. Methods IBD patients treated with eight-weekly maintenance infliximab therapy dosed at 5 mg/kg were included. A recorded infliximab dose was considered dose X if the following was available: three previous infliximab doses, albumin and C-reactive protein at time of dose X, trough infliximab level immediately preceding dose X and the patient’s weight. The Baysient LLC iDOSE® software was then used to predict dose X to maintain therapeutic infliximab trough levels of ≥ either 5-10 or 3-7 µg/ml until the next eight-weekly dose. The predicted dose X was compared to the actual dose X given. Results 174 patients (56% male) were included with 417 dose X recordings. Of those, 135 had Crohn’s disease, 31 ulcerative colitis and 8 IBD-unclassified. Median age was 36 (IQR 29-47) years with a disease duration of 5 (1-13) years. 76% of patients were receiving immunomodulators and 6% were smokers. Duration of infliximab therapy before dose X was 2 (0-4) years. Trough infliximab levels were 5.0 (2.5-7.6) µg/ml, serum albumin was 38 (35-40) g/L and C-reactive protein 3 (3-4) mg/L. Comparing actual dose X with predicted dose X, 52% and 32% of doses were subtherapeutic when aiming for trough levels of 5-10 and 3-7 µg/ml respectively. The underdosing occurred by 5.6 and 5.3 mg/kg per dose, respectively. Cost analysis showed total costs increased by 102% and 29% when aiming for trough levels 5-10 and 3-7 µg/ml. On multivariable regression analysis, significant associations with subtherapeutic infliximab levels were ulcerative colitis compared to Crohn’s disease [OR: 9.81, 95% CI: 1.28-75.40, p = 0.028] and pre-dose X infliximab trough level [OR: 0.07, 95% CI: 0.03-0.15, p &amp;lt; 0.001]. Conclusion More than half of maintenance infliximab drug doses given at our institution were too low to achieve therapeutic infliximab blood levels of at least 5 µg/ml. These patients would likely benefit from an increased dose or reduced dosing interval of infliximab. These findings need to be confirmed prospectively.

Individualized vancomycin dosing in infants: prospective evaluation of an online dose calculator

Empiric vancomycin dosing regimens fail to achieve recommended target trough concentrations of 10-20 mg/L in the majority of infants. This study assessed the performance of a model-based dosing calculator (Vanc App) in achieving target vancomycin concentrations at first steady-state level. This was a multicenter prospective study in four tertiary pediatric hospitals over an 18-month period. Infants aged 0-90 days with suspected Gram-positive sepsis requiring empiric vancomycin treatment were included if they did not meet any of the exclusion criteria: post-menstrual age (PMA) <25 weeks, weight <500 g, glycopeptide allergy, receiving extracorporeal membrane oxygenation, vancomycin use within the previous 72 h, and renal impairment. The Vanc App used a published population pharmacokinetic model to generate a dose based on the infant's PMA, weight, creatinine, and target vancomycin concentration. A total of 40 infants were included; 40% were female, median (range) weight was 2505 (700-4460) g and median (range) PMA was 37.4 (25.7-49.0) weeks. The median (range) vancomycin dose was 45 (24-79) mg/kg/day. All infants had trough vancomycin concentrations measured at steady-state (24-<48 hours) and 30 (75%) infants achieved target concentrations. Five infants had supratherapeutic (median 25, range 21-38 mg/L) and five had subtherapeutic (median 6, range <5-9 mg/L) concentrations. An area under the concentration-time curve (AUC0-24) of 400-650 mg/L.h was achieved in 33 (83%) infants. There were no infusion-related reactions or nephrotoxicity. Individualized intermittent vancomycin dosing using a model-based online calculator resulted in 75% and 83% of infants achieving target trough and AUC0-24, respectively, at first steady-state level. There were no vancomycin-related nephrotoxicity or infusion-related reactions.

Optimal Use and Need for Therapeutic Drug Monitoring of Teicoplanin in Children: A Systematic Review.

Teicoplanin is a glycopeptide antimicrobial that treats serious invasive infections caused by gram-positive bacteria, such as the methicillin-resistant Staphylococcus aureus. Despite some comparable advantages, there is no guideline or clinical recommendation for teicoplanin in the pediatric population, unlike vancomycin where abundant studies and the recently revised guideline on therapeutic drug level monitoring (TDM) exist. The systematic review was performed in accordance with the preferred reporting items for systematic reviews. Two authors (JSC and SHY) searched PubMed, Embase, and Cochrane Library databases using relevant terms independently. Fourteen studies were finally included with a total of 1,380 patients. TDM was available in 2,739 samples collected in the nine studies. Dosing regimens varied widely, and eight studies used recommended dosing regimens. Timing for measuring TDM was mostly 72-96 hours or longer after the initiation of the first dose, which was expected to be a steady-state. The majority of studies had target trough levels of 10 µg/mL or above. Three studies reported that the clinical efficacy and treatment success rate of teicoplanin was 71.4%, 87.5%, and 88%. Adverse events associated with teicoplanin use were described in six studies with a focus on renal and/or hepatic impairment. Except for one study, no significant relation was noted between the incidence of adverse events and trough concentration. Current evidence on teicoplanin trough levels in pediatric populations is insufficient due to heterogeneity. However, target trough levels with favorable clinical efficacy are achievable by recommended dosing regimen in the majority of patients.

Anticoagulation for mechanical heart valves during pregnancy: A case report and a literature review

Most previous treatment guidelines for pregnant women with mechanical heart valves recommend that low molecular weight heparin (LMWH) should be applied once every 12 hours and only as required to reach peak anti-Xa levels of approximately 1.0 to 1.2 IU/mL, but it is commonly associated with subtherapeutic trough levels, consequently with an inadequate level of anticoagulation. Our case report here together with a literature review suggests that dose-adjusted (Target trough anti-Xa levels of 0.6 to 0.7 IU/mL and with peak anti-Xa levels of around 1.0 to 1.2 IU/mL or < 1.5 IU/mL) LMWH should be given thrice daily throughout pregnancy. In addition, the findings of this rare case indicate that a combination of LMWH and warfarin is effective in the treatment of small thromboses in pregnancy. In the 1st trimester of pregnancy, a 28-year old pregnant female with a mechanical valve had a significant increase in the aortic valve flow rate and suspected mechanical valve thrombosis. The peak velocity of the pregnant female aortic mechanical valve increased, and mechanical valve thrombosis was suspected. We adjusted the enoxaparin sodium dose every 12 hours to 1 injection every 8 hours, with a total daily dose of 160 mL. Based on the original application of LMWH, warfarin (3 mg/day) was recommended. The pregnant woman delivered a live baby by cesarean section, and the peak flow velocity of the mechanical valve in the aortic position was reduced to nearly equivalent to the patient's pre-pregnancy status. The mother and the baby were in good health at the time of discharge. LMWH is administered twice daily, and anti-Xa trough levels are mostly in a subtherapeutic state, which may lead to insufficient anticoagulation and thrombosis. Dose-adjusted LMWH thrice daily throughout pregnancy is the recommended treatment for pregnant women with mechanical heart valves. The combination of LMWH and warfarin exhibited good efficacy for the treatment of small thromboses.

613. Novel use of Ritonavir boosting to achieve therapeutic itraconazole levels in disseminated Histoplasmosis

Abstract Background Itraconazole is a poorly soluble antifungal drug with variable pharmacokinetics. Serum levels vary between patients and over time, due to absorption issues and drug-drug interactions. Itraconazole suspension has more predictable absorption than capsules, but is poorly tolerated. Newer formulations dispersing drug in polymer aim to improve bioavailability, but are costly and not widely available. Standard therapy for histoplasmosis is induction with liposomal amphotericin B (LAmB) followed by 12+ months of itraconazole therapy with target pre-dose levels of 1-4 mg/L. Methods A 33yo M presented with weight loss, fever and dyspnoea, having returned to the UK from Nicaragua. He had been taking adalimumab for Crohn’s disease, quiescent for years following a prior small bowel resection. Empiric antifungal therapy with LAmB was commmenced, prior to confirmation of disseminated histoplasmosis by urinary antigen and blood culture. His course was complicated by significant bowel inflammation, requiring subtotal colectomy and end-ileostomy. Since surgery, he has had a high output stoma, with rapid transit time and reduced absorption. Results Despite itraconazole dose titration to 300mg TDS, levels were generally &amp;lt; 0.5 mg/L and maximum serum itraconazole level achieved was 0.64 mg/L. The patient was trained with a view to self-OPAT LAmB. On day 117 of antifungal therapy, ritonavir 100mg once daily was added. Four days after this, itraconazole level was 1.39 mg/L (from 0.34 mg/L) and maintained target concentration even after a switch from itraconazole suspension to capsules (Fig.1) with significant fungal marker response (Fig. 2). Figure 1.Itraconazole dosing and levels pre- and post-ritonavir Total daily itraconazole dose (suspension followed by capsules) was mapped over time. There is a period where LAmB alone was used surrounding the colorectal surgery. Serum itraconazole levels dramatically increased 2 days after the introduction of ritonavir 100mg once daily and remained above target trough even after switching to itraconazole capsules. Figure 2.Fungal marker (B-D-glucan and Histoplasma urinary Ag) response to antifungal therapy The response of serum beta-D-glucan and quantitative urinary Histoplasma antigen EIA (Miravista Labs) is represented alongside concurrent antifungal therapy. Of note, the first four urinary Histoplasma Ag levels were reporte as above the limit of detection (&amp;gt; 20 ng/mL) and are represented here as an arbitrary value of 25 ng/mL. Conclusion Use of ritonavir alone to boost itraconazole has not previously been described. It avoids the longer-term complications of intravenous access and adverse renal and other effects of LAmB. Itraconazole is both a substrate and inhibitor of cytochrome P450 3A4 (CYP3A4) and inhibits P-glycoprotein, resulting in considerable drug:drug interactions. Ritonavir is a more potent inhibitor of CYP3A4. Use of ritonavir-boosted itraconazole amounted to a 99% reduction in cost vs LAmB over 6 months. It may offer a reliable and cost-effective method of boosting itraconazole where other drug:drug interactions do not preclude its use. Disclosures All Authors: No reported disclosures.

Matching Adjusted Indirect Comparisons of Personalized Prophylaxis with Simoctocog Alfa Versus Efmoroctocog Alfa, Damoctocog Alfa Pegol and Rurioctocog Alfa Pegol in Patients with Hemophilia a

Introduction: Prophylactic factor VIII (FVIII) therapy is the gold standard to prevent bleeding in patients with severe hemophilia A and should be individualized to patient needs. Although several FVIII products are available, the lack of head-to-head studies makes it difficult to compare their efficacy. The objective of this analysis was to indirectly compare the efficacy of personalized prophylaxis with simoctocog alfa (Nuwiq®) with three comparator FVIII products - efmoroctocog alfa (Eloctate®), damoctocog alfa pegol (Jivi®) and rurioctocog alfa pegol (Adynovate®) - among adults with severe hemophilia A. Methods: Matching adjusted indirect comparison (MAIC) methodology was used to estimate relative treatment effects during personalized prophylaxis after matching study populations with respect to clinically important baseline characteristics. Individual patient data (IPD) from 65 patients on personalized prophylaxis with simoctocog alfa in the NuPreviq study were compared with aggregated data for efmoroctocog alfa from 117 patients in the personalized prophylaxis arm of the A-LONG study, 110 patients treated with damoctocog alfa pegol in the PROTECT VIII study, and patients treated with rurioctocog alfa pegol in the FVIII target trough level 1-3% arm (57 patients) or the 8-12% arm (58 patients) from the PROPEL study. Following feasibility assessments for all proposed analyses, outcomes and matching variables were determined. Patients in the NuPreviq study who would have not met the inclusion criteria for the comparator studies were excluded from the analyses. Baseline age and body weight were used to re-weight the simoctocog alfa IPD such that the weighted summary statistics for simoctocog alfa matched those reported for efmoroctocog alfa; baseline age and body mass index were used for the comparison with damoctocog alfa pegol; and baseline age for the comparison with rurioctocog alfa pegol. Unanchored indirect treatment comparisons were then performed for each outcome using the weighted data for simoctocog alfa. Results: One patient from the NuPreviq study was excluded from the comparison with damoctocog alfa pegol based on baseline age, and 10 patients from the comparison with rurioctocog alfa pegol based on body weight. After matching the populations based on baseline characteristics, the effective sample sizes (ESS) for simoctocog alfa were 44, 40, 27, and 40 for the MAIC analyses with efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol 1-3% and 8-12%, respectively (Table 1). The percentage of patients with zero bleeds was significantly higher with simoctocog alfa for three of the analyses (Figure 1, Table 1): simoctocog alfa (75%) vs efmoroctocog alfa (45%); simoctocog alfa (76.8%) vs damoctocog alfa pegol (38.2%); and simoctocog alfa (78.4%) vs rurioctocog alfa pegol 1-3% (42.1%). The percentage of patients with zero spontaneous bleeds was significantly higher for simoctocog alfa vs rurioctocog alfa pegol 1-3%; these data were not available for efmoroctocog alfa or damoctocog alfa pegol. The total annualized bleeding rates (ABRs) were generally lower with simoctocog alfa vs the comparators, but the difference only reached statistical significance vs damoctocog alfa pegol (Table 1). Spontaneous and joint ABRs were lower with simoctocog alfa vs rurioctocog alfa pegol 1-3%, but the differences were not statistically significant; these data were not available for efmoroctocog alfa or damoctocog alfa pegol. The mean weekly dose was significantly higher in patients treated with simoctocog alfa compared with comparator products: simoctocog alfa vs efmoroctocog alfa (101 vs 85 IU/kg), vs damoctocog alfa pegol (97 vs 70 IU/kg) and vs rurioctocog alfa pegol 1-3% (99 vs 74 IU/kg) (Table 1). Patients treated with simoctocog alfa required a significantly lower average weekly dose than those treated with rurioctocog alfa pegol 8-12% (99 vs 143 IU/kg). Dosing of all products was consistent with the respective prescribing information. Conclusions: The results of these indirect treatment comparisons indicate that pharmacokinetics-adjusted, individualized treatment with simoctocog alfa can lead to decreased ABRs and significantly increased zero bleed rates compared with extended half-life concentrates, albeit at a higher weekly dose. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Therapeutic Drug Monitoring of Ganciclovir in Cytomegalovirus-Infected Patients With Solid Organ Transplants and Its Correlation to Efficacy and Toxicity.

Cytomegalovirus causes morbidity and mortality, especially in immunocompromised patients, and is treated with (val)ganciclovir. Therapeutic drug monitoring of ganciclovir is often performed; however, clinically established target trough levels corresponding to efficacy are lacking. In 2021, our clinic increased the target trough level for ganciclovir from 1 to 2 mg/L to 2-4 mg/L. This study aims to compare both target trough levels in efficacy, toxicity, and occurrence of resistance. A retrospective cohort study was performed in adult solid organ recipients treated for cytomegalovirus infection with (val)ganciclovir. Clinical efficacy was defined as the absence of treatment failure, defined as > 1 log 10 increase in viral load within 2 weeks of treatment initiation, therapy switch to foscarnet, and/or request for resistance analysis. A total of 46 patients were involved in the study, with 200 ganciclovir trough levels obtained. The composite endpoint was recorded in 23 (69.7%) and 10 (76.9%) patients in the 1-2 mg/L and the 2-4 mg/L group, respectively ( P = 0.18). No association was found between ganciclovir trough levels and the composite endpoint ( P = 1.0). However, a correlation was found between ganciclovir trough levels and the occurrence of lymphopenia ( P = 0.02). Our study could not establish a difference in clinical efficacy or toxicity between target trough levels of 1-2 mg/L or 2-4 mg/L because of the lack of clinical differences between the compared groups. However, a correlation was found between ganciclovir trough levels and lymphopenia, which warrants further investigation.

Effect of Initial Vancomycin Dose and Creatinine Clearance on the Attainment of Target Trough Concentration in Children.

Vancomycin is a glycopeptide antibiotic that is used to treat serious grampositive infections. However, therapeutic drug monitoring for vancomycin is not performed routinely in Vietnam in clinical practices. Monitoring of serum vancomycin concentration or trough levels is necessary to ensure the efficacy and safety of vancomycin therapy. This study aims to determine the impact of initial vancomycin dose and creatinine clearance on target trough attainment in hospitalized Vietnamese children. A prospective study with patients who received vancomycin for at least three days was conducted. Subsequently, demographic data, clinical diagnosis, vancomycin dosage, and serum creatinine levels were recorded. The vancomycin trough level was collected and creatinine clearance and adjusted vancomycin doses were calculated. A total of 40 eligible patients were enrolled. Patients' mean age, body weight, and height were 1.4 years old, 9.8 kg, and 75.5 cm, respectively. The mean vancomycin dose was 55.83 ± 19.34 mg/kg/day. The mean creatinine clearance was 80.18 ± 29.14 ml/min. The median trough level was 11.09 (7.84 - 16.46) μg/ml. There was no significant difference in the mean initial and the adjusted vancomycin doses (p = 0.062). However, there were statistically significant differences of initial (p = 0.004) or adjusted doses (p = 0.016) between groups of creatinine clearance. The trough vancomycin concentration was not statistically significant (p = 0.406) between these groups. Target trough vancomycin level may be associated with creatinine clearance but did not proportionally correspond to the vancomycin dose. Therefore, monitoring vancomycin trough levels is necessary to achieve the target trough and to ensure vancomycin efficacy and safety in treating severely infected Vietnamese children.

Exploration of the minimum necessary FVIII level at different physical activity levels in pediatric patients with hemophilia A.

Physical activity can increase joint stability and reduce the risk of injury in hemophilia patients. There is limited clinical data on target trough FVIII levels during physical activity in hemophilia A patients. Hence, this study aimed to explore the target trough FVIII level required to avoid bleeding during different physical activities in hemophilia A patients. Patients with severe or moderate hemophilia A, who underwent pharmacokinetics (PK) tests at our center were enrolled in this study. Physical activities and clinical information such as bleeding were recorded. The FVIII level during physical activity was calculated by the WAPPS-Hemo. A total of 105 patients were enrolled in this study. A total of 373 physical activities were recorded, of which 57.6% (215/373) was low-risk activities and the remaining 42.4% (158/373) was medium-risk activities. Most common physical activities were bicycling (59.0%), swimming (43.8%), running (48.6%), and jumping rope (41.0%). The FVIII trough level of low-risk physical activity was 3.8 IU/dl (AUC = 0.781, p = 0.002) and moderate-risk physical activity was 7.7 IU/dl (AUC = 0.809, p < 0.001). FVIII trough levels [low-risk activities: 6.1 (3.1, 13.2) IU/dl vs. 7.7 (2.3, 10.5) IU/dl, moderate-risk activities: 9.6 (5.8, 16.9) IU/dl vs. 10.2 (5.5, 11.0) IU/dl] were not statistically different between the mild arthropathy group and the moderate-severe arthropathy group. Multiple bleeding risk tended to increase with physical activities classified as moderate-risk (OR [95% CI]: 3.815 [1.766-8.238], p = 0.001). The minimum necessary FVIII level increased with higher risk physical activity, irrespective of arthropathy.

Review on Population Pharmacokinetics of Amikacin in Paediatrics

Amikacin is an aminoglycoside antibiotic with a broad-spectrum bacterial coverage that is frequently utilized both as monotherapy and in combination with other antibiotics for severe bacterial infections in the paediatric population. The narrow therapeutic index of the drug and high inter-individual variabilities in drug exposure results in either drug toxicity or subtherapeutic concentrations. Thus, therapeutic drug monitoring and population pharmacokinetics are pivotal to facilitate the optimal dosage regimens in paediatrics and negate the adverse outcomes. The therapeutic goal is to maintain the target peak and trough concentrations within 30-40mg/l and &lt;5 mg/l respectively. This review aimed to summarize population pharmacokinetic considerations and the pharmacokinetic parameters of amikacin across the paediatric population.

Dose optimization with population pharmacokinetics of ritonavir-boosted lopinavir for Thai people living with HIV with and without active tuberculosis

BackgroundPrior to dolutegravir availability, ritonavir-boosted lopinavir (LPV/r) was an alternative recommendation when first-line drugs could not be used. A high concentration of protease inhibitors was observed in the Thai people living with HIV (PLWH). Thus, dose reduction of LPV/r may be possible. However, the pharmacokinetics and dose optimization of LPV/r have never been investigated. This study aimed to develop a population pharmacokinetic model of LPV/r and provide dosage optimization in Thai PLWH. MethodsLPV and RTV trough concentrations from Thai PLWH were combined with intensive data. The data were analyzed by the nonlinear mixed-effects modeling approach. The influence of RTV concentration on LPV oral clearance (CL/F) was investigated. ResultsRifampicin (RIF) use increased LPV and RTV CL/F by 2.16-fold and 1.99-fold, respectively. The reduced dose of 300/75 and 200/150 mg twice daily provided a comparable percentage of patients achieving LPV target trough concentration to the standard dose for PI-naïve patients. For HIV/TB co-infected patients receiving RIF who could not tolerate the recommended dose, the reduced dose of 600/150 mg twice daily was recommended. ConclusionThe population pharmacokinetic model was developed by integrating the interaction between LPV and RTV. The reduced LPV/r dosage offers sufficient LPV exposure for Thai PLWH.

Fluoxetine pharmacokinetics and tissue distribution quantitatively supports a therapeutic role in COVID-19 at a minimum dose of 20 mg per day

Background. Various in vitro studies have shown fluoxetine inhibits multiple variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen causing the coronavirus disease 2019 (COVID-19) worldwide pandemic and multiple observational clinical studies have shown that patients receiving fluoxetine experienced clinical benefit by lowering the risk of intubation and death. The aim of this study is to conduct population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 50% (EC50) and 90% (EC90) inhibition of SARS-CoV-2 as reported in Calu-3 human lung cells. Methods. Pharmacometric parameter estimates used in this study were obtained from the U.S. FDA website from a new drug application for fluoxetine hydrochloride. A population of 1,000 individuals were simulated at standard fluoxetine antidepressant doses (20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC50 and EC90 SARS-CoV-2 inhibition. All analyses were conducted in R. Results. By day-10 at 20 mg/day, 93.2% and 47% of the population will achieve the trough target plasma EC50 and EC90 concentrations, respectively, which translates to a lung tissue distribution coefficient of 60-times higher EC50 (283.6 ng/ml [0.82 mM]) and EC90 (1390.1 ng/ml [4.02 mM]). Further, by day-10 at an ideal dose of 40 mg/day, 99% and 93% of patients will reach the trough EC50 and EC90 concentrations, respectfully. Lastly, only a dose of 60 mg/day will reach the SARS-CoV-2 EC90 inhibitory concentration in the brain at pharmacokinetic steady-state. Conclusion. Overall, with a minimum treatment period of 10-days and a minimum dose of 20 mg/day, this study corroborates in vitro studies reporting fluoxetine inhibiting SARS-CoV-2 titers and also multiple observational clinical studies showing therapeutic benefit of fluoxetine in COVID-19 patients.

An Audit to Evaluate Vancomycin Therapeutic Drug Monitoring in a Neonatal Intensive Care Unit.

Therapeutic drug monitoring (TDM) is routinely used for optimization of vancomycin therapy, because of exposure-related efficacy and toxicity, in addition to significant variability in pharmacokinetics, which leads to unpredictable drug exposure. The aim of this study was to evaluate target attainment and TDM of vancomycin in neonates. The authors conducted a retrospective study and collected data from medical records of all neonates who received vancomycin therapy in the neonatal intensive care unit between January 2019 and December 2019. The primary outcome was the proportion of vancomycin courses that reached target trough concentrations of 10-20 mg/L based on appropriate TDM samples collection. Secondary outcomes included proportion of courses with appropriate dose and dose frequency, and proportion of patients who achieved target concentrations after the first dose adjustment. In total, 69 patients were included, with 129 vancomycin courses. The median initial vancomycin trough concentration was 12 (range: 4-36) mg/L. The target trough concentration was achieved in 75% of courses after the initial dose with appropriate TDM, and 84% of courses after TDM-guided dose adjustments. Patients were dosed appropriately in 121/129 courses and TDM was performed correctly according to protocol in 51/93 courses. A dose adjustment was performed in 18/29 courses, to increase target attainment. This study showed that there is a need for an increase in dose to improve target attainment. There is also a need to explore more effective TDM strategies to increase the proportion of neonatal patients attaining vancomycin target trough concentrations.