Target Trough Research Articles

A single center Israeli experience in pregnancy post lung transplantation: Feasibility of successful two or more full-term pregnancies in individual lung transplant recipients.

Female lung transplant recipients (LTRs) of reproductive age are increasingly considering pregnancy due to advances in post-transplant management and improved survival. We report our experience with pregnancy in LTRs, with an emphasis on two or more successful full-term pregnancies in individual transplant recipients. We conducted a retrospective analysis of pregnancies in LTRs at our transplant center and collected maternal and fetal outcomes. In our patient cohort, eight female LTRs conceived a total of 17 pregnancies, resulting in 13 newborns, 12 at full term, and 11 with a birth weight>2.5kg. Three of the LTRs had two or more successful full-term pregnancies. LTRs required a significant tacrolimus dose increase to maintain target trough levels during pregnancy. Six recipients are currently clinically stable and active, three with lung function comparable to pre-pregnancy values, and three with evidence of chronic lung allograft dysfunction (CLAD), but stable lung function. Two of the eight LTRs died subsequent to childbirth secondary to chronic respiratory failure due to CLAD, at a mean of 11years post-transplantation and a mean of 4.5years after childbirth. Pregnancy following lung transplantation is feasible and can be achieved with acceptable maternal and newborn outcomes. Importantly, LTRs can successfully have two or more full-term pregnancies.

Characterization of a recombinant factor IX molecule fused to coagulation factor XIII-B subunit.

Severe haemophilia B (HB) is characterized by spontaneous bleeding episodes, mostly into joints. Recurrent bleeds lead to progressive joint destruction called haemophilic arthropathy. The current concept of prophylaxis aims at maintaining the FIX level >3-5IU/dL, which is effective at reducing the incidence of haemophilic arthropathy. Extended half-life FIX molecules make it easier to achieve these target trough levels compared to standard FIX concentrates. We previously reported that the fusion of a recombinant FIX (rFIX) to factor XIII-B (FXIIIB) subunit prolonged the half-life of the rFIX-LXa-FXIIIB fusion molecule in mice and rats 3.9- and 2.2-fold, respectively, compared with rFIX-WT. However, the mechanism behind the extended half-life was not known. Mass spectrometry and ITC were used to study interactions of rFIX-LXa-FXIIIB with albumin. Pharmacokinetic analyses in fibrinogen-KO and FcRn-KO mice were performed to evaluate the effect of albumin and fibrinogen on in-vivo half-life of rFIX-LXa-FXIIIB. Finally saphenous vein bleeding model was used to assess in-vivo haemostatic activity of rFIX-LXa-FXIIIB. We report here the key interactions that rFIX-LXa-FXIIIB may have in plasma are with fibrinogen and albumin which may mediate its prolonged half-life. In addition, using the saphenous vein bleeding model, we demonstrate that rFIX-FXIIIB elicits functional clot formation that is indistinguishable from that of rFIX-WT.

Using population pharmacokinetics to optimize initial vancomycin dosing guidelines for neonates to treat sepsis caused by coagulase-negative staphylococcus.

Vancomycin dosing tailored for newborns is challenging due to the significant influence of maturation and organ function on pharmacokinetics. Population pharmacokinetic (popPK) models can be used to improve target attainment in neonates. The primary objective was to derive and evaluate a popPK model of intravenous vancomycin for neonates. Second, the predictive performance of this popPK model was compared with published popPK models. This is a retrospective cohort study of neonates admitted to the neonatal intensive care unit receiving intravenous vancomycin. A popPK model was derived with 70% of the dataset using a nonlinear mixed effects modeling method. The predictive performance of the current popPK model was validated and compared with 22 published popPK models using the remaining 30% of the dataset. Monte Carlo simulations (MCS) were performed to derive optimal dosing regimens to treat neonatal sepsis caused by coagulase-negative staphylococci (CoNS). Among 655 vancomycin courses from 448 neonates, 78% of vancomycin trough concentrations were outside target range (10-15 mg/L) for central nervous system infections and 43% were outside target range (5-12 mg/L) for other infections using the institution's vancomycin dosing. A one-compartment model best described the observed data with a mean clearance of 0.11 ± 0.03 L/kg/h and volume of distribution (V) of 1.02 ± 0.08 L/kg. Body weight (WT), postmenstrual age (PMA), and serum creatinine (SCr) were significant covariates associated with clearance (p < 0.001) and body WT was a significant covariate associated with V (p = 0.009). Our study's popPK model has similar or better accuracy and precision than other published models. MCS-derived vancomycin doses from the validated model achieved >90% target attainment for a steady state through target range of 10-15 mg/L in the majority of PMA and SCr categories (78%) to treat CoNS sepsis. A vancomycin dosing guideline derived from a validated popPK model in neonates with CoNS sepsis is recommended to improve target attainment.

Association between vancomycin therapeutic drug monitoring and clinical outcomes in treating neonatal sepsis

BackgroundNeonatal sepsis is commonly treated with vancomycin in the neonatal intensive care unit. Therapeutic drug monitoring of vancomycin is routinely used to personalise dosing to optimise effectiveness and avoid toxicity. ObjectivesThis study aimed to define a target range by evaluating associations between vancomycin trough concentrations or area under the concentration time curve over 24 hours (AUC24h) and clinical outcomes in neonates. MethodsNeonates, who were admitted to the neonatal intensive care unit and received intravenous vancomycin, were included in this retrospective cohort study. For evaluating effectiveness, patients who received vancomycin for < 5 days were excluded. The AUC24h was estimated based on a study-derived population pharmacokinetic model. Primary outcomes were persistent/recurrent infections and mortality within 30 days. Secondary outcomes, including acute kidney injury (AKI), were also assessed. Logistic regression and classification and regression tree analyses were performed. ResultsA total of 448 patients (123 patients for effectiveness analysis) were included. A vancomycin trough > 10 mg/L was associated with 70% lower odds of persistent/recurrent infections (adjusted OR 0.30, 95% CI 0.09–0.86; P = 0.023). Patients who took more than a day to reach target range had 1.4 times higher odds of persistent/recurrent infections or death (P = 0.04). A vancomycin trough > 15 mg/L was associated with a three times higher risk of AKI (P = 0.003). An AUC24h of 420–650 mg*h/L was also associated with the lowest risk of composite outcomes (adjusted OR 0.29, 95% CI 0.08–0.86; P = 0.025). ConclusionA vancomycin trough target range of 10–15 mg/L and achievement of this target within a day of treatment initiation were associated with the most optimal clinical outcomes in treating neonatal sepsis.

Clinical efficacy of simoctocog alfa versus extended half-life recombinant FVIII concentrates in hemophilia A patients undergoing personalized prophylaxis using a matching-adjusted indirect comparison method.

We aimed to indirectly compare the efficacy of personalized prophylaxis with simoctocog alfa (Nuwiq®) versus three extended half-life (EHL) recombinant FVIII (rFVIII) concentrates. Treatment effects were compared using matching-adjusted indirect comparisons after matching individual patient-level baseline characteristics for simoctocog alfa (pharmacokinetic [PK]-guided personalized prophylaxis) against published aggregate personalized prophylaxis data for efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol. A higher percentage (p < .001) of patients with zero bleeds was found with simoctocog alfa compared with efmoroctocog alfa (75% vs. 45%), damoctocog alfa pegol (77% vs. 38%), and rurioctocog alfa pegol (target trough level 1%-3%; 78% vs. 42%). Similar efficacy was found comparing simoctocog alfa against rurioctocog alfa pegol 8%-12% (77% vs. 62%). The mean total annualized bleeding rate was lower (p < .001) with simoctocog alfa than damoctocog alfa pegol (1.5 vs. 4.9). Consistent with approved dosing, the mean FVIII weekly dose was higher (p < .001) for simoctocog alfa than efmoroctocog alfa, damoctocog alfa pegol, or rurioctocog alfa pegol 1%-3%, but lower (p < .001) than rurioctocog alfa pegol 8%-12%. Indirect comparisons demonstrated that PK-guided, personalized prophylaxis with simoctocog alfa can lead to higher zero bleed rates compared with personalized EHL rFVIII concentrate regimens, albeit with higher weekly doses, and a lower percentage of patients treated twice weekly or less.

Impact of model-informed precision dosing on achievement of vancomycin exposure targets in pediatric patients with cystic fibrosis.

Vancomycin is commonly used to treat acute pulmonary exacerbations in pediatric patients with cystic fibrosis (CF) and a history of methicillin-resistant Staphylococcus aureus. Optimizing vancomycin exposure during therapy is essential and area under-the-curve (AUC)-guided dosing is now recommended. Model-informed precision dosing (MIPD) utilizing Bayesian forecasting is a powerful approach that can support AUC-guided dose individualization. The objective of the current study was to examine the impact of implementing an AUC-guided dose individualization approach supported via a MIPD clinical decision support (CDS) tool on vancomycin exposure, target attainment rate, and safety in pediatric patients with CF treated with vancomycin during clinical care. A retrospective chart review was performed in patients with CF at a single children's hospital comparing pre- and post-implementation of a MIPD approach for vancomycin supported by a cloud-based, CDS tool integrated into the electronic health record (EHR). In the pre-MIPD period, vancomycin starting doses of 60 mg/kg/day (<13 years) or 45 mg/kg/day (≥13 years) were used. Dose adjustment was guided by therapeutic drug monitoring (TDM) with a target trough 10-20 mg/L. In the post-MIPD period, starting dose and dose adjustment were based on the MIPD CDS tool predictions with a target 24 h AUC (AUC24 ) 400-600 mg*h/L. Exposure and target achievement rates were retrospectively calculated and compared. Rates of acute kidney injury (AKI) were also compared. Overall, 23 patient courses were included in the pre-MIPD period and 21 patient courses in the post-MIPD period. In the post-MIPD period, an individualized MIPD starting dose resulted in 71% of patients achieving target AUC24 compared to 39% in the pre-MIPD period (p < 0.05). After the first TDM and dose adjustment, target AUC24 achievement was also higher post-MIPD versus pre-MIPD (86% vs. 57%; p < 0.05). AKI rates were low and similar between periods (pre-MIPD 8.7% vs. post-MIPD 9.5%; p = 0.9). An MIPD approach implemented within a cloud-based, EHR-integrated CDS tool safely supported vancomycin AUC-guided dosing and resulted in high rates of target achievement.

1498-P: Preemptive Insulin Supplementation for Islet Graft Protection, Optimal Blood Glucose Control, and Fetal Development during the Pregnancy in Insulin-Independent Patient after Islet Transplantation

Pregnancy increases metabolic demand for insulin, which may lead to the exhaustion of intraportally transplanted islets and postgestational hyperglycemia. Here we report a successful long-term preservation of islet graft function after two subsequent pregnancies while applying preemptive insulin supplementation. 29-year-old female with T1DM achieved long-term insulin independence with HbA1c &amp;lt;5.8% after a single intraportal islet transplant. Before conception, mycophenolate was replaced with azathioprine and tacrolimus target trough level was decreased to 4-6ng/ml. The patient became pregnant twice, 5 years and 7.5 years after her islet transplantation. During the first and second pregnancy patient preemptively supplemented with insulin up to 35-70u/day and up to 35 units daily, respectively to target fasting blood glucose below 90mg/ml. Postpartum the patient was successfully weaned off insulin maintaining optimal blood glucose control with HbA1c below 5.7%. Islet graft function before and after the pregnancy remained optimal as reflected by BETA-2 above 17 and comparable c-peptide secretion and peak blood glucose levels below 130mg/ml during the 8.5-year follow-up in Mixed Meal Tolerance Test. Both newborns were premature and delivered at 34 weeks with emergent c-sections due to preeclampsia. Unfortunately, the first newborn died due to necrotizing enterocolitis. The second child has been developing appropriately up-to-date three months after her birth. Our report confirms that insulin supplementation during pregnancy in insulin-independent patients after islet transplantation was safe and effective in maintaining optimal blood glucose control and islet graft function in the long term. It also underscores the high-risk nature of pregnancy in islet transplant recipients and the need for close clinical monitoring. Disclosure S.Gondek: None. L.Wang: None. M.Tibudan: None. R.Barth: None. J.Fung: None. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.Ogledzinski: None. W.Lin: None. K.Milejczyk: None. B.Juengel: None. L.Potter: None. P.J.Bachul: None. L.Basto: None. L.Perea: None.

Exploration of the optimal GS-441524 trough concentration for treating COVID-19

Remdesivir (RDV) is the cornerstone for treating coronavirus disease 2019 (COVID-19). The active metabolite of RDV, GS-441524 (a nucleoside analog), has high inter-individual variability in plasma concentration; however, its concentration-response relationship is still unclear. This study investigated the target GS-441524 trough concentration for symptom improvement in COVID-19 pneumonia. This single-center, retrospective, observational study included COVID-19 pneumonia patients (≥15 years) who were administered RDV for ≥3 days from May 2020 to August 2021 at Saiseikai Futsukaichi Hospital. To determine the cut-off value of GS-441524 trough concentration on day 3, the achievement of the National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS) ≤3 after RDV administration was evaluated using the cumulative incidence function (CIF) with the Gray test and time-dependent receiver operating characteristic (ROC) analysis. Multivariate logistic regression analysis was performed to determine the factors influencing GS-441524 target trough concentrations. Our analysis comprised 59 patients. The CIF revealed that GS-441524 trough concentration ≥70 ng/mL was associated with the achievement of NIAID-OS ≤3 (p = 0.047), which was significant based on the time-dependent ROC analysis. Factors influencing GS-441524 trough concentration ≥70 ng/mL included a decrease in eGFR (adjusted odds ratio [aOR] 0.96, 95% confidence interval [95% CI] 0.92-0.99, p = 0.027) and BMI ≥25 kg/m2 (aOR 0.26, 95% CI 0.07-0.86, p = 0.031). GS-441524 trough concentration ≥70 ng/mL is a predictor of efficacy in COVID-19 pneumonia. The presence of lower eGFR or BMI ≥25 kg/m2 was associated with achieving GS-441524 trough concentration ≥70 ng/mL.

How Should Acute T Cell-mediated Rejection of Kidney Transplants be Treated: Importance of Follow-up Biopsy From Kidney Transplantation.

Aziz et al1 in Wisconsin published their experience with protocol repeat biopsies in 163 episodes of T cell–mediated rejection (TCMR) between 2015 and 2020. Among their patients with a complete response as assessed by kidney function, 14% had a partial or no response histologically. Among patients with no kidney function response, 68% had a complete response histologically. They concluded that responses based on kidney function alone did not correlate with histology. These findings were echoed in the meta-analysis by Ho et al.2 We present our single-center experience of for-cause renal biopsy in which isolated TCMR was found between 2018 and 2021. There were 22 cases (total 349 transplantations) of isolated TCMR in which a repeat biopsy at a median of 14 (range, 5–30) d was performed. There were 6 episodes of borderline TCMR, 5 episodes of Banff 1A, 2 episodes of Banff 1B, 7 episodes of Banff 2A, and 2 episodes of Banff 2B rejections. Borderline TCMR and 1A Banff rejections were invariably treated with 250 to 500 mg IV methylprednisolone for 3 d. Three episodes of 2A and 2 episodes of 2B rejections were additionally treated with 3 to 7 mg/kg of antithymocyte globulin. The remainder episodes of the 2A rejection were treated with methylprednisolone alone. Seventeen of 22 patients (77%) had improved creatinine with these treatment regimens. Nine of 17 patients (53%) had complete resolution of interstitial inflammation, tubulitis, or vascular lesions. Eight of 17 patients (47%) had residual histology requiring higher target tacrolimus trough levels (n = 5), 2 patients required 3 additional doses of 250 to 500 mg intravenous methylprednisolone, and 1 patient changed from mycophenolate to everolimus. Five of 22 patients (23%) showed no improvement in creatinine (3 had borderline TCMR, 1 had 1A rejection, and 1 had 2A Banff rejection) with repeat biopsies at 6, 14, 14, 14, and 22 d. Complete resolution of histology occurred in 2 of 5 patients (40%). Three of 5 patients (60%) had residual histological features requiring a further 3 doses of 500 mg of methylprednisolone and 2 patients aimed for higher tacrolimus trough targets. Although our data represent for-cause biopsy, rather than protocol biopsy, they reemphasize the data from Aziz et al1 and Ho et al.2 Irrespective of the improvement in creatinine, a repeat biopsy showed complete resolution of histology in only 40% to 53% of patients at a median of 2 wk after the first biopsy. With the global pandemic, delivery of patient care was frequently dictated by the level of lock down, and telehealth was used at a rate unlike ever before. However, the experience of our center together with the published literature highlights the importance of rebiopsy posttreatment of TCMR.

Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial.

Dolutegravir (DTG), combined with a backbone of 2 nucleoside reverse transcriptase inhibitors, is currently the preferred first-line treatment for human immunodeficiency virus (HIV) in childhood. CHAPAS4 is an ongoing randomized controlled trial investigating second-line treatment options for children with HIV. We did a nested pharmacokinetic (PK) substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food as part of their second-line treatment. Additional consent was required for children on DTG enrolled in the CHAPAS4 trial to participate in this PK substudy. Children weighing 14-19.9 kg took 25 mg DTG as dispersible tablets and children ≥20 kg took 50 mg film-coated tablets. Steady-state 24-hour DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 hours after observed DTG intake with food. Reference adult PK data and pediatric data from the ODYSSEY trial were used primarily for comparison. The individual target trough concentration (Ctrough) was defined as 0.32 mg/L. Thirty-nine children on DTG were included in this PK substudy. The geometric mean (GM) area under the concentration-time curve over the dosing interval (AUC0-24h) was 57.1 hours × mg/L (coefficient of variation [CV%], 38.4%), which was approximately 8% below the average AUC0-24h in children in the ODYSSEY trial with comparable dosages, but above the adult reference. The GM (CV%) Ctrough was 0.82 mg/L (63.8%), which was comparable to ODYSSEY and adult reference values. This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY trial and adult references. Clinical Trials Registration.ISRCTN22964075.

Clinical Evaluation of a Vancomycin Dosage Strategy Based on a Serum Trough Concentration Model in Elderly Patients with Severe Pneumonia

ObjectiveThis study aimed to evaluate the clinical benefits of a vancomycin dosage strategy based on a serum trough concentration model in elderly patients. MethodsThis prospective single-center, open-label, randomized controlled trial categorized 66 elderly patients with severe pneumonia into study and control groups. The control group received vancomycin using a regimen decided by the attending physician. Meanwhile, the study group received individualized vancomycin therapy with a dosing strategy based on a serum trough concentration model. The primary endpoint was the proportion of patients with serum trough concentrations reaching the target values. The secondary endpoints were clinical response, vancomycin treatment duration, and vancomycin-associated acute kidney injury (VA-AKI) occurrence. ResultsAll patients were at least 60 years old (median age = 81 years). The proportion of patients with target trough concentration achievement (≥ 15 mg/L) with the initial vancomycin regimen was significantly higher in the study group compared to the control group (75.8% vs. 42.4%, P = 0.006). Forty-five patients (68.2%) achieved clinical success, the median duration of vancomycin therapy was 10.0 days, and VA-AKI occurred in eight patients (12.1%). However, there were no significant differences in these parameters between the two groups. The model for predicting vancomycin trough concentrations was upgraded to: serum trough concentration (mg/L) = 17.194 − 0.104 × creatinine clearance rate (mL/min) + 0.313 × vancomycin daily dose [(mg/(kg·d)]. ConclusionA vancomycin dosage strategy based on a serum trough concentration model can improve the proportion of patients achieving target trough concentrations in elderly patients with severe pneumonia.

Cemiplimab for kidney organ transplant recipients with advanced cutaneous squamous cell carcinoma: CONTRAC-1.

9519 Background: Solid organ transplant recipients are often excluded from immunotherapy trials given the risk of allograft rejection and loss. We report the results of the first prospective study using the PD-1 inhibitor Cemiplimab (Cemi) for kidney transplant recipients (KTR) with advanced, incurable cutaneous squamous cell carcinoma (cSCC), adopting a standardized approach to immunosuppression (IS) with mTOR inhibition and dynamic prednisone (NCT04339062). Methods: This single-arm, open-label prospective clinical trial enrolled KTRs (eGFR ≥30 mL/min without proteinuria) with advanced cSCC, ECOG ≤2, measurable disease (RECIST v1.1), with no prior immunotherapy exposure. KTRs received mTOR inhibition (target trough 4-6 ng/mL) with a prednisone taper each cycle (40 mg on day -1 to 3, 20 mg days 4-6, 10 mg days 7-20) along with Cemi 350 mg IV every 21-days. Primary endpoint: rate of rejection (futility defined as ≥2/3 or 4/6 KTRs with rejection events). Secondary endpoints: overall response rate (ORR), duration of response, progression-free survival (PFS), overall survival (OS), infection rates. Exploratory: baseline tumor PD-L1 score, molecular and immunologic predictors of response. Results: From 11/2020 to 1/2023, 10 KTRs (median years from transplant: 8, range: 3-31) enrolled including 8 (80%) men, median age 64 (range: 43-86), median eGFR 48 (range: 32-60) often with head and neck primaries (9, 90%) and distant metastases (7, 70%). Six (60%) had prior systemic therapy. For mTOR inhibition, 7 (70%) received sirolimus and 3 (30%) everolimus. At a median follow-up of 6.3 months (range: &lt; 1-24.9), no patients experienced kidney allograft rejection or loss. Of 8 evaluable patients, ORR was 50% (2 CR, 2 PRs), while 4 had PD. At data cutoff no responder had progressed, with 2/4 in response &gt; 18 months (range: &lt; 1-22.7+). One patient is pending first restaging; 1 was unevaluable (died before first restaging). One KTR with initial PD experienced a subsequent durable response to cetuximab. Fatigue (40%) and limb edema (30%) were the most common treatment-related adverse events (TRAEs). Grade 3+ TRAEs occurred in 5 (50%) patients including diarrhea, infections (n = 3), and electrolyte derangements; there were no Cemi-related deaths. Median PFS was 7.9 mos (95%CI: 1.2-not reached [NR]); the 3-month OS estimate was 61% (95%CI: 27-83). Baseline tumor PD-L1 scores ranged from 0-5%; median TMB was 49 muts/Mb (range: 10-97). Tumor mutations in TP53, CDKN2A, and NOTCH1 were common. Exploratory tumor/circulating multiparametric immune profiling and circulating tumor (ct)DNA findings will be presented. Conclusions: Using IS with mTOR inhibition and dynamic prednisone resulted in no kidney allograft rejection among KTRs treated with Cemi for advanced cSCC. Durable anti-tumor efficacy was observed. mTOR inhibition with prednisone should be the preferred IS regimen when treating KTRs with anti-PD-1 therapy. Clinical trial information: NCT04339062 .

External validation of population pharmacokinetic models of gentamicin in paediatric population from preterm newborns to adolescents.

The aim of this study was to externally validate the predictive performance of published population pharmacokinetic models of gentamicin in all paediatric age groups, from preterm newborns to adolescents. We first selected published population pharmacokinetic models of gentamicin developed in the paediatric population with a wide age range. The parameters of the literature models were then re-estimated using the PRIOR subroutine in NONMEM®. The predictive ability of the literature and the tweaked models was evaluated. Retrospectively collected data from a routine clinical practice (512 concentrations from 308 patients) were used for validation. The models with covariates characterising developmental changes in clearance and volume of distribution had better predictive performance, which improved further after re-estimation. The tweaked model by Wang 2019 performed best, with suitable accuracy and precision across the complete paediatric population. For patients treated in the intensive care unit, a lower proportion of patients would be expected to reach the target trough concentration at standard dosing. The selected model could be used for model-informed precision dosing in clinical settings where the entire paediatric population is treated. However, for use in clinical practice, the next step should include additional analysis of the impact of intensive care treatment on gentamicin pharmacokinetics, followed by prospective validation.

Patients With Inflammatory Bowel Diseases and Higher Visceral Adipose Tissue Burden May Benefit From Higher Infliximab Concentrations to Achieve Remission.

In patients with inflammatory bowel diseases (IBDs), high visceral adipose tissue (VAT) burden is associated with a lower response to infliximab, potentially through alterations in volume distribution and/or clearance. Differences in VAT may also explain the heterogeneity in target trough levels of infliximab associated with favorable outcomes. The aim of this study was to assess whether VAT burden may be associated with infliximab cutoffs associated with efficacy in patients with IBD. We conducted a prospective cross-sectional study of patients with IBD receiving maintenance infliximab therapy. We measured baseline body composition parameters (Lunar iDXA), disease activity, trough levels of infliximab, and biomarkers. The primary outcome was steroid-free deep remission. The secondary outcome was endoscopic remission within 8 weeks of infliximab level measurement. Overall, 142 patients were enrolled. The optimal trough levels of infliximab cutoffs associated with steroid-free deep remission and endoscopic remission were 3.9 mcg/mL (Youden Index [J]: 0.52) for patients in the lowest 2 VAT % quartiles (<1.2%) while optimal infliximab level cutoffs associated with steroid-free deep remission for those patients in the highest 2 VAT % quartiles was 15.3 mcg/mL (J: 0.63). In a multivariable analysis, only VAT % and infliximab level remained independently associated with steroid-free deep remission (odds ratio per % of VAT: 0.3 [95% confidence interval: 0.17-0.64], P < 0.001 and odds ratio per μg/mL: 1.11 [95% confidence interval: 1.05-1.19], P < 0.001). The results may suggest that patients with higher visceral adipose tissue burden may benefit from achieving higher infliximab levels to achieve remission.

Clinical Manifestations, Current and Future Therapy, and Long-Term Outcomes in Congenital Thrombotic Thrombocytopenic Purpura.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an extremely rare disease characterized by the severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13), caused by ADAMTS13 mutations. While ADAMTS13 supplementation by fresh frozen plasma (FFP) infusion immediately corrects platelet consumption and resolves thrombotic symptoms in acute episodes, FFP treatment can lead to intolerant allergic reactions and frequent hospital visits. Up to 70% of patients depend on regular FFP infusions to normalize their platelet counts and avoid systemic symptoms, including headache, fatigue, and weakness. The remaining patients do not receive regular FFP infusions, mainly because their platelet counts are maintained within the normal range or because they are symptom-free without FFP infusions. However, the target peak and trough levels of ADAMTS13 to prevent long-term comorbidity with prophylactic FFP and the necessity of treating FFP-independent patients in terms of long-term clinical outcomes are yet to be determined. Our recent study suggests that the current volumes of FFP infusions are insufficient to prevent frequent thrombotic events and long-term ischemic organ damage. This review focuses on the current management of cTTP and its associated issues, followed by the importance of upcoming recombinant ADAMTS13 therapy.

Risk of Acute Kidney Injury Based on Vancomycin Target Trough Attainment Strategy: Area-Under-the-Curve-Guided Bayesian Software, Nomogram, or Trough-Guided Dosing.

Guidelines support area-under-the-curve (AUC) monitoring for vancomycin dosing which may lower overall doses and reduce acute kidney injury (AKI). The aim of this study was to compare incidence of AKI across 3 vancomycin dosing modalities: AUC-targeted Bayesian pharmacokinetic software, AUC-targeted empiric dosing nomogram, and trough-guided dosing using clinical pharmacists' judgment. This retrospective study included adult patients with a pharmacy dosing consult who received ≥1 dose of vancomycin and ≥1 serum vancomycin level documented between January 1, 2018, and December 31, 2019. Patients with baseline serum creatinine ≥2 mg/dL, weight ≥100 kg, receiving renal replacement therapy, AKI prior to vancomycin therapy, or vancomycin ordered only for surgical prophylaxis were excluded. The primary analysis was incidence of AKI adjusted for baseline serum creatinine, age, and intensive care unit admission. A secondary outcome was adjusted incidence of an abnormal trough value (<10 or >20 μg/mL). The study included 3459 encounters. Incidence of AKI was 21% for Bayesian software (n = 659), 22% for the nomogram (n = 303), and 32% for trough-guided dosing (n = 2497). Compared with trough-guided dosing, incidence of AKI was lower in the Bayesian (adjusted odds ratio [OR] = 0.72, 95% confidence interval [CI]: 0.58-0.89) and the nomogram (adjusted OR = 0.71, 95% CI: 0.53-0.95) groups. Compared with trough-guided dosing, abnormal trough values were less common in the Bayesian group (adjusted OR = 0.83, 95% CI: 0.69-0.98). Study results suggest that use of AUC-guided Bayesian software reduces the incidence of AKI and abnormal trough values compared with trough-guided dosing.

Pharmacist-Driven Dosing Services and Pharmaceutical Care Increase Probability of Teicoplanin Target Concentration Attainment and Improve Clinical and Economic Outcomes in Non-Critically Ill Patients.

Pharmacist-driven (PD) dosing and monitoring services have been shown to improve the clinical and economic outcomes in patients treated with different antibiotics, other than teicoplanin. This study investigates the impact of PD dosing and monitoring services on the clinical and economic outcomes of non-critically ill patients receiving teicoplanin treatment. A single-center retrospective study was conducted. Patients were divided into the PD group and the non-PD (NPD) group. Primary outcomes included the achievement of target serum concentration, and a composite endpoint of all-cause mortality, intensive care unit (ICU) admission, and sepsis or septic shock development during hospitalization or within 30days of hospital admission. The cost of teicoplanin, overall medication cost, and total cost during hospital stay were also compared. A total of 163 patients from January to December 2019 were included and assessed. Seventy patients were assigned to the PD group and 93 to the NPD group. The PD group had a higher percentage of patients reaching the target trough concentration (54% versus 16%, p < 0.001). Around 26% of the patients in the PD group and 50% of the patients in the NPD group met the composite endpoint during their hospital stay (p = 0.002). The PD group exhibited a significantly lower incidence of sepsis or septic shock, shorter hospital stays, reduced drug costs, and lower total expenses. Our study demonstrates that pharmacist-driven teicoplanin therapy can improve the clinical and economic outcomes for non-critically ill patients. https://www.chictr.org.cn ; identifier, ChiCTR2000033521.

Performance of Bayesian Area Under the Concentration-Time Curve-Based Pharmacokinetic Dosing Based on a One-Compartment Model and Trough-Only Monitoring for Vancomycin.

A novel Bayesian method was developed to interpret serum vancomycin concentrations (SVCs) following the administration of one or more vancomycin doses with potential varying doses and intervals based on superposition principles. The method was evaluated using retrospective data from 442 subjects from three hospitals. The patients were required to receive vancomycin for more than 3 days, have stable renal function (fluctuation in serum creatinine of ≤0.3 mg/dL), and have at least 2 trough concentrations reported. Pharmacokinetic parameters were predicted using the first SVC, and the fitted parameters were then used to predict subsequent SVCs. Using only covariate-adjusted population prior estimates, the first two SVC prediction errors were 47.3 to 54.7% for the scaled mean absolute error (sMAE) and 62.1 to 67.8% for the scaled root mean squared error (sRMSE). "Scaled" refers to the division of the MAE or RMSE by the mean value. The Bayesian method had minimal errors for the first SVC (by design), and for the second SVC, the sMAE was 8.95%, and the sRMSE was 36.5%. The predictive performance of the Bayesian method did degrade with subsequent SVCs, which we attributed to time-dependent pharmacokinetics. The 24-h area under the concentration-time curve (AUC) was determined from simulated concentrations before and after the first SVC was reported. Prior to the first SVC, 170 (38.4%) patients had a 24-h AUC of <400 mg · h/L, 186 (42.1%) had a 24-h AUC within the target range, and 86 (19.5%) had a 24-h AUC of >600 mg · h/L. After the first SVC was reported, 322 (72.9%) had a 24-h AUC within the target range, 68 (15.4%) had low values, and 52 (11.8%) had high values based on the model simulation. Target attainments were 38% before the first SVC and 73% after the first SVC. The hospitals had no policies or procedures in place for targeting 24-h AUCs, although the trough target was typically 13 to 17 mg/L. Our data provide evidence of time-dependent pharmacokinetics, which will require regular therapeutic drug monitoring regardless of the method used to interpret SVCs.

In silico Evaluation of a Vancomycin Dosing Guideline Among Adults with Serious Infections.

This study aimed to compare the achievement of pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for vancomycin using a newly developed dosing guideline with product-information-based dosing in the treatment of adult patients with serious infections. In silico product-information- and guideline-based dosing simulations for vancomycin were performed across a range of doses and patient characteristics, including body weight, age, and renal function at 36-48 and 96 hours, using a pharmacokinetic model derived from a seriously ill patient population. The median simulated concentration and area under the 24-hour concentration-time curve (AUC 0-24 ) were used to measure predefined therapeutic, subtherapeutic, and toxicity PK-PD targets. Ninety-six dosing simulations were performed. The pooled median trough concentration target with guideline-based dosing at 36 and 96 hours was achieved in 27.1% (13/48) and 8.3% (7/48) of simulations, respectively. The pooled median AUC 0-24 /minimum inhibitory concentration ratio with guideline-based dosing at 48 and 96 hours was attained in 39.6% (19/48) and 27.1% (13/48) of simulations, respectively. Guideline-based dosing simulations yielded improved trough target attainment compared with product-information-based dosing at 36 hours and significantly less subtherapeutic drug exposure. The toxicity threshold was exceeded in 52.1% (25/48) and 0% (0/48) for guideline- and product-information-information-based dosing, respectively ( P < 0.001). A Critical care vancomycin dosing guideline appeared slightly more effective than standard dosing, as per product information, in achieving PK-PD exposure associated with an increased likelihood of effectiveness. In addition, this guideline significantly reduced the risk of subtherapeutic exposure. The risk of exceeding toxicity thresholds, however, was greater with the guideline, and further investigation is suggested to improve dosing accuracy and sensitivity.

Clinical Pharmacokinetics and Pharmacodynamics of Voclosporin.

Voclosporin is an approved option for the long-term treatment of lupus nephritis. We aimed to provide a narrative review of the pharmacokinetics and pharmacodynamics of voclosporin. In addition, we derived values for pharmacokinetic and pharmacodynamic parameters by graphical analysis of published diagrams. Compared with cyclosporin, low-dose voclosporin is associated with a lower nephrotoxicity risk and, compared to tacrolimus, with a lower diabetes risk. After repetitive dosing of 23.7 mg twice daily and at target trough concentrations of 10-20 ng/mL, the dominant or effect-indicative half-life is estimated at 7 hours. Compared with the pharmacodynamics of cyclosporin, the potency of voclosporin is stronger, with a lower concentration CE50 of 50 ng/mL already producing the half-maximum immunosuppressive effect. The Hill coefficient can be predicted to be low at H = 1.3, indicating a concentration-dependent effect on the immune system. The corresponding effect bisection time of 10 hours allows for dosing every 12 hours. Accordingly, the trough concentration will be above the threshold concentration that produces 5% of the maximum effect of 5.2 ng/mL for immunosuppression but below both the predicted threshold of 30 ng/mL for nephrotoxicity and the predicted threshold of 40 ng/mL for new-onset diabetes. The pharmacokinetic and pharmacodynamic properties suggest the use of low-dose voclosporin combined with mycophenolate and low-dose glucocorticoids for immunosuppressive maintenance therapy.