Population pharmacokinetics of subcutaneous alemtuzumab in kidney transplantation.

AIM: Alemtuzumab is a monoclonal antibody used as induction immunosuppressive therapy in kidney transplantation. It targets CD52 on lymphocytes, inducing profound immune cell depletion upon administration. Owing to its off-label status in kidney transplantation, its pharmacokinetic characteristics are largely unknown in this setting, and its current fixed dosing algorithm originates from other populations. We developed a population pharmacokinetic model for alemtuzumab in kidney transplant recipients and investigated the potential of personalized alemtuzumab therapy. METHODS: In total, 362 pharmacokinetic observations drawn 0-165 days after transplantation were available from 61 adult kidney transplant recipients who received two consecutive doses of 15 mg alemtuzumab subcutaneously. A population pharmacokinetic model was developed using nonlinear mixed-effects modelling and applied to simulate various dosing regimens. RESULTS: The alemtuzumab concentration-time data were best described by a two-compartmental model with first-order absorption and parallel first-order and time-varying concentration-dependent elimination, with between-subject variability on the first-order elimination (39.6%) and central distribution volume (39.6%). Alemtuzumab pharmacokinetics varied with body size, rendering lighter individuals exposed to lympholytic alemtuzumab concentrations (>0.1 mg/L) for prolonged durations as compared to their heavier peers. This between-subject variability could be reduced through lean bodyweight-adjusted dosing, showing a twofold to threefold reduction in the slope of the median alemtuzumab exposure over the bodyweight range. CONCLUSION: Alemtuzumab displays substantial pharmacokinetic variability in kidney transplant recipients, which may warrant a personalized treatment strategy. Lean bodyweight-adjusted dosing poses an option for individualized dosing, but further evaluation of its potential clinical benefit is warranted.

A prospective pilot study of a novel alemtuzumab target concentration intervention strategy.

Alemtuzumab is used as part of reduced-intensity and reduced-toxicity transplant conditioning regimens for nonmalignant diseases. Prior studies identified an ideal target concentration range of 0.15-0.6 mcg/mL at day 0. However, only 24% of patients fall within this window using standard intermediate dosing. We performed a pilot study of a novel target concentration intervention strategy to target day 0 alemtuzumab concentrations to 0.15-0.6 mcg/mL. Twelve patients received model-informed alemtuzumab dosing of 0.5-0.6 mcg/kg divided over days -14 to -12. Alemtuzumab concentrations were measured, and pharmacokinetic (PK) modeling was performed on day -5 to predict day 0 concentrations. If the day 0 alemtuzumab concentration was predicted to fall below 0.15 mcg/mL, simulations were performed to identify the individual "top-up" dose needed to achieve the target day 0 concentration window. Six (50%) patients achieved day 0 alemtuzumab concentrations between 0.15 and 0.6 mcg/mL (4 received a top-up dose). Five patients had day 0 concentrations above the target window (no top-up doses). One patient had a day 0 concentration below the target range in the presence of anti-alemtuzumab antibodies. A concentration intervention strategy approach to alemtuzumab treatment can successfully target a greater proportion of patients into the ideal therapeutic window. Additional dose-reduction studies are needed to further optimize the initial dosing and achieve target attainment in all patients.

Treatment of Catheter-Related Arterial Thrombosis in Children: A 15-Year Single- Center Experience.

OBJECTIVE: To investigate treatment modalities for children with extremity indwelling catheter (EIC)- or cardiac catheter-related arterial thrombosis. STUDY DESIGN: The treatment of consecutive cases of catheter-related arterial thrombosis (CAT) at our institution between 2002 and 2017 was analyzed retrospectively. RESULTS: A total of 242 CATs developed in 224 children. Of these, 125 (52%) were EIC-related and 117 (48%) were cardiac catheter-related. Treatment included heparin alone in 60 cases (25%), acetylsalicyclic acid (ASA) alone in 6 cases (2%), heparin followed by ASA in 171 cases (71%), heparin followed by vitamin K antagonist (VKA) in 4 cases (1.5%), and VKA alone in 1 case (0.5%). Complete resolution of CAT was observed in 173 cases (71.5%), partial resolution in 13 cases (5.4%), and no resolution in 56 cases (23.1%). No statistical significance in the resolution rate was observed between treatment groups (P = .23). In 66% of cases, complete resolution occurred at a median of 18 days (range, 4-44 days) with heparin alone. A switch from heparin to ASA in children with partial or no resolution of CAT did not increase the resolution rate at follow-up. CONCLUSIONS: Heparin is an efficient treatment modality for CAT in pediatric patients. Long-term, subsequent treatment with ASA does not increase the resolution rate.

Outcome of Non-hematological Autoimmunity After Hematopoietic Cell Transplantation in Children with Primary Immunodeficiency.

PURPOSE: Knowledge of post-hematopoietic cell transplantation (HCT) non-hematological autoimmune disease (AD) is far from satisfactory. METHOD: This multicenter retrospective study focuses on incidence, risk factors, and outcomes of post-HCT AD in 596 children with primary immunodeficiency (PID) who were transplanted from 2009 to 2018. RESULTS: The indications of HCT were severe combined immunodeficiency (SCID, n = 158, 27%) and non-SCID PID (n = 438, 73%). The median age at HCT was 2.3 years (range, 0.04 to 18.3 years). The 5-year overall survival for the entire cohort was 79% (95% cumulative incidence (CIN), 74-83%). The median follow-up of surviving patients was 4.3 years (0.08 to 14.7 years). The CIN of post-HCT AD was 3% (2-5%) at 1 year post-HCT, 7% (5-11%) at 5 years post-HCT, and 11% (7-17%) at 8 years post-HCT. The median onset of post-HCT AD was 2.2 years (0.12 to 9.6 years). Autoimmune thyroid disorder (n = 19, 62%) was the most common post-HCT AD, followed by neuromuscular disorders (n = 7, 22%) and rheumatological manifestations (n = 5, 16%). All patients but one required treatment for post-HCT AD. After multivariate analysis, age at transplant (p = 0.01) and T cell-depleted graft (p < 0.001) were significant predictors of post-HCT AD. None of the T cell-depleted graft recipients developed post-HCT AD. Patients with a lower CD3+ count at 6 months post-HCT had a significant higher incidence of post-HCT AD compared to disease controls. Graft-versus-host disease, viral infection, and donor chimerism had no association with post-HCT AD. CONCLUSION: Post-HCT AD occurred in 11% at 8 years post-HCT and its occurrence was associated with older age at HCT and unmanipulated graft.

Plasma copeptin in preterm infants: a highly sensitive marker of fetal and neonatal stress.

CONTEXT: Copeptin is a stable by-product of arginine-vasopressin synthesis and reflects its secretion by the pituitary. OBJECTIVE: The objective of the study was to investigate perinatal factors affecting copeptin concentrations in preterm infants at birth and at 3 d of life. DESIGN AND SETTING: This was a prospective cross-sectional study at two Swiss university hospitals. PATIENTS: One hundred sixty-seven preterm infants were enrolled, 59 infants born between 24 and 31 wk gestational age, 50 infants between 32 and 34 wk, and 58 between 35 and 36 wk. MAIN OUTCOME MEASURE: Plasma copeptin concentrations, determined by a CT-proAVP-luminescence-immunoassay, were measured. RESULTS: Copeptin at birth was significantly higher in preterm infants born vaginally [median (range) 366 (1-2900) pmol/liter, n = 43] than those born by cesarean section [6.9 (2-1580), n = 124]. In infants born after cesarean without prior labor (n = 66), estimated fetal weight less than the fifth percentile, suspect fetal heart rate, compromised placental perfusion, and chorioamnionitis were each associated with significantly elevated cord copeptin. Copeptin at 3 d of life was not associated with cord blood copeptin but inversely related to gestational age (Rs = -0.6, P < 0.001) and birth weight (Rs -0.612, P < 0.001). Day 3 copeptin increased alongside the level of mechanical respiratory support. CONCLUSION: Copeptin is a highly sensitive marker of perinatal stress.