Pharmacokinetics of 8 doses of rituximab (375 mg/m 2 ) given in combination with 2-week cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/ prednisolone (CHOP-14) was determined by ELISA in 20 elderly patients with diffuse large B-cell lymphoma (DLBCL) 10 minutes before and after each infusion and 1 week and 1, 2, 3, 6, and 9 months after the last infusion. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling software (NONMEM VI). Concentration-time data were fitted into an open 2-compartment model and total clearance, central compartment volume, intercompartment clearance, and volume of distribution at steady-state (Vd ss ) were investigated. Total clearance was 9.43 mL/h and Vd ss was 9.61 l. Rituximab clearance was reduced (8.21 mL/h vs 12.68 mL/h; P ‫؍‬ .003) and elimination half-life was prolonged in women compared with men (t 1/2␤ ‫؍‬ 30.7 vs 24.7 days; P ‫؍‬ .003). Body weight also affected Vd ss (0.1 l increase of Vd ss per kilogram above median of 75 kg). A sexdependent effect and the higher weight of males contribute to their faster rituximab clearance, which might explain why elderly males benefit less from the addition of rituximab to CHOP than females. This trial was registered on www.clinicaltrials. gov as numbers NCT00052936, EU-20243

Key Points• Elderly females have a better outcome than elderly males and a more favorable rituximab pharmacokinetics than all other patients with DLBCL.• Prospective trials aiming at optimizing rituximab dose and schedule are warranted in all DLBCL patients.To determine the effect of gender on outcome, the male hazard ratio for progression-free survival (HR PFS-male ) was determined in patients with diffuse large B-cell lymphoma (DLBCL). In young patients (MapThera International Trial study), HR PFS-male was 1.3 (P 5 .092) without and 1.1 (P 5 .660) with rituximab. In elderly patients (RICOVER-60 study), HR PFS-male was 1.1 (P 5 .348) with CHOP but increased to 1.6 (P 5 .004) with R-CHOP. The similar improvements of outcome in young patients were associated with similar rituximab clearances in young males and females (9.89 vs 10.38 mL/h; P 5 .238), whereas the greater benefit for elderly females was associated with a slower rituximab clearance (8.47 vs 10.59 mL/h; P 5 .005) and hence higher serum levels and longer exposure times, attributable to an age-dependent (P 5 .004) decrease of rituximab clearance in females but not males. Compared with elderly females, all other subgroups had significantly faster rituximab clearances and hence appear to be suboptimally dosed when rituximab is given at 375 mg/m 2 . Although early results of pharmacokinetic-based prospective trials designed to exploit the full therapeutic potential of rituximab suggest that increased doses and/or prolonged exposure times can improve the outcome of elderly males with DLBCL, further studies are warranted that address the optimization of rituximab dose and schedule in all subgroups of DLBCL patients. (Blood. 2014;123(5):640-646)

clinical data were obtained from all SCT recipients at the University Hospital of Cologne undergoing therapeutic drug monitoring (TDM) of serum prophylactic posaconazole concentrations. The posaconazole concentrations were determined by high-performance liquid chromatography. We developed a population pharmacokinetic model using nonlinear mixed-effect modeling (NONMEM). The list of covariates tested included age; body weight; body height; gender; posaconazole dose; race; coadministration of antineoplastic chemotherapy; day of stem cell transplantation; concomitant ranitidine, pantoprazole, cyclosporine, or tacrolimus administration; coincident fever; diarrhea; and plasma gamma-glutamyltransferase activity. A total of 149 serum posaconazole concentrations from 32 patients were obtained. A one-compartment model with first-order absorption and elimination as the basic structural model appropriately described the data, with the apparent clearance being 75. Posaconazole, a new triazole, offers broad-spectrum antifungal activity against Candida, Aspergillus, and Fusarium species, as well as the zygomycetes. The safety and tolerability profile is favorable (6). Its use for antifungal prophylaxis in patients with hematological malignancies is supported by two large phase III clinical trials (2, 15). In the first trial, patients receiving induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome were randomized to receive either oral suspensions of posaconazole 200 mg three times a day (t.i.d.), fluconazole 400 mg once a day (q.d.), or itraconazole oral solution 200 mg twice a day. The incidence rates of proven and probable invasive fungal disease (IFD) as well as the all-cause mortality rates were significantly decreased (2). The second trial assessed prophylactic posaconazole 200 mg t.i.d. administered orally in allogeneic stem cell transplantation (SCT) recipients treated with immunosuppressive drugs for severe graft-versus-host disease (GVHD). The reference prophylaxis in that trial was fluconazole 400 mg q.d. The incidence of IFD was comparable between the two groups (incidence, 9.0% and 5.3%, respectively), but posaconazole was associated with a reduced incidence of invasive aspergillosis (P ϭ 0.006) and improved attributable mortality (P ϭ 0.046) (15).On the basis of these results, posaconazole prophylaxis was implemented in the SCT unit of the University of Cologne, one of the largest referral centers in Germany providing hematology and infectious diseases services to a population of approximately 2.5 million and carrying out about 50 allogeneic SCTs per year. Posaconazole prophylaxis is initiated at the beginning of the conditioning regimen before allogeneic SCT and is administered until the discontinuation of immunosuppressive therapy, which usually occurs at day 100 after SCT.Serum posaconazole concentrations are influenced by several known factors: diarrhea, vomiting, nutritional state, ethnicity, drug-drug interactions, and increased gamma-glutamyltransferase (␥GT) concentrations (9, ...

Clonidine 1 μg/kg/hr in ventilated newborns reduced fentanyl and midazolam demand with deeper levels of analgesia and sedation without substantial side effects. This was not demonstrated in older infants, possibly due to lower clonidine serum levels.

Purpose: Insufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes.Methods: Randomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (n = 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of Pseudomonas aeruginosa in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10.Results: Among 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1-8.7) and without TDM (8.2 points; 95% CI 7.5-9.0) (p = 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5-1.3, p = 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5-6.2, p = 0.30) and microbiological cure (OR 2.4; 95% CI 0.7-7.4, p = 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9-6.9, p < 0.001).

We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted.

A rapid turnaround is a prerequisite of therapeutic drug monitoring (TDM). For antifungals, this need is

BackgroundPediatric patients undergoing hematopoietic stem cell transplantation (HSCT) are at high risk of acquiring fungal infections. Antifungal prophylaxis shortly after transplantation is therefore indicated, but data for pediatric patients under 12 years of age are scarce. To address this issue, we retrospectively assessed the safety, feasibility, and initial efficacy of prophylactic posaconazole in children.Methods60 consecutive pediatric patients with a median age of 6.0 years who underwent allogeneic HSCT between August 2007 and July 2010 received antifungal prophylaxis with posaconazole in the outpatient setting. 28 pediatric patients received an oral suspension at 5 mg/kg body weight b.i.d., and 32 pediatric patients received the suspension at 4 mg/kg body weight t.i.d. The observation period lasted from start of treatment with posaconazole until its termination (maximum of 200 days post-transplant).ResultsPediatric patients who received posaconazole at 4 mg/kg body weight t.i.d. had a median trough level of 383 μg/L. Patients who received posaconazole at 5 mg/kg body weight b.i.d. had a median trough level of 134 μg/L. Both regimens were well tolerated without severe side effects. In addition, no proven or probable invasive mycosis was observed.ConclusionPosaconazole was a well-tolerated, safe, and effective oral antifungal prophylaxis in pediatric patients who underwent high-dose chemotherapy and HSCT. Posaconazole at a dosage of 12 mg/kg body weight divided in three doses produced consistently higher morning trough levels than in patients who received posaconazole 5 mg/kg body weight b.i.d. Larger prospective trials are needed to obtain reliable guidelines for antifungal prophylaxis in children after HSCT.