Pharmacokinetic Monitoring of Aminoglycosides in the Extended Dosing Interval Era/Pharmakokinetisches Monitoring von Aminoglykosiden bei verlängerten Dosierungsintervallen

Objective Rituximab (RTX) is effective in induction and maintenance of remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, uncertainty remains regarding the optimal maintenance dosing regimen. This work evaluates the relationship between variability in RTX dosing and pharmacological response in AAV. Methods A prospective cohort of AAV patients (n=28) with either GPA (n=23) or MPA (n=5) receiving maintenance RTX therapy were followed in a single tertiary care academic medical center over a 2-year period. Patient demographics, RTX dosing information, and trough plasma RTX levels were collected along with laboratory measures of pharmacologic response, including B-cell counts and ANCA titers. Results RTX dosing information from 94 infusions with 59 trough samples were collected with a mean±SD dose of 640±221 mg, dosing interval of 210±88 days, and trough plasma RTX concentration of 622±548 ng/mL. RTX trough concentrations were associated with RTX dose (ρ=0.60, p<0.0001) and dosing interval (ρ=-0.55, p<0.0001). RTX dosing intensity (mg/d) was associated with RTX trough concentrations (ρ=0.57, p<0.0001). Higher dosing intensities were associated with undetectable B-cell repopulation (p<0.0001), but not negative ANCA titers (p=0.6). Stratification of dosing intensities based on the standard dosing regimen of 500 mg every six months (2.4 to 3.3 mg/d) demonstrated that this regimen was associated with B-cell repopulation in 8 of 17 doses (47%) compared to 0 of 23 doses (0%) with the high-dose regimen (>3.3 mg/d) (p<0.0001). Conclusion RTX maintenance dosing of 500 mg every six months may be inadequate to maintain B-cell depletion in the treatment of AAV.

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Clinical Pharmacodynamic Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01057-13 ◽

2013 ◽

Vol 57 (11) ◽

pp. 5714-5716 ◽

Cited By ~ 24

Author(s):

David R. Andes ◽

Daniel K. Reynolds ◽

Scott A. Van Wart ◽

Alexander J. Lepak ◽

Laura L. Kovanda ◽

...

Keyword(s):

Dose Level ◽

Randomized Trials ◽

Clinical Investigation ◽

Time Curve ◽

Content Type ◽

Dosing Interval ◽

Concentration Time ◽

Dosing Regimens ◽

Dosing Strategy ◽

Current Report

ABSTRACTEchinocandins exhibit concentration-dependent effects onCandidaspecies, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant (P= 0.056), outcomes were seen with higher maximum concentrations of drug in serum (Cmax) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00666185 and NCT00665639.)

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Epinephrine dosing interval and survival outcomes during pediatric in-hospital cardiac arrest

Resuscitation ◽

10.1016/j.resuscitation.2017.05.023 ◽

2017 ◽

Vol 117 ◽

pp. 18-23 ◽

Cited By ~ 20

Author(s):

Derek B. Hoyme ◽

Sonali S. Patel ◽

Ricardo A. Samson ◽

Tia T. Raymond ◽

Vinay M. Nadkarni ◽

...

Keyword(s):

Cardiac Arrest ◽

Survival Outcomes ◽

Dosing Interval ◽

Hospital Cardiac Arrest

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AUC Over Dosing Interval Normalized by Surface Area

10.32388/177d2s ◽

2020 ◽

Author(s):

Keyword(s):

Surface Area ◽

Dosing Interval

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17-BI-1206-02 Phase 1/2a Clinical Trial of BI-1206, a Monoclonal Antibody to Fcgriib, in Combination with Rituximab in Subjects with Indolent B-Cell Non-Hodgkin Lymphoma That Has Relapsed or Is Refractory to Rituximab

Blood ◽

10.1182/blood-2020-140219 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Mats Jerkeman ◽

Andres McAllister ◽

Carl Roos ◽

Marie Lindell Andersson ◽

Ingrid Karlsson ◽

...

Keyword(s):

Clinical Trial ◽

Monoclonal Antibody ◽

Clinical Response ◽

Clinical Benefit ◽

Phase 1 ◽

Publicly Traded ◽

Dosing Interval ◽

Non Linear ◽

Dose Levels ◽

Receptor Saturation

Introduction BI-1206 is a fully-human IgG1 monoclonal antibody that exquisitely recognizes and blocks FcγRIIB. BI-1206 enhances the activity of anti-CD20 antibodies such as rituximab by preventing interaction with FcγRIIB and may thus overcome resistance to those treatments. BI-1206 is currently in clinical investigation in combination with rituximab for the treatment of indolent NHL. This report presents a preliminary pharmacokinetic evaluation of the data generated in the trial. Methods The safety and tolerability profile of BI-1206 in combination with rituximab is currently investigated in the Phase 1/2a clinical trial 17-BI-1206-02. The study population includes patients with follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL) who have relapsed or are refractory to rituximab. BI-1206 and rituximab are administered as i.v. infusions once per week for four weeks. In Phase 1a, a 3+3 study design is used, with escalating doses of BI-1206 and a fixed dose of rituximab (375 mg/m2), with the aim of selecting the RP2D of BI-1206 for an expansion cohort in Phase 2a. Patients showing clinical benefit, are eligible for continued maintenance therapy with dosing of BI-1206 and rituximab every 8 weeks. The assessment of the pharmacokinetics (PK) of BI-1206 included non-compartmental analysis (NCA), and the assessment of the pharmacodynamics (PD) included receptor occupancy (RO%). PK modelling was conducted to further characterize the PK behavior and to provide predictions of upcoming dose levels. In addition, the effect of BI-1206 on the PK of rituximab was investigated by comparing PK parameters of rituximab to literature values of rituximab monotherapy. Results Up to 100 mg BI-1206 has been administered in combination with rituximab (375 mg/m2). Increasing doses of BI-1206 from 30 mg to 70 or 100 mg gave rise to a supra-proportional increase in Cmax as well as an increase in the half-life of BI-1206. A trend of accumulation after consecutive doses was also seen. When comparing the serum-concentrations against the associated RO% of FcγRIIB there is a trend that higher doses almost fully saturate the receptors immediately after dosing and for up to 72 hours. It is likely that increasing the dose further, will give rise to full receptor saturation, which should be maintained for an extended period. Clinical response, assessed by reduction of tumour size, has been observed at the 70 mg cohort. This at a dose which typically does not saturate receptors for the entire dose interval. It may therefor be speculated that doses which enable full RO% over the entire dosing interval, may show additional clinical benefit for patients. PK modelling showed that there was a significant contribution of a non-linear component on the elimination of BI-1206, which may be attributed to receptor binding. A two-compartment model with linear (non-saturating) and non-linear (saturating) elimination best describes the data. Using the model for predictions of upcoming doses revealed that doses close to the ones already administered may be sufficient for full receptor saturation during the entire dosing interval. Finally, the Cmax after one dose of rituximab was in the same range as previously reported values, indicating no substantial effect on the PK of rituximab. Consequently, at the current dose levels, there is no apparent need for dose-adjustments for rituximab. Conclusions This report presents preliminary data of the clinical trial 17-BI-1206-02, where BI-1206 is combined with rituximab. The presented data is encouraging, both in terms of first clinical response against tumors, as well as showing signs of overcoming target-mediated drug disposition, which may allow weekly or even less frequent dosing at clinically relevant dose levels. Disclosures Jerkeman: Roche:Research Funding;Celgene:Research Funding;Gilead:Research Funding;Abbvie:Research Funding;Janssen:Research Funding.McAllister:BioInvent International AB:Current Employment, Current equity holder in publicly-traded company.Roos:BioInvent International AB:Current Employment.Lindell Andersson:BioInvent International AB:Current Employment.Karlsson:BioInvent International AB:Current Employment.Borggren:BioInvent International AB:Current Employment.Abrisqueta:Celgene:Consultancy, Honoraria;Janssen:Consultancy, Honoraria, Speakers Bureau;AbbVie:Consultancy, Honoraria, Speakers Bureau;Roche:Consultancy, Honoraria, Speakers Bureau.Teige:BioInvent International AB:Current Employment, Current equity holder in publicly-traded company.Frendéus:BioInvent International AB:Current Employment, Current equity holder in publicly-traded company.

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Pharmacokinetics and Pharmacodynamics of Imipenem during Continuous Renal Replacement Therapy in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.6.2421-2428.2005 ◽

2005 ◽

Vol 49 (6) ◽

pp. 2421-2428 ◽

Cited By ~ 46

Author(s):

Douglas N. Fish ◽

Isaac Teitelbaum ◽

Edward Abraham

Keyword(s):

High Performance ◽

Continuous Venovenous Hemofiltration ◽

Systemic Clearance ◽

Pharmacokinetics And Pharmacodynamics ◽

Drug Infusion ◽

Dosing Interval ◽

Adult Intensive Care Unit ◽

Drug Concentrations ◽

Elimination Half ◽

Higher Doses

ABSTRACT The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n = 6 patients) or hemodiafiltration (CVVHDF; n = 6 patients). Patients (mean ± standard deviation age, 50.9 ± 15.9 years; weight, 98.5 ± 15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre- and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL S ) and elimination half-life (t 1/2) of imipenem were 145 ± 18 ml/min and 2.7 ± 1.3 h during CVVH versus 178 ± 18 ml/min and 2.6 ± 1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL S , respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 μg/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC = 4 to 8 μg/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.

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