Proposal of initial and maintenance dosing regimens with linezolid for renal impairment patients

Abstract Background Linezolid is administered as a fixed dose to all patients despite evidence of overexposure and thrombocytopenia in renal impairment. The aims of this study were to evaluate the risk of thrombocytopenia and the utility of therapeutic drug monitoring (TDM), and to propose alternate dosing regimens in patients with renal impairment. Methods We retrospectively reviewed patients ≥13 years old for whom serum linezolid trough concentration (Cmin) was measured during linezolid treatment. Patients with episodes of infection were divided into groups by presence of renal impairment (RI group) or absence of renal impairment (non-RI group), and by use of Cmin-based TDM (TDM group) or not (non-TDM group) during linezolid treatment. Results In the 108 patients examined by multivariable analyses, renal impairment was independently associated with increased risk of thrombocytopenia (OR 3.17, 95%CI 1.10–9.12) and higher Cmin. Analysis of the utility of TDM in the RI group showed that clinical failure rate was significantly lower in the TDM subgroup than in the non-TDM subgroup. Furthermore, in the RI group, dosage adjustments were needed in 90.5% of the TDM subgroup. All episodes administered a reduced dose of 300 mg every 12 h in the RI group showed Cmin ≥ 2.0 mg/L. Additional analysis of 53 episodes in which Cmin was measured within 48 h after starting administration showed that the initial standard dose for 2 days was sufficient to rapidly reach an effective therapeutic concentration in the RI group. Conclusions Empirical dose reduction to 300 mg every 12 h after administration of the initial fixed dose for 2 days and Cmin-based TDM may improve safety outcomes while maintaining appropriate efficacy among patients with renal impairment.

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Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00605-19 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 10

Author(s):

Ryan L. Crass ◽

Pier Giorgio Cojutti ◽

Manjunath P. Pai ◽

Federico Pea

Keyword(s):

Renal Impairment ◽

Standard Dose ◽

Multivariable Analysis ◽

Cox Proportional Hazards ◽

Adult Patients ◽

Fixed Dose ◽

Simulated Patients ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Data Set

ABSTRACT Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for ≥10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariate-structured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; P < 0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [CI], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of <60 ml/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM are predicted to mitigate this treatment-limiting toxicity.

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Therapeutic drug monitoring of pazopanib: Using cost-neutral PK-guided interventions to optimize exposure.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3598 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3598-3598

Author(s):

Stefanie L. Groenland ◽

Ruben A.G. van Eerden ◽

Stijn L.W. Koolen ◽

Dirk Jan A.R. Moes ◽

Alex Imholz ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Standard Dose ◽

Daily Practice ◽

Fixed Dose ◽

Therapeutic Drug ◽

Fasting State ◽

Reduced Dose ◽

Drug Concentrations ◽

Clinical Trial Information

3598 Background: Pazopanib is an approved treatment for renal cell carcinoma (RCC) and soft tissue sarcoma (STS). At the currently registered fixed dose of 800 mg QD, 20% of patients (pts) do not attain the efficacy threshold of Cmin ≥ 20.5 mg/L (Suttle et al, 2014), providing a strong rationale for therapeutic drug monitoring (i.e. individualizing the dose based on measured plasma drug concentrations). Previous studies provided cost-neutral alternatives to absolute dose increments to optimize exposure (i.e. splitting intake moments or concomitant intake with food (Groenland et al, 2020; Lubberman et al, 2019)). This study aimed to investigate the feasibility, tolerability and efficacy of TDM of pazopanib, using cost-neutral interventions. Methods: Patients starting treatment with pazopanib at the standard dose of 800 mg QD in modified fasting state were included in the prospective DPOG TDM study (www.trialregister.nl, NL6695). PK sampling occurred 4, 8 and 12 weeks after start of treatment, and every 12 weeks thereafter. Pazopanib concentrations were measured with LC-MS/MS and Cmin was calculated. In case of Cmin < 20.5 mg/L and acceptable toxicity, a dose intervention was recommended. As a first step, intake moments were split (i.e. 400 mg BID). Secondly, concomitant intake with food was recommended. Results: In total, 34 pts were included (19 STS, 15 RCC), of whom 158 PK samples were collected. Eleven pts (32%) were underdosed and had at least 1 PK sample below the target. In 24% of the pts a PK-guided intervention could be performed, which was successful in 6 pts (75%). Median Cmin increased from 15 mg/L to 32 mg/L (p = 0.027). Eventually, 3 pts went back to 800 mg QD due to toxicity, after which Cmin remained ≥ 20.5 mg/L in 2 pts. In pts with adequate exposure throughout the study, median Cmin was 32 mg/L (range 23 – 65 mg/L). In 3 pts, a PK-guided intervention could not be performed, due to progression (n = 1) or logistical issues (n = 2). Twelve pts (35%) received a dose reduction due to toxicity (lowest dose was 200 mg QAD), exposure remained adequate at this reduced dose in all pts. For STS pts, median PFS was 19.8 months in pts with Cmin < 20.5 mg/L who did need an intervention vs. 6.4 months in pts with all Cmin ≥ 20.5 mg/L (not significant). For RCC pts, this was 15.5 months vs. 7.4 months, respectively (not significant). Conclusions: This prospective study shows that PK-guided dose optimization of pazopanib using cost-neutral interventions is feasible in daily practice. A PK-guided intervention was performed in 24% of the patients, which was successful in 75% of these patients. Clinical trial information: NL6695 .

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Response rate and safety of standard-dose nivolumab with reduced-dose ipilimumab in metastatic melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.140 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. 140-140

Author(s):

Inderjit Mehmi ◽

Jordan Hill

Keyword(s):

Metastatic Melanoma ◽

Overall Response Rate ◽

Response Rate ◽

Standard Dose ◽

Progression Free Survival ◽

Response To Therapy ◽

Overall Response ◽

Reduced Dose ◽

Increased Risk ◽

Grade 3

140 Background: Reduced-dose nivolumab in combination with standard-dose ipilimumab was shown to improve overall response rate (58%), progression free survival (11.5 months), and overall survival compared to ipilimumab alone in Checkmate 067. Improved outcomes were accompanied by an increased risk of toxicities with a 59% rate of grade 3-4 toxicities for the combination. Keynote 029 evaluated standard-dose pembrolizumab with reduced-dose ipilimumab with a slightly lower risk of grade 3-4 toxicities at 45%. Here we report outcomes for standard-dose nivolumab combined with reduced-dose ipilimumab in metastatic melanoma. Methods: We conducted a retrospective review of metastatic melanoma patients that received standard-dose nivolumab with reduced-dose ipilimumab at West Virginia University Cancer Institute. Response to therapy and incidence of immune-related adverse events were assessed. Results: From February 2017 to October 2018, 11 patients received the alternative dosing regimen. Only 1 (9%) patient experienced a grade 3-4 toxicity, and 3 (27%) additional patients experienced a grade 1-2 toxicity. The overall response rate was 54%. Conclusions: Standard-dose nivolumab in combination with reduced-dose ipilimumab is better tolerated than reduced-dose nivolumab with standard-dose ipilimumab without a loss in overall response rate.

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Effects of Food on the Pharmacokinetics of Nilotinib in Chronic Myeloid Leukemia: Enabling Significant Dose Reduction and Relief of Treatment Burden: The NIFO-Study

Blood ◽

10.1182/blood-2018-99-118149 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1736-1736 ◽

Cited By ~ 1

Author(s):

Christel C. Boons ◽

Yvonne den Hartog ◽

Jeroen J. Janssen ◽

Anthe S. Zandvliet ◽

René Vos ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Food Intake ◽

Myeloid Leukemia ◽

Research Funding ◽

Geometric Mean ◽

Chronic Phase ◽

Therapeutic Drug ◽

Mean Values ◽

Reduced Dose ◽

Dosing Regimens

Abstract Introduction The twice daily dosing of nilotinib in the absence of food is a considerable burden for patients with chronic myeloid leukemia (CML). In order to simplify the dosing regimen and reduce treatment costs while taking advantage of the food dependent bioavailability of nilotinib, in the present study, we investigated the effects of real-life food consumption on the pharmacokinetics (PK) of nilotinib in chronic phase CML patients. Methods Nilotinib 300 mg BID administered under fasting conditions (reference treatment) was compared with nilotinib at a reduced dose of 200 mg BID under fed conditions (test treatment). Food intake was not standardized, in order to increase implementability in general practice. However, to ensure the intended increase in bioavailability, the size and composition of the meal were verified and food intake increased if necessary. Blood samples were collected at two days during each of the two treatments, with sampling time points at 1, 2, 3, 4, 6, 9 and 12 hours after nilotinib intake in the morning and 1, 2, 3, 4 and 12 hours after nilotinib intake in the evening. Plasma concentrations of nilotinib were measured by means of dried blood spot sampling. Geometric means ratio (90% confidence interval [CI]) were determined using a paired samples t-test on log-transformed PK parameters AUC0-12 h, Cmin and Cmax. Bioequivalence was concluded if the 90% CIs were contained within the equivalence limits of 80%-125%. Adverse events were recorded by means of a patient diary and ECG-monitoring. Quality of life was measured using EORTCs QLQ-C30 and QLQ-CML24 questionnaires. Results Fifteen patients aged 40-74 years participated. The arithmetic mean concentration-time profiles of the two dosing regimens studied are shown in Figure 1. Nilotinib absorption was somewhat delayed following the administration of nilotinib with food. The geometric mean values (90% CI) for nilotinib AUC0-12 h, Cmin and Cmax following morning intake with food decreased by 11% (81-98%), 12% (84-92%), and 10% (80-102%), respectively. Following evening intake, the geometric mean values for AUC0-12 h and Cmax decreased by 16% (73-97%) and 20% (68-93%), respectively, and increased by 6% (92-122%) for Cmin. For both dosing regimens considerable intra- and interindividual differences in nilotinib PK occurred. No QT-interval prolongations were observed, and for both regimens the frequency of AEs was similar. The EORTC QLQ-CML24 'symptom burden' score was significantly better for the intake of nilotinib with food (p<0.05). Conclusion Using nilotinib at a reduced dose of 200 mg BID under fed conditions in patients with chronic phase CML seems feasible and safe. Bioequivalence, however, was not completely conclusive. In spite of somewhat decreased PK parameters (10-12%), bioequivalence was established in terms of AUC0-12 h, Cmin and Cmax following morning intake. Following evening intake, bioequivalence was established in terms of Cmin, but not of AUC0-12 h and Cmax. In addition to monitoring high intra-patient variability, it is advisable to use therapeutic drug monitoring when implementing the intake of a reduced dose of nilotinib with food in clinical practice. Disclosures Janssen: Jazz pharmaceuticals: Consultancy; BMS: Research Funding; Novartis: Research Funding; Incyte: Consultancy, Speakers Bureau; Abbvie: Consultancy; Pfizer: Consultancy, Speakers Bureau.

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Abstract 15192: Effectiveness and Safety of Reduced Dose of Dabigatran for High Bleeding Risk Patient Subgroups With Atrial Fibrillation

Circulation ◽

10.1161/circ.142.suppl_3.15192 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Jaejin An ◽

Zoe Bider ◽

Tiffany Luong ◽

T Craig Cheetham ◽

Daniel T Lang ◽

...

Keyword(s):

Renal Impairment ◽

Lower Risk ◽

Index Date ◽

Standard Dose ◽

Bleeding Risk ◽

Moderate Renal Impairment ◽

Systemic Embolism ◽

Reduced Dose ◽

Risk Patients ◽

High Bleeding Risk

Off-label reduced dosing of direct oral anticoagulants is common among patients at high bleeding risk with atrial fibrillation (AF), however, outcomes data of reduced dosing are limited. We evaluated the effectiveness and safety of reduced dose of dabigatran [110 mg twice daily (BID)] vs. standard dose [150 mg BID] in high bleeding risk subgroups with AF. We identified adult patients with AF who initiated dabigatran (index date) with creatinine clearance (CrCl) ≥30 mL/min between 2012-2018 from Kaiser Permanente Southern California. Three high bleeding risk subgroups were identified: 1) patients aged ≥80 years; 2) patients with moderate renal impairment (CrCl 30-49 mL/min) regardless of age; or 3) patients with bleeding within 12 months prior to the index date or HAS-BLED score ≥3. Patients were followed through December 2018 for stroke or systemic embolism, major bleeding requiring hospitalization, and all-cause mortality. Cause-specific hazard regression models were used to investigate associations between dabigatran dose and clinical outcomes adjusting for covariates and considering competing risks of death. Among high bleeding risk patients with AF [3,749 aged ≥80 years; 1,716 with moderate renal impairment; 3,051 with recent bleed or high HAS-BLED score], 34% received reduced dose of dabigatran. Patients who received reduced dose were older, had reduced renal function, and had more comorbidities. Compared with standard dose, reduced dose of dabigatran was not associated with an increased risk of stroke or systemic embolism but was associated with lower risk of major bleed in patients aged ≥80 years ( Table ). Reduced dose of dabigatran was also associated with lower risk of mortality among patients aged ≥80 years and patients with moderate renal impairment. A lower risk of bleeds and mortality associated with reduced vs standard dose of dabigatran in high-risk patients with AF suggest a better dosing strategy for these risk groups.

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Clinical Outcomes in Patients With Gram-Negative Infections Treated With Optimized Dosing Cefepime Over Various Minimum Inhibitory Concentrations

Journal of Pharmacy Practice ◽

10.1177/0897190017696950 ◽

2017 ◽

Vol 31 (1) ◽

pp. 34-39 ◽

Cited By ~ 6

Author(s):

Jerry Altshuler ◽

David J. Guervil ◽

Charles D. Ericsson ◽

Audrey Wanger ◽

Samuel L. Aitken ◽

...

Keyword(s):

Inhibitory Concentration ◽

High Dose ◽

Clinical Failure ◽

Inclusion Criteria ◽

Gram Negative ◽

End Point ◽

Increased Risk ◽

Dosing Regimens ◽

Gram Negative Organisms ◽

Dose Dependent

Background: The Clinical and Laboratory Standards Institute (CLSI) revised cefepime interpretive criteria, introducing the susceptible dose-dependent category for Enterobacteriaceae with a minimum inhibitory concentration (MIC) of 4 to 8 μg/mL in 2014. Limited clinical data support these new categories. This study compares outcomes of patients treated with standard and high-dose cefepime across various MICs. Methods: We retrospectively reviewed cases of pneumonia or bacteremia caused by gram-negative organisms treated with adequate doses of cefepime for ≥48 hours. Outcomes were compared for MICs of ≤2 (low), 4 (medium), and 8 μg/mL (high). The primary end point was clinical failure, the secondary end point was microbiological failure. Results: Ninety cases met the inclusion criteria: 46, 25, and 19 patients with low, medium, or high MIC, respectively. Multivariate logistic regression revealed that the medium (odds ratio [OR]: 9.13, P < .01) and high (OR: 6.79, P = .01) MIC groups had increased clinical failure. Conclusion: Cefepime therapy, even at CLSI-recommended doses, had an increased risk of clinical failure for gram-negative pathogens with MICs of 4 or 8 μg/mL. This finding suggests that higher dosing regimens (2 g every 8 hours or 1 g every 6 hours) may be necessary to treat serious gram-negative infections with elevated MICs.

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Evaluating artesunate-amodiaquine deployment, efficacy and safety: an in silico pharmacological model

10.1101/567008 ◽

2019 ◽

Author(s):

Ki Bae Hong ◽

Ian Hastings ◽

Katherine Kay ◽

Eva Maria Hodel

Keyword(s):

Patient Adherence ◽

Real Life ◽

World Health ◽

Fixed Dose ◽

Multiple Treatment ◽

Increased Risk ◽

Dosing Regimens ◽

Dose Combination ◽

Health Organization ◽

Pharmacological Model

AbstractBackgroundThe World Health Organization currently recommends artesunate-amodiaquine (AS-AQ) as a first-line treatment for uncomplicated falciparum malaria. The clinical efficacy of AS-AQ is very high but its effectiveness in the field varies considerably. This study aimed at comparing the efficacy, effectiveness and safety of AS-AQ fixed dose combination (FDC) and non-fixed formulation (non-FDC) in controlled and real-life settings using a pharmacological model of antimalarial treatment.MethodsThe effectiveness and safety of different drug formulations in different treatment scenarios were investigated using a pharmacological model of AS-AQ treatment. The model simulated multiple treatment scenarios to assess the effects of age-or weight-based dosing bands in three geographically distinct patient populations, and poor patient adherence.ResultsThe model output was consistent with clinical trials in terms of cure rates, recrudescence rates and the pattern of AQ overdosing with age- and weight-based dosing regimens. AS-AQ treatment has good efficacy and effectiveness in fully adherent patients but monotherapy of AS or AQ lead to treatment failure. The weight-based dosing regimen with FDC was the best option for patients in terms of drug safety and had similar efficacies to the other regimens. Asians were more likely to be overdosed with AQ when using age-based dosing regimens.ConclusionsWeight-based dosing is optimal but not always feasible, so age-based dosing regimens are often used as an alternative. The model outputs highlight the importance of optimising these age-based dosing regimens for specific regions, and identify an increased risk of overdosing in young children.

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Which Should be Pursued, Cumulative Dose or Dose Intensity: A Real-World Effectiveness Analysis of Bortezomib-Based First Line Treatment for Untreated Multiple Myeloma Patients

Blood ◽

10.1182/blood.v126.23.4247.4247 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4247-4247

Author(s):

Shenmiao Yang ◽

Aijun Liu ◽

Yuping Zhong ◽

Xiaojun Huang ◽

Wenming Chen ◽

...

Keyword(s):

Dose Reduction ◽

Cumulative Dose ◽

Dose Group ◽

Standard Dose ◽

Dose Intensity ◽

Fixed Dose ◽

First Line ◽

Reduced Dose ◽

First Line Treatment

Abstract Background: The higher cumulative dose of bortezomib associated with better OS was demonstrated by some prospective studies of bortezomib continuing therapy. A cutoff of cumulative bortezomib dose of 39mg/m2 was found in the treatment of multiple myeloma (MM) with VISTA trial recently. However, dose reduction due to adverse events was common. Moreover, many Chinese patients accepted bortezomib injections at a fixed dose of 1.75mg, the half volume of a vial because of economic problems. To clarify if a reasonable cumulative bortezomib dose achieved by prolonged treatment duration with reduced dose intensity can do the same work, we conducted a multicenter retrospective analysis in previously untreated MM patients with the initial treatment of bortezomib-based regimens. Method: From March 2005 to December 2014, 579 previously untreated MM patients received the bortezomib-based chemotherapy with informed consents in three hematologic centers of Beijing. Median age at the diagnosis was 59 years (range: 27~89). Initial chemotherapeutic regimens included BD, PAD, BCD and VMP. After median of 4 cycles (range: 0.25~13.00) of treatment, the median cumulative dose of bortezomib was 28mg (range: 1.75~124.80). The median follow-up of surviving patients was 26.0 months (2.0-123.0). Seventy nine patients recieved autologous hematopoietic cell transplantation (ASCT) according to the eligibility and patients' desire. Results: To overcome confounding effects of early discontinuations/deaths on the cumulative dose, a landmark analysis was conducted at 6 months, eliminating patients who died before this time from the analysis. Among the patients survived the initial 6-month treatment, 450 treated with chemotherapy alone and 78 received ASCT. ROC analysis showed the cumulative bortezomib dose predicted survival in chemotherapy group with the AUC of 0.617 (95%CI: 0.565~0.670, P<0.001). A cutoff value of cumulative bortezomib dose was 20.75mg with optimal sensitivity and specificity of 0.831 and 0.373, respectively. The patients' characteristics of both low (<20.75mg) and high (≥20.75mg) cumulative bortezomib dose groups were comparative. The high cumulative dose group had superior OS than the low cumulative dose group (median OS: 51.0 months (95%CI: 44.66-57.34) vs. 42.0 months (95%CI: 33.24-50.76), P=0.015). However, PFS was not significantly different between the two groups (P=0.994). Two hundred and forty eight (65.3%) patients initiated treatment of bortezomib with the fixed dose of 1.75mg, and 202 (34.7%) patients had the standard dose of 1.3 mg/m2. Bortezomib dose reduction occured in 50 patients. Twenty nine (11.7%) patients of the standard dose intensity group and 2(1.0%) of the fixed dose intensity group had the dose reduction due to adverse events. And the other 19 patients reduced bortezomib dose for other reasons. PFS and OS of the patients with reduced dose intensity were not significantly different from the patients with the standard dose intensity of 1.3 mg/m2 (P=0.183 and 0.482, respectively). However, in the patients with the cumulative bortezomib dose of ≥20.75mg and the standard dose intensity of 1.3mg/m2 was associated with superior survival (P=0.05). Median OS of these patients was 57.0 months (95%CI: 50.62-63.38), while median OS of other patients treated with the cumulative bortezomib dose of <20.75mg or reduced dose intensity was 45.0 months (95%CI: 41.45-48.55). In the ASCT group, we could not find any association between bortezomib dose and the survival. Conclusion: For previously untreated MM patients intend to be treated with chemotherapy alone, we suppose cumulative bortezomib dose ≥20.75mg in the first line treatment should be administered for better OS. Despite reasonable cumulative bortezomib dose, any reduction of the dose intensity from 1.3mg/m2 is associated with inferior OS. For patients treated with ASCT, the association between the bortezomib dose and the survival needs to be elucidated with a long term follow-up. Disclosures No relevant conflicts of interest to declare.

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Rituximab prophylaxis to prevent thrombotic thrombocytopenic purpura relapse: outcome and evaluation of dosing regimens

Blood Advances ◽

10.1182/bloodadvances.2017008268 ◽

2017 ◽

Vol 1 (15) ◽

pp. 1159-1166 ◽

Cited By ~ 39

Author(s):

John-Paul Westwood ◽

Mari Thomas ◽

Ferras Alwan ◽

Vickie McDonald ◽

Sylvia Benjamin ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Standard Dose ◽

Thrombocytopenic Purpura ◽

Reduced Dose ◽

Key Points ◽

Dosing Regimens

Key Points Rituximab is effective in preventing relapse in TTP patients in remission with low ADAMTS13 levels. Reduced-dose rituximab (200 mg) is associated with higher rates of re-treatment than the standard dose (375 mg/m2).

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Comparison of 3 Different Prothrombin Complex Concentrate Regimens for Emergent Warfarin Reversal: PCCWaR Study

Annals of Pharmacotherapy ◽

10.1177/1060028020978568 ◽

2020 ◽

pp. 106002802097856

Author(s):

Scott K. Dietrich ◽

Shaun Rowe ◽

Craig A. Cocchio ◽

Amanda J. Harmon ◽

Steven F. Nerenberg ◽

...

Keyword(s):

Prothrombin Complex Concentrate ◽

Primary Outcome ◽

Standard Dose ◽

Package Insert ◽

International Normalized Ratio ◽

Fixed Dose ◽

Dosing Regimens ◽

Secondary Outcomes ◽

Warfarin Reversal ◽

The Ideal

Background The ideal dose and specific prothrombin complex concentrate (PCC) for warfarin reversal is unknown. Objective To evaluate the reduction in international normalized ratio (INR) of 3 different PCC dosing regimens: fixed-dose activated 4-factor PCC (aPCC), fixed-dose 4-factor PCC (4PCC), and standard-dose 4PCC. Methods This was a multicenter retrospective cohort review. Patients >18 years of age who received PCC for warfarin reversal between January 1, 2017, and December 31, 2017, were screened for inclusion. Patients were excluded if they did not receive the correct PCC dosing regimen, received PCC for nonwarfarin bleeding, had a baseline INR less than 2, or received a massive transfusion protocol. Two institutions utilized aPCC dosed at 500 IU for INR <5 and 1000 IU for INR ≥5. Two institutions utilized fixed-dose 4PCC at 1500 to 2000 units depending on patient factors. Two institutions utilized 4PCC package insert dosing. The primary outcome was achievement of post-PCC target INR ≤1.4. Secondary outcomes included percentage change in INR, lowest 24-hour INR, and mortality. Results A total of 154 patients were included (fixed-dose aPCC: n = 29; fixed-dose 4PCC: n = 53; standard-dose 4PCC: n = 72). There was no statistical difference between groups in achieving the primary outcome (58.6% vs 69.8% vs 79.2%, respectively; P = 0.103) or any secondary outcomes. Conclusion and Relevance: There was no difference in the ability to achieve a post-PCC INR of ≤1.4 between 3 different PCC regimens for warfarin reversal. Additional research is warranted to determine the ideal dose and PCC agent for warfarin reversal.

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