scholarly journals Randomized multicenter noninferiority phase III clinical trial of the first biosimilar of eculizumab

2021 ◽  
Author(s):  
Alexander D. Kulagin ◽  
Vadim V. Ptushkin ◽  
Elena A. Lukina ◽  
Igor L. Davydkin ◽  
Alexander V. Korobkin ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Phase Iii ◽  
Time Curve ◽  
Mean Values ◽  
Treatment Groups ◽  
Concentration Time ◽  
Initial Stage ◽  
Efficacy Parameter ◽  
Secondary Endpoints ◽  
Efficacy Parameters

AbstractCurrently, eculizumab is the main effective treatment for paroxysmal nocturnal hemoglobinuria (PNH). The aim of this randomized multicenter noninferiority study was to evaluate the efficacy and safety of the Biosimilar (Elizaria) in comparison with the Originator (Soliris) in patients with PNH. Biosimilar and Originator were administered at a dose of 600 mg weekly for 4 weeks at the initial stage in naive patients, as well as for maintenance therapy at a dose of 900 mg every 2 weeks in all patients. The primary endpoint was a comparative assessment of hemolytic activity based on the area under the lactate dehydrogenase (LDH) concentration–time curve during the maintenance therapy. Thirty-two (32) patients were randomized for therapy with Biosimilar (n = 16) or Originator (n = 16). The mean values of LDH concentration–time curve were similar in both treatment groups without statistically significant differences (p > 0.05). Evaluation of secondary endpoints has shown no statistically significant differences between the groups. Safety values were comparable in both treatment groups. The data obtained confirm that the Biosimilar is not inferior to the Originator in terms of the main efficacy parameter, and is also comparable with it in terms of safety and additional efficacy parameters. Clinicaltrials.gov identifier: NCT04463056

scholarly journals Phase III Clinical Trial of Elizaria® and Soliris® in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria: Results of Comparative Analysis of Efficacy, Safety, and Pharmacological Data

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3748-3748 ◽  
Author(s):  
Aleksandr Kulagin ◽  
Vadim Ptushkin ◽  
Elena Lukina ◽  
Elena Gapchenko ◽  
Oksana Markova ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Reference Product ◽  
Phase Iii ◽  
Advisory Committees ◽  
Treatment Groups ◽  
Efficacy Parameters

Introduction: Complement C5-inhibitor eculizumab is a current standard of care in patients with paroxysmal nocturnal hemoglobinuria (PNH). Elizaria® is the first registered biosimilar of the reference medicinal product Soliris®. Purpose: To demonstrate Elizaria® comparative efficacy and safety vs. reference product Soliris® in patients with paroxysmal nocturnal hemoglobinuria. Methods: 32 patients with PNH were stratified based on the previous eculizumab treatment status (eculizumab-naive patients/patients treated with eculizumab at a maintenance regimen before enrollment) and randomized to receive Elizaria® (n = 16) or Soliris® (n = 16). Eculizumab-naive patients with baseline LDH level ≥1.5 times the upper limit of normal started induction phase of four weekly infusion of the study medications at dose of 600 mg, with subsequent maintenance therapy at dose of 900 mg every two weeks. Previously treated patients started the study treatment at the maintenance dose. The total treatment duration was 26 weeks. Comparative evaluation of chronic hemolysis based on the area under the curve "LDH concentration-time" (LDH AUC) during the maintenance therapy period was the primary endpoint of the study. The main secondary efficacy parameters were hemoglobin dynamics, breakthrough hemolysis and transfusion dependence. PK profile as well as through eculizumab and membrane attack complex (MAC) concentration were also assessed during the treatment. Results: Thirty patients have completed the study without significant protocol deviations (16 patients in Elizaria® group and 14 patients in Soliris® group). The LDH AUC was highly variable between the patients but the means were not statistically differ between the treatment groups: 62,957.6 ± 46,066.5 U/L*day (95% CI [38,410.4; 87,504.7]) and 49,702.6 ± 26,182.1 U/L*day (95% CI [34,585.5; 64,819.7]) in Elizaria® and Soliris® groups respectively. Point estimation of the intergroup difference in LDH AUC of 13255,0 U/L*days (95% CI [-10492,9; 37002,8]) comprises 12,3% of the pre-specified non-inferiority margin of 150,635 U/L*days, that is not supposed clinically significant difference (Figure 1). The treatment groups were also comparable on all the secondary efficacy parameters (Table 1). The comparative PK parameters of eculizumab and MAC concentration have been demonstrated in the treatment groups in all studied time points. Thus, the median elimination half-life (T1/2) of eculizumab amounted to 187,7 h (IQR 165,7) in Elizaria® group and to 282,0 h (IQR 152,3) in Soliris® group (p = 0.236). The minimum concentration (Cmin) of eculizumab amounted to (64.89 ± 25.96) µg/mL in Elizaria® group and to (94.13 ± 58.76) µg/mL in Soliris® group (p = 0.065). The median residence time (MRT) of eculizumab amounted to 269,5 h (IQR 257.3) in Elizaria® group and to 393,1 h (IQR 240,9) in Soliris® group (p = 0.206). By the end of the study, the mean MAC values one hour after the study products infusion amounted to (170.41 ± 72.21) ng/mL and (214.08 ± 93.57) ng/mL in Elizaria® and Soliris® groups, respectively (Figure 2). Both Elizaria® and Soliris® demonstrated the similar safety profile. Thirteen adverse drug reactions (ADR) in 5 patients were reported in the study: 9 - in 3 Elizaria® patients, whereas 4 were reported in 2 Soliris® patients. ADRs were observed in the following system organ classes: Investigations (9.4%), Blood and lymphatic system disorders (6.3%), Infections and infestations (6.3%), Renal and urinary disorders (3.1%), General disorders and administration site conditions (3.1%), Metabolism and nutrition disorders (3.1%). No new cases of anti-drug antibody formation have been revealed during the study. Conclusion: Thus, the results of the clinical trial confirm that proposed biosimilar Elizaria® is comparable to the reference product Soliris® in term of efficacy, safety, immunogenicity and PK/PD parameters in the treatment of paroxysmal nocturnal hemoglobinuria. Disclosures Kulagin: Alexion Pharmaceuticals, Inc:: Consultancy, Honoraria; JSC GENERIUM: Consultancy, Honoraria, Research Funding. Ptushkin:Alexion Pharmaceuticals, Inc:: Consultancy, Research Funding; JSC GENERIUM: Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Roche: Consultancy. Lukina:JSC GENERIUM: Research Funding; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Reimbursement, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Reimbursement. Gapchenko:JSC GENERIUM: Employment. Markova:JSC GENERIUM: Employment. Zuev:JSC GENERIUM: Employment. Kudlay:JSC GENERIUM: Employment.

scholarly journals Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Elizabeth A. Lakota ◽  
Justin C. Bader ◽  
Voon Ong ◽  
Ken Bartizal ◽  
Lynn Miesel ◽  
...  
Keyword(s):  
Time Course ◽  
Fungicidal Activity ◽  
Control Group ◽  
Time Curve ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Treatment Control Group ◽  
Pharmacological Basis

ABSTRACT CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (∼133 h in humans, ∼70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no-treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC0–168) was administered as a single dose, a >2 log10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens.

scholarly journals Effects of food and sucralfate on a single oral dose of 500 milligrams of levofloxacin in healthy subjects.

1997 ◽  
Vol 41 (10) ◽  
pp. 2196-2200 ◽  
Author(s):  
L J Lee ◽  
B Hafkin ◽  
I D Lee ◽  
J Hoh ◽  
R Dix
Keyword(s):  
Oral Dose ◽  
Healthy Subjects ◽  
High Fat ◽  
Time Curve ◽  
Mean Values ◽  
Treatment Groups ◽  
The Mean ◽  
The Individual ◽  
Individual Profiles ◽  
Fat Meal

The effects of food and sucralfate on the pharmacokinetics of levofloxacin following the administration of a single 500-mg oral dose were investigated in a randomized, three-way crossover study with young healthy subjects (12 males and 12 females). Levofloxacin was administered under three conditions: fasting, fed (immediately after a standardized high-fat breakfast), and fasting with sucralfate given 2 h following the administration of levofloxacin. The concentrations of levofloxacin in plasma and urine were determined by high-pressure liquid chromatography. By noncompartmental methods, the maximum concentration of drug in serum (Cmax), the time to Cmax (Tmax), the area under the concentration-time curve (AUC), half-life (t1/2), clearance (CL/F), renal clearance (CLR), and cumulative amount of levofloxacin in urine (Ae) were estimated. The individual profiles of the drug concentration in plasma showed little difference among the three treatments. The only consistent effect of the coadministration of levofloxacin with a high-fat meal for most subjects was that levofloxacin absorption was delayed and Cmax was slightly reduced (Tmax, 1.0 and 2.0 h for fasting and fed conditions, respectively [P = 0.002]; Cmax, 5.9 +/- 1.3 and 5.1 +/- 0.9 microg/ml [90% confidence interval = 0.79 to 0.94] for fasting and fed conditions, respectively). Sucralfate, which was administered 2 h after the administration of levofloxacin, appeared to have no effect on levofloxacin's disposition compared with that under the fasting condition. Mean values of Cmax and AUC from time zero to infinity were 6.7 +/- 3.2 microg/ml and 47.9 +/- 8.4 microg x h/ml, respectively, following the administration of sucralfate compared to values of 5.9 +/- 1.3 microg/ml and 50.5 +/- 8.1 microg x h/ml, respectively, under fasting conditions. The mean t1/2, CL/F, CLR, and Ae values were similar among all three treatment groups. In conclusion, the absorption of levofloxacin was slightly delayed by food, although the overall bioavailability of levofloxacin following a high-fat meal was not altered. Finally, sucralfate did not alter the disposition of levofloxacin when sucralfate was given 2 h after the administration of the antibacterial agent, thus preventing a potential drug-drug interaction.

scholarly journals Association between the Pharmacokinetics and In Vivo Therapeutic Efficacy of Sulfadoxine-Pyrimethamine in Malawian Children

2005 ◽  
Vol 49 (9) ◽  
pp. 3601-3606 ◽  
Author(s):  
Fraction K. Dzinjalamala ◽  
Allan Macheso ◽  
James G. Kublin ◽  
Terrie E. Taylor ◽  
Karen I. Barnes ◽  
...  
Keyword(s):  
Terminal Phase ◽  
Time Curve ◽  
Mean Values ◽  
Concentration Time ◽  
Elimination Half ◽  
Resistant Genotypes ◽  
Parasitological Response ◽  
Phase Elimination ◽  
Malaria Risk Factors

ABSTRACT Sulfadoxine-pyrimethamine (SP) has been widely used in recent years to treat acute uncomplicated Plasmodium falciparum malaria. Risk factors for SP therapeutic failure include young age, subtherapeutic SP concentrations, and resistance-conferring genetic mutations in parasite target enzymes. A substantial proportion of patients are able to clear genetically highly resistant P. falciparum genotypes. To determine whether blood SP concentrations independently affect the patient's ability to clear resistant genotypes, we compared SP pharmacokinetics of cases of adequate clinical and parasitological response (ACPR) with cases of treatment failure (TF). When patients with ACPR and TF were compared, mean values were similar for the day 3 blood pyrimethamine (205 ng/ml versus 172 ng/ml; P = 0.25) and estimated maximum sulfadoxine (79 ± 6.52 versus 69 ± 6.27 μg/ml; P = 0.60) concentrations, for sulfadoxine terminal-phase elimination half-lives (7.15 versus 6.41 days; P = 0.42), and for the extents of sulfadoxine absorption (areas under the concentration-time curve of 932 ± 100 versus 888 ± 78.9 μg day ml−1; P = 0.72). Among patients infected with the quintuple resistant parasites, day 3 blood pyrimethamine concentrations were higher in those who cleared the infection than in those who did not (305 ± 35.4 versus 228 ± 21.7 ng/ml; P = 0.037). Within this subgroup, this finding remained significant after adjusting for endogenous folate levels, age, site, and resistance-conferring mutations (odds ratio: 1.011 [1.003 to 1.024]; P = 0.018). However, as a subgroup analysis, our biologically plausible observation that higher blood pyrimethamine concentrations enhance the ability of patients to clear resistant P. falciparum should be interpreted with caution and needs further validation.

Pharmacokinetics of an immunomodulating dose of levamisole in weaned pigs

2013 ◽  
Vol 61 (3) ◽  
pp. 376-382
Author(s):  
Jelena Šuran ◽  
Dubravka Flajs ◽  
Maja Peraica ◽  
Andreja Prevendar Crnić ◽  
Marcela Šperanda ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Area Under The Curve ◽  
Maximum Plasma ◽  
Weaned Pigs ◽  
Time Curve ◽  
Treatment Groups ◽  
Parallel Design ◽  
Concentration Time ◽  
Plasma Concentration Time Curve ◽  
Crossbred Pigs

Levamisole has been shown to stimulate the immune response in immunocompromised humans and animals. However, its use as an adjuvant in immunocompromised weaned pigs prone to colibacillosis has only been experimentally tested but not yet officially approved. Therefore, the aim of these studies was to study the pharmacokinetics (PK) of an immunomodulating dose of levamisole in weaned pigs. For that purpose, 20 weaned crossbred pigs were divided into two treatment groups. In this parallel-design study, a single dose of levamisole (2.5 mg/kg body weight) was administered by the intramuscular (i.m.) or oral (p.o.) route. Statistically significant differences between the i.m. and p.o. routes in terminal beta rate constant (β), maximum plasma concentration (Cmax), area under the curve (AUC) for plasma concentration-time curve from time zero to infinity (AUC0-inf), area under the plasma concentration-time curve from time 0 to the last quantifiable time point (AUC0-t) were determined. Further research is needed to establish a relationship between the PK and the immunomodulating effect of levamisole in pigs.

scholarly journals A Randomized, Double-Blind, Single-Dose Phase 1 Comparative Pharmacokinetic Study Comparing SB12 (Eculizumab Biosimilar) with Reference Eculizumab in Healthy Volunteers

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 929-929
Author(s):  
Hyun A Lee ◽  
Hyerin Jang ◽  
Yeonsoo Kim ◽  
Deokyoon Jeong ◽  
Jieun Lee ◽  
...  
Keyword(s):  
Treatment Group ◽  
Research Funding ◽  
Post Dose ◽  
Double Blind ◽  
Time Curve ◽  
Complement Activity ◽  
Treatment Groups ◽  
Concentration Time ◽  
Equivalence Margin ◽  
Terminal Complement

Abstract Background: SB12 has been developed as a biosimilar of the reference product (RP) eculizumab. Eculizumab is a humanized monoclonal antibody (IgG2/4 kappa immunoglobulin) that binds to the human C5 complement protein with high affinity. Binding to this protein blocks its cleavage into C5a and C5b, thereby inhibiting terminal complement-mediated intravascular haemolysis. It is currently indicated for the treatment of patients with paroxysmal nocturnal haemoglobinuria, atypical haemolytic uremic syndrome (aHUS), refractory generalized Myasthenia Gravis (gMG) and Neuromyelitis Optica Spectrum Disorder (NMOSD). Objectives: To demonstrate pharmacokinetic (PK) equivalence and evaluate pharmacodynamic (PD), safety, tolerability, and immunogenicity profiles between SB12 and the RP eculizumab. Methods: This was a double-blind, three-arm, parallel group, and single-dose study in healthy subjects, between 18-55 years of age, randomized in a ratio of 1:1:1 to receive a single 300 mg dose of either SB12, European Union (EU) sourced eculizumab, or United States of America (US) sourced eculizumab via intravenous (IV) infusion for 35 minutes. Blood samples for PK and PD analysis were collected over 64 days. The primary objective of this study was to demonstrate PK similarity between the investigational products (IPs), as assessed by area under the concentration-time curve from time zero to infinity (AUC inf). Secondary PK endpoints included area under the concentration-time curve from time zero to the last quantifiable concentration (AUC last) and maximum observed concentration (C max). Equivalence for the primary endpoint (AUC inf) was determined if 90% confidence intervals (CIs) for the ratio of geometric least squared means (LSMeans) of SB12 to EU sourced eculizumab, SB12 to US sourced eculizumab, and EU sourced eculizumab to US sourced eculizumab was within the equivalence margin of 80.00% to 125.00%, respectively. Other objectives for the study were to evaluate safety, tolerability, immunogenicity, and PD profiles for the IPs. Results: A total of 240 subjects (80 in each treatment group) were enrolled. Back transformation provided the geometric LSMean ratio for the comparison of SB12/EU sourced eculizumab, SB12/US sourced eculizumab and EU sourced eculizumab/US sourced eculizumab for AUC inf were 99.1 % (95.41,102.85), 95.1 % (91.40, 99.04), and 96.0 % (92.16, 100.10), respectively. The corresponding 90% CI was within the pre-defined equivalence margin of 80.00-125.00%, indicating that the each of two treatments are bioequivalent. The profiles of mean terminal complement activity and mean change from baseline of complement activity were superimposable following administration of SB12, EU sourced eculizumab, and US sourced eculizumab. There was a rapid decrease in the complement activity at the end of infusion and then a slow restoration. There was no non-responder in the aspect of the measured complement activity after treatment. There were no deaths or discontinuation of IP due to treatment-emergent adverse events (TEAEs) during the study. Two serious adverse events (SAEs) (renal colic in the SB12 treatment group and back pain in the US eculizumab treatment group) were reported, in 2 subjects. Both events were considered not related to the IP. The proportion of subjects who experienced TEAEs were similar between the SB12, EU sourced eculizumab, and US sourced eculizumab treatment groups (70.0%, 65.0%, and 71.3% of subjects, respectively). The overall incidence of subjects with post-dose anti-drug antibodies (ADA) to eculizumab was 2 (2.5%), 1 (1.3%), and 0 (0.0%) subjects in the SB12, EU sourced eculizumab, and US sourced eculizumab treatment groups, respectively. There was no significant difference between treatment groups. None of the subjects with post-dose ADA to eculizumab had a positive result for neutralizing antibodies. Conclusion: The Phase I study demonstrated PK bioequivalence and showed comparable PD, safety, immunogenicity between SB12 and the RP eculizumab. Disclosures Lee: Samsung Bioepis, Co., Ltd.: Current Employment. Jang: Samsung Bioepis, Co., Ltd.: Current Employment. Kim: Samsung Bioepis, Co., Ltd.: Current Employment. Jeong: Samsung Bioepis, Co., Ltd.: Current Employment. Lee: Samsung Bioepis, Co., Ltd.: Current Employment. Jung: Samsung Bioepis, Co., Ltd.: Current Employment. Demichelis: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol/Celgene: Consultancy, Speakers Bureau; AMGEN: Consultancy, Speakers Bureau; ASH: Research Funding; Jazz: Consultancy; Gilead: Consultancy; Astellas: Consultancy; Abbvie: Consultancy, Speakers Bureau.

Maintenance therapy with bevacizumab with or without erlotinib in metastatic colorectal cancer (mCRC) according to KRAS: Results of the GERCOR DREAM phase III trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3515-3515 ◽  
Author(s):  
Christophe Tournigand ◽  
Benoist Chibaudel ◽  
Benoit Samson ◽  
Werner Scheithauer ◽  
Gérard Lledo ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Primary Analysis ◽  
Phase Iii Trial ◽  
Kras Status ◽  
Secondary Endpoints ◽  
The Impact ◽  
Egfr Tki

3515 Background: The primary analysis of DREAM demonstrated that a maintenance therapy (MT) with bevacizumab (Bev) + EGFR TKI erlotinib (E) significantly improved progression-free survival (PFS) after a 1st-line Bev-based induction therapy (IT) in patients (pts) with unresectable mCRC. Methods: Pts were randomized to MT after an IT with FOLFOX-bev or XELOX-bev or FOLFIRI-bev between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (Bev 7.5 mg/kg q3w, E 150 mg/d ; arm B) until PD or unacceptable toxicity. Primary endpoint was PFS on MT. Secondary endpoints included PFS from inclusion, overall survival (OS) and safety. The impact of KRAS tumor status on treatment efficacy was evaluated in an exploratory analysis. Results: 700 pts were registered and 452 pts were randomized (228 in arm A, 224 in arm B). KRAS status was available for 413/452 (91%) pts. The median duration of MT was 3.6 m. Results for MT are presented below (Table). In the registered population, median OS was 24.9m (22.5 – 27.3). Conclusions: Maintenance treatment with bev + erlotinib increases PFS over maintenance with bev alone in pts with mCRC but does not prolong OS. Further follow-up will determine the impact of 2nd or 3rd line anti-EGFR Mabs in this study. Contrasting with anti-EGFR Mabs, KRAS tumor status is not mandatory to select pts with mCRC for treatment with erlotinib. Clinical trial information: NCT00265824. [Table: see text]

Rivaroxaban Has Predictable Pharmacokinetics (PK) and Pharmacodynamics (PD) When Given Once or Twice Daily for the Treatment of Acute, Proximal Deep Vein Thrombosis (DVT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1880-1880 ◽  
Author(s):  
Wolfgang Mueck ◽  
Giancarlo Agnelli ◽  
Harry Buller
Keyword(s):  
Confidence Intervals ◽  
Plasma Concentrations ◽  
Demographic Factors ◽  
Dose Finding ◽  
Phase Iii ◽  
Total Daily Dose ◽  
Efficacy And Safety ◽  
Time Curve ◽  
Mixed Effect ◽  
Mean Values

Abstract Introduction: Rivaroxaban is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Two large, phase IIb, dose-finding studies investigating rivaroxaban for the treatment of acute, proximal DVT, showed that rivaroxaban once daily (od) and twice daily (bid) had similar efficacy and safety profiles to standard therapy. In order to characterize the population PK/PD of rivaroxaban for DVT treatment, a population model was developed based on data from healthy subjects. Methods: Sparse PK/PD samples from 870 patients across the two studies were analyzed using non-linear, mixed-effect population modeling (NONMEM), version V level 1.1. The program analyzed population data to give estimates of mean values and variability in the population. Prothrombin time (PT) was determined at a central laboratory and was used in the PD investigation. For the PK profile, data was pooled from both clinical trials and specific exposure parameters for rivaroxaban, such as area under the plasma concentration-time curve (AUC), maximum and minimum plasma concentrations (Cmax and Ctrough, respectively) were predicted for each patient according to the dosing regimen received. Results: The PK of rivaroxaban were well described by an oral, one-compartment model, with demographic factors influencing clearance (age, renal function) and volume of distribution (age, body weight, gender); variations due to these factors were moderate, suggesting fixed dosing may be possible. Co-medications (e.g. diuretics, NSAIDs, aspirin) had no relevant effects on the PK of rivaroxaban. Rivaroxaban Cmax and Ctrough concentrations increased dose dependently (Table). As expected, Cmax was higher and Ctrough was lower after od dosing compared with bid dosing, at equivalent total daily doses; however, 90% confidence intervals overlapped, suggesting that od dosing with rivaroxaban should not expose patients to a greater risk of bleeding (at Cmax) or VTE (at Ctrough) than bid dosing. Clinically relevant rivaroxaban plasma concentrations correlated linearly with PT, confirming that it would be suitable for measuring rivaroxaban exposure, if necessary. Conclusions: The PK and PD of rivaroxaban were predictable with od and bid dosing, and affected by expected demographic factors in patients receiving it for DVT treatment. Combined with efficacy and safety results, this analysis aided the selection of an initial, intensified bid regimen followed by convenient, long-term rivaroxaban 20 mg od, for investigation in phase III studies in this indication. Predicted rivaroxaban PK parameters Parameter Rivaroxaban total daily dose *Values are shown as means (90% confidence intervals) 20 mg 30 mg 40 mg 60 mg n (od/bid) 134/117 134/- 252/114 -/119 od Cmax (μg/L)* 270.6 (189.1–418.7) 324.6 (234.2–491.3) 406.5 (268.4–599.9) - bid Cmax (μg/L)* 211.5 (130.3–360.7) - 320.9 (209.9–517.9) 400.6 (244.2–749.5) od Ctrough (μg/L)* 25.5 (5.9–86.9) 33.8 (8.4–132.9) 42.3 (9.7–161.8) - bid Ctrough (μg/L)* 65.1 (17.2–193.6) - 104.2 (31.3–277.8) 143.1 (46.6–347.9)

scholarly journals Comparative Efficacies of Tedizolid Phosphate, Vancomycin, and Daptomycin in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis

2015 ◽  
Vol 59 (6) ◽  
pp. 3252-3256 ◽  
Author(s):  
Liana C. Chan ◽  
Li Basuino ◽  
Etyene C. Dip ◽  
Henry F. Chambers
Keyword(s):  
Staphylococcus Aureus ◽  
Rabbit Model ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Dose Ranging

ABSTRACTTedizolid, the active component of the prodrug tedizolid phosphate, is a novel oxazolidinone that is approximately 4 times more active by weight than linezolid againstStaphylococcus aureusin vitro. Thein vivoefficacy of tedizolid phosphate (15 mg/kg body weight intravenous [i.v.] twice a day [b.i.d.]) was compared to those of vancomycin (30 mg/kg i.v. b.i.d.) and daptomycin (18 mg/kg i.v. once a day [q.d.]) in a rabbit model of aortic valve endocarditis (AVE) caused by methicillin-resistantS. aureusstrain COL (infection inoculum of 107CFU). Median vegetation titers of daptomycin-treated rabbits were significantly lower than those of rabbits treated with tedizolid phosphate (15 mg/kg b.i.d.) (P= 0.016), whereas titers for vancomycin-treated compared to tedizolid-treated rabbits were not different (P= 0.984). The numbers of organisms in spleen and kidney tissues were similar for all treatment groups. A dose-ranging experiment was performed with tedizolid phosphate (2, 4, and 8 mg/kg b.i.d.) compared to vancomycin (30 mg/kg b.i.d.), using a higher infecting inoculum (108CFU) to determine the lowest efficacious dose of tedizolid phosphate. Tedizolid phosphate (2 mg/kg) (equivalent to 60% of the area under the concentration-time curve from 0 to 24 h (AUC0–24) for the human 200-mg dose approved by the U.S. Food and Drug Administration) was not efficacious. Tedizolid phosphate at 4 mg/kg (equivalent to 75% of the AUC0–24for the human 400-mg dose) and 8 mg/kg produced lower vegetation titers than the control, but neither was as efficacious as vancomycin.

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