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.

scholarly journals A randomized, single-dose, pharmacokinetic equivalence study comparing MB02 (proposed biosimilar) and reference bevacizumab in healthy Japanese male volunteers

2021 ◽  
Author(s):  
Takashi Eto ◽  
Yuji Karasuyama ◽  
Verónica González ◽  
Ana Del Campo García
Keyword(s):  
Single Dose ◽  
Japanese Population ◽  
Post Dose ◽  
Double Blind ◽  
Time Curve ◽  
Treatment Groups ◽  
Male Volunteers ◽  
Japanese Male ◽  
Parallel Group

Abstract Purpose MB02 is a biosimilar to bevacizumab that has demonstrated similar physicochemical and functional properties in in vitro studies to the reference bevacizumab (Avastin®). This study aims to assess the pharmacokinetic (PK) similarity of MB02 to the reference bevacizumab in Japanese population. Methods This double-blind, randomized, parallel-group, single-dose PK study, was performed in healthy Japanese male volunteers. Subjects were equally randomized (1:1) to receive a single (3 mg/kg) IV dose of MB02 or reference bevacizumab. PK assessments were done up to 70 days post-dose. Non-compartmental parameters were calculated. PK similarity was determined using predefined equivalence range (0.80–1.25) for the area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC0–∞). Immunogenicity samples were taken pre-dose and up to day 70. Safety was assessed throughout the study. Results In total, 48 subjects (24 in each treatment group) were dosed. Consequently to the observed similar PK profile, the 90% confidence interval for the geometric means ratio for the primary PK endpoint, AUC0–∞, was within the predefined equivalence range (0.981–1.11). Forty-seven treatment-emergent adverse events (TEAEs) were reported in 20 subjects (41.7%) with comparable incidence among MB02 and reference bevacizumab groups (22 and 25, respectively), none of them was severe or serious. Anti-drug antibodies incidence was low and similar between treatment groups. Conclusions Pharmacokinetic similarity of MB02 to reference bevacizumab was evidenced in Japanese healthy subjects, with comparable safety and immunogenicity profile between treatments. This study supports the biosimilarity of MB02 to reference bevacizumab in Japanese population. ClinicalTrials.gov identifier: NCT04238650.

Plasma Vincristine Levels Are 100-Fold Higher with Marqibo® (Vincristine Sulfate LIPOSOME Injection) in Place of Standard Vincristine in Combination Chemotherapy of Patients ≥ 60 Years Old with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2491-2491
Author(s):  
Eunice S. Wang ◽  
Gary J Schiller ◽  
Leonard T. Heffner ◽  
Wendy Stock ◽  
Arati V. Rao ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Treatment Group ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Vincristine Sulfate ◽  
Post Dose ◽  
Treatment Groups ◽  
Median Plasma ◽  
Grade 3

Abstract Background: Marqibo® (vincristine sulfate LIPOSOME injection, VSLI) is currently approved in the US for treatment of adults with Philadelphia negative (Ph-) relapsed or refractory acute lymphoblastic leukemia (ALL). VSLI allows for greater dose intensification compared to standard vincristine sulfate (VCR) because unlike VCR, VSLI is dosed at 2.25 mg/m2 rather than 1.4mg/m2, and is not capped at 2 mg. To date, VSLI exposure has not been directly compared with VCR for the upfront treatment of adult patients with ALL. Methods: This was a phase 3, multicenter, open-label randomized clinical trial for newly diagnosed Ph- ALL patients ≥ 60 years of age. The primary objective compared the safety and efficacy of VSLI to VCR as part of multi-component chemotherapy (induction, intensification and maintenance). The secondary objectives included Objective Response Rate (ORR), safety and pharmacokinetics (PK). The chemotherapy backbone was based on the Cancer and Leukemia Group B (CALGB) Study 8811 (Larson et al, Blood 1995), with vincristine provided as either VCR or VSLI. VCR was dosed at 1.4 mg/m2 with a 2 mg dose cap over 10 minutes, and VSLI at 2.25 mg/m2 dose infused over 60 minutes with no dose cap. Patients with neuropathy or CNS disease were excluded. PK samples, consisting of 5 mL of blood, were collected at Course 1, Day 1 at the following time-points: prior to VSLI/VCR infusion, 15 minutes to 4 hours at the end of the VSLI/VCR infusion, and 24 -48 hours at the end of the VSLI/VCR infusion. Blood samples were processed within one hour by centrifugation at 2,000 rpm for 10 minutes at 2-8°C. PK samples were processed for 13 and 7 patients in the VSLI and VCR Treatment Groups respectively. Results: 26 patients were enrolled from May 2012 to June 2014 (13 randomized to each group). Median age was 67 (range 60-77) years and median study duration was 50 days. 8 patients died during induction therapy, 5 in the VSLI Treatment Group and 3 in the VCR Treatment Group. Treatment-related deaths was 3 (12%): 2 (15%) in the VSLI Treatment Group and 1 (8%) in the VCR Treatment Group. 7 (54%) patients experienced treatment-related serious adverse events in the VSLI Treatment Group compared to 5 (38%) patients in the VCR Treatment Group. 1 patient (8%) in each group had ≥ grade 3 constipation. No patients in the VCR Treatment Group had ≥ grade 3 neuropathy, whereas 4 (31%) patients in the VSLI Treatment Group did. ORR was the same in both treatment groups with 8 (62%) patients in both treatment groups achieving CR/CRi. PK analysis demonstrated a median plasma vincristine level within 4 hours of infusion of 866 ng/mL for VSLI-treated patients, 100-fold higher than the 6 ng/mL for VCR-treated patients. A higher mean plasma vincristine levels of 877.2 ng/mL for VSLI and only 8.8 ng/mL for VCR immediately after infusion (15 minutes - 4 hours), and 153.5 ng/ml for VSLI patients and only 0.5 ng/ml for VCR 12-48 hours after infusion (Table 1). Table 1. Mean Plasma Vincristine Levels by Liquid Chromatography-Mass Spectrometry Timepoints Marqibo (VSLI) Standard Vincristine (VSI) Pre-Dose N 12* 7 Vincristine Concentration, ng/mL 0.0 (0.00) 0.0 (0.00)  Mean (SD)  Median 0 0  Min, Max 0 - 0 0 - 0 15 Min to 4 Hrs Post-Dose N 13 7 Vincristine Concentration, ng/mL Mean (SD) 877.2 (282.36) 8.8 (8.37)  Median 866 6  Min, Max 88 - 1280 0 - 25 12 to 48 Hrs Post-Dose N 13 7 Vincristine Concentration, ng/mL 153.5 (142.69) 0.5 (0.62)  Mean (SD)  Median 101 0  Min, Max 9 - 430 0 - 1 *One sample was incorrectly labeled and couldn't be analyzed. Conclusion: Liposomal vincristine (Marqibo) was successfully administered as part of the CALGB 8811 regimen in newly diagnosed ALL patients as a substitute for standard vincristine. The study was terminated prematurely due to poor enrollment, limiting conclusions that can be made regarding the safety or efficacy of VSLI versus VCR in combination with chemotherapy for older ALL patients. However of note, median plasma levels of vincristine were 100-fold higher in the patients treated with VSLI as compared to VCR. Disclosures Wang: Immunogen: Research Funding. Schiller:Sunesis: Honoraria, Research Funding. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Rao:amgen: Other: ad board; novartis: Other: ad board; Boehringer-Ingelheim: Other: Advisory Board. Goldberg:Novartis: Research Funding, Speakers Bureau; Pfizer: Research Funding; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Ariad: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau.

scholarly journals Ginsenoside Absorption Rate and Extent Enhancement of Black Ginseng (CJ EnerG) over Red Ginseng in Healthy Adults

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 487
Author(s):  
Saebyul Yoo ◽  
Bom-I Park ◽  
Do-hyun Kim ◽  
Sooyoung Lee ◽  
Seung-hoon Lee ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Molecular Weight ◽  
Absorption Rate ◽  
Systemic Exposure ◽  
Red Ginseng ◽  
Double Blind ◽  
Time Curve ◽  
Concentration Time ◽  
Black Ginseng ◽  
Clinically Significant

Red ginseng (RG) and black ginseng (BG, CJ EnerG) were prepared from fresh ginseng using one and nine cycles of steaming and drying, respectively. This process reduces the molecular weight (MW) of ginsenoside-active compounds in ginseng by removing sugar moieties from their dammaranes. We compared the pharmacokinetic characteristics of ginsenosides between BG comprising mainly low-MW ginsenosides (Rg3, Rg5, Rk1, and Rh1) and RG that predominantly contains high-MW ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1). The safety profiles and tolerability were also studied using a randomized, double-blind, single-dose, crossover clinical trial. A combination of Rb1, Rg1, and Rg3, well-known representative and functional RG components, exhibited a 1-h faster absorption rate (Tmax) and 58% higher exposure (24-h area under the concentration–time curve, AUC24) in BG than in RG. Furthermore, the combination of Rg3, Rg5, and Rk1, the major and most efficient components in BG, displayed 824% higher absorption (AUC24) in BG than in RG. The total ginsenoside showed a 5-h rapid intestinal absorption (Tmax) and 79% greater systemic exposure (AUC24) in BG than in RG. No clinically significant findings were observed in terms of safety or tolerability. Thus, BG extract was more effective than RG extract.

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 P78 Pharmacokinetics of intravenous and intranasal nalbuphine in infants

2019 ◽  
Vol 104 (6) ◽  
pp. e49.2-e49
Author(s):  
M Pfiffner ◽  
V Gotta ◽  
E Berger-Olah ◽  
M Pfister ◽  
P Vonbach
Keyword(s):  
Maximum Concentration ◽  
Opioid Analgesic ◽  
Wilcoxon Test ◽  
Noncompartmental Analysis ◽  
Open Label ◽  
Post Dose ◽  
Time Curve ◽  
Acute Setting ◽  
Non Invasive ◽  
Concentration Time

BackgroundNalbuphine is a mixed agonist-antagonist opioid analgesic agent frequently used in paediatrics, and licensed for parenteral use only. Intranasal delivery could be a safe, effective and non-invasive alternative, especially in infants in the acute setting. However, pharmacokinetic (PK) data for this route of administration is completely lacking. The aim of this study was to assess PK of nalbuphine in infants 1–3 months after single intravenous (0.05 mg/kg) and intranasal (0.1 mg/kg) application, respectively.MethodsWe conducted a prospective, single centre, open-label pharmacokinetic study in infants 1–3 months undergoing sepsis workup in the emergency unit. Included infants received alternating nalbuphine as 0.05 mg/kg intravenous bolus or as 0.1 mg/kg intranasal spray. PK samples were taken at 3 pre-defined time points (15, 30 and max. 240 min post-dose before discharge). Area under the concentration-time curve (AUC0-Tlast, and AUC0-infinity for i.v.) was calculated using noncompartmental analysis and was compared between groups using Wilcoxon test. Further parameters derived included maximum concentration (Cmax), time of maximum concentration (Tmax for i.n.) and terminal half-life (t1/2).ResultsA total of 31 patients were included in the analysis. Median age was 55 days [interquartile range 38–63] in the intranasal (N=20) and 42 [37–76] days in the iv group (N=11). Median AUC0-Tlast was 7.6 (5.4–10.4) mcg*h/L following intranasal versus 7.9 (6.0–14.7) mcg*h/L for iv administration (p=0.46). AUC0-Tlast (i.v.) covered 80 [68–83]% of AUC0-infinity. Median Cmax was 4.5 [3.5–5.6] mcg/L (i.n.) versus 6.5 [5.3–15.9] mcg/L (i.v.) (p=0.014), t1/22.4 [1.3–2.8] h (i.n.) versus 1.3 [1.1–1.5] h (i.v.) (p=0.021). Tmax occurred 37 [32–65] min after intranasal administration.ConclusionThis first PK study of intranasal nalbuphine in infants suggests that 0.1 mg/kg i.n. dosing provides similar exposure as 0.05 mg/kg i.v. in infants in terms of AUC, and hence intranasal bioavailability close to 50%.Disclosure(s)Nothing to disclose

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.

Dronabinol or Ondansetron Alone and Combined for Delayed Chemotherapy-Induced Nausea and Vomiting (CINV).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5555-5555
Author(s):  
Haresh Jhangiani ◽  
James J. Vredenburgh ◽  
Lou Barbato ◽  
Haichen Yang ◽  
Hwa-Ming Yang ◽  
...  
Keyword(s):  
Treatment Group ◽  
Active Treatment ◽  
Statistical Significance ◽  
Active Treatment Group ◽  
Total Response ◽  
Standard Regimen ◽  
Double Blind ◽  
Treatment Groups ◽  
End Point ◽  
Group D

Abstract This randomized, double-blind, placebo-controlled, parallel-group study of the antiemetic efficacy and tolerability of oral dronabinol (D) alone, D in combination with ondansetron (O), O alone, or placebo (P) in patients receiving moderate to high emetogenic chemotherapy. All patients received dexamethasone 20 mg PO and O 16 mg IV prechemotherapy. Patients receiving D, O, or D+O also received D 2.5 mg before chemotherapy and after chemotherapy on Day 1 (combined active treatment group); group P did not receive D before or after chemotherapy. Day 2: P or fixed doses of 10 mg D, 16 mg O, or D+O were administered. Days 3–5: patients received P or flexible doses of 10–20 mg D, 8–16 mg O, or D+O. Primary efficacy variable was total response (TR=nausea intensity <5 mm on a 100-mm visual analog scale, no vomiting/retching, no rescue antiemetic). Secondary efficacy parameters included nausea status and intensity and episodes of vomiting/retching. Active treatments were compared with each other and P on Days 2–5, and statistical significance was determined if P≤0.05 (unadjusted). Exploratory analyses were conducted post hoc to examine the effect of combined active treatment on Day 1 vs P. 64 patients were randomized and 61 analyzed for efficacy. On Day 1, in the combined active treatment group (n=50), significant improvement vs P (n=13) was observed for TR (79% vs 40%; P=0.024), mean nausea intensity (8 mm vs 31 mm; P=0.029), and absence of nausea (79% vs 38%; P=0.013), respectively. The end point efficacy results (Days 2–5 LOCF) for TR, nausea status/intensity, episodes of vomiting/retching are shown in the Table. On Days 2–5, TR was comparable for groups D and O. The percentage of patients without nausea was significantly greater in all treatment groups vs P. Nausea intensity was significantly reduced by all treatments vs P. The incidence of treatment-emergent AEs was similar among active treatment groups (71%–88%); AE rate in P-treated patients was 50%. Diarrhea and fatigue were the most common AEs (11%). Group D had a low incidence of CNS-related treatment-emergent AEs compared with Groups O and DO. The highest rates of the CNS-related events of dizziness and fatigue were observed in Group DO. Day 1 data suggest that the addition of dronabinol to the standard antiemetic regimen before and after chemotherapy may offer more benefit than the standard regimen alone. Thereafter, the antiemetic effect of D for delayed CINV was comparable with O. Results for D+O were similar to either agent alone. D was well tolerated. Efficacy Results at End Point Measure Units Group D, n=17 Group O, n=14 Group DO, n=17 Group P, n=13 *Cochran-Mantel-Haenszel. ‡Analysis of variance. †P≤ 0.05 vs P Median daily dose mg 20 16 17.5–20 D 12–16 O 0 Total response* % (frequency/n) 54 (7/13) 58† (7/12) 47 (7/15) 20 (2/10) Absence of nausea* % (frequency/n) 71† (10/14) 64† (9/14) 53† (9/17) 15 (2/13) Mean nausea intensity† mm (n) 10.1† (14) 24.0† (14) 14.3† (17) 48.4 (13) Mean vomiting/retching* episodes/day (n) 0.2 (13) 1.3 (12) 0.7 (17) 1.3 (10)

Maximally Tolerated Busulfan Area Under the Concentration-Time Curve (AUC) In Combination with Fludarabine as Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3499-3499
Author(s):  
Janelle Perkins ◽  
Teresa Field ◽  
Jongphil Kim ◽  
Hugo F. Fernandez ◽  
Lia Perez ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Systemic Exposure ◽  
Hematopoietic Cell ◽  
Time Curve ◽  
Concentration Time ◽  
Gvhd Prophylaxis ◽  
Dose Limiting Toxicity

Abstract Abstract 3499 Intravenous busulfan (IV Bu) dosing in hematopoietic cell transplantation (HCT) conditioning regimens has been based largely on bioequivalence studies done with the oral dosage form. As systemic exposure to Bu has been correlated to both efficacy and toxicity, we used area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to IV Bu when given daily in combination with fludarabine as HCT conditioning. Three AUC levels were planned: 6000, 7500, and 9000 micromole*min/L, in cohorts of 20 patients (pts) each, with an additional 10 pts to be enrolled at the maximally tolerated AUC. To be included, pts had be 16–65 years old and have a hematologic malignancy, an HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor, Karnofsky performance status 70–100%, and adequate organ function. The initial dose of IV Bu for the first AUC level was 170mg/m2/day on day -6 and day -5 then, on day -4 and day -3 doses were adjusted based on pharmacokinetic modeling after the first dose to achieve an average daily AUC of 6000. First doses for the subsequent cohorts were based on the linear correlation between AUC and dose in the previous cohort: 180mg/m2/day for AUC 7500 and 220mg/m2/day for AUC 9000, with dose adjustment on days -4 and -3 as described. Pharmacokinetic analysis was done after the day -3 dose to verify the accuracy of the dose adjustments. The first 20 pts in the AUC 6000 cohort (DL1) were coenrolled onto a randomized trial of GVHD prophylaxis (tacrolimus and methotrexate vs tacrolimus and mycophenolate mofetil) and were analyzed separately from a second cohort of 20 pts receiving an AUC 6000 (DL1A) and GVHD prophylaxis with tacrolimus and methotrexate. 20 pts were then enrolled onto AUC 7500 (DL2), followed by 3 pts on AUC 9000 (DL3). All DL3 pts had dose limiting toxicity so accrual to that level was stopped. An additional 9 pts have been treated to date on DL2 (5 of these are <100 days posttransplant and are not evaluable for toxicity or GVHD). The median (and range) average daily AUC for each of the cohorts were: DL1 5955 (5375-6557); DL1A 6145 (4846-7018); DL2 7555 (5920-8682); DL3 8899 (8784-8955). There were no primary engraftment failures and median times to neutrophil engraftment were: DL1 15 days, DL1A 16 days, DL2 14 days, and DL3 12 days (p=0.01). The dose-limiting toxicity seen at DL3 was hepatic venoocclusive disease (VOD) which developed in all 3 pts; two of these pts died. There were no seizures attributable to IV Bu seen at any dose level. NCI CTCAE toxicities (observed in the first 100 days unrelated to infection or GVHD) that were significantly different between the dose level groups were dermatitis and VOD with more severe toxicity seen in DL2 and DL3. Diarrhea and the use of total parenteral nutrition appeared to be more common on DL2 and DL3 but not significantly so. The cumulative incidence of acute GVHD was similar across the cohorts (p=0.11). There was no difference between the dose levels in cumulative incidence of relapse (p=0.54) or event-free survival (p=0.4). Nonrelapse mortality at 6 months was significantly different: DL1 20%, DL1A 0%, DL2 17.5% and DL3 67% (p=0.008) as was overall survival at 6 months: DL1 75%, DL1A 90%, DL2 80%, DL3 33% (p=0.04). We conclude that in the pts studied, 7500 micromole*min/L is the maximally tolerated AUC based on protocol-defined criteria but exceeding an AUC of 6000 may not provide any survival benefit. Disclosures: Perkins: PDL BioPharma: Research Funding. Off Label Use: IV busulfan was used in combination with fludarabine as conditioning prior to allogeneic hematopoietic cell transplantation in patients with a variety of hematologic malignancies. Field:PDL BioPharma: Research Funding.

scholarly journals Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study

2016 ◽  
Vol 175 (1) ◽  
pp. 85-93 ◽  
Author(s):  
Gudmundur Johannsson ◽  
Hans Lennernäs ◽  
Claudio Marelli ◽  
Kevin Rockich ◽  
Stanko Skrtic
Keyword(s):  
Replacement Therapy ◽  
Plasma Concentrations ◽  
Open Label ◽  
Post Dose ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Endogenous Cortisol ◽  
Dual Release ◽  
Dose Proportional

Objective Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure−time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5–20mg and assess intrasubject variability. Methods Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20−55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3×5), and 20mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography−tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration−time profiles. Results DR-HC 20mg provided higher than endogenous cortisol plasma concentrations 0−4h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (Cmax) was 82.0 and 178.1ng/mL, while mean area under the concentration−time curve (AUC)0−∞ was 562.8 and 1180.8h×ng/mL with DR-HC 5 and 20mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20mg. All exposure PK parameters were less than dose proportional (slope <1). PK differences between ethnicities were explained by body weight differences. Conclusions DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional – an important consideration when managing intercurrent illness in patients with adrenal insufficiency.

scholarly journals Long-Term Safety and Efficacy of rFVIIIFc in Adults and Adolescents with Severe Hemophilia A: A Longitudinal Analysis of A-LONG and ASPIRE

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1087-1087 ◽  
Author(s):  
K John Pasi ◽  
David J Perry ◽  
Johnny Mahlangu ◽  
Barbara A Konkle ◽  
Savita Rangarajan ◽  
...  
Keyword(s):  
Treatment Group ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Treatment Groups ◽  
Equity Ownership

Abstract Background: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care for patients with hemophilia A; however, prophylactic treatment with conventional FVIII products usually requires frequent intravenous infusions (3-4 times/week). Recombinant FVIII Fc fusion protein (rFVIIIFc), which is produced in a human cell line, binds the neonatal Fc receptor and utilizes the natural IgG recycling pathway to prolong the half-life of FVIII. The safety, efficacy and prolonged half-life of rFVIIIFc in adults and adolescents with severe hemophilia A were demonstrated in the phase 3 A-LONG study (NCT01027377, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in participants in these studies. Methods: This longitudinal analysis includes cumulative data from A-LONG and ASPIRE (as of the interim data cut, 6 January 2014) for subjects treated with ≥1 dose of rFVIIIFc (n=164). A-LONG evaluated 2 prophylaxis regimens-individualized (IP): 25 IU/kg on day 1 and 50 IU/kg on day 4 to start, then 25-65 IU/kg every 3-5 days, to target a 1-3 IU/dL FVIII trough level, and weekly (WP): 65 IU/kg dosed once weekly-as well as episodic (on-demand) treatment. Subjects completing A-LONG and meeting enrollment criteria for ASPIRE could participate in the IP, WP, or episodic treatment groups, or, if optimal dosing could not be achieved with IP or WP, in an additional modified prophylaxis (MP) treatment group. Subjects could change treatment groups at any point during ASPIRE. For efficacy analyses, data were summarized according to the treatment group in which each subject participated, for the time period they were in that treatment group; thus, subjects may be included in the analysis of more than one treatment group. Outcomes evaluated included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL as measured by the Nijmegen-modified Bethesda assay at a central laboratory, confirmed upon retesting within 2 to 4 weeks), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and prophylactic dose and dosing interval. Results: Of the 164 subjects dosed with rFVIIIFc during A-LONG, 153 completed the study and 150 enrolled in ASPIRE. At the time of the interim data cut, 140 subjects were ongoing in ASPIRE. Cumulatively, subjects had a median (IQR) of 25.5 (24.6, 26.7) months of rFVIIIFc treatment, and a median (IQR) of 183.0 (120.5, 232.5) rFVIIIFc exposure days (EDs). No inhibitors were reported. The estimated inhibitor incidence rate (95% CI) was 0.0% (0.0, 2.2) overall (N=164), and 0.0% (0.0, 2.7) in subjects with ≥100 rFVIIIFc EDs (n=136). The type and incidence of AEs observed were consistent with those expected for the general hemophilia population. 84.8% of subjects reported ≥1 AE on study, with the majority assessed by the investigator as mild and unrelated to rFVIIIFc treatment. 17.7% of subjects experienced at least 1 SAE; none were assessed by the investigator as related to rFVIIIFc. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP and WP (MP was not an option during A-LONG) were generally lower with rFVIIIFc treatment compared with prestudy FVIII (Figure). In the IP treatment group, the year 1 and year 2 median spontaneous ABRs were 0.0. Overall, 89.1% of bleeding episodes were controlled with 1 infusion; 97.3% with 1 or 2 infusions. Among subjects treated with FVIII prophylaxis prior to entering A-LONG (n=79), 86% were dosed at least 3 times/week. With rFVIIIFc, 96% of these subjects extended their dosing interval compared with their prestudy product, while the median (IQR) total weekly prophylactic dose was comparable (prestudy FVIII: 78.0 [60.0, 102.0] IU/kg; on-study rFVIIIFc: 75.0 [70.0, 113.2] IU/kg). Conclusions: Longitudinal data from patients with severe hemophilia A treated with rFVIIIFc in A-LONG and ASPIRE demonstrate long-term safety, with no inhibitors observed in any subjects, and efficacy in the prevention and treatment of bleeding. Low median ABRs were maintained with extended prophylactic dosing intervals, without an increase in median prophylactic factor consumption. Figure 1. Figure 1. Disclosures Pasi: Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria; Octapharma: Research Funding. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Mahlangu:Roche: Research Funding; Biotest: Speakers Bureau; Bayer, CSL, Novo Nordisk, and Biogen: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Konkle:Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; CSL Behring: Consultancy, Other: IDMC chair; Pfizer: Other: IDMC member; Octapharma: Research Funding; Novo Nordisk: Consultancy. Rangarajan:Grifols, Pfizer, and Baxter: Research Funding; Grifols: Honoraria; Sobi: Membership on an entity's Board of Directors or advisory committees; LFB: Other: Conference support. Brown:Biogen, Novo Nordisk, Baxter, and Pfizer: Other: Sponsorship to meeting. Hanabusa:Novo Nordisk, Baxalta, Bayer, Pfizer, Biogen, and KaketsuKen: Honoraria; Novo Nordisk, Baxalta, KaketsuKen, and Biogen: Membership on an entity's Board of Directors or advisory committees. Jackson:Biogen: Honoraria, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Cristiano:Biogen: Employment, Equity Ownership. Dong:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Pierce:Biogen: Equity Ownership, Other: Former employee. Allen:Biogen: Employment, Equity Ownership.

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