GlycoPEGylated Filgrastim XM22 Demonstrates Dose-Dependent Activity in Comparison to Pegfilgrastim in a Dose-Escalating Study in Healthy Volunteers after Body-Weight Dependent Single Dose.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4081-4081
Author(s):  
Heinz Lubenau ◽  
Rolf Pokorny ◽  
Luis Lopez-Lazaro ◽  
Peter Bias ◽  
Bruce Wallin ◽  
...  
Keyword(s):  
Body Weight ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Cell Count ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Severe Neutropenia ◽  
Fixed Dose ◽  
Duration Of Action ◽  
Dose Dependent

Abstract XM22 is a glycoPEGylated recombinant human G-CSF that interacts with the G-CSF receptor by binding and activation. In pilot studies in non-neutropenic animals, XM22 demonstrated a similar PK/PD profile compared to pegfilgrastim. Because of its longer duration of action compared to filgrastim, XM22 is intended to be dosed once per cycle for the reduction of duration of severe neutropenia and incidence of febrile neutropenia in cancer patients undergoing chemotherapy. METHODS: A single center, randomized, single-blind study of XM22, administered as single escalating body-weight (bw) dependent doses given by the s.c. route was conducted to assess safety, pharmacokinetic profile and pharmacodynamic properties based on absolute neutrophil count (ANC) and CD34+ cell count. Male or female healthy volunteers were assigned to one of 3 XM22 dose groups, at 25 μg/kg bw dose (n=8), at 50 μg/kg bw (n=15), and 100 μg/kg bw (n=15) compared to 100 μg/kg bw pegfilgrastim (n=15). RESULTS: 53 healthy volunteers were enrolled in the three dose groups and completed 21 day follow-up. Injections were generally well-tolerated with no discontinuations due to adverse events or serious adverse events. XM22 at a dose of 100 μg/kg bw exhibited a PK profile with increased bioavailability and extended half life compared to the same dose of pegfilgrastim. ANC area over baseline effect curve (AOBEC) and CD34+ AOBEC were higher after treatment with XM22 100 μg/kg bw (6818.55 hr*neut./nl and 7340.16 hr*cell count/μl geometric mean respectively) compared to the same dose of pegfilgrastim. Antibody data will be presented. CONCLUSIONS: Single body-weight dependent doses up to 100 mg/kg of XM22 administered to healthy volunteers were generally well-tolerated with regard to the expected side effect profile and demonstrated dose-dependent increases in absolute neutrophil count and CD34+ cell count. These data supplement results from another study in healthy volunteers in which XM22 was administered as a fixed dose.

GlycoPEGylated Filgrastim XM22 Fixed Dose Demonstrates Similar Activity in Comparison to Pegfilgrastim in Healthy Volunteers after Single Administration.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4082-4082
Author(s):  
Heinz Lubenau ◽  
Rolf Pokorny ◽  
Luis Lopez-Lazaro ◽  
Peter Bias ◽  
Bruce Wallin ◽  
...  
Keyword(s):  
Body Weight ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Cell Count ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Severe Neutropenia ◽  
Fixed Dose ◽  
Duration Of Action ◽  
Treatment Groups

Abstract XM22 is a glycoPEGylated recombinant human G-CSF that interacts with the G-CSF receptor by binding and activation. In pilot studies in non-neutropenic animals, XM22 demonstrated a similar PK/PD profile compared to pegfilgrastim. By its longer duration of action compared to filgrastim a once per cycle dosing as fixed dose in chemotherapy treated cancer patients for the reduction of duration of severe neutropenia and incidence of febrile neutropenia is intended. METHODS: A single center, randomized, single-blind study of XM22, administered as single fixed dose given by the s.c. route, was conducted to assess safety, pharmacokinetic profile and pharmacodynamic properties based on absolute neutrophil count (ANC) and CD34+ cell count. Male or female healthy volunteers were assigned to either XM22 6 mg or pegfilgrastim 6 mg fixed dose treatment. RESULTS: 36 healthy volunteers were enrolled in two treatment groups and completed 21 day follow-up. Injections were generally well-tolerated with no discontinuations due to adverse events or serious adverse events. Pharmacodynamic data were compared between the fixed doses of 6 mg XM22 and pegfilgrastim and in body weight strata within the treatment groups. Pharmacokinetic and antibody data will be presented. CONCLUSIONS: Single doses of 6 mg fixed dose of XM22 administered to healthy volunteers were generally well-tolerated with regard to the expected side effect profile and demonstrated increases in absolute neutrophil count and CD34+ cell count. These results supplement data from another study in healthy volunteers in which XM22 was administered in ascending single doses adjusted according to body-weight.

scholarly journals Safety and efficacy of rifabutin among HIV/TB-coinfected children on lopinavir/ritonavir-based ART

2019 ◽  
Vol 74 (9) ◽  
pp. 2707-2715 ◽  
Author(s):  
Holly E Rawizza ◽  
Kristin M Darin ◽  
Regina Oladokun ◽  
Biobele Brown ◽  
Babatunde Ogunbosi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Treatment Options ◽  
Severe Neutropenia ◽  
Laboratory Monitoring ◽  
Safety And Efficacy ◽  
Cell Percentage ◽  
Grade 3 ◽  
Cd4 Cell

Abstract Background TB is the leading cause of death among HIV-infected children, yet treatment options for those who require PI-based ART are suboptimal. Rifabutin is the preferred rifamycin for adults on PI-based ART; only one study has evaluated its use among children on PIs and two of six children developed treatment-limiting neutropenia. Methods Since 2009, rifabutin has been available for HIV/TB-coinfected children requiring PI-based ART in the Harvard/APIN programme in Nigeria. We retrospectively analysed laboratory and clinical toxicities at baseline and during rifabutin therapy, and examined HIV/TB outcomes. Results Between 2009 and 2015, 48 children received rifabutin-containing TB therapy with PI (lopinavir/ritonavir)-based ART: 50% were female with a median (IQR) baseline age of 1.7 (0.9–5.0) years and a median (IQR) CD4+ cell percentage of 15% (9%–25%); 52% were ART experienced. Eighty-five percent completed the 6 month rifabutin course with resolution of TB symptoms and 79% were retained in care at 12 months. Adverse events (grade 1–4) were more common at baseline (27%) than during rifabutin treatment (15%) (P = 0.006). Absolute neutrophil count was lower during rifabutin compared with baseline (median = 1762 versus 2976 cells/mm3, respectively), but only one instance (2%) of grade 3 neutropenia occurred during rifabutin treatment. Conclusions With clinical and laboratory monitoring, our data suggest that rifabutin is a safe option for TB therapy among children on PI-based ART. By contrast with the only other study of this combination in children, severe neutropenia was rare. Furthermore, outcomes from this cohort suggest that rifabutin is effective, and a novel option for children who require PI-based ART. Additional study of rifabutin plus PIs in children is urgently needed.

Fatal Neutropenia and Thrombocytopenia Associated with Ticlopidine

1994 ◽  
Vol 28 (11) ◽  
pp. 1236-1238 ◽  
Author(s):  
James A. Carlson ◽  
Jon E. Maesner
Keyword(s):  
Renal Function ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Impaired Renal Function ◽  
Healthcare Professionals ◽  
Severe Neutropenia ◽  
Gram Negative ◽  
Case Summary ◽  
First Case

OBJECTIVE: To report the first case of ticlopidine-associated neutropenia resulting in sepsis and death. CASE SUMMARY: An 83-year-old Filipino man was started on ticlopidine 250 mg bid. By the seventh week of therapy his absolute neutrophil count (ANC) had dropped to 2700 from 7600 × 106 cells/L. The ticlopidine was stopped. Six days later, he was admitted to the hospital. He died 18 hours later of gram-negative sepsis. DISCUSSION: Although ticlopidine therapy was discontinued four days after the patient's ANC was 2700 × 106 cells/L, the ANC dropped to and remained at 0 until his death eight days later. This may be associated with the patient's decreased clearance of ticlopidine given his age and impaired renal function. This is the first reported case of moderate or severe neutropenia in a nonwhite patient and the first reported case of sepsis and death caused by ticlopidine CONCLUSIONS: Healthcare professionals must be aware of the possibility of severe neutropenia and death caused by ticlopidine, even when the manufacturers' monitoring guidelines are followed.

Genetic Variants in the UDP-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan

2004 ◽  
Vol 22 (8) ◽  
pp. 1382-1388 ◽  
Author(s):  
Federico Innocenti ◽  
Samir D. Undevia ◽  
Lalitha Iyer ◽  
Pei Xian Chen ◽  
Soma Das ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Total Bilirubin ◽  
Severe Neutropenia ◽  
Pharmacokinetic Data ◽  
Severe Toxicity ◽  
Genotype 3 ◽  
Count Nadir ◽  
Udp Glucuronosyltransferase

Purpose Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation. Patients and Methods Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m2 every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (−3279G>T, −3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped. Results The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P = .001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P = .02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean ± standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 ± 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 ± 0.03 mg/dL; P < .001). The −3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The −3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r2 = 0.51). Conclusion UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the −3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.

scholarly journals Agranulocytosis Associated with Topiramate: A Case Report and Review of Published Cases

2018 ◽  
Vol 2018 ◽  
pp. 1-3
Author(s):  
Saroj Lohani ◽  
Niranjan Tachamo ◽  
Salik Nazir ◽  
Anthony Donato
Keyword(s):  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Blood Count ◽  
Complete Blood Count ◽  
Case Reports ◽  
Shortness Of Breath ◽  
Data Synthesis ◽  
Rare Side Effect ◽  
Dose Dependent ◽  
Dose Dependent Effect

A 41-year-old female presented to the hospital with sore throat and shortness of breath. She was hypoxic with an oxygen saturation of 87% in room air. Physical examination revealed swollen uvula with exudates. She had been started on topiramate for treatment of migraine few months ago. The dose of topiramate was increased to 100 mg twice daily 2 weeks ago. Complete blood count revealed an absolute neutrophil count (ANC) of 8 c/mm3. She was intubated and started on broad-spectrum antibiotics. She was transferred to our hospital on the fifth day of hospitalization. On arrival, her absolute neutrophil count was 10 c/mm3. Her agranulocytosis was attributed to topiramate after ruling out other possible causes. ANC improved after topiramate was stopped. ANC increased to 1000 after 5 days of stopping topiramate. We also reviewed published cases of topiramate-associated agranulocytosis. Agranulocytosis is a rare side effect of topiramate, and only 3 case reports have been published so far. In all cases, agranulocytosis developed after months of topiramate therapy and when dose was increased to 200 mg daily suggesting a dose-dependent effect. Next steps would be further research on the pathogenesis of agranulocytosis associated with topiramate and creation of registry for data synthesis.

Successful Treatment of Refractory Idiopathic Aplastic Anemia with Rituximab

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4114-4114
Author(s):  
Sreedhar Katragadda ◽  
John C Nelson
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Blood Cell ◽  
Aplastic Anemia ◽  
Cell Count ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Red Blood Cell ◽  
Antithymocyte Globulin ◽  
Blood Cell Count

Abstract We report the first case of refractory idiopathic aplastic anemia who responded to Rituximab (anti-CD 20 monoclonal antibody). The patient is a 22 year old Hispanic male construction worker who presented with a two week history of weakness, dyspnea on exertion and gum bleeding was found to have a platelet count of 11 × 109/L, hemoglobin of 7.4 g/dL, and white blood cell count of 1.6 × 109/L with 30% neutrophils. A bone marrow biopsy showed hypocellular marrow with relative lymphocytosis of mixed B and T cells and a normal chromosome analysis. A paroxysmal nocturnal hemoglobinuria (PNH) panel was negative. Serological studies did not show any evidence of HBV, HCV, CMV or EBV infection, but did show previous infection with parvo B19. He was initially treated with horse antithymocyte globulin (ATG) at a dose of 40 mg/kg for four days and cyclosporine. After ten weeks of treatment he was still requiring weekly packed red blood cell and platelet transfusions and G-CSF support. At that time he was treated with rabbit antithymocyte globulin and cyclosporine was continued. He had a partial recovery with absolute neutrophil count remaining mostly above 1 × 109/L, but he was still requiring red blood cell and platelet transfusions with baseline hemoglobin of 6 gm/dL and platelet count of less than 20 × 109/L. A bone marrow biopsy done ten weeks after the rabbit ATG treatment showed hypocellular marrow (20% cellularity) with trilineage hematopoiesis, with no evidence of dysplasia. Due to his transfusion dependence after eight months from his rabbit ATG treatment, he received Rituximab at a dose of 375 mg/m2 weekly for four weeks. He had a dramatic improvement of hemoglobin to 11.5 gm/dL and white blood cell count to 3.5 × 109/L, with an absolute neutrophil count of 2 × 109/L, although his platelet count remained at 20 × 109/L. He remains transfusion independent for a follow-up period of 8 months after the Rituximab treatment. Review of literature showed partial to good responses with Rituximab in aplastic anemia patient who refused treatment with ATG and cyclosporine (Hansen PB et al), aplastic anemia associated with CLL (Bharwani L et al), severe aplastic anemia induced by fludarabine and cyclophosphamide in a patient with B-CLL (Castiglioni MG et al) and, refractory Diamond-Blackfan anemia (Morimoto A et al).

scholarly journals Meta-analysis and indirect treatment comparison of lipegfilgrastim with pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia-related events

2017 ◽  
Vol 24 (6) ◽  
pp. 412-423 ◽  
Author(s):  
T Christopher Bond ◽  
Erika Szabo ◽  
Susan Gabriel ◽  
Jean Klastersky ◽  
Omar Tomey ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Risk Ratio ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Bone Pain ◽  
Meta Analysis ◽  
Severe Neutropenia ◽  
Random Effects Models ◽  
Treatment Comparison ◽  
Indirect Treatment

Background Granulocyte colony-stimulating factors are effective at reducing the risk and duration of neutropenia. The current meta-analysis compared the neutropenia-related efficacy and safety of lipegfilgrastim to those of pegfilgrastim and filgrastim. Methods Embase was searched for trials examining the efficacy/safety of lipegfilgrastim, pegfilgrastim, or filgrastim. Outcomes included febrile neutropenia, severe neutropenia, duration of severe neutropenia, time to recovery of absolute neutrophil count, and incidence of bone pain. Direct comparisons were made using random-effects models. No trials directly compared lipegfilgrastim and filgrastim. Indirect comparisons were made between lipegfilgrastim and filgrastim with pegfilgrastim as the common comparator. Results This meta-analysis included a total of 5769 patients from 24 studies. Over all cycles, lipegfilgrastim showed a lower, nonsignificant risk of febrile neutropenia compared with pegfilgrastim. Lipegfilgrastim has a lower risk of febrile neutropenia versus filgrastim but was also not statistically significant. The risk ratio for severe neutropenia in cycle 1 was 0.80, a 20% reduction in favor of lipegfilgrastim. For cycles 2–4, the risk ratio was 0.53 (0.35, 0.79) for lipegfilgrastim versus pegfilgrastim. The risk of severe neutropenia in cycles 2–4 was also significantly lower for lipegfilgrastim (risk ratio 0.45, 0.27, 0.75, respectively). No significant differences were found for febrile neutropenia and severe neutropenia in cycle 1. However, in cycles 2–4, lipegfilgrastim was associated with significant and clinically meaningful reductions in risk of severe neutropenia versus either pegfilgrastim or filgrastim. Conclusions Compared with pegfilgrastim or filgrastim, lipegfilgrastim has a statistically significantly lower absolute neutrophil count recovery time; however, differences in duration of severe neutropenia and bone pain were nonsignificant.

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