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Safety, Tolerability, and Efficacy Of Hizentra® In Japanese Patients With Primary Immunodeficiency Over 48 Weeks
AB182 Abstracts
626
MONDAY
Flexible Dosing For HizentraÒ: Pharmacokinetic Simulations Of Various Subcutaneous Dosing Regimens and Compliance In Patients With Primary Immunodeficiency Dr. Mikhail Rojavin, PhD1, Dr. Jagdev S. Sidhu, PhD2, Dr. Martin Bexon, MD3, Dr. Jonathan M. Edelman, MD1; 1Clinical Research and Development, CSL Behring LLC, King of Prussia, PA, 2Clinical Pharmacology & Early Development, CSL Ltd, Parkville, Australia, 3Clinical Research and Development, CSL Behring AG, Berne, Switzerland. RATIONALE: Pharmacokinetic modeling and simulation analyses were performed to evaluate whether the same monthly dose of subcutaneous immunoglobulin (SCIG) can be administered in patients with primary immunodeficiency at various dosing intervals (allowing treatment flexibility) and to assess the effect of non-compliance. METHODS: Simulations of SCIG dosing used a population pharmacokinetic model developed previously, based on four studies of PrivigenÒ and HizentraÒ (data from 151 unique patients). IgG concentration-time profiles and exposure metrics (steady-state area under the IgG concentration-time curve [AUC], IgG peak concentration [Cmax], and IgG trough concentration [Cmin] ratios) were simulated for various infusion intervals or missed doses. RESULTS: The equivalent of the weekly SCIG maintenance dose administered 1, 2, 3, 5, or 7 times/week, or biweekly (every second week) produced overlapping steady-state concentration-time profiles and similar AUC, Cmax, and Cmin ratios (95% CI were 0.98–1.03, 0.95–1.09, and 0.92–1.08, respectively). Three- and 4-weekly administration resulted in higher peaks and lower troughs; the 95% CI of the AUC, Cmax, and Cmin ratios were 0.97–1.04, 1.02–1.26, and 0.86–0.98, respectively. The reduction in median exposure due to treatment non-adherence was minimal: three consecutive missed doses, replaced at the following infusion, resulted in a drop of only 4% in the median concentration relative to consistent daily dosing (recovered within 2–3 days following resumed daily dosing). CONCLUSIONS: The same total monthly SCIG dose can be administered at different intervals, from daily to biweekly, with minimal impact on serum IgG levels. Lowering of trough (Cmin) with 3- and 4-weekly administrations may be clinically relevant.
627
Effect Of Synthetic Steroids and Hydroxychloroquine On BCell IgE Production Dr. Ahila Subramanian, MD, MPH, Yingchun Han, Dr. Fred H. Hsieh, MD; Cleveland Clinic Foundation, Cleveland, OH. RATIONALE: Previous studies have suggested that hydrocortisone may potentiate IgE synthesis by B-lymphocytes. With various synthetic glucocorticoids used widely in the treatment of allergic disorders we aimed to determine if other synthetic glucocorticoids or drugs interacting with the glucocorticoid receptor may have an effect on in vitro IgE production. METHODS: U266, human IgE-producing myeloma B-cells, were treated with selected compounds for 24 to 72 hours. IgE-ELISA was performed on supernatants to quantitate the amount of IgE per sample. The results were normalized to determine the amount of IgE produced per U266 cell under each condition.
RESULTS: Drug treatment suppressed IgE production by U266 cells in the absence of cell apoptosis. At 72 hours, treatment with 1uM Hydrocortisone suppressed IgE production by 32% ( p50.005, n58), 0.1uM Dexamethasone suppressed IgE production by 35% (p50.003, n56), 10uM Budesonide suppressed IgE production by 47% (p50.0004, n58), 1uM Methylprednisone suppressed IgE production by 34% (p50.005, n55), and 100uM Hydroxychloroquine suppressed IgE production by 27% (p50.02, n58). There was no difference in IgE production of U266 cells treated with 0.1uM, 1uM, or 50uM Beclamethasone at 72 hours.
J ALLERGY CLIN IMMUNOL FEBRUARY 2014
CONCLUSIONS: Selected glucocorticoids and Hydroxychloroquine appear to have a suppressive effect on IgE production by U266 cells. No compound tested in these experiments up-regulated IgE production by U266 cells. Safety, Tolerability, and Efficacy Of HizentraÒ In Japanese Patients With Primary Immunodeficiency Over 48 Weeks Prof. Kohsuke Imai, MD, PhD1, Prof. Hirokazu Kanegane, MD, PhD2, Prof. Masafumi Yamada, MD, PhD3, Prof. Hidetoshi Takada, MD, PhD4, Prof. Tadashi Ariga, MD, PhD3, Ms. Midori Kobayashi, BSPharm, MBA5, Dr. Mikhail Rojavin, PhD6, Dr. Martin Bexon, MD7, Prof. Shigeaki Nonoyama, MD, PhD8, Prof. Toshiro Hara, MD, PhD4, Prof. Toshio Miyawaki, MD, PhD2; 1Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan, 2Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan, 3Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan, 4Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 5 Research and Development, CSL Behring K.K., Tokyo, Japan, 6Clinical Research and Development, CSL Behring LLC, King of Prussia, PA, 7 Clinical Research and Development, CSL Behring AG, Berne, Switzerland, 8Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan. RATIONALE: HizentraÒ immunoglobulin for subcutaneous use has been shown to be well tolerated and efficacious in adult and pediatric Japanese patients with primary immunodeficiency (PID) over 24 weeks. This report combines results from Japanese Phase III and Phase III follow-up studies to evaluate the safety and efficacy of HizentraÒ over 48 weeks. METHODS: Twenty-five Japanese patients with PID participated in the Phase III study, with 23 thereof enrolling in a 24-week prospective, multicenter, open-label, single-arm Phase III follow-up study. Patients received weekly HizentraÒ infusions for up to 48 weeks. Safety endpoints were the rate, severity, and relatedness of adverse events (AEs) per infusion. Efficacy evaluations included serum IgG trough levels and serious bacterial infections (SBIs). RESULTS: All patients (25) experienced at least one AE (452 AEs reported, 0.406 AE/infusion). Two serious AEs were reported: encephalitis (severe) and bacterial infection (moderate); both were considered unrelated to HizentraÒ. All other AEs were mild or moderate in intensity. The highest incidence of patients with AEs, excluding infection, involved local reactions (21 patients, 84%), the frequency of which decreased substantially over the course of the studies. The mean HizentraÒ dose/week was 92.8 mg/kg (range: 26.7–177.8) in the follow-up study. Treatment with HizentraÒ maintained high and stable serum IgG levels (mean 7.47–8.05 g/L) and effective passive immunity to control infections (no SBIs reported). CONCLUSIONS: HizentraÒ was well tolerated and efficacious in Japanese patients with PID treated over 48 weeks. These Japanese studies confirm the safety and efficacy profile of HizentraÒ observed in studies conducted in Europe and the US.
628
626
MONDAY
Flexible Dosing For HizentraÒ: Pharmacokinetic Simulations Of Various Subcutaneous Dosing Regimens and Compliance In Patients With Primary Immunodeficiency Dr. Mikhail Rojavin, PhD1, Dr. Jagdev S. Sidhu, PhD2, Dr. Martin Bexon, MD3, Dr. Jonathan M. Edelman, MD1; 1Clinical Research and Development, CSL Behring LLC, King of Prussia, PA, 2Clinical Pharmacology & Early Development, CSL Ltd, Parkville, Australia, 3Clinical Research and Development, CSL Behring AG, Berne, Switzerland. RATIONALE: Pharmacokinetic modeling and simulation analyses were performed to evaluate whether the same monthly dose of subcutaneous immunoglobulin (SCIG) can be administered in patients with primary immunodeficiency at various dosing intervals (allowing treatment flexibility) and to assess the effect of non-compliance. METHODS: Simulations of SCIG dosing used a population pharmacokinetic model developed previously, based on four studies of PrivigenÒ and HizentraÒ (data from 151 unique patients). IgG concentration-time profiles and exposure metrics (steady-state area under the IgG concentration-time curve [AUC], IgG peak concentration [Cmax], and IgG trough concentration [Cmin] ratios) were simulated for various infusion intervals or missed doses. RESULTS: The equivalent of the weekly SCIG maintenance dose administered 1, 2, 3, 5, or 7 times/week, or biweekly (every second week) produced overlapping steady-state concentration-time profiles and similar AUC, Cmax, and Cmin ratios (95% CI were 0.98–1.03, 0.95–1.09, and 0.92–1.08, respectively). Three- and 4-weekly administration resulted in higher peaks and lower troughs; the 95% CI of the AUC, Cmax, and Cmin ratios were 0.97–1.04, 1.02–1.26, and 0.86–0.98, respectively. The reduction in median exposure due to treatment non-adherence was minimal: three consecutive missed doses, replaced at the following infusion, resulted in a drop of only 4% in the median concentration relative to consistent daily dosing (recovered within 2–3 days following resumed daily dosing). CONCLUSIONS: The same total monthly SCIG dose can be administered at different intervals, from daily to biweekly, with minimal impact on serum IgG levels. Lowering of trough (Cmin) with 3- and 4-weekly administrations may be clinically relevant.
627
Effect Of Synthetic Steroids and Hydroxychloroquine On BCell IgE Production Dr. Ahila Subramanian, MD, MPH, Yingchun Han, Dr. Fred H. Hsieh, MD; Cleveland Clinic Foundation, Cleveland, OH. RATIONALE: Previous studies have suggested that hydrocortisone may potentiate IgE synthesis by B-lymphocytes. With various synthetic glucocorticoids used widely in the treatment of allergic disorders we aimed to determine if other synthetic glucocorticoids or drugs interacting with the glucocorticoid receptor may have an effect on in vitro IgE production. METHODS: U266, human IgE-producing myeloma B-cells, were treated with selected compounds for 24 to 72 hours. IgE-ELISA was performed on supernatants to quantitate the amount of IgE per sample. The results were normalized to determine the amount of IgE produced per U266 cell under each condition.
RESULTS: Drug treatment suppressed IgE production by U266 cells in the absence of cell apoptosis. At 72 hours, treatment with 1uM Hydrocortisone suppressed IgE production by 32% ( p50.005, n58), 0.1uM Dexamethasone suppressed IgE production by 35% (p50.003, n56), 10uM Budesonide suppressed IgE production by 47% (p50.0004, n58), 1uM Methylprednisone suppressed IgE production by 34% (p50.005, n55), and 100uM Hydroxychloroquine suppressed IgE production by 27% (p50.02, n58). There was no difference in IgE production of U266 cells treated with 0.1uM, 1uM, or 50uM Beclamethasone at 72 hours.
J ALLERGY CLIN IMMUNOL FEBRUARY 2014
CONCLUSIONS: Selected glucocorticoids and Hydroxychloroquine appear to have a suppressive effect on IgE production by U266 cells. No compound tested in these experiments up-regulated IgE production by U266 cells. Safety, Tolerability, and Efficacy Of HizentraÒ In Japanese Patients With Primary Immunodeficiency Over 48 Weeks Prof. Kohsuke Imai, MD, PhD1, Prof. Hirokazu Kanegane, MD, PhD2, Prof. Masafumi Yamada, MD, PhD3, Prof. Hidetoshi Takada, MD, PhD4, Prof. Tadashi Ariga, MD, PhD3, Ms. Midori Kobayashi, BSPharm, MBA5, Dr. Mikhail Rojavin, PhD6, Dr. Martin Bexon, MD7, Prof. Shigeaki Nonoyama, MD, PhD8, Prof. Toshiro Hara, MD, PhD4, Prof. Toshio Miyawaki, MD, PhD2; 1Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan, 2Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan, 3Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan, 4Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 5 Research and Development, CSL Behring K.K., Tokyo, Japan, 6Clinical Research and Development, CSL Behring LLC, King of Prussia, PA, 7 Clinical Research and Development, CSL Behring AG, Berne, Switzerland, 8Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan. RATIONALE: HizentraÒ immunoglobulin for subcutaneous use has been shown to be well tolerated and efficacious in adult and pediatric Japanese patients with primary immunodeficiency (PID) over 24 weeks. This report combines results from Japanese Phase III and Phase III follow-up studies to evaluate the safety and efficacy of HizentraÒ over 48 weeks. METHODS: Twenty-five Japanese patients with PID participated in the Phase III study, with 23 thereof enrolling in a 24-week prospective, multicenter, open-label, single-arm Phase III follow-up study. Patients received weekly HizentraÒ infusions for up to 48 weeks. Safety endpoints were the rate, severity, and relatedness of adverse events (AEs) per infusion. Efficacy evaluations included serum IgG trough levels and serious bacterial infections (SBIs). RESULTS: All patients (25) experienced at least one AE (452 AEs reported, 0.406 AE/infusion). Two serious AEs were reported: encephalitis (severe) and bacterial infection (moderate); both were considered unrelated to HizentraÒ. All other AEs were mild or moderate in intensity. The highest incidence of patients with AEs, excluding infection, involved local reactions (21 patients, 84%), the frequency of which decreased substantially over the course of the studies. The mean HizentraÒ dose/week was 92.8 mg/kg (range: 26.7–177.8) in the follow-up study. Treatment with HizentraÒ maintained high and stable serum IgG levels (mean 7.47–8.05 g/L) and effective passive immunity to control infections (no SBIs reported). CONCLUSIONS: HizentraÒ was well tolerated and efficacious in Japanese patients with PID treated over 48 weeks. These Japanese studies confirm the safety and efficacy profile of HizentraÒ observed in studies conducted in Europe and the US.
628