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JTF-Recommended Allergen Dosing Used in Multi-Allergen Immunotherapy Induces Loss of Skin Test Reactivity
Abstracts AB109
J ALLERGY CLIN IMMUNOL VOLUME 131, NUMBER 2
JTF-Recommended Allergen Dosing Used in Multi-Allergen Immunotherapy Induces Loss of Skin Test Reactivity Michael Vaughn, MD, PhD1, Adrianne Vaughn, MD2; 1Alamo Asthma & Allergy, San Antonio, TX, 2Alamo Allergy & Asthma, San Antonio, TX. RATIONALE: Immunotherapy can induce immunological changes that can result in long-term remission of symptoms after treatment discontinuation. The loss of skin test reactivity may be a marker for successful desensitization. We have evaluated the relationship between cumulative allergen doses and the loss of skin test reactivity with a retrospective review of our records. METHODS: Records were reviewed from sequential immunotherapy started in 2008; selecting those who had undergone repeat skin testing between 12-24 month on maintenance dosing. Mixing of skin prick positive allergens targeted the Joint Task Force immunotherapy practice parameter –recommended ‘‘optimal’’ dosing ranges for most major allergens. Recommended maintenance dosing frequency was 0.5cc bimonthly, but varied. RESULTS: 77 patients received subcutaneous immunotherapy containing, on average, 19 allergens per patient There was no significant difference in allergen number between groups (p50.73). Serial skin testing changes were compared between those who had received monthly immunotherapy > 0.49cc (group 1) and 0.1-0.49cc (group 2). Groups 1 & 2 received maintenance immunotherapy for a similar average of 16.8 and 16.7 months respectively (p50.76). There was a significant 15.7% difference in mean loss of skin test reactivity between groups (p50.015). A greater than 50% loss of reactivity was seen in 59% of group 1 and 17.6% of group 2. The average administered volumes for groups 1 & 2 were 0.84cc/mo. and 0.35cc/mo. respectively. CONCLUSIONS: Multi-allergen immunotherapy, targeting JTF-recommended ‘‘optimal’’ dosing recommendations, commonly results in the loss of skin test reactivity. Cumulative allergen doses of only 2-3 fold lower than recommended often failed to induce skin test sensitivity loss.
398
Switching From Monthly Intravenous to Biweekly Subcutaneous Immunoglobulin: A Pharmacokinetic Modeling and Simulation Approach Mikhail Rojavin, PhD1, Cornelia Landersdorfer2, Martin Bexon, MD3, Marc Pfister4, Jagdev S. Sidhu5; 1Clinical Research and Development, CSL Behring LLC, King of Prussia, PA, 2Centre for Medicine Use and Safety, Monash University, Parkville, Australia, 3CSL Behring AG, Bern 22, Switzerland, 4Quantitative Solutions, Inc., Bridgewater, NJ, 5 Clinical Pharmacology & Early Development, CSL Ltd, Parkville, Australia. RATIONALE: There is broad clinical experience with switching patients with primary immunodeficiency diseases (PID) from intravenous immunoglobulin (IVIG) infusions every 3 or 4 weeks to weekly administration of subcutaneous immunoglobulin (SCIG). Pharmacokinetic modeling and simulation was conducted to predict the pharmacokinetic outcomes of switching from IVIG to biweekly SCIG dosing. METHODS: A population pharmacokinetic model based on data from clinical trials with IVIG (PrivigenÒ) and SCIG (HizentraÒ) was used to simulate a switch from 3- or 4-weekly IVIG to 2-weekly (biweekly) SCIG administration. In 100 simulated clinical trials each with 25 patients randomly selected from a pool of 151 patients, a switch to SCIG at the same or a 1.53-fold higher 4-weekly dose was modeled. The latter was required to achieve equivalent areas under the concentration-time curve (AUC) as recommended in the US prescribing information for HizentraÒ. RESULTS: With a dose-equivalent switch from IVIG to biweekly SCIG, the AUC ratio was 0.83 (5th–95th prediction interval [PI] 0.79–0.88), while the use of a conversion factor of 1.53 resulted in equivalent AUC (ratio 1.02; 5th–95th PI 0.96–1.09). Serum IgG trough concentrations after the dose-equivalent switch were similar to those achieved on IVIG (ratio 0.97; 5th–95th PI 0.91–1.02), whereas with the conversion factor 1.53, SCIG trough concentrations were considerably higher (ratio 1.15; 5th– 95th PI 1.08–1.22). CONCLUSIONS: These simulations indicate that the pharmacokinetic metrics following a switch from IVIG to biweekly SCIG are similar to
those observed in clinical trials after a switch from monthly IVIG to weekly SCIG.
399
The Role of Murine Myeloid Cells On Stimulation with Amino Acid Copolymers Norio Kawamoto, MD, PhD1,2, Hidenori Ohnishi, MD, PhD1, Naomi Kondo, MD, PhD1, Jack Strominger, MD2; 1Gifu University, Gifu, Japan, 2 Harvard University, Cambridge, MA. RATIONALE: The random amino acid copolymer (poly(Y,E,A,K)n) (CopaxoneÒ), called YEAK, is widely used in the treatment of multiple sclerosis and is a effective inhibitor of experimental autoimmune encephalomyelitis (EAE). Recently, novel additional random amino acid copolymers poly(Y,F,A,K)n, called YFAK, has been synthesized and found better effect on EAE than that of YEAK. However, the mechanisms of the effect of these copolymers are remains unclear, and it has been investigated. METHODS: Surface markers and mRNA levels of type-1 Macrophage (M1) markers (SPHK1, IL-12 and IP-10) and type-2 Macrophage (M2) markers (FIZZ1 and CCL22) of spleen cell after YFAK administration were observed. Cytokine/Chemokine secretion of splenic and bone marrow derived myeloid cells populations in mice were observed. BMDC were coincubated with na€ıve CD4+CD25-T cells with or without the YFAK. RESULTS: After administration of YFAK to mice, CD11b+CD11c- and CD11b+CD11c+myeloid cells were increased and the latter were the major splenic cell type that secreted CCL22 (a T cell chemoattractant) on stimulation with FYAK. The significant decrease of M1 markers and increase of M2 markers were detected with YFAK stimulation, indicating the type-2 polarization of macrophages. Finally, incubation of these BMDC or splenic DC with na€ıve CD4+CD25- T cells resulted in formation of CD4+CD25HIFoxp3+T cells (;25% of which were Foxp3+). The number of these regulatory cells was doubled by pretreatment of BMDC with amino acid copolymers. CONCLUSIONS: YFAK can enhance type-2 polarization in macrophages and induce CCL22 from dendritic cells and drive CD4+CD25HIFoxp3+ T cells.
400
BerinertÒ (C1-Esterase Inhibitor Concentrate) Treatment Is Not Related to Prothrombotic Risk Based On Preclinical Efficacy and Safety Investigations Eva Herzog, Daniel Schuermann, Elmar Raquet, Sabine Zollner, Ingo Pragst; CSL Behring GmbH, Marburg, Germany. RATIONALE: The current preclinical investigations were conducted in the context of recent reports suggesting an increased risk for thromboembolic complications following administration of C1-esterase inhibitor concentrates (C1-INH) and to gather further understanding on the pharmacokinetic and pharmacodynamic (PK/PD) profile of C1-INH. METHODS: The PK/PD behavior of C1-INH (BerinertÒ, CSL Behring, Germany) was determined following subcutaneous (SC) and intravenous (IV) application to rabbits followed by activity measurements of C1-esterase, coagulation factors FXI and FXII. Potential prothrombotic risk was assessed following induction of venous stasis and arterial thrombosis complemented by surrogate markers such as thromboelastographic parameters, thrombin generation, platelet aggregation, clotting times (aPTT, PT), thrombin-antithrombin (TAT) complexes, and prothrombin fragments F1+F2. RESULTS: An overall exposure of 115 and 151 hours*IU/mL, and a maximum plasma level of 1.7 and 7.5 IU/mL, was determined following SC and IV administration of 200 IU/kg, respectively. Intravenous doses of up to 800 IU/kg resulted in a dose-dependent inhibition of C1-esterase, FXI and FXII and did not potentiate thrombus formation following venous stasis induction. Furthermore, inhibition of arterial occlusion was observed compared to placebo treatment. This was corroborated by increased aPTT, decreased thrombin generation, inhibition of platelet aggregation and absence of TAT or F1+F2 fragments. CONCLUSIONS: These results suggest an excellent pharmacokinetic profile of C1-INH and indicate no prothrombotic risk associated with C1-INH treatment at doses up to 800 U/kg based on investigations using a pharmacologically relevant and sensitive animal species in the absence of co-morbidities.
SUNDAY
397
J ALLERGY CLIN IMMUNOL VOLUME 131, NUMBER 2
JTF-Recommended Allergen Dosing Used in Multi-Allergen Immunotherapy Induces Loss of Skin Test Reactivity Michael Vaughn, MD, PhD1, Adrianne Vaughn, MD2; 1Alamo Asthma & Allergy, San Antonio, TX, 2Alamo Allergy & Asthma, San Antonio, TX. RATIONALE: Immunotherapy can induce immunological changes that can result in long-term remission of symptoms after treatment discontinuation. The loss of skin test reactivity may be a marker for successful desensitization. We have evaluated the relationship between cumulative allergen doses and the loss of skin test reactivity with a retrospective review of our records. METHODS: Records were reviewed from sequential immunotherapy started in 2008; selecting those who had undergone repeat skin testing between 12-24 month on maintenance dosing. Mixing of skin prick positive allergens targeted the Joint Task Force immunotherapy practice parameter –recommended ‘‘optimal’’ dosing ranges for most major allergens. Recommended maintenance dosing frequency was 0.5cc bimonthly, but varied. RESULTS: 77 patients received subcutaneous immunotherapy containing, on average, 19 allergens per patient There was no significant difference in allergen number between groups (p50.73). Serial skin testing changes were compared between those who had received monthly immunotherapy > 0.49cc (group 1) and 0.1-0.49cc (group 2). Groups 1 & 2 received maintenance immunotherapy for a similar average of 16.8 and 16.7 months respectively (p50.76). There was a significant 15.7% difference in mean loss of skin test reactivity between groups (p50.015). A greater than 50% loss of reactivity was seen in 59% of group 1 and 17.6% of group 2. The average administered volumes for groups 1 & 2 were 0.84cc/mo. and 0.35cc/mo. respectively. CONCLUSIONS: Multi-allergen immunotherapy, targeting JTF-recommended ‘‘optimal’’ dosing recommendations, commonly results in the loss of skin test reactivity. Cumulative allergen doses of only 2-3 fold lower than recommended often failed to induce skin test sensitivity loss.
398
Switching From Monthly Intravenous to Biweekly Subcutaneous Immunoglobulin: A Pharmacokinetic Modeling and Simulation Approach Mikhail Rojavin, PhD1, Cornelia Landersdorfer2, Martin Bexon, MD3, Marc Pfister4, Jagdev S. Sidhu5; 1Clinical Research and Development, CSL Behring LLC, King of Prussia, PA, 2Centre for Medicine Use and Safety, Monash University, Parkville, Australia, 3CSL Behring AG, Bern 22, Switzerland, 4Quantitative Solutions, Inc., Bridgewater, NJ, 5 Clinical Pharmacology & Early Development, CSL Ltd, Parkville, Australia. RATIONALE: There is broad clinical experience with switching patients with primary immunodeficiency diseases (PID) from intravenous immunoglobulin (IVIG) infusions every 3 or 4 weeks to weekly administration of subcutaneous immunoglobulin (SCIG). Pharmacokinetic modeling and simulation was conducted to predict the pharmacokinetic outcomes of switching from IVIG to biweekly SCIG dosing. METHODS: A population pharmacokinetic model based on data from clinical trials with IVIG (PrivigenÒ) and SCIG (HizentraÒ) was used to simulate a switch from 3- or 4-weekly IVIG to 2-weekly (biweekly) SCIG administration. In 100 simulated clinical trials each with 25 patients randomly selected from a pool of 151 patients, a switch to SCIG at the same or a 1.53-fold higher 4-weekly dose was modeled. The latter was required to achieve equivalent areas under the concentration-time curve (AUC) as recommended in the US prescribing information for HizentraÒ. RESULTS: With a dose-equivalent switch from IVIG to biweekly SCIG, the AUC ratio was 0.83 (5th–95th prediction interval [PI] 0.79–0.88), while the use of a conversion factor of 1.53 resulted in equivalent AUC (ratio 1.02; 5th–95th PI 0.96–1.09). Serum IgG trough concentrations after the dose-equivalent switch were similar to those achieved on IVIG (ratio 0.97; 5th–95th PI 0.91–1.02), whereas with the conversion factor 1.53, SCIG trough concentrations were considerably higher (ratio 1.15; 5th– 95th PI 1.08–1.22). CONCLUSIONS: These simulations indicate that the pharmacokinetic metrics following a switch from IVIG to biweekly SCIG are similar to
those observed in clinical trials after a switch from monthly IVIG to weekly SCIG.
399
The Role of Murine Myeloid Cells On Stimulation with Amino Acid Copolymers Norio Kawamoto, MD, PhD1,2, Hidenori Ohnishi, MD, PhD1, Naomi Kondo, MD, PhD1, Jack Strominger, MD2; 1Gifu University, Gifu, Japan, 2 Harvard University, Cambridge, MA. RATIONALE: The random amino acid copolymer (poly(Y,E,A,K)n) (CopaxoneÒ), called YEAK, is widely used in the treatment of multiple sclerosis and is a effective inhibitor of experimental autoimmune encephalomyelitis (EAE). Recently, novel additional random amino acid copolymers poly(Y,F,A,K)n, called YFAK, has been synthesized and found better effect on EAE than that of YEAK. However, the mechanisms of the effect of these copolymers are remains unclear, and it has been investigated. METHODS: Surface markers and mRNA levels of type-1 Macrophage (M1) markers (SPHK1, IL-12 and IP-10) and type-2 Macrophage (M2) markers (FIZZ1 and CCL22) of spleen cell after YFAK administration were observed. Cytokine/Chemokine secretion of splenic and bone marrow derived myeloid cells populations in mice were observed. BMDC were coincubated with na€ıve CD4+CD25-T cells with or without the YFAK. RESULTS: After administration of YFAK to mice, CD11b+CD11c- and CD11b+CD11c+myeloid cells were increased and the latter were the major splenic cell type that secreted CCL22 (a T cell chemoattractant) on stimulation with FYAK. The significant decrease of M1 markers and increase of M2 markers were detected with YFAK stimulation, indicating the type-2 polarization of macrophages. Finally, incubation of these BMDC or splenic DC with na€ıve CD4+CD25- T cells resulted in formation of CD4+CD25HIFoxp3+T cells (;25% of which were Foxp3+). The number of these regulatory cells was doubled by pretreatment of BMDC with amino acid copolymers. CONCLUSIONS: YFAK can enhance type-2 polarization in macrophages and induce CCL22 from dendritic cells and drive CD4+CD25HIFoxp3+ T cells.
400
BerinertÒ (C1-Esterase Inhibitor Concentrate) Treatment Is Not Related to Prothrombotic Risk Based On Preclinical Efficacy and Safety Investigations Eva Herzog, Daniel Schuermann, Elmar Raquet, Sabine Zollner, Ingo Pragst; CSL Behring GmbH, Marburg, Germany. RATIONALE: The current preclinical investigations were conducted in the context of recent reports suggesting an increased risk for thromboembolic complications following administration of C1-esterase inhibitor concentrates (C1-INH) and to gather further understanding on the pharmacokinetic and pharmacodynamic (PK/PD) profile of C1-INH. METHODS: The PK/PD behavior of C1-INH (BerinertÒ, CSL Behring, Germany) was determined following subcutaneous (SC) and intravenous (IV) application to rabbits followed by activity measurements of C1-esterase, coagulation factors FXI and FXII. Potential prothrombotic risk was assessed following induction of venous stasis and arterial thrombosis complemented by surrogate markers such as thromboelastographic parameters, thrombin generation, platelet aggregation, clotting times (aPTT, PT), thrombin-antithrombin (TAT) complexes, and prothrombin fragments F1+F2. RESULTS: An overall exposure of 115 and 151 hours*IU/mL, and a maximum plasma level of 1.7 and 7.5 IU/mL, was determined following SC and IV administration of 200 IU/kg, respectively. Intravenous doses of up to 800 IU/kg resulted in a dose-dependent inhibition of C1-esterase, FXI and FXII and did not potentiate thrombus formation following venous stasis induction. Furthermore, inhibition of arterial occlusion was observed compared to placebo treatment. This was corroborated by increased aPTT, decreased thrombin generation, inhibition of platelet aggregation and absence of TAT or F1+F2 fragments. CONCLUSIONS: These results suggest an excellent pharmacokinetic profile of C1-INH and indicate no prothrombotic risk associated with C1-INH treatment at doses up to 800 U/kg based on investigations using a pharmacologically relevant and sensitive animal species in the absence of co-morbidities.
SUNDAY
397