J ALLERGY CLIN IMMUNOL

VOLUME 131, NUMBER 2

Abstracts AB109

SUNDAY

397 JTF-Recommended Allergen Dosing Used in Multi-AllergenImmunotherapy 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 discontin-

uation. 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: Recordswere reviewed fromsequential immunotherapy started

in 2008; selecting thosewho had undergone repeat skin testing between 12-24

month onmaintenance dosing.Mixing of skin prick positive allergens targeted

the Joint Task Force immunotherapy practice parameter –recommended

‘‘optimal’’ dosing ranges for most major allergens. Recommended mainte-

nance dosing frequency was 0.5cc bimonthly, but varied.

RESULTS: 77 patients received subcutaneous immunotherapy contain-

ing, on average, 19 allergens per patient Therewas 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 16.7months

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-recom-

mended ‘‘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 BiweeklySubcutaneous Immunoglobulin: A PharmacokineticModeling 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,5Clinical Pharmacology&EarlyDevelopment,CSLLtd, Parkville,Australia.

RATIONALE: There is broad clinical experience with switching patients

with primary immunodeficiency diseases (PID) from intravenous immu-

noglobulin (IVIG) infusions every 3 or 4weeks toweekly 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 (Privigen�) and SCIG (Hizentra�) 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 Hizentra�.

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 frommonthly IVIG toweekly

SCIG.

399 The Role of Murine Myeloid Cells On Stimulation with AminoAcid Copolymers

Norio Kawamoto, MD, PhD1,2, Hidenori Ohnishi, MD, PhD1, Naomi

Kondo, MD, PhD1, Jack Strominger, MD2; 1Gifu University, Gifu, Japan,2Harvard University, Cambridge, MA.

RATIONALE: The random amino acid copolymer (poly(Y,E,A,K)n)

(Copaxone�), called YEAK, is widely used in the treatment of multiple

sclerosis and is a effective inhibitor of experimental autoimmune enceph-

alomyelitis (EAE). Recently, novel additional random amino acid copol-

ymers 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 bonemarrow

derived myeloid cells populations in mice were observed. BMDCwere co-

incubated 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

spleniccell type that secretedCCL22 (aTcell chemoattractant) on stimulation

with FYAK. The significant decrease of M1 markers and increase of M2

markersweredetectedwithYFAKstimulation, indicating the type-2 polariza-

tion 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: YFAKcan enhance type-2 polarization inmacrophages

and induce CCL22 from dendritic cells and drive CD4+CD25HIFoxp3+

T cells.

400 Berinert� (C1-Esterase Inhibitor Concentrate) Treatment IsNot Related to Prothrombotic Risk Based On PreclinicalEfficacy 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 thromboem-

bolic complications following administration of C1-esterase inhibitor

concentrates (C1-INH) and to gather further understanding on the phar-

macokinetic and pharmacodynamic (PK/PD) profile of C1-INH.

METHODS: The PK/PD behavior of C1-INH (Berinert�, CSL Behring,

Germany) was determined following subcutaneous (SC) and intravenous

(IV) application to rabbits followedbyactivitymeasurementsofC1-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-anti-

thrombin (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 IVadministration 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 occlusionwas 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.