farmacocinÉtica de alemtuzumab

FARMACOCINÉTICA DE ALEMTUZUMAB

Javier Bautista PalomaHospital U Virgen del Rocío

What is Alemtuzumab?

• Unconjugated, nonmodulating, humanised IgG1 kappa monoclonal antibody which targets the CD52 antigen

• Recombinant DNA derived

Mechanism of ActionCD52

• 21-28 kD cell surface glycoprotein • Expressed on more than 95% of malignant

and normal T and B cells (lymphocytes, monocytes, macrophages, eosinophils)

• Function is unknown• Alemtuzumab binds to CD52 bearing cells• Causes cell death through host-effector

mechanisms (complement-mediated lysis, antibody dependent cellular cytotoxicity

67% de los pacientes habían recibido >= 3 líneas de tratamiento

Eficacia mayor en pacientes respondedores a ttos previos (37,5% vs 28,9%)

Tiempo hasta la progresión (mediana): 9 meses

Supervivencia (mediana): 16 meses

Seguridad

• Incidencia de efectos adversos graves: 49%• Muertes durante el tratamiento ó inmediatamente después: 10%

(más de la mitad directamente relacionadas con Alemtuzumab: infecciones)

• Muertes durante el seguimiento: 5%(posible relación con el tratamiento)

CAM 307 Preliminary phase III efficacy and safety of alemtuzumab vs chlorambucil as front-line therapy for patients with progressive B-cell chronic lymphociytic leukemia (BCLL)

1er ensayo clínico de Alemtuzumab en 1ª línea de LLC-B297 pacientes: Alemtuzumab vs Clorambucilo

Respuesta Completa: 24% vs 2% (p < 0.0001)

Efectos adversos graves: 34.7% vs 19.7%

EAG directamente relacionados con el fármaco: 21.1% 4.1%

Pharmacokinetic properties

The pharmacokinetics profile of MabCampath administered as a 30 mg intravenous infusion 3 times per week was evaluated in chronic lymphocytic leukaemia patients who were treated for a maximum of 12 weeks.

Peak and trough levels of MabCampath rose during the first few weeks of treatment and then approached steady state by approximately week 6.

The rise in serum concentration corresponded with a marked reduction in lymphocytosis:

Patients with peripheral lymphocyte counts of >30 000/microL at baseline had significantly lower peak and trough levels of MabCampath during the first 4 to 5 weeks of treatment compared to those with lymphocyte counts <30 000/microL.

This suggests that lymphocytosis represents a compartment in the blood in which MabCampath is concentrated.

Volumen de Distribución (SS): 0.15 L/Kg (0.1 – 0.4)

El aclaramiento sistémico disminuye con las dosis repetidas (saturación de los receptores)

Vida media de eliminación inicial: 8 h (2 – 32)

Vida media de eliminación final (SS): 6 días (1 – 14)

NO se observó diferencias por sexos

NO se observó diferencias según la edad

Vía de administración I.V.

• Incidencia elevada de reacciones agudas relacionadas con la liberación de citoquinas• Fiebre• Rigidez• Náuseas y vómitos• Erupción cutanea, urticaria, prurito, disnea broncoespasmo• Cefalea• Diarrea

• Aparecen habitualmente durante la 1ª semana de tto• Se reducen sustancialmente en semanas sucesivas• Raramente: shock anafiláctico, IAM, muerte• Debe utilizarse premedicación antihistamínica y antitérmica-analgésica

Vía de administración Subcutanea

• Intento de disminuir los problemas de la administración IV• Disminuye la incidencia de reacciones agudas• Biodisponibilidad: 50% ó inferior• Dosis acumulada necesaria para obtener los mismos niveles

plasmáticos: 6 veces superior• Se eleva mucho el coste• Mayor producción de anticuerpos frente a Alemtuzumab• Diarrea

• Se está llevando a cabo actualmente un EC aleatorizado y cruzado para comparar las características PK y PD de Alemtuzumab administrado por vía IV y SC

BCCA Protocol Summary

BCCA Protocol Summary for the Treatment of Fludarabine-Refractory B-Chronic Lymphocytic Leukemia (B-CLL) with Alemtuzumab

www.bccancer.bc.ca

Eligibility Criteria

Patients with B-CLL and• 18 years or older • Have not responded to or had early documented

relapse after Fludarabine • Have received at least one alkylating agent-

containing regimen • Life expectancy of at least 12 weeks • Rai Stage II, III or IV with symptomatic splenomegaly,

lymphadenopathy, or cytopenias related to marrow infiltration or sequestration.

• WHO performance status 0-2

Exclusion Criteria

• Hypersensitivity reactions to other monoclonal antibody therapies

• HIV seropositivity • Pregnant or lactating • New York Heart Association grade III or IV

congestive heart failure • Active systemic infection • Bulky (>5 cm) adenopathy at any site • Pre-existing autoimmune cytopenias

Dosage

• Dosing three times each week, usually MWF, for maximum of 12 weeks

• All doses flat dose in mg, not mg/m2

Week 1: 3 mg 10 mg 30 mg

Week 2+: 30 mg 30 mg 30 mg

Dosage (2)

• Escalate to 10 mg, then 30 mg only if toxicities grade I or II, and improving.

• If grade III or IV reactions occur, lower dose to maximum tolerated dose (3 or 10 mg) until well tolerated for one week, then resume escalation to maximum of 30 mg/dose.

• Maximum total weekly dose is 90 mg.• If treatment is interrupted for more than 7

days for any reason, re-initiate treatment at 3 mg, and escalate as above

• SC (thigh)(Note: divide 30 mg dose into two injection sites)

OR• IV in 100 mL NS over 2 hours

• NOTE: Due to ampoule format, draw up dose with a 5 micron filter needle. Discard all unused portions of the ampoule

Administration

Sample Pre-Printed Order

• Have Available in Treatment Room:• Diphenhydramine 50 mg for IV injection (if

required)• Epinephrine 1:1000 1 mL for IV injection (if

required, dilute in 10 mL)• Methylprednisolone 125 mg for IV injection

(if required)

• Salbutamol Nebules plus nebulizer (if required, for inhalation use)

Adverse EffectsInfusion-Related Events (2)

Premedication• Diphenhydramine 50 mg PO prior to

Alemtuzumab• Acetaminophen 650 mg PO prior to

Alemtuzumab• Prednisone 10 mg PO 15-30 minutes

prior to Alemtuzumab for the first two weeks

CONCLUSIONES

• Son necesarios más estudios para establecer el papel de Alemtuzumab

• Se necesitan EECC aleatorizados, comparativos frente a otras alternativas

• Los datos sobre características Farmacocinéticas son escasos

• Se necesitan estudios farmacocinéticos en poblaciones especiales (IR, IH, ancianos, etc.)

• Se precisa más investigación sobre vías alternativas de administración que mejoren la seguridad

Gracias!