Campath Pharmacology, Pharmacokinetics, Studies, Metabolism - Alemtuzumab

Campath Pharmacology, Pharmacokinetics, Studies, Metabolism - Alemtuzumab

CLINICAL PHARMACOLOGY

Alemtuzumab binds to CD52, a non-modulating antigen that is present on the surface of essentially all B and T lymphocytes, a majority of monocytes, macrophages, and NK cells, and a subpopulation of granulocytes. Analysis of samples collected from multiple volunteers has not identified CD52 expression on erythrocytes or hematopoetic stem cells.The proposed mechanism of action is antibody-dependent lysis of leukemic cells following cell surface binding.Campath-1H Fab binding was observed in lymphoid tissues and the mononuclear phagocyte system.A proportion of bone marrow cells,including some CD34⁺ cells,express variable levels of CD52.Significant binding was also observed in the skin and male reproductive tract (epididymis, sperm, seminal vesicle). Mature spermatozoa stain for CD52, but neither spermatogenic cells nor immature spermatozoa show evidence of staining.

The pharmacokinetic profile of Alemtuzumab was studied in a multicenter rising-dose trial in non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL).Campath was administered once weekly for a maximum of 12 weeks. Following intravenous infusions over a range of doses,the maximum serum concentration (C_max) and the area under the curve (AUC) showed relative dose proportionality. The overall average half-life (t ½ ) over the dosing interval was about 12 days. The pharmacokinetic profile of Campath administered as a 30 mg intravenous infusion three times per week was evaluated in CLL patients. Peak and trough levels of Campath rose during the first few weeks of treatment, and appeared to approach steady state by approximately week 6, although there was marked inter-patient variability. The rise in serum Campath concentration corresponded with the reduction in malignant lymphocytosis.

The safety and efficacy of Campath were evaluated in a multicenter, open-label, noncomparative study (Study 1) of 93 patients with B-cell chronic lymphocytic leukemia (B-CLL) who had been previously treated with alkylating agents and had failed treatment with fludarabine. Fludarabine failure was defined as lack of an objective partial (PR) or complete (CR) response to at least one fludarabine-containing regimen, progressive disease (PD) while on fludarabine treatment, or relapse within 6 months of the last dose of fludarabine. Patients were gradually escalated to a maintenance dose of Campath 30 mg intravenously three times per week for 4 to 12 weeks. Patients received premedication prior to infusion and anti-Pneumocystis carinii and anti-herpes prophylaxis while on treatment and for at least 2 months after the last dose of Campath.

Two supportive, multicenter, open-label, noncomparative studies of Campath enrolled a total of 56 patients with B-CLL (Studies 2 and 3).These patients had been previously treated with fludarabine or other chemotherapies. In Studies 2 and 3,the maintenance dose of Campath was 30 mg three times per week with treatment cycles of 8 and 6 weeks respectively. A slightly different dose escalation scheme was used in these trials. Premedication to ameliorate infusional reactions and anti-Pneumocystis carinii and anti-herpes prophylaxis were optional.

Objective tumor response rates and duration of response were determined using the NCI Working Group Response Criteria (1996). A comparison of patient characteristics and the results for each of these studies is summarized in Table 1. Time to event parameters, except for duration of response, are calculated from initiation of Campath therapy. Duration of response is calculated from the onset of the response.