Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis

Abstract

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for treatment of relapsing multiple sclerosis (MS). In the Phase II/III trials, patients received 12 or 24 mg/day of alemtuzumab in two treatment courses (5 days for course 1 and 3 days for course 2), 12 months apart. Serum concentrations of alemtuzumab peaked on the last day of dosing in each course and mostly fell below the limit of quantitation by day 30. Alemtuzumab rapidly depleted circulating T and B lymphocytes, with the lowest observed values occurring within days. Lymphocytes repopulated over time, with B cell recovery usually complete within 6 months. T lymphocytes recovered more slowly and generally did not return to baseline by 12 months post-treatment. Approximately 40 and 80% of patients had total lymphocyte counts, reaching the lower limit of normal by 6 and 12 months after each course, respectively. The clearance of alemtuzumab is dependent on circulating lymphocyte count. A majority of treated patients tested positive for anti-alemtuzumab antibodies, including inhibitory antibodies, during the 2-year studies, and a higher proportion of patients tested positive in course 2 than in course 1. The presence of anti-alemtuzumab antibody appeared to be associated with slower clearance of alemtuzumab from the circulation but had no impact on the pharmacodynamics. No effects of age, race or gender on the pharmacokinetics or pharmacodynamics were observed. Together, the pharmacokinetics, pharmacodynamics and immunogenicity results support the continued development and use of alemtuzumab for the treatment of MS, and probably explain its sustained effects beyond the dosing interval.

Trial registration: ClinicalTrials.gov NCT00530348 NCT00548405 NCT00050778.

Keywords: MS; PK/PD; alemtuzumab; immunogenicity; lymphocyte depletion and repopulation.

Figure 1

Mean (± standard deviation) alemtuzumab serum concentration over time after intravenous (i.v.) administration at 12 mg/day or 24 mg/day for 5 days in courses 1 and 3 days in course 2 with 12 months apart between courses (CARE‐MS II). Shown are profiles for course 1 of the 12‐mg cohort (upper left), course 1 of the 24‐mg cohort (upper right), course 2 of the 12‐mg cohort (lower left) and course 2 of the 24‐mg cohort (lower right). Serum concentrations increased with each daily administration within a treatment course, with the highest observed concentrations occurring following the last dose. The mean maximum serum concentration (C_max) values were comparable between courses. Serum concentrations became low or undetectable (LOQ = 60 ng/ml) within approximately 30 days following each treatment course in the 12‐mg dose group and within approximately 90 days following each treatment course in the 24‐mg dose group. D = day, M = month.

Figure 2

Mean total lymphocyte counts over time (pooled data from CARE‐MS I and CARE‐MS II). Alemtuzumab 12 mg (grey line with solid circles) or 24 mg (black line with solid circles) depleted circulating lymphocytes after each course, and repopulated after depletion. Dashed lines shown are upper limit of normal (ULN) and lower limit of normal (LLN) as marked. Mean total lymphocyte counts were reduced by 88% from baseline at month 1, were at the LLN by month 6 and were 133% of the LLN and 51% of baseline 12 months after course 1. Following the second course of alemtuzumab, mean total lymphocyte count decreased from the month 12 precourse value by 72% at month 13, which corresponded to 38% of the LLN. Mean total lymphocyte counts were at the LLN at month 18. The month 24 mean value was 139% of the LLN and 54% of baseline.

Figure 3

Median anti‐alemtuzumab antibody (ADA) and inhibitory ADA titres over time (pooled data from CARE‐MS I and CARE‐MS II). For ADA (upper panel), in the 12‐mg group (dashed line with open circles) and the 24‐mg group (solid line with filled circle), the median titres were similar and peaked at 1 month post‐dose after each treatment course (months 1 and 13). Peak ADA titres were higher following course 2 than course 1. For inhibitory ADA (lower panel), for both dose groups and in both treatment courses, titres peaked at 1 month after dose (months 1 and 13 for courses 1 and 2, respectively). Peak inhibitory ADA titres were higher in course 2, as was observed for ADA. The observed difference in median inhibitory ADA titre between dose groups was only one dilution, which is considered within the assay variability.

Figure 4

Mean lymphocyte and subset counts over time after each course of alemtuzumab (12 mg/day) by precourse or within‐course anti‐alemtuzumab antibody status in CARE‐MS I and CARE‐MS II. Throughout two courses of treatment, the presence and titre level of ADA or inhibitory ADA generally had no discernible effects on T or B lymphocyte depletion or repopulation for CD3⁺, CD4⁺, CD8⁺ and CD19⁺ lymphocyte subsets. The absolute counts of CD3⁺, CD4⁺, CD8⁺ and CD19⁺ cells were similar for patients with ADA or inhibitory ADA compared with those who were always negative for antibodies. CD3⁺, CD4⁺, CD8⁺ and CD19⁺ cells were depleted by month 1 for patients, irrespective of their ADA or inhibitory ADA status. ADA or inhibitory ADA‐positive status appeared to be associated with reduced depletion of CD16⁺CD56⁺ cells by alemtuzumab. The presence of precourse or within‐course ADA was associated with reduced depletion of CD16⁺CD56⁺ cells by alemtuzumab.

Figure 5

Pharmacokinetic–pharmacodynamic model used to model lymphocyte counts. The basic PD model was an indirect response model and was built based on the assumption that alemtuzumab causes cell lysis and acts to increase the rate of lymphocyte degradation through a direct effect of its concentration in plasma. Under this model, lymphocytes are produced at a constant zero‐order rate per day (K_in) and eliminated by a first‐order degradation rate (K_out), and the baseline lymphocyte count prior to treatment is equal to the ratio of K_in to K_out. The drug effect was linear and was only included on K_out, the rate of removal of the lymphocyte subtype. Sampling compartments are denoted by lines with solid circles at the end. V1 = volume of distribution of the central compartment; V2 = volume of distribution of the peripheral compartment; Q = intercompartmental clearance; CL = total systemic clearance; A(1) = the amount of alemtuzumab in the central compartment; Kin = zero‐order rate of production of lymphocytes; Kout = first‐order rate of lymphocyte degradation; Cp = alemtuzumab serum concentration; S = slope of the linear relationship between alemtuzumab serum concentration and its effect on lymphocyte degradation.

Figure 6

Observed total lymphocyte count versus time by observed anti‐alemtuzumab antibody status (pooled CARE‐MS I and CARE‐MS II data) for the first 100 days after dosing. A covariate in the total lymphocyte PD model was ADA where positive ADA status resulted in a slope of the cell loss–alemtuzumab concentration relationship that was less than negative ADA status, indicating a greater susceptibility of some or all lymphocytes to the effects of alemtuzumab when ADA is not present, or of lower availability of active alemtuzumab in the presence of ADA. During lymphocyte repopulation the profiles of the counts are approximately the same, and there was no apparent difference by ADA status.

Figure 7

Total lymphocyte count percentage of baseline area under the effect curve (AUEC) versus alemtuzumab exposure (pooled CARE‐MS I and CARE‐MS II data) [left panel: area under the curve (AUC); right panel: maximum serum concentration (C_max)]. At each treatment course, there was a decrease in total lymphocyte count upon exposure to alemtuzumab, with no apparent further decrease with increasing AUC or C_max. Lymphocyte depletion was consistently observed upon exposure or second re‐exposure to alemtuzumab, without correlation to C_max or AUC. There appears to be no difference in lymphocyte depletion or repopulation across the exposure range evaluated following administration of 12 or 24 mg alemtuzumab.