Biotransformation

Ofatumumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Classical biotransformation studies have not been performed.

Elimination

Ofatumumab is eliminated in two ways: a target-independent route like other IgG molecules and a target-mediated route which is related to binding to B cells. There was a rapid and sustained depletion of CD20+ B cells after the first ofatumumab infusion, leaving a reduced number of CD20+ cells available for the antibody to bind at subsequent infusions. As a result, ofatumumab clearance values were lower and t½ values were significantly larger after later infusions than after the initial infusion; during repeated weekly infusions, ofatumumab AUC and Cmax values increased more than the expected accumulation based on first infusion data.

Across the studies in patients with CLL, the mean values for CL and t½ were 64 ml/h (range 4.3-1,122 ml/h) and 1.3 days (range 0.2-6.0 days) after the first infusion, 8.5 ml/h (range 1.3-41.5 ml/h) and 11.5 days (range 2.3-30.6 days) after the fourth infusion, 9.5 ml/h (range 2.2-23.7 ml/h) and 15.8 days (range 8.8-61.5 days) after the eighth infusion, and 10.1 ml/h (range 3.3-23.6 ml/h) and 13.9 days (range 9.0-29.2 days) after the twelfth infusion.

Elderly (greater than or equal to 65 years of age)

Age was not found to be a significant factor on ofatumumab pharmacokinetics in a cross-study population pharmacokinetic analysis of patients ranging in age from 21 to 86 years of age.

Children and adolescents

No pharmacokinetic data are available in paediatric patients.

Gender

Gender had a modest effect (14-25%) on ofatumumab pharmacokinetics in a cross-study analysis, with higher Cmax and AUC values observed in female patients (41% of the patients in this analysis were male and 59% were female); these effects are not considered clinically relevant, and no dose adjustment is recommended.

Renal impairment

Baseline calculated creatinine clearance was not found to be a clinically significant factor on ofatumumab pharmacokinetics in a cross-study population analysis in patients with calculated creatinine clearance values ranging from 33 to 287 ml/min. No dose adjustment is recommended for mild to moderate renal impairment (creatinine clearance >30 ml/min). There are no pharmacokinetic data in patients with severe renal impairment (creatinine clearance <30 ml/min).

Hepatic impairment

No pharmacokinetic data are available in patients with hepatic impairment. IgG1 molecules such as ofatumumab are catabolised by ubiquitous proteolytic enzymes, which are not restricted to hepatic tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of ofatumumab.

5.3 Preclinical safety data

 Preclinical data reveal no special hazards for humans.

Intravenous and subcutaneous administration to monkeys resulted in the expected depletion of peripheral and lymphoid tissue B cell counts with no associated toxicological findings. As anticipated, a reduction in the IgG humoral immune response to keyhole limpet haemocyanin was noted, but there were no effects on delayed-type hypersensitivity responses. In a few animals, increased red cell destructio