Ofatumumab is a fully human anti-CD20 monoclonal immunoglobulin G1 (IgG1) antibody. The CD20 molecule is a transmembrane phosphoprotein expressed on B lymphocytes from the pre-B to mature B lymphocyte stage. The CD20 molecule is also expressed on a small fraction of activated T cells.
The binding of ofatumumab to CD20 induces lysis of CD20+ B cells primarily through complement-dependent cytotoxicity (CDC) and, to a lesser extent, through antibody-dependent cell-mediated cytotoxicity (ADCC). Ofatumumab has also been shown to induce cell lysis in both high and low CD20 expressing cells. CD20-expressing T cells are also depleted by ofatumumab.
Peripheral B-cell counts decreased after the first ofatumumab infusion in patients with haematological malignancies. In all patients with CLL, ofatumumab induces rapid and profound B-cell depletion, whether given as a single agent or in combination.
When ofatumumab was administered as single agent in patients with refractory CLL, the median decrease in B-cell counts was 22% after the first infusion and 92% at the eighth weekly infusion. Peripheral B-cell counts remained low throughout the remainder of therapy in most patients and remained below baseline up to 15 months after the last dose in patients who responded.
When ofatumumab was administered in combination with chlorambucil in patients with previously untreated CLL, the median decreases in B-cell counts after the first cycle and prior to the sixth monthly cycle were 94% and >99%. At 6 months after the last dose, the median reductions in B-cell counts were >99%.
When ofatumumab was administered in combination with fludarabine and cyclophosphamide in patients with relapsed CLL, the median decrease from baseline was 60% after the first infusion and complete depletion (100%) was reached after 4 cycles.
There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 1,000 patients across the CLL clinical programme were tested for anti-ofatumumab antibodies during and after treatment periods ranging from 8 weeks to 2 years. Formation of anti-ofatumumab antibodies was observed for less than 0.5% of patients with CLL after treatment with ofatumumab.
In the RMS clinical studies using ofatumumab 20 mg every 4 weeks, after an initial dose regimen of 20 mg on days 1, 7, and 14, administration resulted in a rapid and sustained reduction of B cells to below LLN (defined as 40 cells/µl) as early as two weeks after treatment initiation. Before initiation of the maintenance phase starting at week 4, total B-cell levels of <10 cells/µl were reached in 94% of patients, increasing to 98% of patients at week 12, and were sustained for as long as 120 weeks (i.e. while on study treatment).
Data from RMS phase III clinical studies indicate a median time to B-cell recovery to LLN or baseline value of 24.6 weeks post treatment discontinuation. PK-B cell modelling and simulation for B-cell repletion corroborate this data, predicting median time to B-cell recovery to LLN of 23 weeks post treatment discontinuation.
In RMS phase III studies, the overall incidence of treatment-induced anti-drug antibodies (ADAs) was 0.2% (2 of 914) in ofatumumab-treated patients and no patients with treatment enhancing or neutralising ADA were identified. The impact of positive ADA titers on PK, safety profile or B-cell kinetics cannot be assessed given the low incidence of ADA associated with ofatumumab.
Ofatumumab is administered by intravenous infusion; therefore, absorption is not applicable.
A monthly subcutaneous dose of 20 mg leads to a mean AUCtau of 483 µg*h/ml and a mean Cmax of 1.43 µg/ml at steady state. After subcutaneous administration, ofatumumab is believed to be predominantly absorbed via the lymphatic system similarly to other therapeutic monoclonal antibodies.
Ofatumumab has a small volume of distribution, with mean V~ss~ values ranging from 1.7 to 8.1 l across studies, dose levels, and infusion number.
The volume of distribution at steady state was estimated to be 5.42 litres following repeated subcutaneous administration of ofatumumab at a dose of 20 mg.
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.
Ofatumumab is eliminated in two ways: a target-mediated route that is related to binding to B cells and a target-independent route mediated by non-specific endocytosis followed by intracellular catabolism, as with other IgG molecules. B cells present at baseline result in a greater component of target-mediated clearance of ofatumumab at the start of therapy. Ofatumumab dosing leads to potent depletion of B cells resulting in reduced overall clearance.
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.
The main pharmacokinetic parameters of ofatumumab as a single agent or in combination are summarised in the following table.
Ofatumumab pharmacokinetic parameters (geometric mean):
| Population (treatment) | Dosing regimen | Cycle1 | Cmax (µg/ml) | AUC (µg.h/ml) | CL (ml/h) | t½ (days) |
|---|---|---|---|---|---|---|
| Refractory CLL (ofatumumab) | 1st infusion (300 mg) | Cycle 1 | 61.4 | |||
| 2000 mg: 8 weekly infusions followed by 4 monthly infusions | 12th dose | 827 | 166000 | 12.1 | 11.5 | |
| Previously untreated patients (ofatumumab + chlorambucil) | 1st infusion (300 mg) | Cycle 1 | 51.8 | 2620 | ||
| 1000 mg monthly infusions | Cycle 4 | 285 | 65100 | 15.4 | 18.5 | |
| Relapsed CLL (ofatumumab + FC) | 1st infusion (300 mg) | Cycle 1 | 61.4 | 3560 | ||
| 1000 mg on the 8th day of cycle 1 followed by 1000 mg monthly infusions | Cycle 4 | 313 | 89100 | 11.2 | 19.9 |
1 Cycle for which the pharmacokinetic parameters are presented in this table.
Cmax = maximum ofatumumab concentration at the end of infusion, AUC = exposure to ofatumumab over a dosing period, CL = ofatumumab clearance after multiple doses, T½ = terminal half-life
Numbers rounded to three significant digits
The half-life at steady state was estimated to be approximately 16 days following repeated subcutaneous administration of ofatumumab at a dose of 20 mg.
Ofatumumab had non-linear pharmacokinetics related to its decreasing clearance over time.
Age was not found to be a significant factor for ofatumumab pharmacokinetics in a cross-study population pharmacokinetic analysis of patients ranging in age from 21 to 87 years of age. Paediatric population No pharmacokinetic data are available in paediatric patients.
There are no dedicated pharmacokinetic studies of ofatumumab in patients over 55 years old due to limited clinical experience.
Gender had a modest effect (12%) on ofatumumab central volume of distribution in a cross-study population analysis, with higher Cmax and AUC values observed in female patients (48% of the patients in this analysis were male and 52% were female); these effects are not considered clinically relevant, and no dose adjustment is recommended.
Based on the results of a cross-study population analysis, body weight was identified as a covariate of exposure (Cmax and AUC) to ofatumumab in RMS subjects. However, body weight did not affect safety and efficacy measures evaluated in the clinical studies; therefore, dose adjustment is not required.
No specific studies of ofatumumab in patients with renal impairment have been performed.
Patients with mild renal impairment were included in clinical studies. There is no experience in patients with moderate and severe renal impairment. However, as ofatumumab is not excreted via urine, it is not expected that patients with renal impairment require dose modification.
Baseline calculated creatinine clearance was not found to be a significant factor on ofatumumab pharmacokinetics in a cross-study population analysis in patients with calculated creatinine clearance values ranging from 26 to 287 ml/min. No dose adjustment is recommended for mild to moderate renal impairment (creatinine clearance >30 ml/min). There are limited pharmacokinetic data in patients with severe renal impairment (creatinine clearance <30 ml/min).
No formal studies were conducted to examine the effect of 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.
Non-clinical data revealed no special hazard for humans based on conventional studies of repeated dose toxicity including safety pharmacology endpoints.
Neither carcinogenicity nor mutagenicity studies have been conducted with ofatumumab. As an antibody, ofatumumab is not expected to interact directly with DNA.
The embryo-foetal development (EFD) and the enhanced pre/post-natal development (ePPND) studies in monkeys showed that exposure to ofatumumab given intravenously during gestation caused no maternal toxicity, no teratogenicity, and no adverse effects on embryo-foetal and pre/post-natal development.
In these studies, ofatumumab was detected in the blood of the foetuses and infants, confirming placental transfer and foetal exposure to ofatumumab persisting post-natally (long half-life of the monoclonal antibody). Exposure to ofatumumab during gestation led to the expected depletion of CD20+ B cells in maternal animals and their foetuses and infants, along with a reduced spleen weight (without histological correlate) in foetuses and a reduced humoral immune response to keyhole limpet haemocyanin (KLH) in infants at high doses. All these changes were reversible during the 6-month post-natal period. In infants, early post-natal mortality was observed at a dose 160 times higher than the therapeutic dose (on AUC basis) and was likely due to potential infections secondary to immunomodulation. The NOAEL related to the pharmacological activity of ofatumumab in infants of the ePPND study leads to an AUC-based safety margin of at least 22-fold when maternal exposure at the NOAEL is compared with human exposure at the therapeutic dose of 20 mg monthly.
In a dedicated monkey fertility study, male and female fertility endpoints were unaffected.
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