Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab

Abstract

Eculizumab is the first drug approved for the treatment of complement-mediated diseases, and current dosage schedules result in large interindividual drug concentrations. This review provides insight into the pharmacokinetic and pharmacodynamic properties of eculizumab, both for reported on-label (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis) and off-label (hematopoietic stem cell transplantation-associated thrombotic microangiopathy) indications. Furthermore, we discuss the potential of therapeutic drug monitoring to individualize treatment and reduce costs.

Fig. 1

The complement system, which consists of three pathways that all converge at C3. The classical pathway is depicted in the left upper quadrant, the lectin pathway is depicted in right upper quadrant, and the alternative pathway is depicted in the middle on the right. After activation, C3 convertases (C2aC4a or C3bBb) are formed, and subsequently C5 convertases (C2aC4bC3b or C3bBbC3b), resulting in the formation of the lytic pore and end product of the complement system (C5b-C9).To prevent overactivation, the complement system is tightly controlled by various complement regulators such as factor H and factor I. Eculizumab is a humanized (chimeric) monoclonal antibody and is able to bind one or two C5 molecules, thereby preventing the cleavage of C5 into C5a and C5b, and hence blocking formation of C5b-C9. Fb factor b, MAC membrane attack complex, MBL mannose binding lectin

Fig. 2

Effect of TDM in PNH. TDM can guide therapy adjustments. We simulated 1000 PNH patients and assessed the pharmacokinetics of eculizumab at steady state (after 8 weeks of standard treatment, including the induction phase) and applied a protocol for TDM based on the measurement of the steady-state C_trough, using the following algorithm: the absolute dose at each administration (900 mg) remained the same, but the dosing interval was adjusted, based on the measured C_trough levels. When C_trough levels were below the target of 30 µg/ml, we decreased the dosing interval from 2 weeks to 1 week. When the C_trough was between 30 and 90 µg/ml, the usual 2-week interval was maintained. At higher exposure, the dosing intervals were extended: a C_trough of 90–120 resulted in a 3-week dosing interval, a C_trough between 120 and 210 µg/ml resulted in a 4-week interval, and a C_trough > 210 µg/ml resulted in an interval of 5 weeks. Large variations are observed in C_trough levels when simulated in 1000 PNH patients according to the compartment model, as described by the pharmaceutical company. (a) A substantial number of patients do not reach the target of 35 µg/ml (red dotted line), and, in contrast, some patients reach C_trough levels up to 362 µg/ml. (b) By applying TDM, the distribution can be largely diminished, with almost all patients reaching target attainment and adequate inhibition of C5 activity, as measured by serum complement hemolytic activity. TDM therapeutic drug monitoring, PNH paroxysmal nocturnal hemoglobinuria, C_trough trough concentration