Christophe Passot

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3–4xa0L) and their elimination half-life usually ranges from 2 to 3xa0weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity.

IgG1 Allotypes Influence the Pharmacokinetics of Therapeutic Monoclonal Antibodies through FcRn Binding

Because IgG1 allotypes might have different half-lives, their influence on infliximab (G1m17,1 allotype) pharmacokinetics was investigated in a group of spondyloarthritis patients. Infliximab was found to have a shorter half-life in patients homozygous for the G1m17,1 allotypes than in those carrying the G1m3 with no G1m1 (G1m3,-1) allotype. Because the neonatal FcR (FcRn) is involved in the pharmacokinetics of mAbs, the interaction of different IgG1 allotypes with FcRn was examined using cellular assays and surface plasmon resonance. G1m17,1 mAbs, such as infliximab and rituximab, were shown to bind more efficiently to FcRn and to be transcytosed better than the G1m3,-1 mAb cetuximab, which explains why infliximab is a better competitor for endogenous IgG1 in G1m3,-1 allotype–bearing patients. A set of four allotype variants of adalimumab (G1m17,1; G1m17,-1; G1m3,1; and G1m3,-1) was also tested for its binding to FcRn, revealing that the G1m3,1 variant, not present in commercial mAbs, binds more efficiently to FcRn and is transcytosed better than the other three variants, all of which are found in therapeutic mAbs.

Influence of FCGRT gene polymorphisms on pharmacokinetics of therapeutic antibodies

The neonatal Fc receptor (FcRn) encoded by FCGRT is known to be involved in the pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs). Variability in the expression of FCGRT gene and consequently in the FcRn protein level could explain differences in PK observed between patients treated with mAbs. We studied whether the previously described variable number tandem repeat (VNTR) or copy number variation (CNV) of FCGRT are associated with individual variations of PK parameters of cetuximab. VNTR and CNV were assessed on genomic DNA of 198 healthy individuals and of 94 patients treated with the therapeutic mAb. VNTR and CNV were analyzed by allele-specific PCR and duplex real-time PCR with Taqman® technology, respectively. The relationship between FCGRT polymorphisms (VNTR and CNV) and PK parameters of patients treated with cetuximab was studied. VNTR3 homozygote patients had a lower cetuximab distribution clearance than VNTR2/VNTR3 and VNTR3/VNTR4 patients (p = 0.021). We observed no affects of VNTR genotype on elimination clearance. One healthy person (0.5%) and 1 patient (1.1%) had 3 copies of FCGRT. The PK parameters of this patient did not differ from those of patients with 2 copies. The FCGRT promoter VNTR may influence mAbs’ distribution in the body. CNV of FCGRT cannot be used as a relevant pharmacogenetic marker because of its low frequency.

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

ABSTRACT Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohns disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a one-compartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.

Therapeutic Drug Monitoring of Biopharmaceuticals May Benefit From Pharmacokinetic and Pharmacokinetic–pharmacodynamic Modeling

Abstract: Biopharmaceuticals, especially monoclonal antibodies, have been increasingly used to treat several chronic inflammatory diseases. Due to the complexity of their pharmacokinetics and concentration–effect relationship, therapeutic drug monitoring (TDM) has been used to optimize their dosing regimen. Up to date, several decisional algorithms have been developed to provide tools for monoclonal antibodies therapeutic drug monitoring. However, these algorithms are unable to determine the individual optimal dosing scheme. The aim of this article is to deal with population pharmacokinetic (PK) and pharmacokinetic–pharmacodynamic (PK-PD) modeling. Allowing the quantification of the variability of the dose-concentration–response relationship, population pharmacokinetic–pharmacodynamic modeling may be a valuable tool to determine the optimal dosing scheme. Based on population modeling, Bayesian estimators may be developed to optimize dosing schemes for each patient using limited sampling strategies. These estimators may allow accurate dosing adjustment for each patient individually.

Rationale for therapeutic drug monitoring of biopharmaceuticals in inflammatory diseases.

Abstract: Biopharmaceuticals bring together a number of specific characteristics as compared with other drugs. However, as it is done for most drugs, an individual adjustment of their dose may be necessary. Similar to “chemical” drugs, biopharmaceuticals used in immunoinflammatory diseases have a rather narrow therapeutic range, lack good early clinical or biological marker of response, have variable pharmacokinetics, and their serum concentrations are most often related with response. Monoclonal antibodies have additional specific sources of pharmacokinetic variability. Low concentrations may increase the risks of immunization, plasmapheresis may increase their elimination, and subcutaneous formulations may be associated with decreased adherence. For all these reasons, pharmacokinetic therapeutic drug monitoring may be useful. However, few randomized controlled therapeutic drug monitoring studies have been published. For monoclonal antibodies, a precise definition of the therapeutic concentrations is challenging because of the interindividual variability in their concentration–effect relationship.

Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients

AIMSnRituximab is a monoclonal antibody directed against CD20, which is approved in rheumatoid arthritis (RA). This study aimed at assessing the influence of CD19+ cell counts as target-antigen amount, and of immunoglobulin G (IgG) serum concentrations on rituximab pharmacokinetics in RA patients.nnnMETHODSnIn a cohort of 64 RA patients who had received repetitive courses of rituximab, the influence of CD19+ cell count, IgG serum concentration, body surface area, sex and disease activity score in 28 joints on rituximab pharmacokinetic parameters was assessed using a population pharmacokinetic analysis.nnnRESULTSnA two-compartment model, with first-order distribution and elimination best described the data. The volume of distribution of central compartment and clearance of rituximab were estimated at 4.7xa0l and 0.56xa0lxa0day-1 , respectively. Distribution and elimination half-lives were 0.9xa0days and 17.3xa0days, respectively. As expected, the central volume of distribution increased with body surface area (Pxa0=xa00.012) and was higher in male than in female (Pxa0=xa00.004). We found that the elimination rate constant (k10 ) increased with CD19+ count (Pxa0=xa00.00022) and IgG concentration (Pxa0=xa07.4 × 10-8 ), and that k10 decreased with time (Pxa0=xa00.00015), partly explained by a change in target-antigen amount.nnnCONCLUSIONSnThe association between CD19+ count and k10 may be explained by target-mediated drug disposition, while the association between IgG serum concentration and k10 may be explained by a saturation of the neonatal Fc receptor at high IgG concentrations, resulting in decreased recycling of rituximab.

Gota et al. on their article “the pharmacokinetics of Reditux™, a biosimilar of rituximab”

using the results of the studies. In DLBCL patients, VSS and T1⁄2 − β of RedituxTM are about 80 % lower than what was reported for MabTheraTM. With reason, Gota et al. suggest that RedituxTM pharmacokinetics may be altered by tumor burden, even if no influence of tumor was observed in their study. The influence of tumor burden is usually explained by target-mediated drug disposition (TMDD), a mechanism by which part of antibody elimination is mediated by target antigen burden [2]. For rituximab, increased volumes of distribution in DLBCL patients are associated with decreased concentrations and increased T1⁄2 − β. This phenomenon may be due to retention of rituximab by its tumor target antigen, a phenomenon which was previously suspected for trastuzumab [3] and bevacizumab [4]. Therefore, differences between RedituxTM and MabTheraTM pharmacokinetics might be explained by differences in interaction with their target antigen. An alternate hypothesis explaining differences in pharmacokinetic parameters between studies is the existence of various techniques used to measure the rituximab concentration. Differences in methods may lead to differences in pharmacokinetic parameters [5]. An overestimation of rituximab concentrations would have led to an underestimation of the volumes of distribution. In addition, differences in fractions detected by various assays can lead to differences in T1⁄2 − β estimation. Assays measuring both unbound (“free”) and bound to the target antigen fractions can lead to higher T1⁄2 − β estimation than assays measuring only unbound fraction [5]. A comparison of the analytical technique used by Gota et al. with those previously used to study rituximab pharmacokinetics is therefore needed before the results of this study can be compared with those reported for the originator. Dear editor,

Crucial Role for Immune Complexes but Not FcRn in Immunization against Anti–TNF-α Antibodies after a Single Injection in Mice

The immunogenicity of infliximab and adalimumab is a major concern because patients may develop Abs also called antidrug Abs (ADA), directed against these anti–TNF-α Abs after just a few weeks of treatment. These ADAs can lead to a decrease in biologic concentration, which is associated with lower treatment efficacy. Our aim was to study the involvement of immune complexes and neonatal Fc receptor (FcRn) in the emergence of ADAs in the case of anti–TNF-α Abs. Wild type and FcRn knockout mice were injected once with either infliximab or adalimumab, alone or preincubated with TNF-α. Adalimumab cross-reacts with murine TNF-α whereas infliximab is species specific. When injected alone, only adalimumab elicited a humoral response. By preforming immune complexes with TNF-α, an anti-infliximab response was elicited. Surprisingly, both wild type and FcRn knockout mice were able to mount an immune response against anti–TNF-α Abs, suggesting that immune complexes are a major determinant of this immunization.

Development and validation of an enzyme-linked immunosorbent assay to measure free eculizumab concentration in serum

AIMnEculizumab is a monoclonal antibody toward C5 fraction of the complement system. It is approved to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. To perform pharmacokinetic studies and therapeutic drug monitoring, a validated assay is required.nnnMATERIALS & METHODSnAn indirect ELISA with recombinant human C5 sensitized microtiter plates were developed.nnnRESULTSnThe assay allows the measurement of free eculizumab concentration in human serum. The LOD, LLOQ and ULOQ were 0.091, 0.25 and 82.35 mg/l, respectively. The assay meets EMA and US FDA guidelines criteria for the validation of a ligand-binding assay.nnnCONCLUSIONnThis method is validated and can be used in PK and PK-PD studies as well as to perform therapeutic drug monitoring of free eculizumab.