The potential for therapeutic drug monitoring of belatacept and other biologicals in solid organ transplantation

Abstract

In solid organ transplantation (SOT), biologicals such as recombinant therapeutic proteins, monoclonal antibodies, fusion proteins and conjugates are increasingly used for immunosuppression, desensitization, ABO (blood group) incompatibility, antibody-mediated rejections and atypical haemolytic uremic syndrome. In this paper, we review the medical evidence available for biologicals used in SOT and the potential for improvement by the application of therapeutic drug monitoring (TDM) and model-informed precision dosing. Biologicals are used for off-label indications within the field of SOT, building on the experience from their use on labelled indications. Dosing is currently mostly standard, and experience vs. effect and toxicity is limited. Pharmacokinetic characteristics of these large, partly also immunogenic molecules differ from those of traditional small molecules. Individualization by concentration measurements and modelling has mostly been proof-of-concept or feasibility studies that lack the power to provide evidence for improvement in clinical outcome. For some drugs such as alemtuzumab, eculizumab, rituximab, tocilizumab and belatacept, studies have demonstrated significant interindividual variability in pharmacokinetics. Variability in absorption from subcutaneous administration may increase interindividual variability. There is also an economic aspect of appropriate dosing that needs to be pursued. Available assays and models to refine interpretation are in place, but trials of adequate size to document the usefulness of TDM and MIPD are scarce. Collaboration within the TDM community seems mandatory to establish studies of sufficient strength to provide evidence for the use of biologicals that are currently used off-label in SOT and furthermore to identify the settings where TDM may be beneficial.

1 INTRODUCTION

Biologicals—in this context mostly drugs that are recombinant therapeutic proteins, monoclonal antibodies (mAbs), fusion proteins and conjugates—have entered many therapeutic areas in the last couple of decades.

The pharmacokinetic (PK) characteristics of such drugs differ in several aspects from the traditional small molecule drugs. The route of administration is frequently intravenous (iv) only, occasionally formulations for subcutaneous (sc) administration are available and may introduce a source of variation in bioavailability. Still, the most important factor giving rise to variability within and between patients, is the elimination of biological drugs. The question is whether this leads to variations of a proportion suggesting that individualization of dosing is warranted. Currently, for most of the established therapies with biologicals, the dosage regimens are typically 1 recommended dose for all adults—or in some cases dose adjusted to bodyweight or body surface area.

In solid organ transplantation (SOT) there are only a limited number of biologicals with immunosuppression after transplantation (tx) as the labelled indication. A few more may have labels relevant for treatment of conditions related to tx or the underlying disease. A number of biological drugs, however, are used off-label on various indications in organ transplant recipients. Hopefully, in many cases it will serve the patient well, but unless this transforms into formal clinical studies of the new indication, it is difficult to aggregate experience with dosing vs. response and toxicity and to optimize the treatment further by implementing therapeutic drug monitoring (TDM). Following a period of very few drugs reaching approval for the use in transplant recipients, there is currently a resurgence and a number of biologicals are in clinical testing, mostly for desensitization and treatment of antibody-mediated rejections, but also for some other specific indications. Examples of such drugs are listed alongside drugs with approved indications in Table 1.

TABLE 1. Biologicals currently used in transplantation—on or off-label.

	Target	Label indication	Off-label/in clinical trials
Anti-thymocyte globulin (ATG; iv)	Lymphocytes	Steroid-resistant rejection	Induction of immunosuppression
Basiliximab	IL-2R	Induction of immunosuppression
Imlifidase	Immunoglobulin G	Desensitization	ABMR
Belatacept	CD80/86	Immunosuppression
Abatacept (iv; sc)	CD80/86	RA	Immunosuppression
Rituximab (iv; sc)	CD20	Cancer; RA	Desensitization; ABO mismatched transplantation
Alemtuzumab	CD52	Multiple sclerosis	Induction; treatment of rejection
Tocilizumab (iv; sc)	IL6-R	RA; Covid-19	ABMR
Clazakizumab	IL-6		ABMR
Daratumumab (iv; sc)	CD38	Myeloma	Desensitization; ABMR treatment
Eculizumab	C5 complement	Thrombotic microangiopathy; aHUS	ABMR
Ravulizumab	C5 complement	Thrombotic microangiopathy; aHUS

• Abbreviations: ABO, blood group; aHUS, atypical haemolytic uraemic syndrome; ABMR, antibody-mediated rejection; IL, interleukin; iv, intravenous; RA, rheumatoid arthritis; sc, subcutaneous.

2 PKs OF BIOLOGICALS

The PK characteristics of biologicals differ in important aspects from traditional small molecule drugs. The majority of biologicals are administered by iv infusion. This allows rapid delivery of sufficient amounts of drug and the required volumes that may be too large for other parenteral routes, while also securing complete bioavailability. Some biologicals have a formulation for sc administration, which may introduce variations in bioavailability but allows injections at home and also may provide less fluctuation in exposure if the dosing is split into more frequent administrations. Absorption from sc injection occur via the lymphatic system, but the biologicals with lower molecular weight can also be absorbed by blood capillaries.¹ The lymph fluid drains slowly into the circulation, therefore the absorption into blood may typically continue for days. Bioavailability after sc administration is influenced by physicochemical properties of the antibody, and it is suggested that for these characteristics there may be an inverse correlation between bioavailability and elimination.^1-3 The co-formulation of mAbs with hyaluronidase has facilitated the administration of larger volumes and amounts of drug by sc injections.

Concentrations of mAbs in tissue interstitial fluid are in general lower than in plasma. This is because the large and polar antibodies move slowly across the vascular endothelial cells, and the elimination from tissue can be fast compared to the convective uptake. In highly perfused tissues such as bone marrow, spleen and liver, higher concentrations have been observed.^{1, 3}

The typical processes that determine the PKs of biologicals are recycling mediated by the neonatal Fc receptor (FcRn), target-mediated clearance, anti-drug antibody (ADA) response and off-target binding.³

When circulating immunoglobulin G (IgG), albumin and other serum proteins are taken up by pinocytosis into endothelial cells or monocytes, they will bind to the FcRn in the acidic endosomes (pH ≈ 6). This enables IgG to escape the degradation by lysosomes, and when IgG reaches the cell surface and a physiological pH, it is released back to the circulation. The IgG which is not bound to FcRn will be degraded by the lysosomes. This directed circulation provides regulation of IgG homeostasis. The drug mAb and antigen complexes are recycled in a similar manner as the native IgG. Clever modification of specific sites in the mAbs favours that the bound antigen is split from the mAb and destined to degradation while the mAb is rescued by the FcRn and recycled in a similar manner as native IgG. Increased half-lives of therapeutic mAbs have been achieved by increasing their binding to FcRn at pH 6 while also maintaining or increasing release at pH 7.4.⁴ As an example, eculizumab has a relatively short half-life in the circulation of about 11 days. The introduction of 2 selected amino acid substitutions in the Fc region, to increase the affinity to FcRn, increased the half-life several fold (as in ravulizumab).^{4, 5}

An important feature of the target-mediated clearance (or target-mediated drug disposition [TMDD]) is that it is nonlinear. The binding of drug to its target, whether receptors, enzymes or transporters, and the subsequent dissociation and degradation of the drug-target complex, is dose dependent. At low concentrations of mAb the TMDD contributes significantly to overall elimination of the drug. With increasing mAb concentrations TMDD is gradually saturated and clearance decreases. At the higher mAb concentrations the first-order elimination via FcRn will dominate and eventually the nonlinear pathway becomes negligible.³ The TDMM is mostly relevant for drugs that target surface antigens but may also be important vs. soluble antigens. To appreciate these effects, one must be aware that the nonlinearity of elimination may be masked in clinical practice for drugs that are given in doses that saturate the target.

The repeated administration of biologicals such as mAbs can be highly immunogenic. While the development from chimeric to humanized and fully human mAbs has reduced immunogenicity, the development of ADAs may still occur. In various studies, the frequencies of ADA development across a range of mAbs have been reported from zero up to 70%. The mechanisms for ADA development are not fully understood; both drug and patient characteristics as predisposing factors have been identified.⁶ In addition to the risk of adverse immune reactions, the development of ADAs can lead to reduced or loss of treatment response. The ADAs that develop in patients are characterized as either neutralizing antibodies that directly block the ability of the drug binding to its target, or the non-neutralizing ADA that bind to sites of the drug which does not interfere with target binding. Although the effect may be retained in the latter situation, these non-neutralizing ADA may reduce bioavailability and accelerate the drug clearance.⁷ The binding of ADA to mAbs results in the formation immune complexes. Although the mechanisms are not fully understood, it is suggested that depending on the size of these immune complexes, the clearance may be increased—probably via elimination of the complex via the FcRn. Alternatively, some complexes may escape this elimination if the size and structure of the formed complex is insufficient to trigger the elimination process. Thereby the immune complex may rather serve as a storage depot for the drug and increase its half-life.⁸

Off-target binding of mAbs may also contribute to altered PK, including tissue distribution and drug elimination. Specific preclinical screens as well as sophisticated modelling have been applied in order to identify mAbs with a higher risk of fast clearance.^{9, 10} There are examples where mAbs with identical Fc regions but slightly different variable regions appear to have diverging elimination rates that could be attributed to off-target binding.⁹ Obviously these are aspects of biologicals PK variability that need to be investigated in the preclinical development of biologicals. However, it is difficult to decipher to what degree the off-target binding contributes to PK variability of a biologic drug when used in the clinical setting.

3 MOTIVATION FOR TDM AND MODEL-INFORMED PRECISION DOSING IN SOT

3.1 TDM in general

When considering whether a drug in general should be a candidate for TDM, there are several criteria that should be assessed. The most important can be summarized as to whether there is:

• a known relationship between the obtained exposure, that is, normally the concentration in plasma (or other relevant matrix) and the effect or toxicity of the drug.
• a suggested therapeutic range for the exposure, identified as a narrow range.
• variability in exposure between individuals when given similar dose, and that this variability is large enough that some of the obtained concentrations will be outside the presumed therapeutic range; that is, whether it is a narrow index drug.
• still a significant variability between patients when attempts have been made to normalize dosage according to body weight, body surface area, age or parameters characterizing organ function (i.e., serum creatinine).
• an available, validated assay to measure the drug concentrations or another relevant biomarker.

3.2 TDM for drugs in SOT

For TDM in SOT, specifically the drugs used to prevent and treat rejection, additional motivation applies:

• the alternative to TDM, to titrate the dose individually depending on response, is not a relevant strategy. If a rejection episode occurs (i.e., lack of response), a dose increment of the immunosuppressant comes too late.
• evidence supporting an increased probability of successful treatment—effect without toxicity—if dosing is adjusted to obtain a suggested target concentration range,
• there may be a need for lower or higher exposure in special subpopulations (e.g., transplant recipients with high risk),
• despite systematic information to patients, nonadherence to prescribed treatment is a frequent problem,
• financial toxicity of biologicals has been addressed; high prices may hamper availability of adequate treatment for patients, especially in lower economy regions. Personalized dosing can be used to explore whether lower doses or increased dose intervals can be effective, as has been demonstrated for immune checkpoint inhibitors in cancer treatment.¹¹

3.3 Model-informed precision dosing

If the criteria for TDM are met, the application in the clinical setting can be improved by the use of population PK/pharmacodynamic (PD) models to facilitate model-informed precision dosing (MIPD). Such models have been developed, validated and applied in research for decades—for small molecule drugs and increasingly also for biologicals. However, the implementation of such tools into the clinical use of biologicals has been limited, which may also reflect the sparse evidence for the role of TDM in this setting. There are examples especially in the therapy of inflammatory bowel disease and some other immune diseases where MIPD has been explored to guide personalization.^12-15 Also for a drug such as alemtuzumab a PK/PD model was developed for patients treated for chronic lymphocytic leukaemia (CLL).¹⁶ Although the model performed well in this setting, the study highlighted the nonlinear and time-dependent PKs due to changes in white blood cell count for the CLL patients, which again illustrates that models may not be applied in other patient populations such as transplanted patients unless the model also describes the influence of white blood cells. A lot of work has been invested to better understand the contributions of physiological processes and drug characteristics that govern the PK and PD, and hence can guide the model development. The more complex descriptions may be relevant in the process of mAbs development^{10, 17}; however, there may also be lessons to learn for models. How the application of a PK/PD model can improve the personalization of a biologic such as eculizumab, has been elegantly demonstrated by the work of a group at Cincinnati Children's Hospital. The treatment of transplant-associated thrombotic microangiopathy (TMA) in children and young adults undergoing haematopoietic stem cell tx (HSCT) was prospectively individualized by support of a model that was proven effective for eculizumab vs. outcome of these severe adverse effects of the HSCT.^{18, 19}

4 ASSAYS FOR MEASUREMENT OF BIOLOGICALS

The measurement of biologicals in clinical samples faces different challenges from traditional small molecules assays, some of which are obvious given their large and complex structures. Ligand-binding assays, both commercially available and in-house developed, have been used for quantifications of mAbs, including several among those relevant in SOT.^20-22 These methods can also be adapted to or complemented with assays for the detection of ADAs.^{21, 23} Recent technological advances in mass spectrometry based analysis have enabled the development of multiplex bioanalysis, which means that several mAbs can be analysed in the same setup,²⁴ as exemplified for some of the drugs that are discussed in the following.^25-28 The detailed discussion of the analytical challenges and pitfalls are beyond the scope of this paper, and readers are referred to the cited reviews for details.

5 OVERVIEW OF MEDICAL EVIDENCE FOR BIOLOGICALS USED IN SOT AND THE POTENTIAL FOR TDM

In many situations when TDM is considered an option for dose individualization, one may find that the final limiting factor for introduction in the clinic is the lack of prospective randomized trials that prove the benefit in terms of outcome measures. Such trials will normally need a large number of patients, and there are challenges related to design, infrastructure and funding. Regarding the use of biologicals in SOT, additional challenges arise when many of the drugs are used off-label, such as the lack of systematic aggregation of the results obtained with this treatment. This calls for collaboration between centres in which such drug use is frequent. As several of these biologicals are now being tested in clinical trials to demonstrate efficacy on the new indications, there is an opportunity to include the systematic collection of PK data from a larger population. It may even be possible in some cases to add a sub-protocol to such trials, in order to systematically investigate the potential for TDM. This could be a way forward to provide the data that are still needed for individual biologicals, as indicated in the summaries below.

5.1 Belatacept

Belatacept is a soluble fusion protein combining the human IgG1 Fc domain with the modified extracellular domain of cytotoxic T lymphocyte-associated antigen 4 (CTLA4). As a CD28 homologue it binds to CD80 and CD86 on the antigen-presenting cells, thus inhibiting CD28-mediated T cell co-stimulation and thereby selectively preventing the activation of T cells. Belatacept is approved for rejection prophylaxis in renal transplant recipients as an alternative to calcineurin inhibitors (CNIs) and in combination with basiliximab, mycophenolate and glucocorticoids. Further clinical trials have tested alternative approaches such as belatacept plus mechanistic target of rapamycin (mTOR) inhibitor, weaning of glucocorticoids and the replacement of basiliximab with alemtuzumab in a belatacept-based regimen. A common finding in these studies is a somewhat increased incidence of acute rejections but the decline in renal function and other typical CNI-related adverse effects has been avoided.

5.1.1 Belatacept variability

Based on available reports from the early belatacept trials (see refs in de Graav et al.²⁹), we concluded in a previous review that the variability in belatacept concentrations seemed to be low—in itself an argument against the need of TDM for this drug.²⁹ The quoted papers mostly reported geometric means and coefficients of variation of the concentrations and the PK parameters from the applied PK-modelling. However, to get insight into the variability in belatacept PK between individuals, one may re-examine the actual observed individual concentrations in the period (32–52 weeks after first dose) when dosing was similar in the 2 arms, less intensive and more intensive. Here trough concentrations ranged from <0.1 to ~20 μg/L, and although the authors concluded that “model-predicted time-varying distributions of trough concentrations were in excellent agreement with observed values … and interindividual variability in PK was low, illustrating that belatacept exposure is predictable and suggesting that the need for therapeutic drug monitoring of belatacept may not be needed for [kidney transplant recipients]”, one could still argue that the interindividual variability on this dosing was quite large when compared to therapeutic ranges for other narrow index drugs that are monitored in SOT. In a couple of later publications similar ranges of observed belatacept concentrations has been reported as part of the validation of new assays for belatacept concentrations.^{22, 25} The patients in both of these reports, n = 5²² and n = 108²⁵ were followed in the stable phase of belatacept maintenance following switch from tacrolimus.

5.1.2 TDM of belatacept

The interindividual variability in belatacept exposure seems large enough in relation to the therapeutic window that a potential for optimized treatment by TDM should be considered. Also, although the switch from CNI based immunosuppression to belatacept in renal transplant recipients has been proven noninferior with respect to long term graft and patient survival, there is still an increased incidence of rejection episodes and the incidence of severe adverse effects is not negligible. So far, none of the reported analyses of a potential association between belatacept concentrations and treatment failure or side effects have found correlations that could indicate a therapeutic range. A weak point in this argumentation, is that studies with the aim to elucidate a PK/PD relationship for belatacept have been hampered since the drug has been unavailable in periods due to manufacturing problems. All considered, the conclusion remains that based on the data currently available, there is not sufficient evidence to recommend TDM of belatacept when used in SOT.

6 OTHER BIOLOGICALS USED IN SOT

6.1 Antithymocyte globulin preparations and basiliximab

According to definition (Food and Drug Administration, https://www.fda.gov/files/drugs/published/Biological-Product-Definitions.pdf; last visit 26.03.24), antithymocyte globulin (ATG) preparations are biological drugs although not designed and produced such as current biologicals. In the USA, immunosuppressive protocols frequently include ATG for induction therapy, while in most of Europe the specific interleukin (IL)-2 receptor antagonist basiliximab is preferred. In these regimens, only 1 or 2 doses are given, leaving limited space for personalized dosing except if one would try to individualize the initial dose more than current practice. In steroid-resistant rejections, ATG is an important treatment option. To reverse the rejection repeated doses will often be required, and in this setting the dosing intervals are adjusted based in part on the absolute CD3 cell counts—which may be considered a form of PD monitoring already established.³⁰

6.2 Imlifidase

Imlifidase is an enzyme that rapidly degrades and depletes IgG from circulation. This drug is approved for desensitization in highly sensitized patients awaiting kidney tx. It is also in trials for treatment of antibody-mediated rejection (ABMR).³¹ For desensitization a single dose is recommended pretransplant while a small study also explored the use of 1 repetition.³² Dosage is body weight adjusted, otherwise no further personalization has been discussed. Of specific note is that several other mAbs may be degraded by imlifidase if administered concurrently.

6.3 Abatacept

Abatacept was the predecessor of belatacept; in the latter, 2 amino acid substitutions provided a more potent binding of its ligands CD80 and CD86. This led to the approval of belatacept for use in kidney tx while abatacept is used in rheumatoid arthritis. While belatacept is available for iv use only, abatacept can also be given by sc injections. This led a French group to test the replacement of belatacept by abatacept sc in stable transplant recipients, as a feasible alternative to belatacept to reduce their need to visit the hospital during the initial stay-at-home order in France under the Covid-19 pandemic. Data on the use of abatacept in kidney tx are scarce, patients in the study were switched from abatacept after 3 months. In this perspective the treatment was successful with only 2 rejection episodes (n = 176) while 19 patients (11%) had abatacept discontinued for various reasons. In this study, the abatacept dosage was 125 mg sc every week for all patients.³³

This study raises questions as to whether abatacept sc could be an alternative to belatacept in stable kidney transplant recipients long term. Another alternative, if feasible, would be to have a formulation of belatacept for sc administration. If these options should be further explored, it could also provide an opportunity to investigate the potential for a more individualized dosing. So far this has not been advocated for abatacept on any of its indications.³⁴

6.4 Rituximab

Rituximab induces a depletion of blood CD20+ B cells followed by reconstitution over subsequent months, and also reducing the number of these cells in spleen and lymph nodes. In kidney tx, rituximab has been tested for reduction of blood group antibodies in blood group incompatible tx, in reducing the concentration of donor specific antigens (DSA) in highly immunized recipients and to treat antibody-mediated rejection (ABMR).³¹ In an early trial using rituximab in renal transplant recipients the authors concluded that a single dose of rituximab, as opposed to repeated doses, was sufficient for sustained depression of B cells in peripheral blood. In that study all patients received 375 mg/m².³⁵ In contrast to what was suggested by retrospective studies, later clinical trials using similar rituximab dose have not been able to confirm a significant benefit of rituximab on ABMR.³¹ From the perspective of personalized dosing, it is of interest that in the study by Sautenet et al.,³⁶ 1 or 2 extra rescue administrations of rituximab were allowed. In the control group and in the rituximab group, this occurred for 42 and 32% of the patients respectively. Also, adverse reactions from rituximab are frequent, therefore 1 hypothesis would be that the introduction of MIPD might better predict the effective dose regimen already from the start; however, this has not been addressed for transplanted populations.

Since rituximab has been used in several years for other diseases such as rheumatoid arthritis and cancers, the PK/PD studies in these areas might indicate if and how personalized dosing could be introduced. A recent review on TDM of biologicals in rheumatoid arthritis³⁴ concluded that for rituximab the evidence was insufficient, but still that rituximab concentrations could predict the occurrence of ADAs and also in retrospect that lower rituximab levels preceded flares.³⁷ Studies in patients with lymphomas revealed log-fold interindividual variability in rituximab concentrations indicating that median levels are not representative³⁸ and that time-changes in clearance could serve as a predictive marker of response.³⁹ This has also been suggested from recent trials of rituximab in multiple sclerosis.⁴⁰ Although different from the tx setting, these experiences with rituximab in divergent diseases, dosing regimens and drug combinations may be relevant for further trials were the potential benefit of MIPD could be explored.

6.5 Alemtuzumab

The approved indication for alemtuzumab is relapse-remitting multiple sclerosis. Alemtuzumab is a humanized, monoclonal IgG1 antibody directed against CD52 that is expressed on T and B lymphocytes, as well as on natural killer cells and monocytes. In renal tx the drug is used off-label both for induction and as antirejection therapy. Although PK data exist from the use of this drug in CLL, this is an example where target-mediated clearance will differ from the tx setting, due to the much higher load of CD52-positive cells in patients with CLL, hence the extrapolation of PK data cannot be precisely extrapolated. The PK of alemtuzumab has been investigated in renal transplant recipients from a clinical trial where all patients received alemtuzumab sc immediately before and 24 h after tx for induction of immunosuppression.⁴¹ A large between-patient variability in distribution and elimination was observed, and a PK model was developed that showed an adequate concordance of the observed and population and individual predicted alemtuzumab concentrations. The PK variability was to a large degree explained by body size and the authors suggested that lean body weight-adjusted dosing can be applied to correct for this phenomenon, showing potential as a marker to reduce between-subject variability in alemtuzumab exposure.

Another recent study presented a model predicting the response to alemtuzumab for acute kidney transplant rejection.⁴² From the 115 patients, a set of clinical and histological characteristics were collected and logistic regression modelling was used to construct a prognostic score enabling the accurate prediction of response, which was even further improved by including a set of targeted gene expressions. This study did not include measurement of alemtuzumab concentrations. Taking into account the efficient depletion of immune cells following an alemtuzumab dose and the associated risk of infections, malignancy and autoimmunity, and the fact that a single 30-mg dose is used, it is conceivable that many patients may be overdosed when treated for acute rejection.

Taken together these recent studies suggest that follow-up studies on the relation between alemtuzumab PK, lymphocyte dynamics and clinical outcomes are warranted to further substantiate the clinical potential and rationale for personalized alemtuzumab therapy in kidney tx.⁴¹ As pointed out in an accompanying editorial⁴³: the combination of clinical and histological data with molecular analysis of renal allograft biopsies and PK data of the drug of interest is the way forward.

6.6 Daratumumab

Daratumumab is directed against CD38 and it has been suggested that it may be effective in reducing preformed antibodies and desensitizing patients, given its effect on plasma cell elimination. Only case reports have been published so far, and there has been concerns whether this drug could cause depletion also of regulatory B cells and thus induce a T cell-mediated rejection.⁴⁴ Currently 2 clinical trials are in progress including highly human leucocyte antigen-sensitized patients awaiting kidney tx. From the summaries of study plans (ClinicalTrials.gov ID NCT05145296 and NCT04204980) it is not clear whether samples to estimate PK will be collected. Obviously this would be of particular interest in the situation where one may expect toxicity to be a limiting factor.

6.7 Tocilizumab and clazakizumab

The currently approved indications for tocilizumab are rheumatoid arthritis and some other autoimmune diseases as well as the treatment of Covid-19 for selected patients. This drug is acting via inhibition of the IL-6 receptor. Tocilizumab has shown some promising results both in the treatment of ABMR and in desensitization, and the potential for such treatment both in kidney, lung and heart tx has been discussed in several recent papers.^{31, 45-48} More rigorous and sufficiently large trials are needed to clarify the role for tocilizumab as well as other IL-6 or IL-6 receptor inhibitors in these settings. Meanwhile there are also studies that indicate large variability in the PK of tocilizumab. Such data have been collected for tocilizumab when used on its label indications; however, there are also recent studies in transplant recipients showing the significant variability in PK. A few of these studies have also used PK models in order to characterize the parameters in detail and even indicated association between tocilizumab concentrations and effects such as reduction in anti-HLA antibodies²⁷ and albuminuria,⁴⁹ while others did not find such correlations.⁵⁰ It is a challenge to arrange prospective studies that are able to provide evidence for the benefit of TDM. One opportunity that could be pursued, is to involve the measurement of drug concentrations as a subprotocol in clinical trials that are planned to demonstrate effectiveness by clinical endpoints.

Clazakizumab is an IL-6 antagonist that has also been suggested for the treatment of ABMR. So far only small studies have been reported.³¹ However, a large phase 3 multicentre clinical trial is ongoing, and according to the protocol (Clazakizumab for the Treatment of Chronic Active Antibody Mediated Rejection in Kidney Transplant Recipients [IMAGINE]-trial: ClinicalTrials.gov identifier: NCT03744910) samples will be collected during the first 3 weeks to provide individual PK parameters. The anticipated study population of 350 patients should guarantee that these data will be of great interest for clazakizumab as well as for the discussion of the personalization of biologicals in general in the post-tx setting.

6.8 Eculizumab

Eculizumab binds to complement component C5, thereby blocking its cleavage and the subsequent formation of the C5b-C9 membrane attack complex, the final common pathway effector of the complement system. Approved indications for eculizumab are paroxysmal nocturnal haemoglobinuria, atypical haemolytic uraemic syndrome (aHUS), myasthenia gravis and neuromyelitis optica spectrum disorder. Besides the prevention and treatment of atypical haemolytic uraemic syndrome and TMA, in SOT there are reports from its use for desensitization, prevention and as supplement in the treatment of ABMR.^{31, 51-53} Although these studies are too small to provide definitive conclusions on the role of eculizumab in these situations, there is already an example of how eculizumab concentration measurements combined with a PK/PD model can be used for MIPD in the treatment of TMA in children undergoing HSCT.¹⁹

Although no formal economic cost–benefit analysis was reported, for an expensive drug such as eculizumab it is worth noting that the remarks from the authors that by using MIPD in their study each patient only received the required therapy course, which minimizes the risk of over treating and reduces the clinical and financial burden of eculizumab therapy.¹⁸ The approach that was used in this study could also serve to suggest how to tailor the application of eculizumab and other biologicals in solid organ transplant recipients.

7 CONCLUSION

The use of biologicals such as recombinant therapeutic proteins, mAbs, fusion proteins and conjugates is expanding. Many of these biologicals are currently used for off-label indications within the field of SOT based on available experience from their use on other, labelled indications. However, PK characteristics of these large, partly also immunogenic molecules differ from those of traditional small molecules, and the variability may depend on factors such as target-mediated elimination, which complicates extrapolation from 1 disease to another. So far the studies that have explored individualization by concentration measurements and modelling, have been proof-of-concept or feasibility studies that lack the power to provide evidence for eventual improvement in clinical outcome.

For some drugs such as alemtuzumab, eculizumab, rituximab, tocilizumab and belatacept, studies have demonstrated significant interindividual variability in PKs, compared to their anticipated therapeutic ranges. As the option for sc administration is increasingly offered, interindividual variability in exposure may reinforce the need and the potential for individualization by TDM. Implementation of tools for MIPD may be of particular value in this field. For a few of the drugs mentioned—probably also for some in the pipeline, there is an economic aspect of appropriate dosing that needs to be pursued. Available assays and models to refine interpretation are in place, the obstacles are in the challenges to perform trials of adequate size to document the usefulness of TDM and MIPD. Collaboration between centres and the TDM community seems mandatory to establish studies of sufficient size and strength to provide the evidence for the use of biologicals that are currently used off-label in SOT and furthermore to identify the settings where TDM may be beneficial.

7.1 Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20.⁵⁴

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.