Biologics in Kidney Transplantation: Why and How Should We Personalize Their Dosage?

Key Points

The therapeutic arsenal of immunosuppressive drugs for kidney transplantation has recently expanded with the introduction of biologics, approved or used off-labe. This review evaluated whether these biologics could be suitable candidates for therapeutic drug monitoring. Biologics exhibit high interindividual variability (coefficient of variation >40%) in their pharmacokinetics; however, the relationship between their plasma exposure and pharmacological effects remains to be further determined. Emerging clinical evidence suggests that individualized dosing strategies could improve both therapeutic outcomes and cost effectiveness.

Introduction

Patients undergoing kidney transplantation require lifelong immunosuppressive therapy to prevent organ rejection. Small-molecule drugs, including calcineurin inhibitors (tacrolimus and cyclosporine), mechanistic target of rapamycin inhibitors (everolimus, sirolimus), corticosteroids, and mycophenolate mofetil have long been the cornerstone of immunosuppressive regimens. However, these drugs expose recipients to metabolic, neurological, and nephrotoxic effects, carry a high risk of drug–drug interactions, and have a narrow therapeutic index. As a result, longitudinal therapeutic drug monitoring (TDM) of their blood or plasma concentrations [ 1 – 5 ] is essential to enable patient-specific dose adjustments and thus optimize the benefit-risk ratio of these treatments.

The therapeutic arsenal of immunosuppression in kidney transplantation has recently expanded with the introduction of biologics that target additional pharmacological targets. Some of these biologics are approved for immunosuppression after transplantation, while others are used off-label.

These agents may help optimize immunosuppressive regimens and offer a safety profile distinct from that of small-molecule drugs. However, because of their protein nature and their parenteral administration, biologics exhibit different pharmacokinetic (PK) properties.

Numerous reports have described a high interindividual variability (coefficient of variation [CV] >40% [ 6 , 7 ]) in the plasma concentrations of certain biologics [ 8 , 9 ]. Some studies reported concentration–effect relationships for therapeutic monoclonal antibodies, particularly those targeting tumor necrosis factor-α (TNF-α) in inflammatory bowel diseases [ 10 ] and rheumatoid arthritis [ 11 ], suggesting the relevance of TDM for biologics in specific indications. However, few studies have evaluated the PK variability and PK/pharmacodynamic (PD) relationships of biologics used in kidney transplantation [ 12 ].

The objective of this narrative review was to assess whether biologics used to prevent or treat renal allograft rejection could be candidates for TDM (see Electronic Supplementary Material for details on the methodology). We first present the PD and PK properties of biologics used for desensitization and post-transplant immunosuppression, either as approved or off-label therapies. To determine whether these biologics meet the prerequisites for TDM, we then review the relationships between their plasma concentrations and pharmacological effects, the interindividual variability in their plasma concentrations and associated explanatory factors, the potential therapeutic windows for their plasma concentrations, and the available analytical methods for their precise quantitation in the context of TDM. Finally, we discuss future directions for improving PK/PD knowledge on biological therapies in kidney transplant recipients (KTRs) and put in perspective the potential of a personalized dosing adjustment to improve the benefit-risk ratio and cost effectiveness of these biologics.

Biologics in Kidney Transplantation

Mechanisms of Action

Biologics used in kidney transplantation comprise a diverse range of molecular structures—including monoclonal antibodies, enzymes, and fusion proteins—each designed to target specific components of the immune and inflammatory response. These biologics intervene at various stages of the immune cascade to modulate or suppress rejection mechanisms. Table 1 and Fig. 1 summarize the main biologics currently used in KTRs, along with their respective targets and mechanisms of action. Table 1 Type, classification, targets, and mechanisms of action of the biologics used in kidney transplant recipients Biologics Type Classification Target Action mechanism Belatacept Fusion protein (CTLA4-Ig) T-cell co-stimulation blocker CD80/86 Complete inhibition of T-cell activation through interference with antigen-presenting cell signaling and blockade of co-stimulatory signals essential for initiating an immune response [ 14 ] Abatacept Fusion protein (CTLA4-Ig) T-cell co-stimulation blocker CD80/86 Blockade of CD28-mediated T-cell co-stimulation [ 116 ] Basiliximab Chimeric monoclonal antibody IL-2 pathway inhibitor IL-2 receptor α-chain (CD25) Inhibition of T-cell activation and proliferation [ 117 ] Tocilizumab Humanized monoclonal antibody IL-6 pathway inhibitor IL-6 receptor Inhibition of the IL-6 receptor involved in chronic inflammation and antibody production [ 15 ] Eculizumab Humanized monoclonal antibody Complement inhibitor C5 complement Inhibition of the formation of the membrane attack complex and terminal complement activation [ 31 ] Ravulizumab Humanized monoclonal antibody Complement inhibitor C5 complement Inhibition of the formation of the membrane attack complex and terminal complement activation. Long-acting, allowing for extended dosing intervals [ 32 ] Rituximab Chimeric monoclonal antibody B-cell-depleting agent CD20 Induction of antibody-dependent and complement-dependent cytotoxicity and inhibition of antibody production [ 17 ] Alemtuzumab Humanized monoclonal antibody Lymphocyte-depleting agent CD52 Induction of a profound depletion of both T and B lymphocytes through direct cytolysis and immune-mediated mechanisms [ 30 ] Imlifidase Recombinant cysteine protease enzyme IgG-degrading enzyme IgG Rapid neutralization of circulating alloantibodies and induction of immune modulation within hours [ 118 ] Daratumumab Human monoclonal antibody Plasma cell-depleting agent CD38 Inhibition of alloantibody production through antibody-dependent cytotoxicity [ 119 ] Clazakizumab Humanized monoclonal antibody IL-6 pathway inhibitor IL-6 Neutralization of circulating IL-6, reducing proinflammatory and humoral immune responses [ 120 ] Felzartamab Human monoclonal antibody Plasma cell-depleting agent CD38 Depletion of alloantibody-producing plasma cells and natural killer cells [ 121 ] CD cluster of differentiation, CTLA4-Ig cytotoxic T lymphocyte-associated antigen 4 immunoglobulin, IgG immunoglobulin G, IL interleukin Fig. 1 A Molecular targets and mechanisms of action of biologics used in kidney transplantation. Rituximab binds CD20 on B cells, inducing antibody- and complement-dependent cytotoxicity. Alemtuzumab targets CD52, resulting in profound depletion of both T and B cells. Basiliximab blocks the interleukin (IL)-2 receptor (CD25), inhibiting T-cell activation and proliferation. Clazakizumab neutralizes IL-6, reducing proinflammatory and humoral immune responses, while tocilizumab inhibits the IL-6 receptor (IL-6R), attenuating chronic inflammation and antibody production. Belatacept and abatacept disrupt T-cell co-stimulation by blocking CD80/86–CD28 interactions. B Eculizumab and ravulizumab inhibit complement activation by blocking the cleavage of C5, thereby preventing the generation of the anaphylatoxin C5a, the formation of C5b, and the assembly of the membrane attack complex. Imlifidase, an immunoglobulin G (IgG)-degrading enzyme, rapidly neutralizes circulating alloantibodies by cleaving immunoglobulins into F(ab')₂ and Fc fragments. Daratumumab, targeting CD38 on plasma cells, induces their depletion through antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis mediated by effector cells. CD cluster of differentiation, TCR T-cell receptor

Rituximab binds to CD20 on B cells, inducing antibody- and complement-dependent cytotoxicity. Alemtuzumab targets CD52, leading to profound lymphocyte depletion. Basiliximab binds to the interleukin (IL)-2 receptor α-chain (CD25), thereby inhibiting T-cell activation and proliferation. Clazakizumab neutralizes circulating IL-6, while tocilizumab blocks both soluble and membrane-bound IL-6 receptors, collectively attenuating proinflammatory and humoral immune responses. Belatacept and abatacept, both CTLA-4-Ig fusion proteins, prevent T-cell co-stimulation by disrupting CD80/86–CD28 signaling between antigen-presenting cells and T lymphocytes. Eculizumab and ravulizumab inhibit complement activation by blocking the cleavage of C5, thus preventing the generation of C5a and C5b and the formation of the membrane attack complex. Imlifidase, an immunoglobulin G (IgG)-cleaving enzyme, rapidly degrades circulating alloantibodies into F(ab')₂ and Fc fragments, facilitating prompt desensitization. Finally, daratumumab and felzartamab target CD38 on plasma cells and natural killer cells, promoting their depletion through antibody- and complement-dependent cytotoxicity and apoptosis.

Indications and Clinical Use in Kidney Transplantation

While certain biologics, such as belatacept, have received formal approval for maintenance immunosuppression in kidney transplantation, the majority are currently used off-label. These biologics often originate from treatments developed for hematologic malignancies, autoimmune diseases, or cytokine storm syndromes. Their potential for repurposing in transplantation including desensitization protocols, antibody-mediated rejection (ABMR), or corticosteroid-resistant T-cell-mediated rejection, is now under evaluation. Biologics in kidney transplantation can be used either for induction (basiliximab, alemtuzumab) and maintenance (belatacept) of immunosuppression or for anti-rejection or desensitization treatment (rituximab, eculizumab, ravulizumab, tocilizumab, imlifidase). Table 2 summarizes both approved and off-label biologic therapies currently used or under investigation in KTRs. It includes details on routes of administration, transplant-related indications, and dosing regimens as reported in clinical trials or expert protocols. Table 2 Routes of administration, approved and off-label indications of biologics used or under investigation in kidney transplant patients Biologics Route of administration Approved indications Off-label use in kidney transplantation Kidney transplant dosing protocols, examples and associated treatments Biologics used for immunosuppression induction treatment Basiliximab IV Prevention of acute rejection in patient with allogenic kidney graft TCMR Approved use : IV 20 mg on days 0 (within 2 hours before graft) and 4 post-transplant [ 117 ] Off-label : repeat dose of IV 20 mg [ 122 ] Alemtuzumab IV or SC Chronic lymphoid leukaemia, T-cell prolymphocytic leukaemia, B-cell chronic lymphocytic leukemia, remitting-relapsing multiple sclerosis Induction immunosuppressive therapy in high-immunological risk patients, TCMR or ABMR IV or SC 15–30 mg just before transplantation and 24 hours thereafter or at 2 subsequent days [ 12 , 20 , 21 , 123 – 126 ] Biologic used for immunosuppression maintenance treatment Belatacept IV Prophylaxis of graft rejection in adult recipients of a renal transplant CNI to belatacept rescue conversion after TCMR or ABMR or calcineurin inhibitor toxicity Since October 2022, owing to the implementation of a new manufacturing process, the maintenance belatacept dose of all protocols changed from 5 mg/kg to 6 mg/kg monthly Approved use : IV 10 mg/kg at days 1, 5, 14, 28, 56, and 84 then 6 mg/kg monthly [ 14 ] Other treatment protocols: belatacept initiation after transplantation: 11 infusions of 10 mg/kg over the first 6 months, followed by 5 mg/kg every 4–8 weeks; or 5 infusions of 10 mg/kg over the first 3 months, followed by 5 mg/kg every 4–8 weeks [ 127 , 128 ] CNI to belatacept conversion: 5 mg/kg IV at days 0, 14, 28, 42, and 56 and then monthly; with mycophenolate mofetil, corticosteroids, and gradual discontinuation of CNI [ 129 – 131 ] Biologics used for anti-rejection or densensitization treatment Abatacept IV, SC Rheumatoid arthritis, juvenile idiopathic arthritis Experimental use in kidney transplant (rare); some case reports in graft rejection No standardized regimen; monthly IV doses of 10 mg/kg or a weekly fixed SC dose of 125 mg reported in the literature with corticosteroids or MMF [ 132 ] Tocilizumab IV, SC Rheumatoid arthritis, juvenile idiopathic arthritis, cytokine release syndrome Chronic active/acute ABMR, desensitization before graft IV 8 mg/kg monthly (maximum 800 mg) or SC 162 mg SC or SC 162 mg every 15 days with MMF, tacrolimus/belatacept, and corticosteroids [ 25 , 26 , 43 , 133 ] Eculizumab IV aHUS, paroxysmal nocturnal hemoglobinuria, neuromyelitis optica spectrum disorder Refractory ABMR, recurrent and de novo aHUS post-transplant 1200 mg before transplantation followed by 4 doses of 900 mg weekly and then 1200 mg every 2 weeks, or 900 mg weekly for 4 weeks, then 1200 mg every 2 weeks [ 55 , 134 – 137 ] Ravulizumab IV aHUS, paroxysmal nocturnal hemoglobinuria, neuromyelitis optica spectrum disorder aHUS in kidney transplant patients Loading dose: 2400–3000 mg; Maintenance dose: 3000–3600 mg every 8 weeks [ 32 , 138 , 139 ] Rituximab IV Non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, pemphigus vulgaris Desensitization, immunosuppressive induction therapy, acute and chronic ABMR, TCMR, post-transplant lymphoproliferative disease 375 mg/m 2 or 200mg or 200–500mg or 500 mg, single IV dos. Optional second administration depending on CD19+ cell count [ 44 , 48 , 49 , 140 – 143 ] Imlifidase IV Desensitization treatment of highly sensitized patients with positive crossmatch against an available deceased donor Desensitization treatment of highly sensitized candidates for kidney transplant without an identified donor, ABMR Approved use : 0.25 mg/kg, 1 IV injection within 24 hours before graft (optional second administration) [ 118 ] Off-label : 0.12–0.25 mg/kg, 1 or 2 administrations [ 73 , 144 – 147 ] Daratumumab IV Multiple myeloma, light chain amyloidosis Desensitization before kidney transplantation acute and chronic ABMR IV 16 mg/kg weekly for 8 weeks (desensitization) [ 148 , 149 ] or for 2–6 weeks (ABMR) [ 150 , 151 ] IV 8–10 mg/kg weekly for 19 weeks then monthly for 4 months (desensitization) [ 68 ] Clazakizumab SC None (investigational, ongoing phase III trials) Chronic active ABMR, late ABMR, desensitization in highly sensitized patients SC 12.5–25 mg monthly for 4 months, 6 months or 5 years, depending on the protocols [ 62 , 120 , 152 ] Felzartamab IV None (investigational, ongoing phase III trials) ABMR IV 16 mg/kg weekly for 4 weeks then once per month for 5 months [ 153 – 155 ] ABMR antibody-mediated rejection, aHUS atypical hemolytic uremic syndrome, CD cluster of differentiation, CNI calcineurin inhibitor, DSA donor-specific antibodies, IV intravenous, MMF mycophenolate mofetil, SC subcutaneous, TCMR T cell-mediated rejection

PK Characteristics of Biologics in Kidney Transplantation

Absorption

Because of their proteinaceous structure and high molecular weight, biologics are not orally bioavailable and must be administered parenterally, either intravenously or subcutaneously. Although subcutaneous (SC) bioavailability is lower than that of intravenous (IV) administration, it still achieves high systemic exposure (e.g., approximately 80% for tocilizumab) [ 13 ]. For example, in inflammatory bowel disease, this relatively high SC bioavailability is sufficient to attain therapeutic plasma concentrations and sustain clinical efficacy. Subcutaneous absorption is slower than IV because of lymphatic uptake, but it allows for more flexible and patient-friendly dosing regimens without compromising efficacy. Intravenous biologics are typically administered every 2–4 weeks, depending on their elimination half-life, PD profile, and clinical indication, whereas SC formulations are usually given weekly or every 2 weeks and are preferred for long-term maintenance because of their convenience and sustained systemic exposure.

Distribution

Biologics are high-molecular-weight molecules (>150 kDa) and thus exhibit a limited volume of distribution (Vd), generally confined to the extracellular fluid compartment. For instance, belatacept has a steady-state Vd of approximately 0.15 L/kg (CV 21%), indicating distribution mainly within plasma and interstitial spaces [ 14 ]. The Vd of tocilizumab varies from 4 and 7 L depending on the indications and route of administration [ 15 ]. The Vd of basiliximab is approximately 8.0 ± 4.2 L [ 13 , 16 ], and the Vd of rituximab ranges from 4.0 to 9.6 L [ 17 – 19 ]. Population PK modeling in kidney transplantation shows that alemtuzumab has a central Vd of approximately 6.3 L (CV 39.6%) and a peripheral compartment of approximately 7.0 L, resulting in a total Vd of around 13–14 L [ 20 , 21 ]. Interindividual variability in Vd is generally low, with demographic covariates such as body weight, age, or sex exerting only a minor influence, as observed with alemtuzumab [ 21 ]. Unlike small molecules, biologics penetrate tissues more slowly and are largely confined to vascular and interstitial spaces. While they generally do not cross the blood–brain barrier, limited central nervous system penetration can occur under specific conditions, particularly when barrier permeability is increased (e.g., during inflammation). In the context of kidney transplantation, local inflammation or changes in vascular permeability may transiently alter drug distribution.

The distribution of biologics in particular subgroups of kidney transplant patients (obese, critical patients, children) is very poorly described owing to their frequent off-label use. However, given their low Vd, no significant change in their distribution within these groups is expected. Very few data are also available for pregnant women who have received solid organ transplants [ 22 ]. As most biologics are IgG based, an active placental transfer to the fetus, particularly in the later trimesters is likely.

Metabolization

Unlike small-molecule immunosuppressive agents, biologics are not substrates for hepatic metabolizing enzymes or transporters and do not undergo phase I or phase II metabolic transformations [ 13 , 21 ]. Their PK profiles are instead determined by distribution and elimination processes, without intermediate hepatic biotransformation by cytochrome P450 (CYP) and UDP-glucuronosyltransferase enzymes. This metabolic independence means that co-administration with other drugs typically does not result in direct CYP-mediated PK interactions, a significant advantage in poly-immunosuppressed transplant patients [ 21 , 23 ].

However, some biologics can indirectly influence the metabolism of concomitant medications that are substrates of CYP by modulating cytokine-mediated regulation of CYP enzymes. For instance, IL-6 receptor blockade with tocilizumab can reverse IL-6-induced down-regulation of CYP3A4, CYP2C9, and CYP2C19 [ 24 ], potentially increasing the clearance of drugs that are CYP substrates such as calcineurin inhibitors or corticosteroids. This represents a disease drug–drug interaction altering the patient’s metabolic capacity, rather than direct metabolism of the biologic itself [ 15 , 25 ].

Elimination

Renal excretion of biologics is negligible owing to their large molecular size, which prevents their glomerular filtration. An exception may occur in patients with nephrotic syndrome receiving rituximab, where structural alterations in the glomerular filtration barrier permit abnormal leakage of macromolecules such as IgG. Similarly, the presence of tocilizumab (2.9 mg/L) was detected in the urine of a patient with significant macroalbuminuria (urinary albumin-to-creatinine ratio = 948 mg/mmol) [ 26 ]. This urinary loss of the therapeutic antibody could contribute to accelerate their clearance and reduce their systemic exposure [ 27 ].

Biologics are eliminated primarily through two complementary mechanisms: non-linear target-mediated drug disposition (TMDD) and linear proteolytic catabolism. In TMDD, high-affinity binding of biologics to their pharmacologic targets (e.g., CD20, IL-6R) forms drug–target complexes characterized by a negligible dissociation. These complexes are subsequently cleared from circulation either via internalization and degradation for cell-surface targets or via phagocytosis by macrophages for circulating targets [ 28 ]. At low drug concentrations, this pathway often dominates elimination, leading to saturable clearance. At higher concentrations, when target sites are saturated, TMDD becomes less significant, and clearance shifts toward non-specific catabolic pathways.

This non-specific degradation of antibodies occurs in the reticuloendothelial system. Immunoglobulin molecules are internalized by macrophages, monocytes, or endothelial cells, trafficked to lysosomes, and degraded into amino acids and small peptides as part of normal protein turnover. This process occurs at a relatively constant rate, as it is independent of target expression and is mainly determined by baseline catabolic activity and the binding affinity of biologics for the neonatal Fc receptor (FcRn). The neonatal Fc receptor plays a central role in the prolonged systemic persistence of IgG-based biologics: following cellular uptake, FcRn binds the Fc region of IgG molecules at acidic pH within endosomes, rescues them from lysosomal degradation, and recycles them intact to the circulation at neutral pH [ 15 , 21 ]. This salvage pathway is specific to antibodies and Fc-fusion proteins, explaining their extended half-lives compared with biologics lacking an Fc region. For instance, the terminal half-lives are approximately 8–10 days for belatacept (IgG1 fusion protein) [ 14 ], 11–13 days for tocilizumab (IgG1) [ 15 ], 7 days for basiliximab (IgG1) [ 13 ], 18–22 days for rituximab (IgG1) [ 29 ], 6–8 days for alemtuzumab (IgG1) [ 21 , 30 ], 11 days for eculizumab (IgG2/4 hybrid) [ 31 ], and up to 50 days for ravulizumab (engineered IgG2/4 with enhanced FcRn binding) [ 32 ]. In contrast, non-Fc-containing biologics, such as Fab fragments, undergo rapid catabolism and have half-lives that range from hours to a few days.

Therapeutic biologics sometimes trigger an immune response, during which the immune system produces anti-drug antibodies (ADAs). For example, 5.3% of kidney transplant patients treated with belatacept (and who have also received basiliximab as induction and mycophenolate mofetil and corticosteroids taper) presented with anti-belatacept antibodies [ 33 ]. The biologic-ADA immune complexes are cleared by FcγR-mediated endocytosis, leading to an enhanced elimination of therapeutic biologics.

Last, a drug–drug interaction can accelerate the elimination of therapeutic biologics. Imlifidase, a bacterial enzyme that cleaves IgG, can degrade co-administered IgG-based biologics. Consequently, biologics such as basiliximab, rituximab, alemtuzumab and belatacept should not be administered concurrently as they risk degradation. For instance, a dosing interval of 4–7 days post-imlifidase is recommended for these biotherapies. Conversely, eculizumab appears to be resistant to imlifidase cleavage at standard doses [ 34 ].

In summary, the high interindividual variability of the elimination phase of biologics is driven by several physiological and pathological factors. A high antigen load effectively consumes the drug through TMDD. The efficiency of FcRn-mediated recycling and the development of ADAs significantly impact catabolism. Specific comedications, such as imlifidase, can rapidly degrade circulating IgG-based biologics.

Are Biologics Used in Kidney Transplantation Suitable Candidates for TDM?

In general, a drug is considered a strong candidate for TDM when there is a well-defined relationship between its systemic exposure and clinical efficacy or toxicity, and when it has a narrow therapeutic range. Such drugs often exhibit substantial interindividual variability in exposure at standard doses, leading some patients to achieve concentrations outside the target window, even after accounting for patient-specific factors such as body weight, body surface area, and renal or hepatic function. Furthermore, a validated and reliable assay must be available to accurately measure drug concentrations or relevant biomarkers. Together, these criteria identify drugs as suitable candidates for TDM, ensuring that individualized dose adjustments can optimize therapeutic efficacy while minimizing toxicity risks [ 12 ]. Given the high cost of biologics, their “financial” toxicity could be an additional criterion to consider, based on studies showing a cost effectiveness of dose personalization based on TDM.

Interindividual Variability and PK/PD Relationship

Belatacept

Pharmacokinetic studies performed on phase II clinical trials data reported a dose-proportional increase in belatacept plasma exposure between 5 and 10 mg/kg in KTRs, suggesting linear pharmacokinetics [ 33 ]. The CV for belatacept maximum concentrations were 20% and 27% for the 5-mg/kg and 10-mg/kg doses, respectively, while the CV of the area under the curve (AUC) were 27% and 35%, respectively [ 33 ]. These findings, obtained from carefully selected KTRs, initially suggested that belatacept exposure was predictable and exhibited low interindividual variability, arguing against the need for belatacept TDM [ 35 ].

However, phase III trials (BENEFIT and BENEFIT-EXT) revealed much higher interindividual variability in serum trough concentrations, with CV that ranged from 38% to 102% regardless of the dosing regimen (less intensive vs more intensive regimen) or of the time elapsed since the treatment was initiated [ 33 ]. Additionally, a retrospective study in KTRs also reported a high interindividual variability (46%) of belatacept plasma trough concentration, whereas the intraindividual variability was low (17 %) [ 36 ].

Pharmacokinetic/pharmacodynamic studies performed on data from phase II clinical trials and using an inhibitory Emax model identified effective concentrations of 2.4 mg/L (95% confidence interval [CI] 1.2–3.5) and 21.2 mg/L (95% CI 10.7–31.7) as required to reduce monocyte free CD86 receptors levels by 50% and 90%, respectively [ 33 ]. These data suggest that 90% CD86 receptor occupancy is achievable after each belatacept infusion. A belatacept PK/PD study using data from phase I, II, and III trials (BENEFIT and BENEFIT-EXT) showed that belatacept concentration was not a significant predictor of the hazard of acute biopsy-proven rejection event, up to 1-year post-transplantation [ 23 ]. Retrospective analysis of data from the phase III clinical trial BEST (Belatacept Early Steroid Withdrawal Trial) showed that overall estimated cumulative AUC and average concentrations of belatacept were not significantly correlated to acute rejection, except during the 6- to 12-month period where rejecting patients had lower belatacept plasma exposure [ 37 ]. Conversely, at any timeframe, estimated cumulative AUC and average concentrations of belatacept were significantly higher in patients with any infection than those without infection [ 37 ]. The probability of serious infections increased by 17% with each 10-mg/L increase of belatacept time-average concentration over 6 months of treatment [ 23 ]. This point is of high clinical importance as concentrations of belatacept above 21 mg/L were not associated with increased CD86 receptor occupation [ 38 ] and should therefore be avoided to limit the risk of infections. However, the lower belatacept concentration that is required to prevent acute rejection remains to be determined as CD86 occupancy in KTRs was not associated with a clinical renal outcome [ 39 ]. Taken together, these findings underscore the need for further studies before considering routine TDM.

Tocilizumab

Tocilizumab targets the soluble and membrane-bound IL-6 receptor, thereby inhibiting the development, maturation, and activation of T and B lymphocytes and reducing inflammation. In KTRs with chronic ABMR, uncontrolled observational studies suggest that tocilizumab may reduce donor-specific antibodies (DSAs) levels over time, decrease microvascular inflammation, and stabilize kidney function (53,54). Tocilizumab has also been investigated as an adjunct in desensitization protocols, where an IL-6 pathway blockade may enhance B-cell depletion and promote sustained suppression of DSA production [ 40 ]. However, the biological and clinical effects of tocilizumab appear highly heterogeneous. A systematic review of 117 patients found inconsistent outcomes across studies [ 41 ] and a cohort study of 38 KTRs treated with a standard dose of tocilizumab (8 mg/kg monthly) reported a slow decline in estimated glomerular filtration rate and improved interstitial inflammation scores, but no significant reduction in DSAs or chronic histological lesions [ 25 ]. Moreover, tocilizumab treatment discontinuation occurred in nearly half of the patients because of infections, cancer, or a lack of efficacy [ 25 ]. However, none of these studies was randomized or controlled, limiting the robustness of any conclusion.

Tocilizumab presents a high interindividual variability of its plasma trough concentrations at steady state. The CVs of tocilizumab plasma concentrations were 55% and 44% in kidney-transplant candidates undergoing desensitization [ 42 ] and KTRs with chronic ABMR [ 26 ], respectively. Lower early exposure was independently associated with persistent macroalbuminuria at months 3 and 6, highlighting a potential link between pharmacokinetics and clinical outcome. In addition, albuminuria itself was a significant determinant of minimum concentration variability, while urinary elimination of tocilizumab was negligible [ 26 ].

Pharmacokinetic/pharmacodynamic studies showed that tocilizumab trough concentration was not correlated to IL-6, soluble IL-6 receptor levels, or the reduction of anti-HLA antibodies [ 42 ]. In addition, tocilizumab AUC was not correlated to the estimated glomerular filtration rate slope in KTRs with chronic ABMR (Arrivé et al, unpublished data). However, it should be noted that most of the PK/PD papers were derived from retrospective and small sample size cohorts. The upcoming randomized, controlled, open-label multi-center trial (INTERCEPT study) will provide the definitive proof of evidence of the potential interest of tocilizumab in the treatment of chronic active ABMR [ 43 ]. The determination of tocilizumab plasma exposure in patients enrolled in the INTERCEPT trial would be of great interest in the perspective of tocilizumab personalized dose adjustments.

Rituximab

Rituximab is a chimeric anti-CD20 monoclonal antibody that induces B-cell depletion. In kidney transplantation, rituximab exhibits marked interindividual variability in both pharmacokinetics and pharmacodynamics. Following standard dosing (375 mg/m 2 ), CD19+/CD20+ B-cell counts decrease by over 95% within 1 week. However, the duration of depletion varies widely, with a range from 3 months to more than 18 months, with only about 30% of patients achieving full B-cell recovery by 12 months; others remain profoundly depleted [ 44 , 45 ]. Pharmacokinetic analyses reveal up to a three-fold variability in clearance, partly attributable to the baseline B-cell burden and antibody titers, consistent with a target-mediated clearance mechanism [ 29 ]. In patients with aggressive B-cell lymphoma, rituximab has a terminal half-life of approximately 20–22 days, with clearance values around 9–11 mL/h and an interindividual variability up to 30–35% CV [ 46 , 47 ]. However, comparable PK data in KTRs are lacking.

In nephrotic syndrome, the severity of proteinuria is associated with higher rituximab clearance, leading to lower plasma exposure. Patients with severe hypoalbuminemia (albumin level < 22.5 g/L) face up to an eight-fold higher risk of undetectable rituximab concentrations at 3 months, which is correlated with treatment failure in membranous nephropathy cohorts [ 29 ]. Similarly, the plasmapheresis used for desensitization or ABMR, can significantly reduce circulating rituximab concentrations, often necessitating dose adjustments or repeated administrations to maintain effective B-cell depletion [ 44 , 48 ]. Although rituximab pharmacokinetics in KTRs remains poorly characterized, proteinuria and plasmapheresis could contribute to interindividual PK variability and heterogeneous clinical responses. In immunosuppression induction, despite complete B-cell depletion, 15–20% of patients still experience acute rejection [ 49 ]. In refractory ABMR, DSA reduction reaches 40–60% in responders but remains below 20% in non-responders, despite similar rituximab exposure [ 48 ].

Similarly, a systematic review reports opportunistic infections in 8–12% of patients, particularly those with prolonged B-cell depletion [ 50 ]. Data from membranous nephropathy patients provide conflicting evidence regarding the relationship between rituximab concentration, CD20+ B-cell depletion, and antibody reduction [ 29 ]. Concentration–response relationships have not been yet determined in kidney transplantation.

Alemtuzumab

Alemtuzumab is a humanized anti-CD52 monoclonal antibody characterized by important interindividual PK variability in kidney transplantation. Population PK modeling estimates a clearance of 5.8 mL/h, with an interindividual variability of 64% in clearance, and a half-life that ranges from 8 to 21 days, both influenced by the baseline lymphocyte burden and soluble CD52 antigen levels [ 20 ]. Clinical pharmacology studies further confirm wide interindividual exposure variability, with trough concentrations spanning from less than 1 mg/L to over 25 mg/L following a 30-mg dose [ 51 ].

Treatment with alemtuzumab induces profound depletion of both T and B cells, but the tempo of immune reconstitution varies markedly among recipients: B-cell counts typically recover within 6–12 months, whereas CD4+ T-cell reconstitution can extend beyond 3 years in some patients [ 20 , 51 ]. Moreover, memory T cells and DSAs may persist despite depletion, explaining why acute rejection may still occur despite complete lymphocyte clearance [ 20 , 52 ]. Importantly, ADAs have been reported in approximately 10–20% of KTRs [ 20 , 52 ], while higher rates (30–40%) have been observed in autoimmune and oncology cohorts [ 20 , 51 ]. However, the neutralizing potential and clinical significance of ADAs in transplantation remain unclear. In kidney transplant recipients, a population PK/PD model demonstrated that higher alemtuzumab exposure was directly associated with deeper and more prolonged T-cell depletion, suggesting that lower induction doses (15 mg instead of 30 mg) could significantly accelerate T-cell recovery without compromising initial efficacy [ 53 ]. Similarly, in children with hematopoietic stem cell transplantation, high alemtuzumab concentrations at the time of transplant have been shown to correlate with delayed CD4+ and CD8+ T-cell reconstitution and with an increased risk of graft failure [ 54 ]. Despite these recent findings, validated concentration targets that could be routinely used in clinical practice for transplant patients remain to be fully established. The limited PK studies available in renal transplantation highlight significant interindividual variability and suggest that body weight and lymphocyte burden may be relevant covariates. However, current data are insufficient to guide individualized dosing strategies [ 20 ]. As such, suggestions for TDM remain exploratory and hypothesis generating rather than evidence-based practice [ 21 , 51 ].

Eculizumab and Ravulizumab

Eculizumab is used in renal transplantation for both the treatment of refractory ABMR and the prevention of recurrent atypical hemolytic uremic syndrome (aHUS). A recent meta-analysis [ 55 ] restricted to KTRs with aHUS reported a reduced risk of rejection recurrence (odds ratio = 0.05; 95% CI 0.00–0.13), decreased dialysis requirements (odds ratio = 0.13; 95% CI: 0.01–0.32), and improved renal function with a mean estimated glomerular filtration rate increase of approximately 59 mL/min and a serum creatinine reduction of about 127 µmol/L.

In contrast, most PK data originate from non-transplant indications, such as paroxysmal nocturnal hemoglobinuria and aHUS. Population PK analyses report a clearance of 0.3 mL/h/kg (range 0.22–0.42), with interindividual variability of 20–40% and a terminal half-life of 11–17 days [ 56 ]. A complete complement blockade is achieved at trough concentrations higher than 35–50 µg/mL; concentrations below 35 µg/mL risk breakthrough complement activity, while levels above 100 µg/mL may indicate excessive dosing [ 57 ]. Intraindividual variability in clearance is reported at approximately 34%, with interindividual variability reaching up to 50% in some cohorts [ 58 , 59 ].

Ravulizumab is a long-lasting complement C5 inhibitor also approved for the treatment of paroxysmal nocturnal hemoglobinuria. It presents the PK advantage of a four-times longer elimination half-life than eculizumab, allowing IV infusion every 8 weeks or 4 weeks according to body weight (>20 kg or <20/kg, respectively) [ 60 ]. In a recent pilot study on nine pediatric patients with aHUS in remission, the mean concentration of ravulizumab at steady state was 399.1 µg/mL (range 263.5–437.9), much higher in all patients than the threshold of 175 mg/L required for a complete blockade of C5 complement [ 61 ]. Conversely, the link between plasma exposure to eculizumab or ravulizumab and the risk of infection remains to be determined in view of concomitant treatment with other immunosuppressants.

Daratumumab

Daratumumab is being increasingly investigated in renal transplantation, particularly in the context of ABMR and desensitization protocols [ 62 , 63 ]. While its PK parameters have been well characterized in multiple myeloma, they remain unexplored in kidney transplantation. In oncology, population PK analyses have reported a mean clearance of approximately 4.9 mL/h with high interindividual variability (CV 44–59%) and a half-life that is strongly dependent on target saturation [ 64 , 65 ]. At a dose of 8 mg/kg, half-life and AUC exhibited interindividual variability of up to 88% and 64%, respectively, whereas at 16 mg/kg, this variability decreased (CV 38–48%) [ 66 ]. Effective target saturation requires trough concentrations of at least 236 mg/L, achieved in approximately 82% of patients at 16 mg/kg compared with about 67% at 8 mg/kg. Trough concentrations exceeding 270 mg/L have been associated with longer progression-free survival (6.6 vs 1.9 months) in hematologic indications [ 67 ].

Conversely, interindividual variability in PD responses may be influenced by biological heterogeneity among patients. Key factors include differences in plasma-cell burden and CD38 expression, baseline DSA characteristics, and the potential co-administration of proteasome inhibitors (synergistic effect on plasma cells) [ 68 – 71 ]. Subtherapeutic concentrations could lead to incomplete CD38 saturation and impaired DSA clearance, especially in patients at high immunological risk. Higher drug exposure, while associated with deeper and more sustained responses in multiple myeloma, also increases the risk of infections and cytopenias [ 64 , 65 ]. Theoretically, monitoring daratumumab exposure could help optimize efficacy and limit risks. To date, no validated PK/PD targets have been established for transplantation, and the interest of monitoring plasma daratumumab exposure remains to be demonstrated. Further studies are needed to determine whether TDM could improve the benefit-risk profile in this context.

Basiliximab

Basiliximab, a chimeric monoclonal antibody targeting the IL-2 receptor α-chain (CD25), exhibits interindividual PK variability in KTRs. Population PK studies have reported a clearance of 36.7 ± 15.2 mL/h and a half-life of 7.4 ± 3 days, with interindividual variability of approximately 40%. This variability is partly explained by covariates such as age, body weight, renal function [ 13 ], and concomitant immunosuppressive regimen. Consequently, the duration of the IL-2 receptor blockade varies significantly among patients, averaging 36 ± 14 days but ranges from 12 to 91 days. A cross-study comparison revealed that mycophenolate mofetil decreased by 48% basiliximab clearance, and consequently prolonged CD25 saturation duration (from approximately 5 weeks in the absence of mycophenolate mofetil to 10 weeks in the presence of mycophenolate mofetil) [ 72 ]. Clinical data indicate that complete receptor saturation does not uniformly prevent acute rejection. Moreover, a prolonged blockade beyond 4 weeks does not consistently further reduce the incidence of rejection, suggesting that PD and immunological factors (such as the degree of T-cell activation, concomitant immunosuppression, and infection status) may be stronger determinants of clinical outcomes than PK exposure alone. Given the weak PK/PD relationship and the limited number of administrations, routine PK-based TDM does not appear to be justified for basiliximab.

Imlifidase

Imlifidase shows relatively predictable pharmacokinetics but marked interindividual variability in PD response. In patients with chronic kidney disease, plasma concentrations are best described by a two-compartment model, with a rapid distribution half-life of approximately 5 hours and a slower elimination half-life of about 70 hours (range, 50–300). In phase I studies involving healthy volunteers, the mean terminal half-life was 4.9 ± 2.8 hours, with IgG removal occurring within minutes and peak effect observed between 6 and 24 hours post-infusion [ 73 , 74 ]. Pharmacodynamically, a single infusion of imlifidase reduces total IgG levels to less than 1% within 48 hours, maintaining this suppression for up to 7 days, and effectively abolishing C1q-binding anti-HLA activity. However, the duration of IgG suppression and the kinetics of rebound exhibit substantial interindividual variability [ 73 ]. In highly sensitized transplant candidates, the Highdes study demonstrated conversion of 89.5% of positive crossmatches to negative within 24 hours, although DSAs rebounded between days 3 and 14 [ 75 ]. A further source of variability is the development of anti-imlifidase antibodies, which typically emerge by day 7, peak at day 14 with a median imlifidase concentration of 875 mg/L (range, 190–1000 mg/L), limiting the benefit of readministration and showing substantial interindividual variability [ 74 ]. Taken together imlifidase reliably achieves rapid and profound clearance of IgG and DSAs. However, the duration of suppression, DSA rebound kinetics, and ADA responses are key drivers of inter-individual differences in clinical outcomes. These findings suggest that PD monitoring, specifically of IgG/DSA levels and ADA responses, may be more informative than PK monitoring for guiding personalized use of imlifidase in renal transplantation [ 75 ].

Analytical Methods Allowing the Quantitation of Monoclonal Antibodies or Fusion Proteins Exist

Historically, the detection and quantification of therapeutic monoclonal antibodies or fusion proteins in biological matrices have relied on ligand-binding assays such as the enzyme-linked immunosorbent assay (ELISA) [ 76 ]. The ELISA relies on the specific interaction between antigens and antibodies. In most cases, the sandwich format is used: the antigen is immobilized on a solid support and binds the target therapeutic biologics, which is then recognized by an enzyme-labeled detection antibody targeting a different epitope. Upon addition of a substrate, an enzymatic reaction produces a measurable signal that is proportional to the concentration of the therapeutic biologic. While these methods are simple and sensitive, they often suffer from limited specificity, poor correlation among different commercial versions, and restricted multiplexing capabilities [ 77 , 78 ]. Additionally, the drug tolerance of available ADA assays remains a significant concern [ 79 , 80 ]. Commercial and in-house ELISA kits are available for belatacept [ 81 , 82 ], tocilizumab [ 83 , 84 ], rituximab [ 85 , 86 ], alemtuzumab [ 87 , 88 ], eculizumab [ 57 , 89 ], daratumumab [ 71 , 90 ], basiliximab [ 91 , 92 ], or imlifidase [ 73 , 93 ].

In recent years, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has become the gold standard for quantifying therapeutic monoclonal antibodies and fusion proteins. Most published methods employ a bottom-up proteomic approach requiring an enzymatic digestion (typically using trypsin) of the antibody or fusion protein to generate peptides. Quantification is then performed by targeting surrogate peptides, unique to each therapeutic biologic, that are identified in silico through proteotypic peptide prediction and basic local alignment search tool (BLAST) alignment. These peptides are quantified using multiple reaction monitoring on triple quadrupole instruments [ 94 ], or based on the exact parent ion mass using high-resolution mass spectrometry, such as those using Orbitrap instruments [ 95 ].

A variety of sample preparation techniques have been developed to improve specificity, robustness, and throughput. For instance, the nSMOL ® method (nano-surface and molecular-orientation limited proteolysis) enables Fab-specific tryptic digestion by restricting protease access to the antigen-binding region, thereby reducing background from plasma proteins [ 96 , 97 ].

Another approach, the mass spectrometric immunoassay (MSIA ® ), uses biotinylated antigen-coated tips for highly specific immuno-enrichment of target monoclonal antibodies, such as TNF-α inhibitors, before LC-MS/MS analysis [ 98 ]. While this method is highly specific, its applicability is limited to antibodies targeting the antigen used for enrichment, for example, anti-TNF-α monoclonal antibodies can only be analyzed using TNF-α-coated tips. Currently, most published protocols rely on immuno-capture on Protein A/G resins, which selectively enrich IgG1 and IgG4 subclasses. This approach may also capture endogenous immunoglobulins [ 99 ], potentially compromising specificity for the therapeutic target. Despite this limitation, Protein A/G-based strategies enable multiplex quantification of therapeutic monoclonal antibodies against different molecular targets, offering a practical advantage for clinical laboratory workflows especially compared with ELISA methods, which are dedicated to a single analyte.

For LC-MS quantification, two main types of internal standards are commonly employed. The first involves stable-isotope labeled peptides, either cleaved or synthetic, which are spiked in after digestion. These standards enable more accurate correction for variability during the detection phase [ 100 ]. The second approach uses stable isotope-labeled monoclonal antibodies, which are added prior to digestion. Stable isotope-labeled monoclonal antibodies correct for variability throughout the entire workflow, including immunocapture, digestion, and LC-MS analysis, and are increasingly recognized as the reference method for quantitative monoclonal antibody assays [ 99 , 101 ].

Trypsin digestion strategies have also seen significant improvements: rapid digestion protocols (including surfactant-assisted or on-pellet digestion, immobilized trypsin cartridges, or microwave-accelerated techniques) now achieve efficient digestion in less than 1 hour while maintaining quantitative reliability [ 102 ]. Additionally, rapid tryptic digestions without IgG purification using an immobilized trypsin column have also been described [ 83 ].

Another major advancement in standardization and reproducibility is the development of CE-IVD commercial kits such as MabXmise ® . These kits integrate immunocapture, on-bead digestion, and stable isotope-labeled monoclonal antibodies as internal standards, thereby enhancing inter-laboratory consistency and reducing analytical variability. However, these benefits come at the cost of reduced flexibility and increased expense [ 103 ]. Commercial and in-house liquid chromatography-mass spectrometry methods exist for the quantification of belatacept [ 36 , 101 ], tocilizumab [ 83 , 99 , 104 ], rituximab [ 77 , 95 , 105 ], daratumumab [ 106 , 107 ], eculizumab [ 99 , 108 ], and ravulizumab [ 109 ].

Narrow Therapeutic Range

Unlike calcineurin inhibitors, most biologics used in kidney transplantation are not classified as narrow therapeutic range drugs. Their therapeutic windows tend to be broad, as exposure–response relationships are less strictly defined. However, for some biologics (such as belatacept, daratumumab, ravulizumab, eculizumab), threshold concentrations associated with 90% inhibition of their PD target have been proposed. For belatacept, the risk of infection increases with higher plasma concentrations, and concentrations exceeding 21.2 mg/L do not further improve CD86 receptor saturation [ 38 ]. Similarly, full inhibition of the complement pathway is achieved at trough plasma concentrations above 35–50 µg/mL for eculizumab or 175 µg/L for ravulizumab, suggesting that higher exposure does not enhance the PD effect. Recent preliminary results demonstrated that the standard weight-based dosing scheme of ravulizumab was associated with ravulizumab concentrations at steady state that were two- or three-fold higher than 175 µg/L, and that dose reduction by extending the dosing interval by 2 additional weeks appeared effective in keeping complement pathway inhibition [ 61 ].

This Emax-type relationship suggests that once maximal target inhibition is achieved, further dose increases provide no additional therapeutic benefit but may increase the risk of adverse effects. Higher alemtuzumab exposure is strongly associated with profound and prolonged T-cell lymphopenia. This increases the risk of opportunistic infections and has been linked to the development of secondary autoimmunity during the immune reconstitution phase [ 53 ]. Prolonged rituximab induced B-cell depletion can lead to secondary hypogammaglobulinemia, significantly increasing the risk of severe infections [ 110 – 112 ].

Indeed, current protocols use fixed-dose or even “flat-dose” regimens, which generally fall within the plateau of the concentration–response curve. Such a plateau effect may explain why a clear concentration–response relationship has not been demonstrated for most biologics, as previously demonstrated in oncology [ 113 ] .

Financial Toxicity of Biologics

Biologic therapies used in kidney transplantation impose a significant financial burden on healthcare systems, which is recognized as “financial toxicity.” Fixed or flat dosing regimens, which yield little to no additional PD benefit at higher doses, contribute to this burden. For instance, PK/PD studies of belatacept have shown that CD86 receptor occupancy rapidly reaches saturation, exceeding 90% shortly after administration [ 38 ]. Once maximal target inhibition is achieved, there is no need to increase the doses to enhance efficacy.

Few studies have investigated the cost effectiveness of precision-guided dosing strategy of biologics. In patients with aHUS, model-informed precision dosing (MIPD) of eculizumab enabled the implementation of a novel weight-based individualized loading dose strategy resulting in improved treatment efficacy associated with fewer infusions of eculizimab as well as a 12% cost reduction in the first month of treatment [ 58 ]. Furthermore, this same study demonstrated that the combination of MIPD and TDM during the maintenance phase of treatment could extend the interval between administrations in 33% of patients, while maintaining therapeutic efficacy and reducing the cost of treatment [ 58 ]. A retrospective study in patients with inflammatory bowel disease found that MIPD led to improved disease control, reduced hospitalizations, and shorter hospital stays, resulting in lower healthcare utilization and significant cost savings [ 114 ]. Another study confirmed that simulated cost effectiveness of such strategies were associated with both clinical benefits and improved quality of life [ 115 ]. Given the lifelong immunosuppressive treatment required for KTRs and the associated costs, investigations are urgently needed. These studies could optimize the benefit-risk ratio and enhance the cost effectiveness of biologic therapies in transplantation.

Discussion

Only a limited number of biologics (most notably belatacept) are approved for use in kidney transplantation as maintenance immunosuppression, replacing calcineurin inhibitors. Many others are used off-label.

The majority of available PK/PD data for belatacept originate from highly selected patient populations enrolled in manufacturer-sponsored phase I–III trials. Initially, these data did not support the potential value of TDM, given the low interindividual variability observed in these controlled studies. However, real-life data have since highlighted significant interindividual variability in belatacept plasma and serum concentrations [ 33 ], as well as a possible association between plasma exposure and infectious risk [ 23 ]. Unfortunately, the premature interruption of independent studies due to drug shortages has impeded the generation of robust real-world evidence. Further independent clinical and in silico studies are therefore required to better understand the determinants of this variability and to determine whether TDM could optimize the benefit-risk profile of belatacept.

For biologics used off-label in transplantation, most available PK and PK/PD data are derived from patients treated for hematological or autoimmune conditions. Relying on extrapolated data limits our ability to establish transplant-specific exposure–response relationships, particularly in contexts where concomitant immunosuppressive therapy, systemic inflammation, antigenic burden, macroalbuminuria, and altered drug clearance can significantly increase intraindividual and interindividual variability. However, measuring plasma biologic concentrations or AUC can be useful tools for assessing and comparing plasma exposure of biologics in different clinical settings (i.e., hematological diseases and kidney transplantation) and serve as preliminary data ​​for further PK/PD evaluation in kidney transplantation.

Among biologics, tocilizumab has been the most extensively studied in KTRs or for desensitization before transplantation. However, most PK/PD data come from retrospective and uncontrolled studies with small sample sizes, which limits the robustness of available evidence.

High interindividual variability in the pharmacokinetics is a common feature of most biologics used in transplantation (alemtuzumab, rituximab, belatacept, tocilizumab, eculizumab). This variability can translate into clinically significant differences in pharmacological response: underexposure may lead to inadequate lymphocyte or B-cell depletion (rituximab, alemtuzumab), increasing the risk of graft rejection, while overexposure can prolong immunosuppression and predispose patients to severe infections (rituximab, alemtuzumab, belatacept, eculizumab), including opportunistic complications [ 20 , 44 , 45 ]. Importantly, these risks are not uniformly distributed, but are concentrated in specific patient subgroups characterized by extreme body weight, systemic inflammation, or the development of ADAs, factors that profoundly affect drug clearance and exposure [ 26 , 52 ]. Additionally, changes in the route of administration (e.g., IV vs SC tocilizumab), and concomitant interventions such as plasmapheresis or IV immunoglobulin administration, which can accelerate drug clearance, further contribute to intraindividual and interindividual PK variability [ 9 ].

The availability of robust mass spectrometry methods has overcome previous limitations in quantifying biologics, enabling comprehensive PK/PD studies. This advancement should facilitate further research to better assess the efficacy and safety of biologics repurposed for use in kidney transplantation.

It is now possible to consider offering individualized dosing for some biologics. This should be based on previous studies conducted in patients with aHUS treated with complement inhibitors or in patients with inflammatory bowel disease treated with anti-TNFα.

Given the lifelong immunosuppressive therapy required in KTRs, whether to prevent graft rejection (belatacept) or to treat acute and chronic ABMR, the following strategies could be proposed for better personalization of biologic dosing: an a priori strategy based on the MIPD model, centered on the patient’s baseline characteristics and disease activity, could help improve early achievement of the therapeutic target during the loading dose. A retrospective adjustment of the dose and/or dosing intervals, based on TDM or TDM combined with the MIPD model, could be considered for the maintenance dose of belatacept, tocilizumab, and daratumumab.

As basiliximab, rituximab, and imlifidase are administered only once or twice, either at a fixed dose or according to a standard dosing regimen adjusted for body weight, the use of TDM for dose adjustment does not appear to be beneficial. Last, given the lifelong immunosuppressive treatment required for KTRs, potential improvements in patient quality of life, and the related biologic costs, the potential benefits of TDM or MIPD on the benefit-risk ratio, and cost effectiveness should be evaluated.

Conclusions

Biologics present a high interindividual PK variability. Analytical methods for their quantitation are available and easily implementable in clinical pharmacology laboratories. However, the definitive proof of PK/PD relationships for each biologic are lacking probably given that they are administrated at flat doses, which also contributes to their financial toxicity. Collectively, these findings underscore the urgent need for dedicated studies in KTRs to determine whether TDM and/or MIPD of biologics could improve their benefit-risk balance. Achieving this goal will require close collaboration between transplant nephrologists and pharmacologists to expand study cohort sizes, deepen our understanding of PK/PD relationships, and identify patients who may benefit most from TDM of biologics.

Supplementary Information

Below is the link to the electronic supplementary material. Supplementary file1 (PDF 43 KB)

Capucine Arrivé and Marie Hotot equal contribution.

Funding

No funding was received to assist with the preparation of this article.

Declarations

Conflicts of Interest

Capucine Arrivé, Marie Hotot, Jean-François Jourdil, and Françoise Stanke-Labesque have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

Not applicable.

Code Availability

Not applicable.

Authors’ Contributions

FSL had the idea for the article, MH, CA, JFJ, and FSL performed the literature search and data analysis, and all authors drafted and/or critically revised the work.

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