Abstract
In this study, plasma belimumab concentrations were measured over the course of treatment in systemic lupus erythematosus (SLE) patients on belimumab therapy, and intra‐ and interindividual variations in plasma belimumab concentration were evaluated. A single‐center prospective study was conducted at Oita University Hospital to evaluate trough plasma concentrations over the course of treatment in 13 SLE patients treated with intravenous belimumab. Plasma belimumab concentrations were measured by a validated ultra‐high performance liquid chromatography with tandem mass spectrometry method. The median age of the patients was 40 (interquartile range: 35–51) years and the median weight was 51.8 (47.0–58.1) kg. A mean of 9.4 (range: 1–13) blood samples was collected per patient at routine visits. The mean (± SD) plasma belimumab concentration was 33.4 ± 11.9 μg/mL in the patient with the lowest concentration and 170.0 ± 16.6 μg/mL in the patient with the highest concentration, indicating a 5‐fold difference between patients. On the other hand, the within‐patient coefficient of variation ranged from 7.1% to 35.7%, showing no large variations. No significant correlation was observed between plasma belimumab concentration and belimumab dose (mg/kg) (Spearman's rank correlation coefficient = 0.22, p = .54). Examinations of trough plasma belimumab concentrations over the course of treatment in patients with SLE showed small intraindividual variation but large interindividual variation. Plasma belimumab trough concentration varied widely among patients administered the approved dose.
Keywords: belimumab, pharmacokinetics, systemic lupus erythematosus, therapeutic drug monitoring
Plasma belimumab concentrations in individual SLE patients.
Abbreviations
- ADAs
anti‐drug antibodies
- BLyS
B‐lymphocyte stimulator
- CV%
coefficient of variation
- FcRn
neonatal Fc receptor
- FcγR
Fcγ receptor
- IgG
immunoglobulinG
- IQR
interquartile range
- Q1
first quartile
- Q3
third quartile
- RCT
randomized controlled trial
- SD
standard deviation
- SLE
systematic lupuserythematosus
- TDM
therapeutic drug monitoring
- TMDD
target‐mediated drug disposition
- UHPLC–MS/MS
ultra‐high performance liquid chromatography with tandemmass spectrometry
1. INTRODUCTION
Belimumab is a human monoclonal antibody that specifically inhibits the biological activity of B‐lymphocyte stimulator (BLyS). 1 Belimumab is currently being used worldwide to treat patients with systematic lupus erythematosus (SLE) not responding adequately to other existing treatments. 2 , 3
Recently, researchers have shown increased interest in blood concentrations of antibody drugs and the necessity of therapeutic drug monitoring (TDM) of these drugs. The most studied antibody drug is infliximab. Study has shown a significant correlation between serum infliximab concentration and therapeutic response, and that clinical response increases when serum infliximab trough concentrations are above a certain level. 4 Furthermore, the usefulness of TDM in infliximab treatment has been investigated in a randomized controlled trial (RCT). 5 In this RCT, subjects were randomized to TDM group, in which infliximab dosage was adjusted according to TDM results, and non‐TDM group, in which infliximab dosage was decided by physicians without knowing the blood concentrations. Serum infliximab concentrations were measured and compared between the two groups. No significant difference in efficacy between the TDM and non‐TMD groups was observed in the infliximab induction phase, whereas disease control was significantly more effectively sustained in the TDM group in the maintenance phase. 6 , 7 Currently, no conclusion has been reached regarding TDM of antibody drugs. Intra‐ and interindividual variabilities have been reported for antibody drugs other than infliximab. Studies have indicated that blood concentrations of cetuximab and rituximab vary greatly from patient to patient. 8 , 9 Regarding intraindividual variability, decreased blood concentrations have been reported with continued use of adalimumab and infliximab. 10 Pharmacokinetic parameters such as the rate of occurrence of anti‐drug antibodies (ADAs), clearance, and volume of distribution differ among antibody drugs. 11 , 12 Therefore, it is important to clarify the status of intra‐ and interindividual variabilities of each drug product, to examine the relationship between blood concentration and safety, and to evaluate the need for TDM.
For belimumab, there are limited reports on the status of intra‐ and inter‐individual variability. A population pharmacokinetic analysis of belimumab was performed using the data of a phase III study. 13 , 14 The population pharmacokinetic analysis showed modest interindividual variability in total clearance, central distribution volume, and terminal volume. A simulation study reported an approximately 1.5‐fold difference in steady‐state trough plasma belimumab concentration among patients. 13 , 14 On the other hand, there are limited reports of plasma belimumab concentrations and their variability in actual clinical practice.
In this study, plasma belimumab concentrations were measured over the course of treatment in SLE patients on belimumab therapy, and intra‐ and interindividual variations in plasma belimumab concentration were evaluated. Furthermore, the relationship between belimumab dose and plasma belimumab concentration was analyzed.
2. METHODS
2.1. Study design
We performed a prospective study to examine the variation in plasma concentration of belimumab. Patients who received intravenous administration of belimumab at Oita University Hospital between October 2021 and December 2022 were recruited. All patients received 10 mg/kg of belimumab administered as an intravenous infusion on days 0, 14, and 28, and at 4‐week intervals thereafter. The dose of belimumab was calculated based on the body weight at the time of administration, but physicians could decide to increase or decrease the dose.
Blood samples were collected within 2 h prior to administration of belimumab at scheduled visits, and trough concentrations were measured.
This study was approved by the ethics committees of Meiji Pharmaceutical University (approval number: 201919) and Oita University Hospital (approval number: 1628). All patients received prior explanations about the purpose and procedures of this study and gave written informed consent prior to participation.
2.2. Measurement of plasma belimumab concentrations
We measured trough plasma belimumab concentration using a validated ultra‐high performance liquid chromatography with tandem mass spectrometry (UHPLC–MS/MS) method that we reported previously. 15 The lower limit of quantification for belimumab was 2 μg/mL. Because belimumab is unstable in plasma, samples were stored at −80°C after the addition of the enzyme inhibitor aprotinin (10 μg/mL, 1000:1 v/v) and measured within 1 month.
2.3. Statistical analysis
Categorical variables are expressed as number and percentage, and continuous variables as mean ± standard deviation (SD) or median and interquartile range [IQR: first quartile (Q1)—third quartile (Q3)]. Variation of plasma belimumab trough concentrations was evaluated using the coefficient of variation (CV%).
Correlation between plasma belimumab concentration and dose of belimumab was analyzed by Spearman's rank correlation coefficient (r s). Statistical analysis was performed using Graph Pad Prism 8 (GraphPad Software, La Jolla, CA, USA), and p values less than .05 were considered statistically significant.
2.4. Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY, 16 and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20. 17
3. RESULTS
3.1. Patient characteristics
A total of 13 patients were included in this study. Patient characteristics are summarized in Table 1. They were diagnosed with SLE and administered belimumab in addition to standard of care, because their disease activity was difficult to control with other existing medications. The doses of belimumab ranged from 8.95 to 10.64 mg/kg. The average number of blood sample collections was 9.4, ranging from 1 to 13.
TABLE 1.
Patient characteristics.
| Sex: Men/women (n) | 2/11 |
| Women (%) | 84.6 |
| Age (years) | |
| Median (Q1–Q3) | 40 (35–51) |
| Body weight (kg) | |
| Median (Q1–Q3) | 51.8 (47.0–58.1) |
| BSA (m2) | |
| Median (Q1–Q3) | 1.51 (1.46–1.61) |
| Belimumab dose (mg/kg)/infusion/patient | |
| Mean (SD) | 9.87 (0.45) |
| CRP (mg/L) | |
| Median (Q1–Q3) | 0.8 (0.5–1.2) |
| Albumin (g/L) | |
| Median (Q1–Q3) | 40.4 (37.9–42.8) |
Abbreviations: BSA, body surface area; CRP, C‐reactive protein; Q1, first quantile; Q3, third quantile; SD, standard deviation.
3.2. Trough plasma belimumab trough concentrations
The trough plasma belimumab concentrations over time in individual subjects are shown in Figure 1. The mean (range) observation period from the date of the first measurement was 355.2 (0–767) days. For plasma trough concentration of all patients, mean ± SD was 79.6 ± 49.5 μg/mL, and median (IQR) was 63.7 (43.2–108.9) μg/mL. The lowest and highest plasma concentrations were 13.8 μg/mL and 211.2 μg/mL, respectively.
FIGURE 1.
Trough concentrations of belimumab in plasma over time of treatment. Trough plasma belimumab concentrations are plotted against days from the date of the first measurement.
We observed large individual differences in trough plasma belimumab concentration of more than 10‐fold. In the patient with the lowest plasma trough concentration, the mean (±SD) trough plasma belimumab concentration was 33.4 ± 11.9 μg/mL. In contrast, the highest plasma trough concentration in 13 patients had mean (±SD) trough plasma belimumab concentration of 170.0 ± 16.7 μg/mL.
The intraindividual variation (CV%) of trough belimumab concentration in plasma ranged from 7.1% to 35.7% (Figure 2). The CV was more than 30% in three patients with lower mean trough belimumab concentrations and one patient with only 2 measurements. CV could not be calculated in one patient with only one measurement. Other patients had lower CV%, ranging from 7.1% to 18.0%.
FIGURE 2.
Box‐and‐whisker diagrams of plasma belimumab concentrations in individual patients. Patient 3 had one blood sample and patient 11 had two blood samples for measurement. SD, standard deviation; CV, coefficient of variation.
The analysis by gender showed that the mean (±SD) trough plasma belimumab concentration was 88.8 ± 49.9 μg/mL in 12 women and 50.2 ± 5.5 μg/mL in 2 men.
3.3. Correlation between plasma belimumab concentration and belimumab dose
The correlation between single dose per patient (mg) and mean trough plasma belimumab concentration, and that between single dose per body weight (mg/kg) and mean trough plasma belimumab concentration were evaluated (Figure 3).
FIGURE 3.
Correlation between mean belimumab concentration in plasma and belimumab dose. (A) Correlation between mean plasma belimumab concentration and belimumab dose per patient (mg); (B) correlation between mean plasma belimumab concentration and dose per body weight (mg/kg).
The data of 10 patients were used in the evaluation of the correlation between belimumab dose and mean trough plasma belimumab concentration, after excluding two patients who were considered to have not reached steady state in the first four doses of belimumab and one patient who changed doses during the period. The correlation coefficient between dose per patient (mg) and mean belimumab concentration in plasma was 0.013 (p = .98). The correlation coefficient between dose per body weight (mg/kg) and mean trough plasma belimumab concentration was −0.224 (p = .54). No correlation was found between single dose per patient (mg) and mean trough plasma belimumab concentration, and between single dose per body weight (mg/kg) and mean trough plasma belimumab concentration. Even at the approved dose of 10 mg/kg, a large range of trough plasma belimumab concentrations was observed.
4. DISCUSSION
In this study, we investigated whether intra‐ and interindividual variations in trough plasma belimumab concentration exist in SLE patients on belimumab therapy. Our results revealed small intraindividual variation but large interindividual variation. There was no correlation between belimumab dose and trough plasma belimumab concentration. These findings indicate that trough plasma belimumab concentrations vary widely even when patients are treated with the approved dose of 10 mg/kg, and that it is difficult to predict trough plasma belimumab concentration from the dose. To the best of our knowledge, this is the first report of the evaluation of trough plasma belimumab concentrations in patients with SLE in actual clinical practice.
The mean trough plasma concentration in clinical patient samples was 79.6 μg/mL and the median was 63.7 μg/mL (range, 13.8 to 211.2 μg/mL). The mean concentration in this study was slightly higher than that reported by Marin et al. 18 (67.4 μg/mL; range, 19 to 171 μg/mL), and the median concentration was comparable to that reported by Tanaka et al. 19 (63 μg/mL). Several patients in this study were found to have higher trough concentrations compared to previous reports.
The interindividual variability of trough plasma belimumab concentration observed in our study and the differences compared with previous reports are probably due to the following three factors: (1) individual differences in the elimination pathways of antibody drugs, (2) variability in patient background, and (3) differences in measurement methods. We consider that 1 and 2 are important factors for inter‐individual variation, while 2 and 3 are important factors for the differences compared with previous reports.
The possible elimination pathways for antibody drugs include target‐mediated drug disposition (TMDD) and recycling via the neonatal Fc receptor (FcRn), which is involved in immunoglobulin G (IgG) catabolism. 20 , 21 , 22 , 23 , 24 Other factors include binding to ADAs, which has been shown to increase the rate of drug disappearance. 11 , 25 Regarding TMDD, belimumab pharmacokinetics has been suggested to be mediated by BLyS. 13 However, although BLyS concentrations are higher in SLE patients compared to healthy subjects, BLyS concentrations are several orders of magnitude lower than belimumab. 14 , 26 Therefore, the effect of BLyS on the elimination of belimumab is considered small. 13 However, the clearance of immune complexes by the Fcγ receptor (FcγR) of phagocytes in the spleen has been reported to be affected by the genotype of FcγR. 27 , 28 Furthermore, the FcγR expression rate changes depending on disease activity of SLE, which affects the clearance of immune complexes. 29 Individual differences in FcγR due to disease activity and genotype may affect plasma belimumab concentrations. Regarding the FcRn‐mediated antibody recycling mechanism, although the effect of FcRn on the pharmacokinetics of antibody drugs is still under investigation and many aspects remain unclear, it has become clear that antibody drugs compete with IgG to bind FcRn and are recycled in the blood. 22 , 30 Ternant et al. 30 showed that the half‐life of infliximab differed significantly depending on the IgG allotype. The expression rates of IgG1 allotypes differ greatly between Japanese and French studies, and both intraracial and interracial differences have been observed. 31 , 32 Genetic polymorphisms of IgG may explain why some patients had high plasma concentrations in this study and that the plasma concentration were different from those reported previously. For ADAs, the incidence of anti‐belimumab antibodies was reported to be 0.7% (4 of 563 patients) in the phase III trials BLISS‐52 and BLISS‐76, and 0.2% (1 of 470 patients) in the phase III trial BLISS‐NEA in Asian patients. 33 , 34 Although ADAs were not measured in this study, the incidence of ADAs for belimumab is low and is unlikely to be the cause of intra‐ or interindividual variabilities.
The more diverse comorbidities and concomitant medications in the 13 patients included in this study compared to the subjects included in the preapproval clinical trials may have contributed to the wider range of blood concentrations of belimumab in this study. In a pharmacokinetic analysis of belimumab, an increase in clearance was reported with concomitant use of steroids and angiotensin‐converting enzyme inhibitors, although the effects were small. 13 On the other hand, studies in rat cells showed that dexamethasone downregulates mRNA levels of the rat FcRn gene. 35 The relationship of dosage and duration of steroid treatment with plasma belimumab concentration may need further study. The majority of drugs used in the treatment of SLE were found to have no significant effect on the pharmacokinetics of belimumab, but drugs used to treat comorbidities were not examined in clinical trials. Although there are no reports to date of comorbidities affecting the pharmacokinetics of antibody drugs, it is possible that catabolism via the FcRn recycling mechanism may be affected during exacerbation of SLE symptoms or infection when IgG production is increased.
Regarding the difference in measurement methods, immunoassay was used in the clinical trials of belimumab, while the UHPLC–MS/MS method was used in this study. Previous studies of immunoassays have reported lower readings at higher concentrations of the substance being assayed. 36 , 37 Belimumab is used at higher dosage compared to other antibody drugs, and higher blood concentrations may be expected. At the high concentration range, there is a possibility that the readings obtained by immunoassays may be lower than the actual blood concentrations.
The factors affecting interindividual variation, as discussed above, are not clear and need to be clarified in future research. Also, although further study is required to examine the relationship between changes in plasma belimumab concentration and treatment efficacy, TDM may be useful for belimumab treatment. As reported by Syversen et al., 7 TDM for infliximab, a representative example of antibody drugs, improves the remission maintenance rate. Although advanced techniques of sample pretreatment such as trypsin digestion and advanced technology of drug concentration measurement such as using mass spectrometry are needed for TDM of antibody drugs, TDM of belimumab is anticipated to improve the success rate of belimumab treatment.
A limitation of this study is that the sample size was small. The difference in mean plasma belimumab concentration by gender may be due to the small number of patients and predominance of women in this study. However, even in a small number of patients, we believe that it is meaningful to measure blood concentrations of individual patients over a long treatment period to evaluate intraindividual variability.
5. CONCLUSION
This study of intra‐ and interindividual variations in plasma belimumab concentration in SLE patients showed that intraindividual variation was small while interindividual variation was large, suggesting the potential usefulness of measuring trough plasma belimumab concentrations. These results warrant further large‐scale studies to evaluate the usefulness of TDM of belimumab to promote appropriate use of this antibody drug.
AUTHOR CONTRIBUTIONS
C.Y., Y.S., A.O., and K.O. contributed to the conception and design of the study. C.Y., Y.S., R.T., H.O., A.O., T.O., H.S., H.I., and K.O. acquired the data. C.Y., Y.S., A.O., and K.O. analyzed and interpreted the data. C.Y., Y.S., A.O., and K.O. drafted the manuscript. R.T., H.O., T.O., H.S., and H.I. revised the manuscript critically for important intellectual content. All authors finally approved the version to be submitted.
FUNDING INFORMATION
The research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
CONFLICT OF INTEREST STATEMENT
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.
ETHICS STATEMENT
This study was reviewed and approved by the ethics committees of Meiji Pharmaceutical University (approval number: 201919) and Oita University Hospital (approval number: 1628).
CONSENT
All patients received prior explanations about the scientific purpose of the study and gave written informed consent prior to participation in this study.
Supporting information
Data S1.
6. ACKNOWLEDGMENTS
The authors thank Kazue Ogata of Department of Clinical Pharmacy, OitaUniversity Hospital, for technical assistance.
Yoshijima C, Suzuki Y, Tanaka R, et al. Evaluation of intra‐ and inter‐individual variations in plasma belimumab concentrations in adult patients with systemic lupus erythematosus. Pharmacol Res Perspect. 2024;12:e1255. doi: 10.1002/prp2.1255
DATA AVAILABILITY STATEMENT
The data presented in this study are available on request from the corresponding author. The data are not publicly available for protection of patients' privacy.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available for protection of patients' privacy.