Abstract
Introduction
An increasing number of patients in clinical practice are transitioning from intravenous (IV) to subcutaneous (SC) dosing of infliximab. In this simulation study, we evaluated hypothetical dosing scenarios both for typical adults and adults with obesity and for children switching from steady-state IV to SC infliximab, as well as those initiating SC infliximab therapy.
Methods
By combining two previous published infliximab models, we were able to simulate both IV and SC dosing in adults and children. Various dosing regimens were simulated using a large virtual population. In each scenario, the distribution of trough concentrations and area under the plasma concentration–time curve (AUC) was calculated.
Results
Peak levels were higher after IV dosing compared with SC dosing, while trough levels were higher after SC dosing, leading to more stable infliximab levels over time. Overall exposure remained largely similar when switching from a standard IV to SC dosing regimen. Patients with a high body mass index and those on high-frequency IV dosing regimens of infliximab demonstrated reduced exposure when transitioned to the fixed SC dose. Paediatric patients exhibited higher exposure on the fixed SC dose. Simulation of SC induction schemes demonstrated early achievement of steady-state plasma levels.
Conclusion
Infliximab exposure (AUC) remains largely similar when transitioning from standard IV to SC dosing. Current dosing regimens may not be optimal for patients with severe obesity, paediatric patients and patients on high-frequency infliximab regimens. These findings provide a foundation for future clinical research to refine SC infliximab dosing in these populations.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13318-025-00959-y.
Key Points
| While trough concentrations are significantly higher with SC dosing compared with IV dosing, overall exposure (AUC) to infliximab remains largely similar when administered in a standard dose IV and SC. |
| Current dosing regimens may not be optimal for patients with severe obesity, paediatric patients and patients on high-frequency IV infliximab regimens. |
Introduction
The introduction of biologics at the beginning of this century marked a significant advancement in the treatment of patients with inflammatory bowel disease (IBD). Infliximab (Remicade®), a tumour necrosis factor (TNF)-alpha inhibitor, was the first biologic approved for IBD, followed by several others. While most were introduced as subcutaneous (SC) injections, infliximab was only available as intravenous (IV) infusion. Recently, a fixed-dose SC formulation of infliximab (CT-P13; Remsima®) was approved, following clinical trials that demonstrated its noninferior efficacy and safety compared with the IV formulation [1, 2]. Subcutaneous administration results in more sustained drug concentrations with higher trough levels and reduced fluctuation, which may contribute to lower immunogenicity and increased drug survival [1–4]. Besides, SC administration enables patients to self-administer their treatment at home, eliminating the need for hospital visits for infusions. This not only enhances patient convenience but also reduces the workload on hospital personnel, as SC administration requires neither IV access nor preparation of infusion solutions. As a result, an increasing number of patients in clinical practice are transitioning from IV to SC dosing of infliximab.
A concern when switching therapies in these patients is the risk of a relapse. A relapse may occur due to increased clearance and lower exposure to infliximab. For IV therapy, a clear relationship between infliximab concentration (trough levels) and clinical efficacy has been established [5–8]. With SC dosing, the drug is released more gradually from the subcutaneous tissue into the systemic circulation, resulting in a distinct concentration–time curve with lower peak drug levels and higher trough levels compared with IV infliximab [9, 10]. Recent research from two independent research groups also suggests a concentration–effect relationship for SC therapy [4, 11]. Monitoring of plasma levels through therapeutic drug monitoring (TDM) may therefore be used to signal an increased clearance and adjust dosages accordingly. This was demonstrated in a simulation study by Wang et al. [10], who hypothesized that TDM can guide the IV-to-SC switch. However, their study did not account for covariates such as serum albumin levels, body weight, or the presence of anti-drug antibodies – factors known to significantly influence infliximab clearance [9]. Moreover, their article focussed on average adult patients. In our simulation study, we evaluate hypothetical dosing scenarios for various subpopulations switching from steady-state IV infliximab to SC infliximab both in typical adults and adults with obesity and in (young) children, as well as those initiating SC infliximab therapy.
Methods
Models
In this study we performed simulations based on combined infliximab models from two studies [9, 12]. Fasanmade et al. [12] published their model on IV infliximab with a dataset for children and adults, as well as a combined dataset. In addition, we used the Hanzel model [9] that describes a SC model of infliximab in adults but not in children. The pharmacokinetic (PK) model of Fasanmade et al. [12] was used to simulate infliximab concentrations in adults and children, for both IV and SC dose administrations. To be able to perform SC simulations in both children and adults, the Fasanmade model was extended using the SC absorption model as described in Hanzel et al. [9]. To ensure the combined model was unbiased, we tested this approach by visually and numerically comparing how well SC simulations from this new Fasanmade SC model compares with simulations from the SC Hanzel model in adults. Overall, these simulations show that the PK simulations for the Fasanmade adults model with an added SC absorption compartment match the Hanzel model well (Electronic Supplementary Material). It can thus be expected that the Fasanmade children model, when similarly adapted to include the SC compartment from the Hanzel model, will provide reasonably accurate predictions of PK in children for infliximab SC administration. In the Electronic Supplementary Material more details and the model code are provided.
Populations
The covariates included in the Fasanmade model were: antibodies to infliximab (ATI), serum albumin (ALB), weight (WT) and concomitant administration of immunomodulatory drugs (IMM).
Simulations were done on the basis of typical individuals and across a virtual population.
A typical patient was defined as a patient of 70 kg (WT), with a serum albumin of 44 g/L (ALB), co-medicated with immunomodulatory drugs (IMM), and no proven antibodies against infliximab (ATI).
For simulations in an adult population, covariate correlations were determined from an existing adult cohort in InsightRX Nova (70 patients with IBD from a medium-sized teaching hospital with 443 infliximab concentrations). Mean albumin concentration was 43.3 g/L [standard deviation (SD) = 5.5 g/L) and correlated with weight. No correlation was assumed between ATI and the two other covariates, and the univariate probability of ATI was 7.6% as observed in our population.
For simulations in adults with obesity, the data for the typical patient was altered to have a range of higher BMIs, with weights calculated according to BMI.
For simulations in children, a range of ages was studied (8, 12, 15 and 20 years of age). For each age in this range the typical weight and height were obtained using data from the Centers for Disease Control and Prevention (CDC)/National Institutes of Health (NIH) [13]. Serum albumin was assumed to be 44 g/L.
Simulations and Analyses
IV-to-SC Switching
Initially, switching from the standard IV dosing regimen (5 mg/kg every 8 weeks) to the standard SC regimen (120 mg every 2 weeks) was simulated in typical patients, and the resulting distribution of trough concentrations and area under the plasma concentration–time curve (AUC) were quantitatively characterized. Subsequently, the correlation between trough levels and between AUCs were evaluated.
Thereafter, various IV and SC dosing regimens (Table 1) were simulated using a virtual adult population. For each scenario, the distribution of trough concentrations and area under the plasma concentration–time curve (AUC) were calculated. In addition, the timing of switching was examined by simulating different moments of initiating SC dosing after the last IV dose.
Table 1.
Overview of simulated scenarios for switching from IV to SC and for initiating infliximab
| Scenarios | IV dosing regimens | SC dosing regimens | Timing of switch |
|---|---|---|---|
| IV-to-SC switch (all different regimens studied) | 5 mg/kg every 8 weeks | 120 mg every 2 weeks | 2 weeks after IV dose |
| 5 mg/kg every 6 weeks | 120 mg/week | 4 weeks after IV dose | |
| 5 mg/kg every 4 weeks | 240 mg every 2 weeks | 6 weeks after IV dose | |
| 7.5 mg/kg every 8 weeks | 8 weeks after IV dose | ||
| 7.5 mg/kg every 6 weeks | |||
| 7.5 mg/kg every 4 weeks | |||
| 10 mg/kg every 8 weeks | |||
| 10 mg/kg every 6 weeks | |||
| 10 mg/kg every 4 weeks | |||
| Induction regimen 1 | W0 5 mg/kg | ||
| “SmPC_IV induction_1” | W2 5 mg/kg | ||
| W6 120 mg/2 week | |||
| Induction regimen 2 | W0 5mg/kg | ||
| “SmPC_IV induction_2” | W2 5 mg/kg | ||
| W6 5 mg/kg | |||
| W10 120 mg/2 week | |||
| Induction regimen 3 | W0 240 mg | ||
| “DirectCD_SC induction_1” | W2 240 mg | ||
| W4 120 mg/2 week | |||
| Induction regimen 4 | < 80 kg | ||
| “DirectCD_SC induction_2” | W0 480 mg | ||
|
W2 240 mg W4 120 mg every 2 weeks ≥ 80 kg W0 480 mg W2 240 mg W4 240 mg every 2 weeks |
SmPC summary of product characteristics; W week
Induction Schemes
Four different induction regimens were simulated in typical patients. For each regimen, plasma concentration–time curves were derived.
Subpopulations
For the populations with obesity and paediatric population, a fixed SC dose of 120 mg every 2 weeks was simulated for typical patients at various BMI values (with obesity) and across various ages (paediatric patients). The distribution of expected AUCs were collected and summarized (Table 2).
Table 2.
Summary of pharmacokinetic parameters used in simulation of IV and SC regimens in children and adults (full code with covariate–parameter relationships in supplementary)
| Children | Adults | |||
|---|---|---|---|---|
| Parameter | IIV | Parameter | IIV | |
| CL (L/day) | ||||
| Clearance | 5.43 | 53% | 5.39 | 60% |
| V (L) | ||||
| Volume of distribution | 54.2 | 42% | 52.7 | 32% |
| Q (L/day) | ||||
| Inter-compartmental clearance | 29.2 | — | 19 | — |
| V2 (L) | ||||
| Peripheral volume | 3.52 | 65% | 2.15 | 92% |
| Ka (per hour) | ||||
| Absorption rate | 0.273 | 42% | 0.273 | 42% |
| F (%) | ||||
| Bioavailability | 79.1 | 79% | 79.1 | 79% |
Software
R version 4.3.3 was used for the analysis. The PKPDsim package (https://insightrx.github.io/PKPDsim/) for R was used for simulating concentrations, and tidyverse packages for data parsing and plotting.
The PK model implementation in R was validated against the same model implemented in NONMEM, to ensure accurate results (full verification reports included in Supplementary).
Results
Switching from IV to SC Infliximab Dosing
Figure 1 presents an example of the pharmacokinetics over time for a typical patient switching from IV to SC infliximab. Figure 2 presents the expected distribution of trough concentrations for both the IV and SC regimens at steady state. Peak levels were higher after IV dosing compared with SC dosing, while trough levels were higher after SC dosing leading to more stable infliximab levels over time after SC dosing. This is further demonstrated by the expected reduced variability in trough levels with SC administration in Fig. 2.
Fig. 1.
Expected concentration–time plots for typical patients switching from IV to SC infliximab. Typical patients were defined as having a body weight of 70 kg and albumin 44 g/L, co-medication with immunomodulatory drugs and no proven antibodies against infliximab
Fig. 2.
Expected distribution of trough concentrations for typical patients before and after switching from 5 mg/kg IV every 8 weeks to 120 mg SC every 2 weeks. Typical patients were defined as having a body weight of 70 kg and albumin 44 g/L, co-medication with immunomodulatory drugs and no proven antibodies against infliximab
Correlation IV and SC Trough Levels and AUC for a Typical Individual
Figures 3 and 4 present the correlation between the IV and SC trough levels (Fig. 3) and AUCs (Fig. 4) after switching from 5 mg/kg every 8 weeks IV to 120 mg every 2 weeks SC. The red line shows the line of unity. It is clear that trough concentrations (Fig. 3) are not similar, with SC dosing yielding higher troughs compared with IV dosing. However, AUC values (Fig. 4) are expected to be largely similar with SC dosing leading to slightly higher AUCs on average (for the default regimens used in these simulations).
Fig. 3.
Correlation between trough levels (Cmin) at steady state after IV dosing and SC dosing for a typical patient. Typical patients were defined as having a body weight of 70 kg and albumin 44 g/L, co-medication with immunomodulatory drugs and no proven antibodies against infliximab. The blue ribbon depicts the interquartile range (IQR) of AUCs for the SC regimen, and the grey ribbon depicts IQR for AUCs following the IV regimen
Fig. 4.
Correlation between 8-week exposure (AUC) at steady state after IV dosing and SC dosing for a typical patient. Typical patients were defined as having a body weight of 70 kg and albumin 44 g/L, co-medication with immunomodulatory drugs and no proven antibodies against infliximab. The blue ribbon depicts the interquartile range (IQR) of AUCs for the SC regimen, and the grey ribbon depicts IQR for AUCs following the IV regimen
Trough Levels and AUCs in a Virtual Adult Population
In Figs. 5 and 6, the expected distributions of respectively trough concentrations and AUCs at steady state for the simulated scenarios are shown across a virtual adult population. For these patients, no adjustments were made on the basis of therapeutic drug monitoring; i.e., the maintenance dose was assumed to be continued indefinitely.
Fig. 5.
Expected distribution of trough concentrations at steady state for various IV and SC dosing regimens across a virtual adult population
Fig. 6.
Expected distribution of AUCs at steady state for various IV and SC dosing regimens across a virtual adult population.
Timing of Switching
Figure 7 presents the expected concentration profiles with various switching scenarios in a typical patient. As can be seen, switching 4 weeks after the last IV dose will result most quickly in steady-state plasma levels of SC infliximab.
Fig. 7.
Expected plasma concentration–time curves during various switching scenarios in a typical patient. Typical patients were defined as having a body weight of 70 kg and albumin 44 g/L, co-medication with immunomodulatory drugs and no proven antibodies against infliximab. The week above the graph refers to the time after the last IV dose when SC dosing was started. The grey ribbon depicts the 80% confidence interval for the predicted plasma concentrations
Induction schedules SC Infliximab
Figure 8 presents the expected concentration profiles of various schemes in a typical patient (including uncertainty). As can be seen, most result in early achievement of steady-state plasma levels, while induction scheme ‘DirectCD SC induction 2’ expected to have the highest trough levels after the first doses, gradually decreasing to steady state.
Fig. 8.
Expected plasma concentration–time curves of various induction schemes in a typical patient. Typical patients were defined as having a body weight of 70 kg and albumin 44 g/L, co-medication with immunomodulatory drugs and no proven antibodies against infliximab. The grey ribbon depicts the 80% confidence interval for the predicted plasma concentrations
Subpopulations
Obesity
Figure 9 presents the expected AUC for typical patients at various BMI values when using 120 mg SC infliximab every 2 weeks. The dotted line shows the exposure for a typical adult patient with a BMI of 20 kg/m2. The figure demonstrates that, in patients more severe obesity, we are expected to see lower exposure if the same SC dose is administered. Especially in the population with severe obesity (BMI ≥ 40 kg/m2), exposure is much lower than in typical patients.
Fig. 9.
Expected distribution of exposure in typical patients with various body mass indexes following SC dosing 120 mg every 2 weeks. Typical patients were defined as having an albumin of 44 g/L, co-medication with immunomodulatory drugs and no proven antibodies against infliximab
Paediatric patients
Figure 10 demonstrates the expected AUC across various ages for typical paediatric patients receiving 120 mg every 2 weeks SC. The dotted line shows typical exposure for a 20-year old patient. The figure demonstrates that in younger patients we can expect to see higher exposure if the same SC dose is administered.
Fig. 10.
Exposure in typical paediatric patients across various ages following SC dosing 120 mg every 2 weeks. For each age in this range the typical weight and height were obtained using data from the CDC/NIH [13]. The typical weights for age were 25.6, 40.5, 56.3, and 70.6 kg for the four age groups, respectively. Serum albumin was assumed to be 44 g/L.
Discussion
In this study, we simulated various IV and SC infliximab dosing scenarios for adults and children initiating or switching to SC therapy. While trough concentrations are significantly higher with SC dosing compared with IV dosing, overall exposure (AUC) to infliximab remains largely similar when administered in a standard dose IV (5 mg/kg every 8 weeks) and SC (120 mg every 2 weeks). While this is true for the typical patient, an important finding is that certain patients are at risk of underdosing or overdosing when given the fixed SC dose. Patients with a high body mass index (BMI) are expected to experience much lower exposure compared with the typical patient, while paediatric patients exhibit higher exposure. Additionally, patients on high-frequency dosing regimens of infliximab may experience reduced exposure when transitioned to the fixed SC dose and may require a higher dose.
Trough concentrations following SC dosing were significantly higher than those observed with IV dosing, consistent with previous research and the expected PK profile of SC administration [4, 11]. In our simulations in an adult population, steady-state trough concentrations after SC standard dosing were roughly in line with the studies of Roblin and Schreiber, who reported median trough levels around 10–15 mg/L after SC standard dosing [2, 4]. However, these concentrations are lower than recent studies that propose a target range of at least 15–20 mg/L for more stringent endpoints in SC infliximab therapy [4, 11, 14], which raises concerns that SC infliximab may be underdosed in some patients for this purpose. For the average patient this is not reflected in clinical studies demonstrating non-inferior or even better efficacy compared with IV infliximab [2, 15]. Possibly, only certain patients may require trough levels above 15 mg/L for optimal efficacy, for instance; patients with more aggressive disease (juvenile IBD) or fistulizing disease. Interestingly, overall drug exposure (AUC) was comparable between the standard IV regimen (5 mg/kg every 8 weeks) and the SC regimen (120 mg every 2 weeks). This raises the possibility that AUC, rather than through levels, may be a better reflection of exposure and thereby more closely associated with therapeutic efficacy. Future research should explore this hypothesis and aim to define an optimal target AUC. Implementing therapeutic drug monitoring (TDM) based on AUC in clinical practice may, however, present practical challenges. Unlike trough level monitoring, AUC-based strategies require multiple time-point sampling and the use of precision dosing software to reliably estimate exposure.
Although the observed differences in exposure across subgroups were modest, they may still carry clinical significance, particularly in patients with aggressive disease phenotypes or a history of loss of response. Conversely, higher exposure in children raises concerns about the potential for overtreatment. Taken together, these findings highlight the importance of validating AUC-guided strategies across diverse patient populations to ensure safe and effective individualized dosing.
Fixed dosing regimens pose a risk of underdosing or overdosing in specific patient populations. Consistent with previous studies [3, 10], we confirmed that patients receiving 7.5 or 10 mg/kg IV every 4 weeks require a more frequent SC dosing interval (120 mg SC weekly) to achieve a similar exposure. This finding was also supported by the REMSWITCH clinical trial, in which switching to 120 mg SC every 2 weeks was ineffective for those very patients [3]. Our simulations further indicate that patients with a high BMI are at risk of underdosing, while those with low body weight, such as (very young) paediatric patients, may be at risk of overdosing. Recent epidemiological data suggest that between 15% and 40% of patients with IBD meet criteria for being overweight or for obesity, emphasizing the need for appropriate dose evaluation in this subgroup [16]. The impact of weight (and consequently BMI) on infliximab clearance is well-documented for IV administration [17, 18]. Our study suggests that patients with severe obesity (BMI ≥ 40 kg/m2) may require more frequent dosing (120 mg weekly) to achieve exposure comparable to a typical patient, though this should be validated in clinical trials. In fact, in an weight-based analysis of LIBERTY-CD data presented at both the European Crohn’s and Colitis Organisation (ECCO) and Digestive Disease Week (DDW) 2024, patients with obesity demonstrated a significant lower median serum level of infliximab at week 54 compared with patients with a typical weight. Clinical outcomes however did not differ significantly between the several weight categories although a trend was clearly visible [19, 20]. In the preliminary findings of the DIRECT-CD study also presented at both ECCO and DDW 2024, 67% of patients with a body weight < 80 kg reached clinical remission, while only 33% of patients with a body weight > 80 kg did so [21, 22].
Conversely, our simulations suggest that, in patients of 12 years or younger (with an average body weight of approximately 40 kg), an extended dosing interval will result in similar exposure compared with adults with a regular dosing interval. However, young children often already use higher IV dosing regimens due to more aggressive disease, lower albumin levels and subsequently higher infliximab clearance [23]. Further research is needed to optimize dosing strategies in paediatric populations.
We simulated several induction schemes for initiating infliximab and switching from IV to SC dosing. Regardless of administration route of induction, steady-state levels were achieved within 10 weeks, with high plasma concentrations after the initial doses. This raises the question of whether IV induction, as currently recommended in the drug label, is truly necessary [24]. Clinical studies demonstrate that SC administration is associated with lower rates of antibody formation, potentially eliminating the need for combination therapy (with an immunomodulatory) during SC induction [2, 25]. The SC induction schemes warrant further clinical investigation with special consideration to patients with acute severe ulcerative colitis (ASUC), as some studies indicate they may require an intensified induction regimen due to increased faecal drug loss and substantially higher infliximab clearance [26].
For patients switching from IV to SC infliximab, we demonstrated that steady-state SC plasma levels are rapidly achieved when SC therapy is initiated at the time of the next scheduled IV dose. This approach is suitable for patients in remission with stable disease. However, in patients at higher risk of relapse – such as those previously on high-frequency IV dosing – earlier initiation of SC therapy (2–4 weeks after the last IV dose) may be beneficial, as steady-state infliximab levels and sufficient exposure are reached earlier.
Our study has overlap with the study of Wang et al. [10], yet their study did not account for key covariates such as serum albumin levels, body weight, or the presence of anti-drug antibodies – factors known to significantly influence infliximab clearance [9]. Moreover, their article focussed on average adult patients, whereas we also simulated paediatric patients and explored a broader range of dosing scenarios, including initiation strategies and dosing in individuals with obesity. Our study also had limitations, the first and foremost being that is was a simulation study without patient data. However, our results can serve as a foundation for future clinical research, especially in non-regular patient cohorts such as (very young) children or patients with (severe) obesity. In our analysis we combined two published pharmacokinetic models of infliximab to be able to simulate more subpopulations [9, 12]. The predictions for individuals with obesity were based on the Fasanmade model with added SC absorption component [12]. While the Fasanmade publication did include some high-weight individuals (exact BMI distribution not reported) and hence may be expected to predict well in patients with obesity, the Hanzel publication seemed to have included patients with less severe obesity. Therefore, the extrapolation to subpopulations with obesity must be interpreted with caution, especially for patients with severe obesity. The Fasanmade models for children and adults were based on large clinical trials (REACH and ACCENT I, respectively), and body weight was explicitly modelled as a covariate in the structural model. Unfortunately the exact weight and BMI distributions are not publicly available, but obesity was not an exclusion criteria in either study. So it is likely that a considerable fraction of the study populations were patients with obesity, which would have informed the relationship between (high) weight and pharmacokinetic parameters. We therefore believe the simulated exposures are plausible. Additionally, the Hanzel publication did not include any paediatric data. Hence, the absorption characteristics (rate and bioavailability) may be different in children and patients with obesity, and this potentially may have influenced our results. Despite these limitations we think our approach was plausible. Future research will tell whether our results are valid in these cohorts, but the first indications are already there [19–22].
To conclude, this simulation study evaluated hypothetical dosing scenarios for various subpopulations switching from steady-state IV to SC infliximab or initiating SC infliximab therapy. A key finding is that overall infliximab exposure (AUC) remains largely similar while trough levels significantly increased when transitioning from standard IV to SC dosing, suggesting that AUC may be a better measure of exposure than trough levels. Additionally, patients with a high BMI experience significantly lower exposure, while paediatric patients exhibit higher exposure, indicating that current dosing may not be optimal for these groups. These findings provide a foundation for future clinical research to refine SC infliximab dosing in these populations.
Supplementary Information
Below is the link to the electronic supplementary material.
Declarations
Funding
The authors did not receive support from any organization for the submitted work.
Conflicts of Interests
R.W. has no conflicts of interest. R.K. is an employee and stockholder of Insight RX, a company developing clinical decision software. L.D. has served as a speaker for AbbVie, Celltrion, Janssen-Cilag and Takeda and has developed continuing education materials for Ferring, all outside the submitted work.
Availability of Data and Material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Author Contributions
L.D. came up with the original idea for this study and supervised the research project. All authors contributed to the study design, analysis and interpretation of the data. R.K. contributed to the statistical analysis. R.W. wrote the manuscript. All authors contributed to the drafting and critical revision of the manuscript and approved the final version of this manuscript.
Ethical approval
Not applicable.
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Footnotes
Ron J. Keizer and Luc J. J. Derijks share last authorship.
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