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. 2023 Mar 31;16(6):978–986. doi: 10.1111/cts.13503

Evidence‐based rationale for low dose nivolumab in critically ill patients with sepsis‐induced immunosuppression

Demy A C van den Haak 1, Leila‐Sophie Otten 1, Hans J P M Koenen 2, Ruben L Smeets 2, Berber Piet 3, Peter Pickkers 4, Matthijs Kox 4, Rob ter Heine 1,✉
PMCID: PMC10264964  PMID: 37002646

Abstract

A substantial part of critically ill patients suffer from sepsis‐induced immunosuppression. Reversal of immunosuppression through PD‐1 checkpoint inhibition has been proposed as a treatment strategy to overcome immunosuppression in these patients. The PD‐1 inhibitor nivolumab, currently used in treatment of cancer, has been evaluated in phase I/II studies in patients with sepsis, demonstrating tolerability and signs of clinical efficacy. No proper dose finding was performed in these studies and, after a single high dose of 480 mg or 960 mg nivolumab, PD‐1 inhibition persisted beyond 90 days in the majority of cases. As the duration of sepsis is ~7–10 days, prolonged PD‐1 inhibition may unnecessarily induce longer‐term immune‐related side effects. Based on previously published pharmacokinetic and pharmacodynamic data of nivolumab, a thorough in silico dose finding study for nivolumab in critically ill patients was performed. We found that volume of distribution and clearance of nivolumab were not higher in patients with sepsis compared to the cancer population for which nivolumab is currently approved and showed profound variability. We found that with a single dose of 20 mg nivolumab, the PD‐1 receptor occupancy is predicted to stay above the 90% threshold for a median of 23 days (90% prediction interval of 7–78 days). We propose to investigate this dose in critically ill patients as a potential safe and cost‐effective pharmacotherapeutic intervention to treat sepsis‐induced immunosuppression.

Study Highlights.

  • WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Sepsis remains one of the leading causes of death in critically ill patients. Programmed cell death protein 1 (PD‐1) inhibition with nivolumab is a promising treatment modality in patients with sepsis‐induced immunosuppression. Preliminary studies show promising results, yet the optimal nivolumab dose is unknown.

  • WHAT QUESTION DID THIS STUDY ADDRESS?

What is the optimal dose for nivolumab in sepsis‐induced immune suppression?

  • WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Using model‐informed drug development, we show that a low dose of nivolumab could be a safe pharmacotherapeutic intervention to treat sepsis‐induced immunosuppression.

  • HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Model‐informed drug development enables rational dose development of novel treatment modalities for sepsis‐induced immunosuppression, based on previous studies.

INTRODUCTION

Sepsis is defined as life‐threatening organ dysfunction caused by a dysregulated host response to infection. 1 , 2 It is a serious threat to human health worldwide and, with 11 million deaths annually, remains to be one of the most common causes of death in patients in intensive care . 1 , 3 It is now recognized that a significant pathophysiologic process in sepsis is the development of impaired host immunity. 4 This immunosuppression has important clinical consequences, including an increased risk of secondary infections, organ dysfunction, and mortality. 4 It is thought that increased expression of the immune checkpoint receptor programmed cell death 1 (PD‐1) plays a major role in this process. 5 , 6 , 7 Therefore, PD‐1 inhibitors, currently used for treatment of cancer, may benefit patients with sepsis‐induced immunosuppression through reactivation of T lymphocyte function resulting in immune resurrection to fight underlying infections. One of such inhibitors, nivolumab, has already proven to be safe in two phase I studies performed in patients with sepsis. 8 , 9

In both of these phase I studies in critically ill patients with sepsis, a single high dose of nivolumab, 480 mg or 960 mg, was administered based on the approved dose in patients with cancer. 8 , 9 Although the pharmacokinetics of drugs in critically ill patients are likely different due to altered pathophysiology, nivolumab was proven to be relatively safe and indications for adequate PD‐1 inhibition were demonstrated. 8 , 9 Even though the concept of PD‐1 inhibition in sepsis appears to be promising, these high doses may have their downsides. First, with these high doses, PD‐1 inhibition of blood lymphocytes persisted for 3 months or longer in the majority of patients. 9 The duration of sepsis is ~7–10 days, 4 with the immunosuppressive phenotype generally prevailing in the second window of the septic episode, with a fraction of patients developing dysregulated immunity after sepsis. 10 We argue it is questionable whether over 3 months of immune activation is of benefit for the patient, considering the fact that treatment with PD‐1 inhibitors is associated with considerable immune‐related toxicity. 11 , 12 Second, nivolumab is an expensive drug, costing up to $27,660 for a single nivolumab dose of 960 mg. 13 A lower dose could mitigate these challenges. We here propose an evidence‐based low‐dose nivolumab regimen, accounting for the potentially altered pharmacokinetics of nivolumab in patients with sepsis.

METHODS

Study design

The following systematic stepwise approach was used:

  1. The previously published individual‐level pharmacokinetic data of nivolumab in Japanese patients with sepsis 8 were extracted and a population pharmacokinetic model was fitted to these data.

  2. The developed pharmacokinetic model was externally validated using summary level pharmacokinetic data of nivolumab in patients with sepsis from the United States. 9

  3. Based on the developed model and the relationship between circulating nivolumab concentrations and peripheral PD‐1 inhibition, 14 a dose exploration study for low single doses of nivolumab was conducted to predict nivolumab's pharmacokinetics and its associated PD‐1 inhibition. The objective was to attain at least 90% PD‐1 inhibition for 7–10 days, with a quick cessation of PD‐1 inhibition thereafter. Although the 90% is an arbitrary threshold, it was chosen as a surrogate for effective treatment in earlier studies. 9

Data extraction

All data used in this investigation were extracted from previously published studies. Individual‐level pharmacokinetic data of nivolumab from 13 Japanese patients with sepsis were extracted from plots showing individual pharmacokinetic curves, as presented in the supplemental material by Watanabe et al. 8 For external validation of the developed pharmacokinetic model, summary level pharmacokinetic data of nivolumab from 15 US patients with sepsis were extracted. 9 Finally, the relationship between circulating nivolumab concentration and PD‐1 inhibition was extracted. 15 Data extraction was performed using WebPlotDigitizer version 4.5, 16 a computer‐assisted application used to extract numerical data underlying graphs and figures. Patient characteristics of both studies are described in the Supplementary Material S1.

Population pharmacokinetic modeling

Nivolumab pharmacokinetics were analyzed using nonlinear mixed effects modeling. Flow and volume parameters were allometrically scaled to total body weight with allometric exponents of 0.597 and 0.566, respectively, based on extensive pharmacokinetic data obtained in cancer patients. 14 All individuals in the dataset were assigned the mean weight reported for each dosing group, 8 because individual weights were not reported in the publication. Details of the model development and results are described in the Supplementary Material S1.

External validation

External validation of the developed pharmacokinetic model for nivolumab in sepsis was performed by comparing the mean (±SD) circulating nivolumab concentrations over time reported by Hotchkiss et al. 9 with the simulated mean (±SD) nivolumab concentrations over time using a Monte Carlo simulation (n = 1000) for both a single dose of 480 and 960 mg. The data of the study 9 were collected in a US population, with a likely higher bodyweight than the Japanese sepsis population, 8 used for model development. Therefore, a mean bodyweight of 79.07 and 77.11 kg were assigned to the individuals in the 480 mg and 960 mg group, based on the American demographic data and the expected corresponding weight according to the National Health and Nutrition Examination Survey (NHANES) database, 17 to allow extrapolation of the Japanese pharmacokinetic data to a US population, considering the weight dependency of nivolumab pharmacokinetics. 14 Furthermore, a sensitivity analysis in the external was performed, investigating the effect of a high body weight of 100 kg.

Nivolumab concentration and prediction of PD‐1 receptor occupancy

As PD‐1 inhibition (measured as PD‐1 receptor occupancy) on T‐cells is a robust predictor of the clinical effects of PD‐1 inhibitors, 18 the relationship between circulating nivolumab concentration and leukocyte PD‐1 receptor occupancy was extracted. 15 To describe this pharmacokinetic‐pharmacodynamic relationship, a maximum effect (E max) formula was fitted to the obtained data, using least squares regression. 19 , 20 The obtained relationship between nivolumab concentrations and PD‐1 receptor occupancy was carried forward to the dose exploration study (see below).

Dose exploration study

Based on the availability of nivolumab in 40 mg vials, the pharmacokinetics and PD‐1 receptor occupancy for doses of 10 and 20 mg nivolumab in patients with sepsis were predicted. These were compared with predicted pharmacokinetics and PD‐1 receptor occupancy of the previously clinically tested 480 and 960 mg doses. For this purpose, a Monte Carlo simulation (n = 1000 for each scenario) was performed to predict circulating nivolumab concentrations and PD‐1 receptor occupancy during 91 days (2184 h). The population bodyweight was obtained from the NHANES database to mimic a US population. 17 A PD‐1 receptor occupancy on T‐cells of 90% was set as a minimum effective target, based on the same assumption by Hotchkiss et al. in their study of nivolumab in patients with sepsis. 9

Software

Nonlinear mixed effects modeling was performed using the software package NONMEM version 7.5 (Icon). All graphs were plotted using Excel 2108 (Microsoft Corporation).

RESULTS

Population pharmacokinetic and PD‐1 receptor occupancy modeling

A linear two‐compartment pharmacokinetic model best described the pharmacokinetic data of nivolumab in patients with sepsis. The estimated central and peripheral volume of distribution, intercompartmental clearance, systemic clearance, and their respective relative standard error of estimate (RSE) were 5.37 L (9% RSE), 6.94 L (9% RSE), 0.0362 L/h (27% RSE), and 0.0221 L/h (9% RSE), respectively. The unexplained interindividual variability of the central and peripheral volume of distribution were 31.8% (18% RSE) and 68.3% (39% RSE). The unexplained interindividual variability in clearance was estimated to be 63.7% (33% RSE). The residual proportional error was estimated to be 21.5% (43% RSE). Details of the population pharmacokinetic analysis, including the goodness‐of‐fit plots, are described in the Supplementary Material S1.

The results of external validation are based on a population with an average bodyweight of 79.07 and 77.11 kg, based on the NHANES database with American demographic data. The results of the external validation are depicted in Figure 1. As observed for both high doses of 480 mg and 960 mg, the simulated mean (SD) concentrations from the pharmacokinetic model correspond well with those observed in the study performed in a US sepsis population, 9 showing external validity of the developed population pharmacokinetic model for nivolumab in patients with sepsis. The sensitivity analysis with an average bodyweight of 100 kg showed a slight overprediction during the very early distribution phase, but not during the elimination phase of nivolumab (data not shown) and was considered irrelevant as it did not notably impact predicted saturated PD‐1 receptor occupancy during the distribution phase. Results of the sensitivity analysis are presented in the Supplementary Material S1.

FIGURE 1.

FIGURE 1

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External validation of the created model with data from Hotchkiss et al. The graphs show circulating nivolumab concentrations over time after a single dose of (a) 480 mg or (b) 960 mg nivolumab at t = 0. The black dots represent the extracted mean nivolumab concentrations and corresponding standard deviation. These are compared to the simulated nivolumab concentration (gray solid line) and its standard deviation (gray shaded area).

The circulating nivolumab concentration for which 50% PD‐1 receptor occupancy on T‐cells was attained is estimated to be 0.128 mg/L. Details of the curve fitting are described in the Supplementary Material S1.

Dose exploration study

Results of the dose exploration simulations are depicted in Figures 2 and 3. The median predicted nivolumab concentrations over time, including the 90% prediction interval for the doses of 10, 20, 480, and 960 mg, are shown in Figure 2. The corresponding predicted PD‐1 receptor occupancy on T lymphocytes versus time, including the 90% prediction interval of the respective doses are shown in Figure 3.

FIGURE 2.

FIGURE 2

Open in a new tab

Simulated high and low dose nivolumab concentration over time. The median nivolumab concentration and 90% prediction interval over time after a simulated single dose of (a) 10, (b) 20, (c) 480, or (d) 960 mg nivolumab.

FIGURE 3.

FIGURE 3

Open in a new tab

Simulated PD‐1 receptor occupancy over time. Simulated median (solid line) PD‐1 receptor occupancy over time with the corresponding 90% prediction interval (gray area) after a single dose of (a) 10 mg, (b) 20 mg, (c) 480 mg, and (d) 960 mg at t = 0. The red line depicts the proposed 90% receptor occupancy threshold.

As shown in Figure 3, the receptor occupancy for the lower doses of 10 and 20 mg fell below the 90% threshold at a median of 10 days (90% prediction interval of 4–33 days) and 23 days (90% prediction interval of 7–78 days), respectively.

For reference, the clinically tested 480 and 960 mg doses were simulated as well. Notably, the predicted receptor occupancy above the 90% threshold at doses of 480 and 960 mg correspond well with the previously reported receptor occupancy, 9 where a small proportion of the population is predicted to have a PD‐1 receptor occupancy below the 90% threshold in the 50–90 day period after administration.

DISCUSSION AND CONCLUSION

Here, we predict that a low single dose of 20 mg nivolumab results in a PD‐1 receptor occupancy on T‐cells above the 90% threshold for a median time of 23 days, with a prediction interval of 7–78 days. This dose is therefore likely sufficient to overcome the immunosuppressive episode in the majority of critically ill patients with sepsis. 4 This dosing strategy exposes the vulnerable critically ill population to a reduced period of immune activation compared to the higher doses of nivolumab used in previous clinical studies. Because toxicity studies have not yet been performed in large populations, we hypothesize that this reduced time of immunosuppression may be associated with less immune‐related toxicity in the months after the sepsis episode.

In the pharmacokinetic analysis, it was found that the total volume of distribution of nivolumab in patients with sepsis is approximately two‐fold higher than observed previously in patients with cancer. 14 , 21 The clearance of nivolumab and the associated interindividual variability were also higher in patients with sepsis than previously observed in patients with cancer. 14 , 22 Although the exact pathophysiological causes for these observed pharmacokinetic differences between patients with sepsis and patients with cancer remain unknown, pharmacokinetics are notoriously different and more variable in critically ill patients. 23 It may be postulated that sepsis‐associated fluid overload 24 directly impact the volume of distribution of monoclonal antibodies, which primarily distribute over body water. 25 Another phenomenon that could explain the two‐fold higher volume of distribution is an increased capillary permeability resulting in capillary leakage of proteins in patients with sepsis. 26 The augmented clearance and high variability in clearance may be a result of the catabolic state of the critically ill patient. 27 It has been previously shown that elevated catabolic clearance of monoclonal antibodies can be a result of cancer cachexia, 28 , 29 underlining the potential of augmented antibody clearance in critically ill patients as well. To the best of our knowledge, we are the first to describe the population pharmacokinetics of nivolumab in critically ill patients. Proper dose finding of PD‐1 inhibitors in critically ill patients with sepsis should be based on the underlying pharmacokinetics and pharmacodynamics of a drug. The observed fundamental differences in pharmacokinetics in patients with sepsis underscore the necessity of our analysis. Although the proposed dosing strategy of a 20 mg single dose has not yet been clinically evaluated, the developed pharmacokinetic model for nivolumab in patients with sepsis was validated using data from a second study in a critically ill population with sepsis and, therefore, shows external validity of the pharmacokinetic analysis.

Although external validity was demonstrated, the developed pharmacokinetic model did not take potential targeted‐mediated drug disposition (TMDD) into account, as this cannot not be identified at high doses. TMDD is the result of specificity of targeted drugs, and its extent is concentration‐dependent. 30 In the developed model, linear drug elimination is assumed. At lower doses, however, this linear elimination is possibly followed by a more rapid (receptor‐mediated) clearance when PD‐1 saturation decreases. 30 Therefore, circulating nivolumab concentrations for the lower doses of 10 mg and 20 mg are likely overpredicted when PD‐1 receptor occupancy falls below the 90% threshold. Although this may seem like a shortcoming of our study, lower concentrations at later points in time (t > 10 days) could be desirable to prevent prolonged exposure after sepsis has resolved. Nevertheless, underdosing should be avoided as well, as this could render patients unable to clear their primary infection and (again) more susceptible toward secondary infections. This risk should be weighed against the risks of immune‐related toxicity with higher dosages and explored in future studies.

An important role in the outcome of sepsis is influenced by the PD‐1 receptor pathway. Previous preclinical studies have shown that PD‐1 receptor expression is increased on circulating monocytes up until 7 days after onset of septic shock. 6 , 7 It is, however, unknown if long‐term consequences of immunosuppression are also mediated by this upregulation of PD‐1. We think that by tackling the immunosuppressive episode during the first days of sepsis, nivolumab treatment covering this time window is enough and PD‐1 inhibition for several will therefore not be necessary. The relationship between nivolumab exposure and PD‐1 receptor occupancy was based on previous ex vivo experiments with circulating T‐cells of patients with cancer. 15 One may debate whether these findings can be extrapolated to critically ill patients with sepsis. However, as receptor affinity of PD‐1 is unlikely to be disease‐dependent, as the PD‐1 receptor protein remains unchanged and because the dose exploration study of previously tested doses 480 mg and 960 mg resulted in a similar PD‐1 occupancy, as shown in patients with sepsis, 9 we have confidence that the predictions can be used for guide dosing in a clinical study. It may be debated whether the arbitrary PD‐1 receptor occupancy threshold of 90% is suitable. However, a high PD‐1 inhibition is desired for immune activation.

Recently, a low 40 mg twice weekly dose of nivolumab has been investigated in patients with relapsed/refractory Hodgkin's lymphoma. 31 Not only was an almost complete reduction in PD‐1‐positive CD3+ cells observed after the first infusion of nivolumab, preliminary efficacy data indicated that the administered dose might have been as effective as the approved 240 mg twice weekly or 480 mg monthly dose for the same indication. This supports our findings that low dose nivolumab can already modulate the immune system.

We consider it likely that a single 20 mg dose of nivolumab is sufficient for immune resurrection during the critical phase of immune suppression during sepsis. We propose to carry the 20 mg nivolumab dose forward in clinical studies in critically ill patients as a potential safe and cost‐effective pharmacotherapeutic intervention to treat sepsis‐induced immunosuppression.

AUTHOR CONTRIBUTIONS

L.S.O., H.J.P.M.K., R.L.S., B.P., P.P., M.K., R.tH., and D.vdH. wrote the manuscript. R.tH. designed the research. R.tH. and D.vdH. performed the research and analyzed the data.

FUNDING INFORMATION

There has been no significant financial support for this work that could have influenced its outcome.

CONFLICT OF INTEREST STATEMENT

The authors declared no competing interests for this work.

Supporting information

Supplementary Material S1

Click here for additional data file. (413.3KB, pdf)

van den Haak DAC, Otten L‐S, Koenen HJPM, et al. Evidence‐based rationale for low dose nivolumab in critically ill patients with sepsis‐induced immunosuppression. Clin Transl Sci. 2023;16:978‐986. doi: 10.1111/cts.13503

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material S1

Click here for additional data file. (413.3KB, pdf)

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