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Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties
Drug Metabolism and Pharmacokinetics xxx (xxxx) xxx
Contents lists available at ScienceDirect
Drug Metabolism and Pharmacokinetics journal homepage: http://www.journals.elsevier.com/drug-metabolism-andpharmacokinetics
Review
Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties Chiyo K. Imamura Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 September 2018 Received in revised form 27 November 2018 Accepted 28 November 2018 Available online xxx
Monoclonal antibodies (mAbs) have dramatically improved clinical outcomes for inflammatory and malignant diseases. The elimination route of mAbs is cellular uptake by nonspecific pinocytosis or receptor-mediated endocytosis followed by proteolytic degradation which is protected by neonatal Fcreceptor or mediated by antigenic target. There is a wide-interindividual variability in mAbs exposure due to target burden and other factors affecting unique their pharmacokinetics. It has been reported that higher exposures are correlated with better clinical outcomes of various therapeutic mAbs. On the other hand, flat exposure-efficacy relationships of anti-PD-1 antibodies nivolmab and pembrolizumab mean ensuring absolute maximum efficacy in each patient by the approved dose regardless of their large interpatient variability in pharmacokinetics. Administration of mAbs can induce production of anti-drug antibodies (ADAs), which impact on their pharmacokinetics and pharmacodynamics. In therapeutic drug monitoring (TDM) of mAbs, when total (free, soluble target bound and ADAs bound) mAbs concentration is measured, ADAs content (concentration/titer) should be also monitored because mAbs exists in inactive complex with ADAs. Along with determination of appropriated therapeutic windows taking into account ADAs content, treatment algorithms for TDM-guided clinical decision-making must be developed and prospectively shown to be superior to traditional clinical care for each mAb in each indication.
Keywords: Anti-drug antibody Exposure-response relationship Cancer Inflammatory disease Malignant disease Monoclonal antibody Therapeutic drug monitoring
© 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
1. Introduction
2. Pharmacokinetics of mAbs
The aim of therapeutic drug monitoring (TDM) is to adjust the dose of the drug individually according to the pharmacokinetic characteristics of each patient. Therefore, TDM allows for reaching an effective concentration more rapidly while minimizing drug toxicity. The main prerequisites for TDM are a narrow therapeutic window and a wide inter-individual variability in exposure, a welldefined concentration-effect relationship, and the availability of reliable and clinically feasible assays. TDM is routinely applied with selected small-molecule drugs such as antibiotics, antiepileptics, immunosuppressives and anticancer drugs. Monoclonal antibodies (mAbs) have dramatically improved clinical outcomes for inflammatory and malignant diseases. This review article discusses the applicability of TDM for mAbs based on their unique pharmacokinetic properties.
After parenteral administration (intravenous or subcutaneous), mAbs are distributed mainly in the central compartment. The volume of distribution of therapeutic mAbs is relatively small (5e10 L) because the ability to cross cell membrane is significantly hindered by its large molecular weight, around 150 kDa, and their hydrophilicity/polarity [1]. The distribution characteristics of mAbs are determined by the distribution and density of the specific antibody target and the morphology of vascular capillaries. The elimination pathways differ from those of conventional drugs, small molecules, metabolized in the liver and excreted in the bile or the kidney. The elimination route of mAbs is cellular uptake by nonspecific pinocytosis or receptor-mediated endocytosis followed by proteolytic degradation. There are two distinct catabolic pathways: (i) neonatal Fc-receptor (FcRn)eprotected elimination by nonspecific interaction between the antibody's Fc region and Fc receptors and (ii) target-mediated elimination by specific interaction between the antibody Fab region and its antigenic target [2,3]. FcRn-protected elimination is a common pathway shared by both
E-mail address: [email protected]. https://doi.org/10.1016/j.dmpk.2018.11.003 1347-4367/© 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Imamura CK, Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2018.11.003
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endogenous Immunoglobulin G (IgG) and therapeutic mAbs. The half-life of IgG1, which is a major subclass of approved mAbs, is around 20 days [4], depending on binding affinity to FcRns [5]. Target-mediated endocytosis involves binding of the mAb to a receptor or antigen, which triggers effect of internalization and subsequent lysosomal degradation of the mAb-receptor complex [6]. The number of receptors within the distribution space of a mAb is limited, and the receptors may therefore become saturated at therapeutic mAb doses, resulting in nonlinear clearance [2]. If a therapeutic mAb binds to a soluble antigen, it would be reasonable to anticipate faster clearance of the soluble mAb-antigen complex than of the free mAb. Generally, mAbs targeting cell-surface receptors tend to exhibit nonlinear clearance that is dependent on antigen expression, whereas mAbs directed against soluble antigens typically exhibit dose-proportional behavior with linear clearance, which is often affected by body weight [6]. Therefore, target-mediated elimination of mAbs can be either linear or nonlinear.
3. Factors affecting clearance of mAbs A wide inter-individual variability in exposure of mAbs is caused by various factors that differ from those for small molecule drugs (Table 1).
3.1. Amount of antigenic target burden The number of receptors within the mAbs distribution space affect clearance of mAbs in target-mediated elimination. A higher C-reactive protein (CRP) concentration, which is considered as an indirect marker of the tumor necrosis factor (TNF)-a concentration, was found to increase the target-mediated clearance of infliximab, which is an anti-TNF-a antibody, in patients with rheumatoid arthritis (RA) [7]. In patients with Crohn disease (CD), increased serum CRP concentration is similarly associated with increased infliximab elimination and a risk of relapse after discontinuation of the therapy [8]. The study of rituximab for RA found an association between the CD19þ cell count, representing the amount of target antigen, and elimination rate constant (k10) [9]. In a population pharmacokinetic analysis of trastuzumab in patients with HER2positive metastatic breast cancer, the number of metastatic sites was identified as the most influential covariate associated with trastuzumab clearance, which was 22% faster in patients with four or more sites compared with those with fewer metastases [10]. And the baseline concentration of the HER2 extracellular domain (ECD) was also correlated with trastuzumab clearance. This impact of ECD levels on the clearance of trastuzumab is in line with nonclinical studies which suggested that the trastuzumab-ECD complex has a higher clearance than unbound trastuzumab [11]. A population pharmacokinetic analysis of bevacizumab found that patients with a large tumor burden (at or above the median value of the tumor surface area) had a clearance value of 0.249 L/day versus 0.199 L/ day in patients with tumor burdens below the median [12].
mAbs are exogenous proteins and can thus induce an immune response leading to the production of endogenous anti-drug antibodies (ADAs). In general, humanized and fully human mAbs are less immunogenic as compared with murine antibodies, but they also can induce ADAs formation. Development of ADAs can affect the safety profile of these drugs due to hypersensitivity reactions. In addition, formation of immune complex (mAb-ADAs complex) accelerate mAbs clearance because binding of the mAb to ADAs triggers lysosomal degradation in the same manner as targetmediated elimination. ADAs are produced in more than one-third of healthy subjects after a single intravenous dose of infliximab and result in faster infliximab clearance, shorter elimination time, and lower serum infliximab levels [13]. Timing of occurrence and persistence of ADAs is affected by administration schedule [14]. In a cohort of 125 patients with CD treated with infliximab infusions (5 mg/kg at 0, 2, and 6 weeks, then every 8 weeks), 76 patients (61%) had detectable antibodies after the fifth infusion. And the incidence did not increase further with repeated infusions reportedly [15]. 3.3. Concomitant drugs Coadministration of immunosuppressives (azathioprine, mercaptopurine, and methotorexate) with anti-TNF-a antibodies increases the concentrations of serum mAbs [16] and decreases the formation of ADAs [15,17]. In a randomized trial of infliximab to treat active CD, patients receiving combination therapy with azathioprine had higher median trough infliximab concentrations than those receiving monotherapy (3.5 mg/mL vs. 1.6 mg/mL, respectively; P < 0.001). These findings correlated with better outcomes of higher corticosteroid-free remission rates in the combination therapy arm [16]. The concomitant use of immunosuppressive (azathioprine or methotrexate) with infliximab was associated with a lower incidence of detected ADAs (53/115; 46%) compared with patients not receiving concomitant immunosuppressive (43/59; 73%; p < 0.001). Patients not receiving immunosuppressive had lower infliximab levels (median 2.42 mg/mL (interquartile range (IQR) 1e10.8), maximum 21 mg/mL) 4 weeks after any follow-up infusion than patients receiving concomitant immunosuppressive (median 6.45 mg/mL (IQR 3e11.6), maximum 21 mg/mL; P ¼ 0.065) [17]. Although the underlying mechanism by which immunosuppressives increase the exposure of anti-TNF-a antibodies is not well established, they are likely to act by reducing the formation of ADAs and/or decreasing amount of target burden. 3.4. Concentration of serum IgG In FcRn-protected elimination, FcRns are saturated by high IgG concentrations due to limited number of FcRn. An association between an increasing IgG serum concentration and an increasing the elimination rate constant (k10) of rituximab in patients with RA was explained by saturation of FcRns at high IgG concentrations, resulting in decreased protection of rituximab elimination [9]. 4. Issue of interpreting TDM of mAbs
Table 1 Factors affecting clearance of monoclonal antibodies. Impact on clearance Target-mediated elimination Large target burden Presence of anti-drug antibodies Concomitant drugs reducing target burden Neonatal Fc-receptoreprotected elimination High immunoglobulin G
3.2. Presence of antidrug antibodies
increase increase decrease increase
A mAb in serum exists in free (unbound), complex with either the target antigen or ADAs. The mAbeADAs complex is inactive, and presence of ADAs may ensure impaired efficacy due to reducing free mAbs which binds to antigenic target for pharmacological action. A high proportion of patients who initially respond to mAbs lose response over time, owing, in part, to development of ADAs [15,18,19]. In a combined retrospective analysis of four studies, it
Please cite this article as: Imamura CK, Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2018.11.003
C.K. Imamura / Drug Metabolism and Pharmacokinetics xxx (xxxx) xxx
was observed that both infliximab concentration (odds ratio, 1.8; 95% CI, 1.3e2.5) and ADAs concentration (odds ratio, 0.57, 95% CI, 0.39e0.81) were independently associated with biochemical remission (CRP 5 mg/L) in patients with CD on maintenance infliximab therapy [20]. On the other hand, the impact of ADAs of anticancer mAbs is unclear, although ADAs have been detected [21]. Therefore, interpreting TDM result of serum mAbs concentration is necessary for assessment of ADAs content (titer/concentration) for clinical decision, increasing the dose of mAbs (decreasing the interval between drug administrations) or switching drug/therapy. A novel assay to distinguish free, soluble target bound and ADAs bound mAbs in serum should be developed for accurate TDM. Free drug concentration is more reliable than that total drug concentration for TDM of highly protein bound small molecule drugs. However, free mAbs concentration might not appropriate to interpret the relationship between exposure and response because free mAbs in serum is considered as the excess resulting from binding to their antigenic targets and ADAs. 5. Current status of TDM and exposure-response relationship of anti-inflammatory mAbs In registration study of infliximab to treat RA, higher trough serum concentrations of infliximab were observed to be significantly correlated with better clinical responses and greater inhibition of progression of joint damage in patients treated with infliximab and methotrexate (Table 2) [22]. According to this result that most of patients with trough serum infliximab level with 1.0 mg/mL achieved moderate or good response defined by the European League Against Rheumatism (EULAR), above 1 mg/mL is regarded as the target level of infliximab to treat RA. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs updated in 2016 raised “Is measurement of serum drug or antidrug antibody levels useful in clinical practice?” as one of 15 research agenda [23]. Regarding utility of TDM for mAbs in the treatment of inflammatory bowel disease (IBD) including CD and ulcerative colitis (UC), emerging data indicate a strong relationship between drug exposure and efficacy of anti-TNF (Table 2) [19,24]. The American Gastroenterology Association prioritized clinical guidelines on the role of TDM in the management of IBD [25]. They suggested that there may be benefit of reactive TDM to guide to treatment change over empirically escalating dose or switching therapies according to very-low quality evidence. In addition, interventions based on TDM of mAbs and status of ADAs (detectable or undetectable) in the reactive setting in patients with secondary loss of response were proposed although they have been yet prospectively validated. On the other hand, IBD Sydney Organization and the Australian Inflammatory Bowel Diseases Consensus Working Group suggested that TDM of anti-TNF agents including infliximab and adalimumab should be performed upon treatment failure, following successful Table 2 Exposure-response relationships of anti-inflammatory monoclonal antibody drugs.
induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management, as the consensus statement [26]. They also proposed algorithms based on symptoms, serum mAbs concentrations and ADAs status (positive-high or low, or negative). 6. Applicability of TDM and exposure-response relationship of anti-cancer mAbs Higher rituximab levels correlated with longer progression-free survival (PFS) and higher response rates (Table 3) [29,30]. A phase I dose escalation study of cetuximab revealed that patients with partial response/stable disease had a higher-grade rash and higher cetuximab trough levels than those with progressive disease (P ¼ 0.032 and 0.002, respectively) (Table 3) [28]. In registration studies of trastuzumab and ramucirumab to treat advanced gastric cancer, exposure-response relationships were observed to be shorter overall survival for patients with lower trough concentrations even by adjusting for some disease risk factors (Table 3) [31,32]. However, it should be interpreted with caution as the subgroups (quartiles of trough levels) were not randomized, so that confounders could not be accounted for, and statistical analysis was underpowered because of the small numbers. In an integrated analysis of data from 4 phase II studies of ipilimumab with wide dose range (0.3e10 mg/kg), it suggested that higher exposure was associated with better survival, higher rates of immune-related adverse events in patients with advanced melanoma (Table 3) [33]. Nivolmab exposure produced by doses of 1e10 mg/kg every 2 weeks was not associated with overall survival and hazards of adverse events leading to discontinuation or death in patients with squamous or non-squamous non-small cell lung cancer [34]. Similarly, nivolmab exposure produced by doses of 0.1e10 mg/kg every 2 weeks was not a significant predictor of tumor response, overall survival and the risk of grade 3 drug-related adverse events and adverse events leading to drug discontinuation or death in patients with advanced melanoma [35]. Therefore, approved dose of nivolmab has been changed to 240 mg flat dose from per body weight dose based on population pharmacokinetic modeling analysis [36]. Exposure-efficacy relationship of pembrolizumab produced by doses of 2 mg/kg (or 200 mg fixed dose) every three weeks was not also observed in various types of cancer
Table 3 Exposure-response relationships of anti-cancer monoclonal antibody drugs. Drug
Exposure
Disease
Response
Reference
Cetuximab
Average trough concentration
Epithelial malignancies
[28]
Rituximab
Median concentration Trough concentration in cycle 2
Non-Hodgkin's lymphoma B-cell lymphoma Mantle cell lymphoma Gastric cancer
Tumor response Rash Tumor response PFS
[30]
OS
[31]
Gastric cancer
OS
[32]
Melanoma
Tumor response OS Immunerelated AEs
[33]
Trastuzumab
Drug
Exposure
Disease Response
Reference
Infliximab
Trough concentration
RA UC
[22] [19]
Ramcirumab
[24]
Ipilimumab
CD Adalimumab Trough concentration
UC
EULAR response Clinical remission Endoscopic improvement Clinical remission Endoscopic improvement Clinical remission
[27]
RA, rheumatoid arthritis; UC, ulcerative colitis; CD, Crohn's disease; EULAR, European League Against Rheumatism.
3
Trough concentration in cycle 1 Trough concentration in cycle 1 Trough concentration at steady state
[29]
PFS, progression-free survival; OS, overall survival; AEs, adverse events.
Please cite this article as: Imamura CK, Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2018.11.003
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[37]. These flat exposure-response relationships of nivolmab and pembrolizumab mean ensuring absolute maximum efficacy in each patient even though large interpatient variability in exposure. PD-1, which is a target of nivolmab and pemblorizumab, expresses on surface of immune cells not on surface of tumor. Therefore the dose range including approved dose can achieve full target saturation due to limited amount of PD-1 on immune cells. 7. Assays for TDM of mAbs Availability of a standardized and validated methods for measurement of concentrations is essential for TDM. Most commonly assays for mAbs are the enzyme-linked immunosorbent assay (ELISA), homogenous mobility shift assay (HMSA) and electrochemiluminescence Immunoassay (ECLIA). A rapid lateral flow (LF)-based immunochromatographic assay was available for on-site monitoring of serum levels of infliximab [38]. LC-MS/MS method is applicable for TDM of mAbs by kit-based approach for sample preparation by proteolysis with simple protocol (ProteinWorks, Waters Co., MA, USA; nSMOL, Shimadzu Co., Kyoto, Japan). As discussed above, it is essential to recognize whether the measurement by using assay method is free mAb or total (free, soluble target bound and ADAs bound) mAb concentration according to their specificity and cross-reactivity. 8. Conclusion If higher circulating concentration of a mAb are correlated with better clinical outcomes by approved dose, TDM might be useful for the mAb treatment. However, when total mAbs concentration is monitored, ADAs content (concentration/titer) should be also monitored because ADAs produce inactive mAb-ADAs complex. Along with determination of appropriated therapeutic windows taking into account ADAs contain, treatment algorithms for TDMguided clinical decision-making must be developed and prospectively shown to be superior to traditional clinical care for each mAb in each indication. Conflicts of interest The author declares no conflict of interest. References [1] Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 2004;93:2645e68. [2] Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 2010;49:633e59. [3] Wohlrab J. Pharmacokinetic characteristics of therapeutic antibodies. J Dtsch Dermatol Ges 2015;13:530e4. [4] Morell A, Terry WD, Waldmann TA. Metabolic properties of IgG subclasses in man. J Clin Invest 1970;49:673e80. [5] Stapleton NM, Andersen JT, Stemerding AM, Bjarnarson PS, Verheul RC, Gerritsen J, et al. Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential. Nat Commun 2011;2: 599. [6] Tabrizi MA, Tseng C-ML, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today 2006;11:81e8. [7] Ternant D, Ducourau E, Perdriger A, Corondan A, Le Goff B, DevauchellePensec V, et al. Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis. Br J Clin Pharmacol 2014;78:118e28. [8] Ternant D, Berkane Z, Picon L, Gouilleux-Gruart V, Colombel J-F, Allez M, et al. Assessment of the influence of inflammation and FCGR3A genotype on infliximab pharmacokinetics and time to relapse in patients with Crohn's disease. Clin Pharmacokinet 2015;54:551e62. [9] Lioger B, Edupuganti SR, Mulleman D, Passot C, Desvignes C, BejanAngoulvant T, et al. Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients. Br J Clin Pharmacol 2017;83:1773e81.
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Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012;142:257e65. [28] Fracasso PM, Burris 3rd H, Arquette MA, Govindan R, Gao F, Wright LP, et al. A phase 1 escalating single-dose and weekly fixed-dose study of cetuximab: pharmacokinetic and pharmacodynamic rationale for dosing. Clin Cancer Res 2007;13:986e93. [29] Berinstein NL, Grillo-Lopez AJ, White CA, Bence-Bruckler I, Maloney D, Czuczman M, et al. Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 1998;9:995e1001. [30] Igarashi T, Kobayashi Y, Ogura M, Kinoshita T, Ohtsu T, Sasaki Y, et al. Factors affecting toxicity, response and progression-free survival in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma treated with rituximab: a Japanese phase II study. Ann Oncol 2002;13:928e43. 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Contents lists available at ScienceDirect
Drug Metabolism and Pharmacokinetics journal homepage: http://www.journals.elsevier.com/drug-metabolism-andpharmacokinetics
Review
Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties Chiyo K. Imamura Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 September 2018 Received in revised form 27 November 2018 Accepted 28 November 2018 Available online xxx
Monoclonal antibodies (mAbs) have dramatically improved clinical outcomes for inflammatory and malignant diseases. The elimination route of mAbs is cellular uptake by nonspecific pinocytosis or receptor-mediated endocytosis followed by proteolytic degradation which is protected by neonatal Fcreceptor or mediated by antigenic target. There is a wide-interindividual variability in mAbs exposure due to target burden and other factors affecting unique their pharmacokinetics. It has been reported that higher exposures are correlated with better clinical outcomes of various therapeutic mAbs. On the other hand, flat exposure-efficacy relationships of anti-PD-1 antibodies nivolmab and pembrolizumab mean ensuring absolute maximum efficacy in each patient by the approved dose regardless of their large interpatient variability in pharmacokinetics. Administration of mAbs can induce production of anti-drug antibodies (ADAs), which impact on their pharmacokinetics and pharmacodynamics. In therapeutic drug monitoring (TDM) of mAbs, when total (free, soluble target bound and ADAs bound) mAbs concentration is measured, ADAs content (concentration/titer) should be also monitored because mAbs exists in inactive complex with ADAs. Along with determination of appropriated therapeutic windows taking into account ADAs content, treatment algorithms for TDM-guided clinical decision-making must be developed and prospectively shown to be superior to traditional clinical care for each mAb in each indication.
Keywords: Anti-drug antibody Exposure-response relationship Cancer Inflammatory disease Malignant disease Monoclonal antibody Therapeutic drug monitoring
© 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
1. Introduction
2. Pharmacokinetics of mAbs
The aim of therapeutic drug monitoring (TDM) is to adjust the dose of the drug individually according to the pharmacokinetic characteristics of each patient. Therefore, TDM allows for reaching an effective concentration more rapidly while minimizing drug toxicity. The main prerequisites for TDM are a narrow therapeutic window and a wide inter-individual variability in exposure, a welldefined concentration-effect relationship, and the availability of reliable and clinically feasible assays. TDM is routinely applied with selected small-molecule drugs such as antibiotics, antiepileptics, immunosuppressives and anticancer drugs. Monoclonal antibodies (mAbs) have dramatically improved clinical outcomes for inflammatory and malignant diseases. This review article discusses the applicability of TDM for mAbs based on their unique pharmacokinetic properties.
After parenteral administration (intravenous or subcutaneous), mAbs are distributed mainly in the central compartment. The volume of distribution of therapeutic mAbs is relatively small (5e10 L) because the ability to cross cell membrane is significantly hindered by its large molecular weight, around 150 kDa, and their hydrophilicity/polarity [1]. The distribution characteristics of mAbs are determined by the distribution and density of the specific antibody target and the morphology of vascular capillaries. The elimination pathways differ from those of conventional drugs, small molecules, metabolized in the liver and excreted in the bile or the kidney. The elimination route of mAbs is cellular uptake by nonspecific pinocytosis or receptor-mediated endocytosis followed by proteolytic degradation. There are two distinct catabolic pathways: (i) neonatal Fc-receptor (FcRn)eprotected elimination by nonspecific interaction between the antibody's Fc region and Fc receptors and (ii) target-mediated elimination by specific interaction between the antibody Fab region and its antigenic target [2,3]. FcRn-protected elimination is a common pathway shared by both
E-mail address: [email protected]. https://doi.org/10.1016/j.dmpk.2018.11.003 1347-4367/© 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Imamura CK, Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2018.11.003
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endogenous Immunoglobulin G (IgG) and therapeutic mAbs. The half-life of IgG1, which is a major subclass of approved mAbs, is around 20 days [4], depending on binding affinity to FcRns [5]. Target-mediated endocytosis involves binding of the mAb to a receptor or antigen, which triggers effect of internalization and subsequent lysosomal degradation of the mAb-receptor complex [6]. The number of receptors within the distribution space of a mAb is limited, and the receptors may therefore become saturated at therapeutic mAb doses, resulting in nonlinear clearance [2]. If a therapeutic mAb binds to a soluble antigen, it would be reasonable to anticipate faster clearance of the soluble mAb-antigen complex than of the free mAb. Generally, mAbs targeting cell-surface receptors tend to exhibit nonlinear clearance that is dependent on antigen expression, whereas mAbs directed against soluble antigens typically exhibit dose-proportional behavior with linear clearance, which is often affected by body weight [6]. Therefore, target-mediated elimination of mAbs can be either linear or nonlinear.
3. Factors affecting clearance of mAbs A wide inter-individual variability in exposure of mAbs is caused by various factors that differ from those for small molecule drugs (Table 1).
3.1. Amount of antigenic target burden The number of receptors within the mAbs distribution space affect clearance of mAbs in target-mediated elimination. A higher C-reactive protein (CRP) concentration, which is considered as an indirect marker of the tumor necrosis factor (TNF)-a concentration, was found to increase the target-mediated clearance of infliximab, which is an anti-TNF-a antibody, in patients with rheumatoid arthritis (RA) [7]. In patients with Crohn disease (CD), increased serum CRP concentration is similarly associated with increased infliximab elimination and a risk of relapse after discontinuation of the therapy [8]. The study of rituximab for RA found an association between the CD19þ cell count, representing the amount of target antigen, and elimination rate constant (k10) [9]. In a population pharmacokinetic analysis of trastuzumab in patients with HER2positive metastatic breast cancer, the number of metastatic sites was identified as the most influential covariate associated with trastuzumab clearance, which was 22% faster in patients with four or more sites compared with those with fewer metastases [10]. And the baseline concentration of the HER2 extracellular domain (ECD) was also correlated with trastuzumab clearance. This impact of ECD levels on the clearance of trastuzumab is in line with nonclinical studies which suggested that the trastuzumab-ECD complex has a higher clearance than unbound trastuzumab [11]. A population pharmacokinetic analysis of bevacizumab found that patients with a large tumor burden (at or above the median value of the tumor surface area) had a clearance value of 0.249 L/day versus 0.199 L/ day in patients with tumor burdens below the median [12].
mAbs are exogenous proteins and can thus induce an immune response leading to the production of endogenous anti-drug antibodies (ADAs). In general, humanized and fully human mAbs are less immunogenic as compared with murine antibodies, but they also can induce ADAs formation. Development of ADAs can affect the safety profile of these drugs due to hypersensitivity reactions. In addition, formation of immune complex (mAb-ADAs complex) accelerate mAbs clearance because binding of the mAb to ADAs triggers lysosomal degradation in the same manner as targetmediated elimination. ADAs are produced in more than one-third of healthy subjects after a single intravenous dose of infliximab and result in faster infliximab clearance, shorter elimination time, and lower serum infliximab levels [13]. Timing of occurrence and persistence of ADAs is affected by administration schedule [14]. In a cohort of 125 patients with CD treated with infliximab infusions (5 mg/kg at 0, 2, and 6 weeks, then every 8 weeks), 76 patients (61%) had detectable antibodies after the fifth infusion. And the incidence did not increase further with repeated infusions reportedly [15]. 3.3. Concomitant drugs Coadministration of immunosuppressives (azathioprine, mercaptopurine, and methotorexate) with anti-TNF-a antibodies increases the concentrations of serum mAbs [16] and decreases the formation of ADAs [15,17]. In a randomized trial of infliximab to treat active CD, patients receiving combination therapy with azathioprine had higher median trough infliximab concentrations than those receiving monotherapy (3.5 mg/mL vs. 1.6 mg/mL, respectively; P < 0.001). These findings correlated with better outcomes of higher corticosteroid-free remission rates in the combination therapy arm [16]. The concomitant use of immunosuppressive (azathioprine or methotrexate) with infliximab was associated with a lower incidence of detected ADAs (53/115; 46%) compared with patients not receiving concomitant immunosuppressive (43/59; 73%; p < 0.001). Patients not receiving immunosuppressive had lower infliximab levels (median 2.42 mg/mL (interquartile range (IQR) 1e10.8), maximum 21 mg/mL) 4 weeks after any follow-up infusion than patients receiving concomitant immunosuppressive (median 6.45 mg/mL (IQR 3e11.6), maximum 21 mg/mL; P ¼ 0.065) [17]. Although the underlying mechanism by which immunosuppressives increase the exposure of anti-TNF-a antibodies is not well established, they are likely to act by reducing the formation of ADAs and/or decreasing amount of target burden. 3.4. Concentration of serum IgG In FcRn-protected elimination, FcRns are saturated by high IgG concentrations due to limited number of FcRn. An association between an increasing IgG serum concentration and an increasing the elimination rate constant (k10) of rituximab in patients with RA was explained by saturation of FcRns at high IgG concentrations, resulting in decreased protection of rituximab elimination [9]. 4. Issue of interpreting TDM of mAbs
Table 1 Factors affecting clearance of monoclonal antibodies. Impact on clearance Target-mediated elimination Large target burden Presence of anti-drug antibodies Concomitant drugs reducing target burden Neonatal Fc-receptoreprotected elimination High immunoglobulin G
3.2. Presence of antidrug antibodies
increase increase decrease increase
A mAb in serum exists in free (unbound), complex with either the target antigen or ADAs. The mAbeADAs complex is inactive, and presence of ADAs may ensure impaired efficacy due to reducing free mAbs which binds to antigenic target for pharmacological action. A high proportion of patients who initially respond to mAbs lose response over time, owing, in part, to development of ADAs [15,18,19]. In a combined retrospective analysis of four studies, it
Please cite this article as: Imamura CK, Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2018.11.003
C.K. Imamura / Drug Metabolism and Pharmacokinetics xxx (xxxx) xxx
was observed that both infliximab concentration (odds ratio, 1.8; 95% CI, 1.3e2.5) and ADAs concentration (odds ratio, 0.57, 95% CI, 0.39e0.81) were independently associated with biochemical remission (CRP 5 mg/L) in patients with CD on maintenance infliximab therapy [20]. On the other hand, the impact of ADAs of anticancer mAbs is unclear, although ADAs have been detected [21]. Therefore, interpreting TDM result of serum mAbs concentration is necessary for assessment of ADAs content (titer/concentration) for clinical decision, increasing the dose of mAbs (decreasing the interval between drug administrations) or switching drug/therapy. A novel assay to distinguish free, soluble target bound and ADAs bound mAbs in serum should be developed for accurate TDM. Free drug concentration is more reliable than that total drug concentration for TDM of highly protein bound small molecule drugs. However, free mAbs concentration might not appropriate to interpret the relationship between exposure and response because free mAbs in serum is considered as the excess resulting from binding to their antigenic targets and ADAs. 5. Current status of TDM and exposure-response relationship of anti-inflammatory mAbs In registration study of infliximab to treat RA, higher trough serum concentrations of infliximab were observed to be significantly correlated with better clinical responses and greater inhibition of progression of joint damage in patients treated with infliximab and methotrexate (Table 2) [22]. According to this result that most of patients with trough serum infliximab level with 1.0 mg/mL achieved moderate or good response defined by the European League Against Rheumatism (EULAR), above 1 mg/mL is regarded as the target level of infliximab to treat RA. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs updated in 2016 raised “Is measurement of serum drug or antidrug antibody levels useful in clinical practice?” as one of 15 research agenda [23]. Regarding utility of TDM for mAbs in the treatment of inflammatory bowel disease (IBD) including CD and ulcerative colitis (UC), emerging data indicate a strong relationship between drug exposure and efficacy of anti-TNF (Table 2) [19,24]. The American Gastroenterology Association prioritized clinical guidelines on the role of TDM in the management of IBD [25]. They suggested that there may be benefit of reactive TDM to guide to treatment change over empirically escalating dose or switching therapies according to very-low quality evidence. In addition, interventions based on TDM of mAbs and status of ADAs (detectable or undetectable) in the reactive setting in patients with secondary loss of response were proposed although they have been yet prospectively validated. On the other hand, IBD Sydney Organization and the Australian Inflammatory Bowel Diseases Consensus Working Group suggested that TDM of anti-TNF agents including infliximab and adalimumab should be performed upon treatment failure, following successful Table 2 Exposure-response relationships of anti-inflammatory monoclonal antibody drugs.
induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management, as the consensus statement [26]. They also proposed algorithms based on symptoms, serum mAbs concentrations and ADAs status (positive-high or low, or negative). 6. Applicability of TDM and exposure-response relationship of anti-cancer mAbs Higher rituximab levels correlated with longer progression-free survival (PFS) and higher response rates (Table 3) [29,30]. A phase I dose escalation study of cetuximab revealed that patients with partial response/stable disease had a higher-grade rash and higher cetuximab trough levels than those with progressive disease (P ¼ 0.032 and 0.002, respectively) (Table 3) [28]. In registration studies of trastuzumab and ramucirumab to treat advanced gastric cancer, exposure-response relationships were observed to be shorter overall survival for patients with lower trough concentrations even by adjusting for some disease risk factors (Table 3) [31,32]. However, it should be interpreted with caution as the subgroups (quartiles of trough levels) were not randomized, so that confounders could not be accounted for, and statistical analysis was underpowered because of the small numbers. In an integrated analysis of data from 4 phase II studies of ipilimumab with wide dose range (0.3e10 mg/kg), it suggested that higher exposure was associated with better survival, higher rates of immune-related adverse events in patients with advanced melanoma (Table 3) [33]. Nivolmab exposure produced by doses of 1e10 mg/kg every 2 weeks was not associated with overall survival and hazards of adverse events leading to discontinuation or death in patients with squamous or non-squamous non-small cell lung cancer [34]. Similarly, nivolmab exposure produced by doses of 0.1e10 mg/kg every 2 weeks was not a significant predictor of tumor response, overall survival and the risk of grade 3 drug-related adverse events and adverse events leading to drug discontinuation or death in patients with advanced melanoma [35]. Therefore, approved dose of nivolmab has been changed to 240 mg flat dose from per body weight dose based on population pharmacokinetic modeling analysis [36]. Exposure-efficacy relationship of pembrolizumab produced by doses of 2 mg/kg (or 200 mg fixed dose) every three weeks was not also observed in various types of cancer
Table 3 Exposure-response relationships of anti-cancer monoclonal antibody drugs. Drug
Exposure
Disease
Response
Reference
Cetuximab
Average trough concentration
Epithelial malignancies
[28]
Rituximab
Median concentration Trough concentration in cycle 2
Non-Hodgkin's lymphoma B-cell lymphoma Mantle cell lymphoma Gastric cancer
Tumor response Rash Tumor response PFS
[30]
OS
[31]
Gastric cancer
OS
[32]
Melanoma
Tumor response OS Immunerelated AEs
[33]
Trastuzumab
Drug
Exposure
Disease Response
Reference
Infliximab
Trough concentration
RA UC
[22] [19]
Ramcirumab
[24]
Ipilimumab
CD Adalimumab Trough concentration
UC
EULAR response Clinical remission Endoscopic improvement Clinical remission Endoscopic improvement Clinical remission
[27]
RA, rheumatoid arthritis; UC, ulcerative colitis; CD, Crohn's disease; EULAR, European League Against Rheumatism.
3
Trough concentration in cycle 1 Trough concentration in cycle 1 Trough concentration at steady state
[29]
PFS, progression-free survival; OS, overall survival; AEs, adverse events.
Please cite this article as: Imamura CK, Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2018.11.003
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[37]. These flat exposure-response relationships of nivolmab and pembrolizumab mean ensuring absolute maximum efficacy in each patient even though large interpatient variability in exposure. PD-1, which is a target of nivolmab and pemblorizumab, expresses on surface of immune cells not on surface of tumor. Therefore the dose range including approved dose can achieve full target saturation due to limited amount of PD-1 on immune cells. 7. Assays for TDM of mAbs Availability of a standardized and validated methods for measurement of concentrations is essential for TDM. Most commonly assays for mAbs are the enzyme-linked immunosorbent assay (ELISA), homogenous mobility shift assay (HMSA) and electrochemiluminescence Immunoassay (ECLIA). A rapid lateral flow (LF)-based immunochromatographic assay was available for on-site monitoring of serum levels of infliximab [38]. LC-MS/MS method is applicable for TDM of mAbs by kit-based approach for sample preparation by proteolysis with simple protocol (ProteinWorks, Waters Co., MA, USA; nSMOL, Shimadzu Co., Kyoto, Japan). As discussed above, it is essential to recognize whether the measurement by using assay method is free mAb or total (free, soluble target bound and ADAs bound) mAb concentration according to their specificity and cross-reactivity. 8. Conclusion If higher circulating concentration of a mAb are correlated with better clinical outcomes by approved dose, TDM might be useful for the mAb treatment. However, when total mAbs concentration is monitored, ADAs content (concentration/titer) should be also monitored because ADAs produce inactive mAb-ADAs complex. Along with determination of appropriated therapeutic windows taking into account ADAs contain, treatment algorithms for TDMguided clinical decision-making must be developed and prospectively shown to be superior to traditional clinical care for each mAb in each indication. Conflicts of interest The author declares no conflict of interest. References [1] Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 2004;93:2645e68. [2] Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 2010;49:633e59. [3] Wohlrab J. Pharmacokinetic characteristics of therapeutic antibodies. J Dtsch Dermatol Ges 2015;13:530e4. [4] Morell A, Terry WD, Waldmann TA. Metabolic properties of IgG subclasses in man. J Clin Invest 1970;49:673e80. [5] Stapleton NM, Andersen JT, Stemerding AM, Bjarnarson PS, Verheul RC, Gerritsen J, et al. Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential. Nat Commun 2011;2: 599. [6] Tabrizi MA, Tseng C-ML, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today 2006;11:81e8. [7] Ternant D, Ducourau E, Perdriger A, Corondan A, Le Goff B, DevauchellePensec V, et al. Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis. Br J Clin Pharmacol 2014;78:118e28. [8] Ternant D, Berkane Z, Picon L, Gouilleux-Gruart V, Colombel J-F, Allez M, et al. Assessment of the influence of inflammation and FCGR3A genotype on infliximab pharmacokinetics and time to relapse in patients with Crohn's disease. Clin Pharmacokinet 2015;54:551e62. [9] Lioger B, Edupuganti SR, Mulleman D, Passot C, Desvignes C, BejanAngoulvant T, et al. Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients. Br J Clin Pharmacol 2017;83:1773e81.
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Please cite this article as: Imamura CK, Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2018.11.003