Pharmacokinetics Of Monoclonal Antibodies Research Articles

Comparative pharmacokinetics of porcine and human anti-influenza hemagglutinin monoclonal antibodies in outbred pigs and minipigs.

Assessing the pharmacokinetics of monoclonal antibodies (mAbs) in relevant animal models is essential for designing improved formulations and developing mAb delivery platforms. We have established the pig, a large natural host animal for influenza with many similarities to humans, as a robust model for testing the therapeutic efficacy of anti-influenza mAbs and evaluating mAb delivery platforms. Here, we compared the pharmacokinetic characteristics of two anti-influenza hemagglutinin mAbs, human 2-12C and porcine pb27, in Göttingen minipigs and Landrace × Large White outbred pigs. Minipigs offer the advantage of a more stable weight, whereas outbred pigs are more readily available but exhibit rapid growth. Outbred pigs and minipigs showed similar pharmacokinetics and a similar porcine pb27 half-life (half-life of 15.7 days for outbred pigs and 16.6 days for minipigs). In contrast, the half-life of human 2-12C was more rapid in two of the minipigs but not in the outbred pigs, correlating with the development of antidrug antibodies in the two minipigs. Our results demonstrate that both outbred pigs and minipigs are appropriate models for pharmacokinetic studies and the evaluation of mAb delivery platforms, potentially bridging the gap between small animals and human trials.

Inter-Antibody Variability in the Clinical Pharmacokinetics of Monoclonal Antibodies Characterized Using Population Physiologically Based Pharmacokinetic Modeling.

The objective of this work was to develop a population physiologically based pharmacokinetic (popPBPK) model to characterize the variability in the clinical PK of monoclonal antibodies (mAbs) following intravenous (IV) and subcutaneous (SC) administration. An extensive literature search was conducted and clinical PK data for FDA-approved as well as non-approved mAbs were collected. Training and validation datasets of 44 and 9 mAbs exhibiting linear pharmacokinetics were used for model development. The variability in antibody PK was captured by accounting for different rate constants of pinocytosis (CLup) and intracellular degradation (kdeg) for different mAbs. Typical values for CLup and kdeg and their respective inter-antibody variabilities (ωClup, ωKdeg) were estimated to be 0.32 L/h/L and 26.1 h-1 (73% and 46%). Varied absorption profiles following SC dosing were characterized by incorporating inter-antibody variability in local degradation (kSC) and rate of lymphatic uptake (S_Lu) of mAbs. Estimates for typical kSC and S_Lu values, and ωKsc,ωS_Lu, were found to be 0.0015 h-1 and 0.54 (193%, and 49%). FDA-approved mAbs showed less local degradation (0.0014 h-1 vs. 0.0038 h-1) compared with other clinically tested mAbs, whereas no substantial differences in physiological processes involved in disposition were observed. To evaluate the generalizability of estimated PK parameters and model validation, the final popPBPK model was used to simulate the range of expected PK for mAbs following SC administration of nine different mAbs that were not used for model-building purposes. The predicted PK of all nine mAbs was within the expected range specified a priori. Thus, the popPBPK model presented here may serve as a tool to predict the clinical PK of mAbs with linear disposition before administering them to humans. The model may also support preclinical-to-clinical translation and 'first-in-human' dose determination for mAbs.

A multi-scale numerical study of monoclonal antibodies uptake by initial lymphatics after subcutaneous injection

This paper studies the transport of monoclonal antibodies through skin tissue and initial lymphatics, which impacts the pharmacokinetics of monoclonal antibodies. Our model integrates a macroscale representation of the entire skin tissue with a mesoscale model that focuses on the papillary dermis layer. Our results indicate that it takes hours for the drugs to disperse from the injection site to the papillary dermis before entering the initial lymphatics. Additionally, we observe an inhomogeneous drug distribution in the interstitial space of the papillary dermis, with higher drug concentrations near initial lymphatics and lower concentrations near blood capillaries. To validate our model, we compare our numerical simulation results with experimental data, finding a good alignment. Our parametric studies on the drug molecule properties and injection parameters suggest that a higher diffusion coefficient increases the transport and uptake rate while binding slows down these processes. Furthermore, shallower injection depths lead to faster lymphatic uptake, whereas the size of the injection plume has a minor effect on the uptake rate. These findings advance our understanding of drug transport and lymphatic absorption after subcutaneous injection, offering valuable insights for optimizing drug delivery strategies and the design of biotherapeutics.

Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies in Migraine: Focus on Clinical Pharmacokinetics.

The calcitonin gene-related peptide transmission was the target for recent development of drugs that effectively prevent attacks of both episodic and chronic migraine. The aim of this narrative review was to offer deeper insight into pharmacokinetics of monoclonal antibodies approved for prevention of migraine attacks. For this narrative review, relevant literature was searched for in MEDLINE and Google Scholar databases, covering periods 1966-2023 and 2006-2023, respectively. The ClinicalTrials.gov database was also searched for relevant clinical studies whose results had not been published previously in medical journals, covering the period 2000-2023. The monoclonal antibodies from this group are distributed mainly in the plasma and part of the extracellular space; they are neither metabolized in the liver nor excreted via the kidneys. The elimination of galcanezumab, eptinezumab and fremanezumab takes place only by a non-specific linear process via the reticuloendothelial system in the liver, while erenumab is eliminated by a non-specific process and by a specific, saturable process because of binding to receptors located on the cell membrane. Since the elimination processes do not have a large capacity, the half-life is about 2 weeks for erenumab and about 4 weeks for other monoclonal antibodies. Variability in the pharmacokinetics of these monoclonal antibodies is small in different subpopulations, and body weight is the only parameter to consider when choosing the dose of these drugs.

Multiphysics Simulation of Local Transport and Absorption Coupled with Pharmacokinetic Modeling of Systemic Exposure of Subcutaneously Injected Drug Solution.

Subcutaneous (SC) injectables have become more acceptable and feasible for administration of biologics and small molecules. However, efficient development of these products is limited to costly and time-consuming techniques, partially because absorption mechanisms and kinetics at the local site of injection remain poorly understood. To bridge formulation critical quality attributes (CQA) of injectables with local physiological conditions to predict systemic exposure of these products. We have previously developed a multiscale, multiphysics computational model to simulate lymphatic absorption and whole-body pharmacokinetics of monoclonal antibodies. The same simulation framework was applied in this study to compute the capillary absorption of solubilized small molecule drugs that are injected subcutaneously. Sensitivity analyses were conducted to probe the impact by key simulation parameters on the local and systemic exposures. This framework was capable of determining which parameters had the biggest impact on small molecule absorption in the SC. Particularly, membrane permeability of a drug was found to have the biggest impact on drug absorption kinetics, followed by capillary density and drug diffusivity. Our modelling framework proved feasible in predicting local transport and systemic absorption from the injection site of small molecules. Understanding the effect of these properties and how to model them may help to greatly expedite the development process.

Pharmacokinetics of Monoclonal Antibody and Antibody Fragments in The Mouse Eye Following Intravitreal Administration

Mice are rarely used in pharmacokinetic (PK) studies of ocular therapeutics due to the small size of their eyes and challenges in drug administration, tissue collection, and analysis of drug concentrations. Therefore, ocular PK of protein therapeutics in mouse eye following intravitreal (IVT) administration is not known. Here, we have presented the first of its kind investigation, to study the PK of 4 different size non-binding protein therapeutics in mouse plasma, cornea/ICB, vitreous humor, retina, and posterior cup (including choroid) following IVT administration. Administered proteins include trastuzumab (150 kDa) and F(ab)2 (100 kDa), Fab, and scFv (27 kDa) fragments of trastuzumab. An imaging and injection apparatus suitable for performing small (50 nL) IVT injections in mice was developed, and techniques for enucleation of the eye and dissection of ocular tissues were developed. Furthermore, a sensitive enzyme-linked immunosorbent assay (ELISA) for detection of proteins in very small amounts of ocular tissues were developed. It was observed that elimination from the vitreous chamber was the primary driver of PK in the cornea/ICB, retina, posterior cup, and plasma. Trastuzumab displays first-order kinetics in the vitreous humor with a half-life of 18.8 h. F(ab)2, Fab, and ScFv show biphasic PK profiles with distribution phases becoming more rapid as molecular weight decreases, and terminal elimination becoming longer as molecular weight decreases, with terminal half-lives of 16.3, 20.6, and 48.9 h, respectively. The mean residence times of trastuzumab, F(ab)2, Fab, and scFv in the vitreous humor were 26.0, 12.2, 10.7, and 8.16 h, respectively. It was found that the mean residence time in vitreous humor doubles with an increase in molecular weight of ∼69 kDa. Interestingly, the PK of proteins measured in the un-injected eye suggest the presence of a pathway for drug transfer between the eyes, which needs to be further validated. Overall, the findings presented here pave the way for drug discovery and development studies of protein therapeutics for ophthalmic indications in mice.

Monoclonal Antibody Pharmacokinetics in Cynomolgus Monkeys Following Subcutaneous Administration: Physiologically Based Model Predictions from Physiochemical Properties.

An integrated physiologically based modeling framework is presented for predicting pharmacokinetics and bioavailability of subcutaneously administered monoclonal antibodies in cynomolgus monkeys, based on in silico structure-derived metrics characterizing antibody size, overall charge, local charge, and hydrophobicity. The model accounts for antibody-specific differences in pinocytosis, transcapillary transport, local lymphatic uptake, and pre-systemic degradation at the subcutaneous injection site and reliably predicts the pharmacokinetics of five different wild-type mAbs and their Fc variants following intravenous and subcutaneous administration. Significant associations were found between subcutaneous injection site degradation rate and the antibody's local positive charge of its complementarity-determining region (R = 0.56, p = 0.0012), antibody pinocytosis rate and its overall positive charge (R = 0.59, p = 0.00063), and antibody paracellular transport and its overall charge together with hydrophobicity (R = 0.63, p = 0.00096). Based on these results, population simulations were performed to predict the relationship between bioavailability and antibody local positive charge. In addition, model simulations were conducted to calculate the relative contribution of absorption pathways (lymphatic and blood), pre-systemic degradation pathways (interstitial and lysosomal), and the influence of injection site lymph flow on antibody bioavailability and pharmacokinetics. The proposed physiologically based modeling framework integrates fundamental mechanisms governing antibody subcutaneous absorption and disposition, with structured-based physiochemical properties, to predict antibody bioavailability and pharmacokinetics in vivo.

Algorithmic multiscale analysis for the FcRn mediated regulation of antibody PK in human

A demonstration is provided on how algorithmic asymptotic analysis of multi-scale pharmacokinetics (PK) systems can provide (1) system level understanding and (2) predictions on the response of the model when parameters vary. Being algorithmic, this type of analysis is not hindered by the size or complexity of the model and requires no input from the investigator. The algorithm identifies the constraints that are generated by the fast part of the model and the components of the slow part of the model that drive the system within these constraints. The demonstration is based on a typical monoclonal antibody PK model. It is shown that the findings produced by the traditional methodologies, which require significant input by the investigator, can be produced algorithmically and more accurately. Moreover, additional insights are provided by the algorithm, which cannot be obtained by the traditional methodologies; notably, the dual influence of certain reactions depending on whether their fast or slow component dominates. The analysis reveals that the importance of physiological processes in determining the systemic exposure of monoclonal antibodies (mAb) varies with time. The analysis also confirms that the rate of mAb uptake by the cells, the binding affinity of mAb to neonatal Fc receptor (FcRn), and the intracellular degradation rate of mAb are the most sensitive parameters in determining systemic exposure of mAbs. The algorithmic framework for analysis introduced and the resulting novel insights can be used to engineer antibodies with desired PK properties.

Model-Based Assessment of the Contribution of Monocytes and Macrophages to the Pharmacokinetics of Monoclonal Antibodies.

We have hypothesized that a high concentration of circulating monocytes and macrophages may contribute to the fast weight-based clearance of monoclonal antibodies (mAbs) in young children. Exploring this hypothesis, this work uses modeling to clarify the role of monocytes and macrophages in the elimination of mAbs. Leveraging pre-clinical data from mice, a minimal physiologically-based pharmacokinetic model was developed to characterize mAb uptake and FcRn-mediated recycling in circulating monocytes, macrophages, and endothelial cells. The model characterized IgG disposition in complex scenarios of site-specific FcRn deletion and variable endogenous IgG levels. Evaluation was performed for predicting IgG disposition with co-administration of high dose IVIG. A one-at-a-time sensitivity analysis quantified the role of relevant cellular parameters on IgG elimination in various scenarios. The plasma AUC of mAbs was highly sensitive to endothelial cell parameters, but had near-nil sensitivity to monocyte and macrophage parameters, even in scenarios with 90% loss of FcRn expression/activity. In mice with normal FcRn expression, simulations suggest that less than 2% of an IV dose is eliminated in macrophages, while endothelial cells are predicted to dominate mAb elimination. The model suggests that the role of monocytes and macrophages in IgG homeostasis includes extensive uptake and highly efficient FcRn-mediated protection, but not appreciable degradation when FcRn is present. Therefore, it is very unlikely that a high concentration of circulating monocytes can contribute to explaining the fast weight-based clearance of mAbs in very young children, even if FcRn expression/activity was 90% lower in children than in adults.

Pharmacokinetics of Monoclonal Antibody and Antibody Fragments in the Mouse Eye Following Systemic Administration

The ocular pharmacokinetics (PK) of antibody-based therapies are infrequently studied in mice due to the technical difficulties in working with the small murine eye. This study is the first of its kind to quantitatively measure the PK of variously sized proteins in the plasma, cornea/ICB, vitreous humor, retina, and posterior cup (including choroid) of the mouse and to evaluate the relationship between molecular weight (MW) and antibody biodistribution coefficient (BC) to the eye. Proteins analyzed include trastuzumab (150 kDa), trastuzumab-vc-MMAE (T-vc-MMAE, 155 kDa), F(ab)2 (100 kDa), Fab (50 kDa), and scFv (27 kDa). As expected, ocular PK mirrored the systemic PK as plasma was the driving force for ocular exposure. For trastuzumab, T-vc-MMAE, F(ab)2, Fab, and scFv, respectively, the BCs in the cornea/ICB were 0.610%, 0.475%, 1.74%, 3.39%, and 13.7%; the BCs in the vitreous humor were 0.0198%, 0.0427%, 0.0934%, 0.234%, and 5.56%; the BCs for the retina were 0.539%, 0.230%, 0.704%, 2.44%, and 20.4%; the BCs for the posterior cup were 0.557%, 0.650%, 1.47%, 4.06%, and 13.9%. The relationship between BC and MW was best characterized by a log–log regression in which BC decreased as MW increased, with every doubling in MW leading to a decrease in BC by a factor of 3.44 × , 6.76 × , 4.74 × , and 3.43 × in cornea/ICB, vitreous humor, retina, and posterior cup, respectively. In analyzing the disposition of protein therapeutics to the eye, these findings enhance our understanding of the potential for ocular toxicity of systemically administered protein therapeutics and may aid in the discovery of systemically administered protein therapeutics for ocular disorders.Supplementary InformationThe online version contains supplementary material available at 10.1208/s12248-021-00647-0.

The Use of Biotechnological Drugs in Pediatrics on the Example of Monoclonal Antibodies: Clinical Pharmacology View

The article reviews monoclonal antibodies, its structure, classifications, pharmacodynamics, pharmacokinetics, and adverse effects. There are examples for each section. Approaches to the research and criteria for drug selection in paediatrics are discussed in detail: the role of clinical trials, extrapolation and pharmacometrics. It has been shown that the differences in the pharmacokinetics of monoclonal antibodies between adults and children present due to the age-related characteristics of various physiological processes. The authors analyse such parameters as absorption, bioavailability, distribution, and elimination. The role of monoclonal antibodies immunogenicity in the structure of adverse effects in children is fully presented. Pharmacometrics is reviewed in the form of modelling and simulation in monoclonal antibodies dosing in paediatrics. It is important to consider the growth and development as “moving targets" in pediatrics regardless the principle of monoclonal antibodies dosage in children. The conclusions were made, and the guidelines were prepared based on the article results.

Prediction of Non-Linear Pharmacokinetics of Monoclonal Antibodies in Human from Nonclinical Data: Are We There Yet?

Prediction of Non-Linear Pharmacokinetics of Monoclonal Antibodies in Human from Nonclinical Data: Are We There Yet?

A Physiologically‐Based Pharmacokinetic Model for the Prediction of “Half‐Life Extension” and “Catch and Release” Monoclonal Antibody Pharmacokinetics

Monoclonal antibodies (mAbs) can be engineered to have “extended half‐life” and “catch and release” properties to improve target coverage. We have developed a mAb physiologically‐based pharmacokinetic model that describes intracellular trafficking, neonatal Fc receptor (FcRn) recycling, and nonspecific clearance of mAbs. We extended this model to capture target binding as a function of target affinity, expression, and turnover. For mAbs engineered to have an extended half‐life, the model was able to accurately predict the terminal half‐life (82% within 2‐fold error of the observed value) in the human FcRn transgenic (Tg32) homozygous mouse and human. The model also accurately captures the trend in pharmacokinetic and target coverage data for a set of mAbs with differing catch and release properties in the Tg32 mouse. The mechanistic nature of this model allows us to explore different engineering techniques early in drug discovery, potentially expanding the number of “druggable” targets.

Simple Approach to Accurately Predict Pharmacokinetics of Therapeutic Monoclonal Antibodies after Subcutaneous Injection in Humans

The subcutaneous injection of therapeutic monoclonal antibodies is increasingly used in the treatment of several diseases because of its convenience. Thus, a simple and accurate method of predicting the pharmacokinetics of monoclonal antibodies after a subcutaneous injection in humans would be a valuable tool for preclinical/clinical development. In this study, we investigated whether the pharmacokinetics of monoclonal antibodies after a subcutaneous injection in humans can be predicted using only pharmacokinetic data after a subcutaneous injection in cynomolgus monkeys. First, we compared the accuracy of three approaches to predict the apparent clearance (CL/F) and apparent volume of distribution (Vd/F) for 15 monoclonal antibodies in humans (1) allometric scaling from cynomolgus monkeys; (2) geometric mean of reported values in humans; (3) estimation from a regression line based on CL/F in humans [only Vd/F]). Then, using the predicted CL/F and Vd/F, and the geometric mean of reported absorption rate constant of mAbs the plasma concentration-time profiles of 13 monoclonal antibodies after subcutaneous injections in humans were simulated. In a comparison of approaches, the first approach showed the best prediction accuracy for CL/F with an exponent of 0.9 (100% and 73% prediction accuracy within 2- and 1.5-fold of the observed value),and the third approach was the best for Vd/F (100% prediction accuracy within 1.5-fold of the observed value). Next, using the first approach for CL/F and the third approach for Vd/F, we accurately predicted the plasma concentration-time profiles of 13 monoclonal antibodies after subcutaneous injections in humans. This simple approach can be applied in preclinical and clinical settings to predict the pharmacokinetics of monoclonal antibodies after subcutaneous injections in humans. Further, this approach requires only CL/F after a subcutaneous injection in cynomolgus monkeys, contributing to animal welfare and reducing costs.

Predicting monoclonal antibody pharmacokinetics following subcutaneous administration via whole-body physiologically-based modeling.

Use of the subcutaneous (SC) route for administering monoclonal antibodies (mAbs) to treat chronic conditions has been hindered because of an incomplete understanding of fundamental mechanisms controlling mAb absorption from the SC site, and due to the limited translatability of preclinical studies. In this paper, we report on the development and evaluation of a whole-body physiologically-based model to predict mAb pharmacokinetics following SC administration. The circulatory model is based on the physiological processes governing mAb transport and includes two mAb-specific parameters representing differences in pinocytosis rate and the diffusive/convective transport rates among mAbs. At the SC administration site, two additional parameters are used to represent mAb differences in lymphatic capillary uptake and in pre-systemic clearance. Model development employed clinical intravenous (IV) plasma PK data from 20 mAbs and SC plasma PK data from 12 of these mAbs, as obtained from the literature. The resulting model reliably described both the IV and SC measured plasma concentration data. In addition, a metric based on the positive charge across the mAb's complementarity determining region vicinity was found to positively correlate with the model-based estimates of the mAb-specific parameter governing organ/tissue pinocytosis transport and with estimates of the mAb's SC lymphatic capillary clearance. These two relationships were incorporated into the model and accurately predicted the SC PK profiles of three out of four separate mAbs not included in model development. The whole-body physiologically-based model reported herein, provides a platform to characterize and predict the plasma disposition of monoclonal antibodies following SC administration in humans.

Основы фармакокинетики моноклональных антител

Основы фармакокинетики моноклональных антител

Pharmacokinetic Variability of Therapeutic Antibodies in Humans: A Comprehensive Review of Population Pharmacokinetic Modeling Publications.

The pharmacokinetics of monoclonal antibodies is highly variable among patients. Several factors of variability, referred to as covariates in pharmacokinetic modeling, are known to influence this variability, such as body size, sex, antigen mass, serum albumin levels, or the presence of anti-drug antibodies. We propose a quantitative overview of the occurrence of assessment and detection of the main covariates associated with monoclonal antibody pharmacokinetics by comprehensively examining all population pharmacokinetic studies of monoclonal antibodies in humans. If some covariates are often assessed and detected (such as body size, antigen mass, or serum albumin levels), others are less frequently assessed but still may be relevant (e.g., anti-drug antibodies or endogenous immunoglobulin G levels). There is still a large heterogeneity in the relevance, availability, measurement, coding, detection, and interpretation of covariates. These issues deserve thorough investigation, which will help to design the optimal dosing strategy for every monoclonal antibody during its entire lifespan.

Does Hepatic Impairment Affect the Exposure of Monoclonal Antibodies?

Limited information is available regarding the effect of hepatic impairment (HI) on the pharmacokinetics of monoclonal antibodies (mAbs). The results of an earlier report based on therapeutic proteins, including mAbs, approved through the end of 2012 were inconclusive due to limited HI data available at that time. New HI data for mAbs or antibody-drug conjugates (ADCs; with a focus on the mAb component) available between 2013 and 2018 were evaluated. The investigation indicates there is almost no data for severe HI, limited data for moderate HI, and abundant data for mild HI. A significant exposure decrease was found for several mAbs or ADCs and a trend for decreasing area under the concentration-time curve (AUC) was observed for other mAbs. Multiple potential mechanisms may contribute to the exposure decrease. Dose may need to be adjusted for patients with HI, after taking into account the exposure-response relationships for both efficacy and safety.

A Physiologically-Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data.

Monoclonal antibody (mAb) pharmacokinetics (PK) have largely been predicted via allometric scaling with little consideration for cross‐species differences in neonatal Fc receptor (FcRn) affinity or clearance/distribution mechanisms. To address this, we developed a mAb physiologically‐based PK model that describes the intracellular trafficking and FcRn recycling of mAbs in a human FcRn transgenic homozygous mouse and human. This model uses mAb‐specific in vitro data together with species‐specific FcRn tissue expression, tissue volume, and blood‐flow physiology to predict mAb in vivo linear PK a priori. The model accurately predicts the terminal half‐life of 90% of the mAbs investigated within a twofold error. The mechanistic nature of this model allows us to not only predict linear PK from in vitro data but also explore the PK and target binding of mAbs engineered to have pH‐dependent binding to its target or FcRn and could aid in the selection of mAbs with optimal PK and pharmacodynamic properties.

Population Pharmacokinetics of an Anti-PD-L1 Antibody, Durvalumab in Patients with Hematologic Malignancies.

Background and ObjectivesDurvalumab, a human monoclonal antibody targeting programmed cell death ligand 1, has been approved for urothelial carcinoma and stage III non-small cell lung cancer by the US Food and Drug Administration and is being evaluated in various malignancies. The objective of this study was to develop a population-pharmacokinetic model of durvalumab in patients with various hematologic malignancies and to investigate the effects of demographic and disease factors on the pharmacokinetics in this population.MethodsA total of 1812 concentrations from 267 patients with myelodysplastic syndromes, acute myeloid leukemia, multiple myeloma, non-Hodgkin lymphoma, or Hodgkin lymphoma were included in the analysis.ResultsThe pharmacokinetics of durvalumab was adequately described by a two-compartment model with first-order elimination. A decrease in durvalumab clearance over time was mainly explained by incorporation of time-dependent changes in albumin (in all patients) and immunoglobulin G (in patients with multiple myeloma) into the model. For multiple myeloma, patients with immunoglobulin G ≥ 20 g/L showed a 30% lower area under the concentration–time curve at cycle 1 compared with patients with immunoglobulin G < 20 g/L. The impact of any baseline covariates on durvalumab pharmacokinetics did not appear to be clinically relevant. The pharmacokinetics of durvalumab in hematologic malignancies was generally consistent with previously reported pharmacokinetics in solid tumors.ConclusionsThese results support the same dosing regimen (1500 mg every 4 weeks) for both solid tumors and hematologic malignancies from the perspective of adequate exposure. Additionally, total immunoglobulin G level could be a critical covariate for the pharmacokinetics of monoclonal antibodies in patients with multiple myeloma.Electronic supplementary materialThe online version of this article (10.1007/s40262-019-00804-x) contains supplementary material, which is available to authorized users.