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Predicting the Pharmacokinetic Characteristics of Edaravone Intravenous Injection and Sublingual Tablet Through Modeling and Simulation
Clinical Therapeutics/Volume xxx, Number xxx, xxxx
Predicting the Pharmacokinetic Characteristics of Edaravone Intravenous Injection and Sublingual Tablet Through Modeling and Simulation Xia Chen, MD, PhD1,2,3,5; Zhuo Sun, Msc1,2,3,5; Jiaqing Wang, MSc1,3; Wu Liang, MSc4; Xingquan Zhao, MD, PhD1,2,3; Yilong Wang, MD, PhD1,2,3; and Yongjun Wang, MD, PhD1,2,3 1
China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China; 2Phase I Unit, Beijing Tiantan Hoapital, Capital Medical University, Beijing, PR China; 3Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, PR China; and 4Changsha VALS Technology Co Ltd, Hunan, PR China ABSTRACT Purpose: Edaravone is a free-radical scavenger with relatively favorable properties of brain penetration. It has been approved for the indications of acute ischemic stroke and amyotrophic lateral sclerosis (ALS). This study aimed to establish a pharmacokinetic (PK) model to fit the PK profile of edaravone after a single sublingual (SL) dose of a novel edaravone tablet and single IV infusion of injectable edaravone in healthy Chinese volunteers participating in a bioavailability study. The model is expected to be useful for predicting the concentrationetime profiles of edaravone following different dosing regimens in a healthy Chinese population. The purposes were to identify an optimal dose and dosing regimen for the new SL formulation and to support future clinical exploration of this tablet product in its approved indications and other therapeutic fields being developed. Methods: The PK profiles after a single SL dose or IV infusion of edaravone 30 mg can be well described by a 3-compartment linear disposition model, on which a first-order absorption model with a lag time and a parameter for bioavailability was incorporated to fit the absorption phase of the SL dose. Performance of these PK models was evaluated for
goodness of fit, residual trends, visual predictive checks, as well as precision of model predictions against external data. The validated models were employed for simulating the PK profiles of edaravone after a single SL dose of 60 mg and IV infusion of 60 mg for 60 min. Findings: The resultant estimates support the possibility and feasibility of demonstrating bioequivalence between an SL administration of edaravone 60 mg and the currently approved dosing regimen for ALS (ie, 60 mg IV over 60 min) once per day. The calculation of sample size suggested that the requirement for subject number was acceptable considering the general capacity of a Phase I study center, and so were the procedures defined in the protocol. Implication: The models can be further applied to simulate favorable concentrationetime profiles in diseases with different underlying courses of oxidative stress, and hence facilitate the optimization of current dosing regimens. (Clin Ther. xxxx;xxx:xxx) © 2020 Elsevier Inc. All rights reserved. Key words: acute ischemic stroke, ALS, bioequivalence, model, simulation.
Accepted for publication January 10, 2020 https://doi.org/10.1016/j.clinthera.2020.01.006 0149-2918/$ - see front matter 5
Co-first authors.
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© 2020 Elsevier Inc. All rights reserved.
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Clinical Therapeutics
INTRODUCTION Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one)* is a low-molecular-weight, amphiphilic antioxidant that scavenges both lipids and water-soluble peroxidic free radicals.1 The drug has been approved for >10 years in Japan and in China for the indication of cerebral infarction as a 30-mg, 30-min IV BID infusion therapy administered for 14 successive days commencing within 24 h after the onset of ischemic stroke.2,3 In 2015, 2017, and 2018, the IV-injectable formulation of edaravoney gained regulatory approval from Japanese, US, and Canadian health authorities for the treatment of amyotrophic lateral sclerosis (ALS) with a regimen of 60 mg over 60 min of IV infusion once per day.4 Compared to other antioxidants and radical scavengers, edaravone is rather favored for its ability to react with a wide range of reactive oxygen species and its activity in both the lipid phase and the water phase of the human body, which allows it to act not only extracellularly on the vascular endothelial cell membrane, but also on cells located in the cerebral parenchyma.5,6 Nonetheless, from a clinical practical point of view, the use of edaravone is somewhat limited by its commercially available formulations. The mechanism of action of edaravone for acute ischemic stroke was inferred to be the scavenging of peroxynitrite. In one study, in response to cerebral ischemia, microglia were rapidly activated,7 as characterized by the release of a variety of proinflammatory cytokines, reactive oxygen species, nitric oxide, and proteolytic enzymes within 1 or 2 h following the onset of infarction.8 In studies in humans,9e11 plasma monounsaturated fatty acids, oxidized low-density lipoprotein, 3-nitrotyrosine in cerebrospinal fluid, and N-acetyl aspartate quantified by Hydrogen Proton e Magnetic Resonance Spectroscopy were used as biomarkers reflecting oxidative stress, peroxynitrite-induced injury, and brain tissue damage. The studies were conducted in patients with cerebral infarctions, and the results indicated that the level of oxidative stress reached its
® * Trademark: Radicut injection (Mitsubishi Tanabe Pharma Corporation, Tokyo). ® y Trademark: Radicava (Mitsubishi Tanabe Pharma Corporation).
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peak by around 24 h after onset,9 and the administration of edaravone was associated with a significant decrease in acute ischemic strokeeinduced oxidized low-density lipoprotein elevation,10 accompanied with a reduction in tissue damage11 and improvement of neurologic function at hospital discharge.10 The time course of oxidative stress after infarction onset and the concentration-dependent free-radicalescavenging effect of edaravone suggest that the timing of administration and the dosing regimen are 2 key elements determining the therapeutic outcome of edaravone. However, in clinical practice, most patients could not receive the IV infusion before their arrival at the hospital; hence, more attention has been paid to prehospital treatment in recent years. In the case of ALS, the chronic and progressive features of this disease warrant long-term use of potential pharmacotherapy. Moreover, the short elimination half-life of edaravone12 may increase the inconvenience of parenteral administration and weaken patients' compliance to the approved IV formulation of edaravone. A novel edaravone formulation, a sublingual (SL) tablet, was recently developed by a Chinese manufacturer. SL administration of the edaravone 30-mg SL tablet resulted in a 92% bioavailability of edaravone versus the IV infusion of the same dose over 30 min. The 90% CIs were 0.732e0.962 for Cmax, 0.868 to 0.974 for AUClast, and 0.870 to 0.974 for AUCinf.12 Since the SL route bypasses the swallowing process, it is even preferred over oral administration in patients with neurologic deficits of the CNS. In addition, the ease of use in both the prehospital setting in stroke patients and the outpatient setting in ALS patients adds value to this new formulation. The present study aimed to describe the pharmacokinetic (PK) profile of the edaravone SL tablet with an empirical compartmental model and to simulate the concentrationetime profiles of this drug following different dosing regimens, in comparison with the PK profiles of the clinically recommended IV dosage of edaravone. Other purposes were to find an optimal dose and dosing regimen of this new formulation and to support future clinical exploration of this drug in its approved indications and other therapeutic fields in development.
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MATERIALS AND METHODS The data used in this analysis were collected from a pilot bioavailability study that compared PK profiles between the edaravone SL tablet and the edaravone IV injection.12 The trial protocol was approved by the Ethics Committee of Beijing Tiantan Hospital of Capital Medical University (registration number KY 2018-043-02; Beijing, People's Republic of China). It was conducted in accordance with the ethics principles originating from the Declaration of Helsinki, as well as the Chinese Good Clinical Practices and applicable regulatory requirements. All subjects participating in the trial signed informed consent prior to any trial procedure.
Participants A total of 10 male subjects were enrolled into the study and received the investigational medicinal products in both study periods. The age of the subjects ranged from between 20 and 32 years; weight, 55e80 kg. The health status of each subject was determined with the collection of medical history, physical examinations, ECG examinations, and laboratory tests performed during the medical screening. Eligible subjects had no history or evidence of drug or alcohol abuse, no clinically significant abnormalities in medical history or laboratory tests, and no oral or buccal ulceration or related diseases. Eligible subjects had no smoking habit or smoked <5 cigarettes/d during the 3 months before the first study dose and were prohibited from smoking during the study period. They were required to refrain from prescribed and over-the-counter medications (including traditional Chinese medicines), excessive consumption of caffeine- or alcohol-containing beverages, and strenuous physical activity during the study.
Study Design The single-center, randomized, open-label, 2-waycrossover study was conducted in 10 healthy Chinese male volunteers. The subjects were randomly assigned in a 1:1 ratio to 1 of 2 dosing sequences: (1) the test treatment in the first period and the reference treatment in the second period, or (2) the other way around; the test treatment was edaravone 30-mg SL tablet, and the reference treatment was edaravone 30mg IV infusion for 30 min. As the mean half-life of edaravone is only 2e3 h,12 the washout period was set as 24 h to cover >5 half-lives.
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In each dosing period, blood samples (4 mL) for the bioassay of edaravone were taken with EDTA K2 tubes from an ulnar vein free from IV infusion at predose and 5, 10, 15, 30, and 45 min and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 h postdose. The plasma concentrations of edaravone were determined by a validated HPLC (Shimadzu, Kyoto, Japan) method with MS/MS (QTRAP 5500; AB Sciex Inc, Foster City, California).12
Model-building Process Model fitting was performed using a populationanalysis approach (Phoenix64 software version 8.1; Pharsight Corporation, Cary, North Carolina) with 1 integrated PK model for concentration data obtained both after the SL dose and after the IV dose, in which a model parameter of bioavailability (F) was estimated for the SL dosing period and the interperiod variability was explored. Diagnostic graphics and model simulation were performed using the same software. Data preparation and visualization were performed on the concentration measurements of each participant. Based on preliminary examination of the concentrationetime profiles, both 2- and 3-compartment mamillary models were assessed for their appropriateness in describing the PK data. For the SL-administered edaravone tablet, a first-order absorption with or without absorption lag time was assumed and incorporated into the PK model. Diagnostic goodness-of-fit plots, the values of Akaike information criterion (AIC) and objective function value, and relative SEs for parameter estimates were all considered for model selection. A decrease in the AIC or Bayesian information criterion (BIC) values between 2 nested models of >3.84 with 1 degree of freedom or of >5.99 with 2 degrees of freedom was considered a statistically significant model improvement on the basis of c2 test results. Thereafter, the covariate effects (ie, age [years] and weight [kg]) were explored for their ability to explain variability in the PK model parameters using stepwise forward selection and backward elimination. A likelihood ratio test was applied to investigate significant covariates with a significance level of P < 0.05 (decrease in AIC of >3.84 with 1 degree of freedom) for selection and P < 0.01 (decrease in AIC of >6.64) for elimination.13 In stepwise covariate
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Clinical Therapeutics modeling, both age and weight were evaluated for compartmental clearances and volumes of distribution, respectively. Model performance was assessed internally with visual predictive checks. The observed plasma concentrations with 90% prediction intervals were depicted with 1000 datasets simulated using the final PK parameters with significant covariates. Moreover, external model validation for IV infusion was performed by comparing the predicted PK parameters (ie, AUClast, Cmax, Tmax, t1/2), clearance [CL for IV edaravone or CL/F for SL edaravone], and volume of distribution [Vz for IV edaravone or Vz/F for SL edaravone] derived from noncompartmental analysis
Table I.
to those obtained from a previous PK study conducted in adult Chinese volunteers (Tables I and II).14
Model Application Finally, the model was applied to predict the PK profiles and PK parameters after single IV or SL dosing of edaravone 60 mg. The geometric SL/IV ratios derived from the model simulated PK parameters, together with the largest intrasubject variability observed in the previous bioavailability study,14 were used for estimating the sample size with an 80% power that is required for a bioavailability study bridging the SL use to the approved IV-administered edaravone for ALS.
Comparison of the demographic characteristics between the dataset for model fitting12 and the dataset for external validation.14
Characteristic Male sex, % Age, mean (range), y Weight, mean (range), kg BMI, mean (range), kg/m2
Table II.
Model Fitting (n ¼ 10)
External Validation (n ¼ 30)
100 26.4 (20e32) 62.2 (56.8e79.4) 23.0 (20.2e27.3)
50 31.4 (20e42) 59.7 (46e78) 21.6 (18.8e23.9)
Pharmacokinetic parameters derived from non-compartmental analysis (NCA) obtained based on model-simulated pharmacokinetic profiles after single intravenous administration of different doses of edaravone, compared to those reported in a published study conducted in Chinese healthy subjects. Data are given as mean (SD).14
Parameter
20 mg Literature Data*
AUClast, h mg/L AUCinf, h mg/L Cmax, mg/L CL, L/h V,z L t1/2, h
3.64 3.79 1.60 6.00 19.3 2.34
(1.37) (1.40) (0.38) (1.80) (7.3)* (0.69)
30 mg Simulated Datay 3.87 3.90 1.48 5.32 25.2 3.80
(0.78) (0.81) (0.24) (1.00) (6.74) (0.35)
Literature Data* 5.17 5.29 2.38 6.00 18.5 2.25
(0.93) (0.98) (0.32) (1.20) (2.6)* (0.42)
60 mg Simulated Datay 5.79 5.83 2.50 5.32 25.2 3.30
(1.05) (1.07) (0.44) (1.01) (6.74) (0.74)
Literature Data* 11.3 11.6 4.54 5.40 20.7 2.57
(3.42) (3.62) (0.90) (1.80) (6.5)* (0.32)
Simulated Datay 11.5 11.6 5.04 5.32 25.0 3.35
(2.10) (2.15) (0.89) (1.01) (6.68) (0.63)
* The y
NCA parameter results of the phase I clinical trial. The NCA parameter results of the model simulation. z The unit of V is corrected from L/kg to L based on the values of CL and t1/2, and the known relationship of these three parameters, ie, V ¼ CL $ t1/2/ln2.
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RESULTS
Evaluation of Model Performance
The PK analyses were based on 300 concentration measurements from 10 subjects (including 140 measurements from the IV period and 160 measurements from the SL period). The age of the subjects ranged from 20 to 32 years, and their body weights were between 56.8 and 79.4 kg.
Model-selection criteria suggested the appropriateness of the models. The attempts at using a 2-compartment linear disposition model were rejected by the comparison of 2 structural models, in which larger AIC and objective function values and higher parameter %CV were observed with the 2compartment model (3- vs 2-compartment model: AIC, −488.7 vs −486.0; Objective Function Value, −526.7 vs −516.0). The actual measurements versus individual predictions approximated the identity line; the same was also observed in population predictions (Figure 2). The residual plots (Figure 2) did not indicate skewness or a trend of the residuals versus the population predictions and time. The predictive performance of the final models was assessed by an evaluation of whether the distribution of the observed data was contained within the empirical distribution of the estimates predicted by the final model over a number of simulations. For this evaluation, 1000 datasets were simulated from the final model (and its uncertainty in parameter estimates) using the original dataset. Figure 3 shows the visual prediction checks as the time course of edaravone plasma concentrations with the 90% prediction intervals of each dosing route. Most of the observed data lay within the 5th and 95th percentiles of the simulations, and the observed and predicted percentiles were similar, indicating good model estimations. All of these results suggest that the final model prediction was reasonable for both the point estimates as well as the distributions.
Establishment of Pharmacokinetic Model The parameter estimates for the final model are summarized in Table III. Overall, the final model parameters were estimated with reasonable CIs. Neither age nor body weight was identified as a significant covariate in the PK models of edaravone. The plasma concentrationetime profile of edaravone was well described by the 3-compartment model with a parameter of F representing SL bioavailability and a first-order absorption model with an initial lag time assumed for the tablet dissolution (Table III and Figure 1).
Table III.
Parameter estimates of the final pharmacokinetic model.
Parameters Estimate %CV tvV, L tvCl, L/h tvKa, 1/h tvV2, L tvCl2, L/h tvTlag, h tvF tvV3, L tvCl3, L/h Stdev0
11.17 4.76 3.75 51.91 0.58 0.16 0.93 3.85 1.60 0.15
8.0 7.0 14.6 9.7 11.6 8.9 8.9 7.0 16.1 11.5
95% CI 9.41e12.93 4.10e5.42 2.67e4.82 42.01e61.81 0.45e0.71 0.13e0.19 0.77e1.09 3.32e4.38 1.09e2.10 0.11e0.18
IIV (%) 17.2 19.6 23.5 e e 24.7 19.5 e e e
CL ¼ clearance of central compartment; CL2 ¼ clearance of peripheral compartment 2; CL3 ¼ clearance of peripheral compartment 3; F ¼ bioavailability of sublingual administration; IIV ¼ inter-individual variability of the PK parameters (%CV); Ka ¼ absorption rate constant; Stdev0 ¼ intraindividual variability of the proportional residual model (SD); Tlag ¼ lag time after sublingual administration; V ¼ volume of distribution in the central compartment; V2 ¼ volume of distribution in the peripheral compartment 2; V3 ¼ volume of distribution in the peripheral compartment 3.
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External Model Validation External model validation was conducted by simulating the PK profiles of edaravone after IV doses from 20 to 60 mg and comparing the resultant PK parameters to those from the literature report.14 Table II presents the simulated PK parameters versus PK parameters reported in a published article. For each dose, the deviations of the simulated PK parameters from the corresponding observations were generally small, particularly in the estimates of Cmax and AUC. These results further confirm the good performance of the final disposition model of edaravone and justify its application in decision making and future study design.
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Clinical Therapeutics
Figure 1.
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Comparison of individual prediction (IPRED) versus independent variable (IVAR) (time) and observed concentration (DV, CObs) versus IVAR for 2 periods (30 mg IV for 30 min and 30 mg sublingual [SL]) per subject (1001e1010). The pink line and the red circles are the predicted concentration and the observed concentrations with IV administration, respectively; the green line and the blue circles present the predicted concentration and the observed concentration with SL administration, respectively.
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Figure 2.
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Goodness-of-fit plots and residual scatterplots of the IV final model. A, Population modelepredicted concentration versus observed concentration (DV, CObs). B, Population modelepredicted concentration versus DV. C, conditional weighted residuals (CWRES) versus independent variable (IVAR; time). D, CWRES versus model-predicted concentration. Blank hollow dot is the observed concentration. E, Quantile-Quantile plots of CWRES. F, histogram of CWRES. IPRED ¼ individual prediction; PRED ¼ population prediction.
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Clinical Therapeutics
Figure 3.
Visual predictive checks for the simulated pharmacokinetic (PK) profiles on the final PK model after IV infusion and after sublingual (SL) administration, respectively. In each panel, the pink-shaded area represents the 90% CI of the 50th percentile of the predicted concentrationetime profiles; the upper and lower blue-shaded areas represent the 90% CIs of the 5th and 95th percentiles of the predicted concentrationetime profiles, respectively.
Model Application The final PK models were used for simulating the PK profiles of edaravone after a dose of two 30-mg SL tablets and a 60-min IV infusion of 60-mg injections.
Table IV.
Pharmacokinetic parameters derived from noncompartmental analysis based on model-simulated pharmacokinetic profiles after the administration of a single dose of edaravone 60 mg IV injection (60-min infusion) or of edaravone 60 mg sublingual (SL) tablet.
Parameter
AUClast, h $ mg/L AUCinf, h $ mg/L Cmax, mg/L Tmax, h
SL
IV Injection
SL/IV Ratio, %*
10.98 11.06 4.16 0.83
11.57 11.66 4.41 1.04
94.90 94.85 94.33 NA
NA ¼ not applicable. * The ratio of the pharmacokinetic parameter after IV administration versus that after SL administration.
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Table IV provides the predicted PK parameters for both dosing routes. As is shown in the table, the ratios of SL PK exposure parameters versus the corresponding IV PK parameters ranged from 94.33% to 94.90%. According to the intrasubject %CV acquired in the pilot bioavailability study,12 the sample sizes of future bioavailability studies between a 60-min IV infusion of edaravone 60 mg and SL administration of 2 edaravone 30-mg tablets are estimated to be 14 and 4 for Cmax and for AUC, respectively. Given these estimations, it is feasible to design a bioavailability study for the dose of 60 mg between IV infusion and SL administration to support the marketing registration of SL edaravone for the indication of ALS.
DISCUSSION The present study established a mathematic model for describing the PK profile of edaravone administered in an IV injection or SL tablet, using data obtained from a bioavailability study.12 Although the concentration measurements were derived from the same subjects in 2 separate periods, the 2 dosing routes shared the same disposition kinetics in the model. Such a modelling approach not
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X. Chen et al. only enables us to perform partial model validation with external IV PK data but also intensifies the robustness of evidence for sample-size estimation regarding future 2-way crossover bioavailability studies as well. In fact, model validation with external data provides more confidence than do the validations with goodness-of-fit diagnostic graphs, residual scatterplots, and even visual predictive checks, because external validation could avoid datadriven bias in model construction. Given these advantages, the validity of our models was confirmed despite the small amount of source data. The final IV PK model reported in this article was different from that reported by Nakamaru et al15 in that the latter was a 3-compartment model with MichaeliseMenten plus linear elimination. The model reported by Nakamaru et al was more complicated than our current model. The nonlinear element of Nakamaru's model plays a dominant role only at the time that a little amount of edaravone was left in the central compartment. This finding implies that the nonlinear elimination property of edaravone has a minimal and therefore ignorable contribution to its total plasma exposure after administration. Moreover, the present linear PK model was also supported by the fact that the PK exposure of edaravone increased dose proportionally within the dose range of 20e60 mg.14,16,17 The population PK analysis of Nakamaru et al included 86 subjects derived from 5 studies in Japanese and white healthy volunteers.15 As in our study, age and weight were not identified as statistically significant covariates for the model. However, race was detected as a statistical covariate for 1 of the 2 peripheral volumes of distribution (V2), which demonstrated a 26% increase in white subjects versus Japanese subjects. However, on model simulation, such a covariate effect was translated to a difference in Ct of only 1 ng/mL after IV infusion. Hence the authors concluded that neither race, sex, weight, nor age is expected to introduce clinically relevant differences into the PK profiles of edaravone.15 In the PK model, a lag time of ~0.16 h was identified to describe the PK profile after SL dosing. This duration coincides with the median time required for the SL tablet to be dissolved,12 suggesting that tablet dissolution might be the underlying process for the value of Tlag. Adjusting the pharmaceutical characteristics of the SL tablet may lead to a
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modification in this model parameter. Compared to the observed PK results using the dataset for external validation, a relatively longer half-life and larger volume of distribution were seen in the simulated PK data. These observation deviations from the predictions might have been explained by the much shorter blood-sampling duration designed for that study, in which PK samples were collected for only 9 h postdose.14 In this study, the validated final model was used for predicting the PK differences between the SL and IV doses of 60-mg edaravone, namely, the test/reference ratios of Cmax and AUC, so as to evaluate the possibility of demonstrating PK bioequivalence between the 2 formulations and to support the regulatory approval of the novel SL tablet. The estimates seemed promising. On one hand, the test/ reference ratios were all close to 1.00; on the other hand, the small intrasubject variability obtained from the pilot bioavailability study12 further supports the feasibility of the PK bioequivalence study. Taken together, it is even plausible to waive the findings from the second bioavailability study based on the original bioavailability study and the subsequent modeling and simulation. The PK models obtained in the present study can be used even more extensively. For instance, the edaravone dosing regimen approved for the treatment of acute ischemic stroke is 30 mg IV BID for up to 14 days. However, mounting evidence has suggested that early administration and keeping a constant and effective concentration are 2 key points contributing to the clinical efficacy of edaravone in stroke patients.18 The half-life of edaravone is only 2e3 h. Assuming that the effective plasma level of edaravone is between 250 and 1000 ng/mL,19 a 30-mg dose with a 12-h IV dosing interval keeps the plasma drug concentration within the effective range for only 50% of the time within 24 h. The development of the SL edaravone tablet and its PK model also give us an opportunity to manage the therapeutic target concentration through a much more convenient and efficient approach for other potential indications.20,21 Last but not least, the dataset used for the present model development included only 10 Chinese male subjects aged between 20 and 32 years and weighing in the range of 55e80 kg. The small sample size of the dataset might explain the relatively large variability of the estimated model parameters for Ka,
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Clinical Therapeutics CL2, and CL3. Moreover, a population approach with such a homogeneous population may not be appropriate for covariate detection on PK parameters; hence, a larger dataset with a wider range of population characteristics should be considered in future modeling analyses.
CONCLUSIONS The present study developed a 3-compartment linear disposition model to describe the PK profile of edaravone after either IV infusion or SL administration. Additionally, a first-order absorption, bioavailability of SL administration, and an absorption lag time incorporated to the model fit the process of SL absorption. The validity of this model was proved by its goodness of fit, absence of residual trend, and comparability between predicted and observed values, as well as by the consistency of its predicted PK parameters with those reported by other research teams. The final model was used for supporting the assessment of PK bioequivalence between IV infusion and SL administration of 60-mg edaravone.
CONFLICTS OF INTEREST The authors have indicated that they have no other conflicts of interest with regard to the content of this article.
ACKNOWLEDGMENTS This study was supported by National Grant for New Drug Development 2017ZX09304018 and Chinese National Natural Fund grant 81671369. Xia Chen contributed writing, review, editing, model establishment and analysis. Zhuo Sun contributed writing the original draft model establishment and analysis. Jiaqing Wang contributed project administration. Wu Liang contributed model establishment and analysis. Xingquan Zhao contributed writing, review, and editing. Yilong Wang contributed writing, review, and editing. Yongjun Wang contributed writing, review, and editing.
REFERENCES 1. Watanabe K, Tanaka M, Yuki S, et al. How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J Clin Biochem Nutr. 2018;62:20e38.
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2. Tanaka M, Sugimura N, Fujisawa A, Yamamoto Y. Stabilizers of edaravone aqueous solution and their action mechanisms. 1. Sodium bisulfite. J Clin Biochem Nutr. 2017;61:159e163. 3. Shao F, Hu XL, Liu X, Shan MT. A novel LC-MS-MS method with an effective antioxidant for the determination of edaravone, a free-radical scavenger in dog plasma and its application to a pharmacokinetic study. J Chromatogr Sci. 2017;55:595e602. 4. Bhandari R, Kuhad A. Edaravone: a new hope for deadly amyotrophic lateral sclerosis. Drugs Today. 2018;54:349. 5. Hallenbeck JM. Inflammatory reactions at the bloodendothelial interface in acute stroke. Adv Neurol. 1996;71: 281e300. 6. Hall ED. Lazaroids: mechanisms of action and implications for disorders of the CNS. Neuroscientist. 1997;3:42e51. 7. Li Q, Barres BA. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol. 2018;18: 225e242. 8. Patel AR, Ritzel R, McCullough LD, Liu F. Microglia and ischemic stroke: a double-edged sword. Int J Physiol Pathophysiol Pharmacol. 2013;5:73e90. it 9. Z nanov a I, Siarnik P, Koll ar B, et al. Oxidative stress markers and their dynamic changes in patients after acute ischemic stroke. Oxid Med Cell Longev. 2016;2016: 9761697. 10. Uno M, Kitazato K-T, Suzue A, et al. Inhibition of brain damage by edaravone, a free radical scavenger, can be monitored by plasma biomarkers that detect oxidative and astrocyte damage in patients with acute cerebral infarction. Free Rad Biol Med. 2005;39:1109e1116. 11. Houkin K, Nakayama N, Kamada K, Noujou T, Abe H, Kashiwaba T. Neuroprotective effect of the free radical scavenger MCI-186 in patients with cerebral infarction: clinical evaluation using magnetic resonance imaging and spectroscopy. J Stroke Cerebrovasc Dis. 1998;7: 315e322. 12. Wang J, Chen X, Yuan B, et al. Bioavailability of edaravone sublingual tablet versus intravenous infusion in healthy male volunteers. Clin Ther. 2018;40:1683e1691. 13. Wahlby U, Jonsson EN, Karlsson MO. Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis. AAPS Pharm Sci. 2002;4:E27. 14. Li H, Xu K, Wang Y, et al. Phase I clinical study of edaravone in healthy Chinese volunteers: safety and pharmacokinetics of single or multiple intravenous infusions. Drugs Res Dev. 2012;12:65e70. 15. Nakamaru Y, Kinoshita S, Kawaguchi A, Takei K, Palumbo J, Suzuki M. Pharmacokinetic profile of edaravone: a comparison between Japanese and Caucasian populations. Amyotroph Lateral Scler Frontotemporal Degeneration. 2017;18(suppl 1):80e87.
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X. Chen et al. 16. Us Food and Drug Administration, Center for Drug Evaluation and Research. Application number 209176Orig1s000: summary review [FDA website]. Available at: https:// www.accessdata.fda.gov/ drugsatfda_docs/nda/2017/ 209176Orig1s000SumR.pdf. Accessed August 1, 2019. 17. Dash RP, Babu RJ, Srinivas NR. Two decades-long journey from riluzole to edaravone: revisiting the clinical pharmacokinetics of the only two amyotrophic lateral sclerosis therapeutics. Clin Pharmacokinet. 2018;57:1385e1398. 18. Markku K, Satoru Murayama GA, Ford DW, Dippel MR, Walters TT. For the MCI-186 Study Group. Safety, tolerability and pharmacokinetics of MCI-186 in patients with acute ischemic stroke: new formulation and dosing regimen. Cerebrovasc Dis. 2013;36: 196e204. 19. Shibata H, Arai S, Izawa M, et al. Phase I clinical study of MCI-186 (edaravone, 3-methyl1-phenyl-2pyrazolin-5-one) in healthy volunteers: safety and pharmacokinetics of single and multiple administrations. Jpn J Clin Pharmacol Ther. 1998;29:863e876. 20. Kikuchi K, Takeshige N, Miura N, et al. Beyond free radical scavenging: beneficial effects of edaravone (Radicut) in various diseases. Exp Ther Med. 2012;3:3e8. 21. Jiao SS, Yao XQ, Liu YH, et al. Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits. Proc Natl Acad Sci USA. 2015;112:5225e5230.
Address correspondence to: Xia Chen, MD, PhD, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, PR China. E-mail: connie_6096@126. com
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Predicting the Pharmacokinetic Characteristics of Edaravone Intravenous Injection and Sublingual Tablet Through Modeling and Simulation Xia Chen, MD, PhD1,2,3,5; Zhuo Sun, Msc1,2,3,5; Jiaqing Wang, MSc1,3; Wu Liang, MSc4; Xingquan Zhao, MD, PhD1,2,3; Yilong Wang, MD, PhD1,2,3; and Yongjun Wang, MD, PhD1,2,3 1
China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China; 2Phase I Unit, Beijing Tiantan Hoapital, Capital Medical University, Beijing, PR China; 3Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, PR China; and 4Changsha VALS Technology Co Ltd, Hunan, PR China ABSTRACT Purpose: Edaravone is a free-radical scavenger with relatively favorable properties of brain penetration. It has been approved for the indications of acute ischemic stroke and amyotrophic lateral sclerosis (ALS). This study aimed to establish a pharmacokinetic (PK) model to fit the PK profile of edaravone after a single sublingual (SL) dose of a novel edaravone tablet and single IV infusion of injectable edaravone in healthy Chinese volunteers participating in a bioavailability study. The model is expected to be useful for predicting the concentrationetime profiles of edaravone following different dosing regimens in a healthy Chinese population. The purposes were to identify an optimal dose and dosing regimen for the new SL formulation and to support future clinical exploration of this tablet product in its approved indications and other therapeutic fields being developed. Methods: The PK profiles after a single SL dose or IV infusion of edaravone 30 mg can be well described by a 3-compartment linear disposition model, on which a first-order absorption model with a lag time and a parameter for bioavailability was incorporated to fit the absorption phase of the SL dose. Performance of these PK models was evaluated for
goodness of fit, residual trends, visual predictive checks, as well as precision of model predictions against external data. The validated models were employed for simulating the PK profiles of edaravone after a single SL dose of 60 mg and IV infusion of 60 mg for 60 min. Findings: The resultant estimates support the possibility and feasibility of demonstrating bioequivalence between an SL administration of edaravone 60 mg and the currently approved dosing regimen for ALS (ie, 60 mg IV over 60 min) once per day. The calculation of sample size suggested that the requirement for subject number was acceptable considering the general capacity of a Phase I study center, and so were the procedures defined in the protocol. Implication: The models can be further applied to simulate favorable concentrationetime profiles in diseases with different underlying courses of oxidative stress, and hence facilitate the optimization of current dosing regimens. (Clin Ther. xxxx;xxx:xxx) © 2020 Elsevier Inc. All rights reserved. Key words: acute ischemic stroke, ALS, bioequivalence, model, simulation.
Accepted for publication January 10, 2020 https://doi.org/10.1016/j.clinthera.2020.01.006 0149-2918/$ - see front matter 5
Co-first authors.
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© 2020 Elsevier Inc. All rights reserved.
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Clinical Therapeutics
INTRODUCTION Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one)* is a low-molecular-weight, amphiphilic antioxidant that scavenges both lipids and water-soluble peroxidic free radicals.1 The drug has been approved for >10 years in Japan and in China for the indication of cerebral infarction as a 30-mg, 30-min IV BID infusion therapy administered for 14 successive days commencing within 24 h after the onset of ischemic stroke.2,3 In 2015, 2017, and 2018, the IV-injectable formulation of edaravoney gained regulatory approval from Japanese, US, and Canadian health authorities for the treatment of amyotrophic lateral sclerosis (ALS) with a regimen of 60 mg over 60 min of IV infusion once per day.4 Compared to other antioxidants and radical scavengers, edaravone is rather favored for its ability to react with a wide range of reactive oxygen species and its activity in both the lipid phase and the water phase of the human body, which allows it to act not only extracellularly on the vascular endothelial cell membrane, but also on cells located in the cerebral parenchyma.5,6 Nonetheless, from a clinical practical point of view, the use of edaravone is somewhat limited by its commercially available formulations. The mechanism of action of edaravone for acute ischemic stroke was inferred to be the scavenging of peroxynitrite. In one study, in response to cerebral ischemia, microglia were rapidly activated,7 as characterized by the release of a variety of proinflammatory cytokines, reactive oxygen species, nitric oxide, and proteolytic enzymes within 1 or 2 h following the onset of infarction.8 In studies in humans,9e11 plasma monounsaturated fatty acids, oxidized low-density lipoprotein, 3-nitrotyrosine in cerebrospinal fluid, and N-acetyl aspartate quantified by Hydrogen Proton e Magnetic Resonance Spectroscopy were used as biomarkers reflecting oxidative stress, peroxynitrite-induced injury, and brain tissue damage. The studies were conducted in patients with cerebral infarctions, and the results indicated that the level of oxidative stress reached its
® * Trademark: Radicut injection (Mitsubishi Tanabe Pharma Corporation, Tokyo). ® y Trademark: Radicava (Mitsubishi Tanabe Pharma Corporation).
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peak by around 24 h after onset,9 and the administration of edaravone was associated with a significant decrease in acute ischemic strokeeinduced oxidized low-density lipoprotein elevation,10 accompanied with a reduction in tissue damage11 and improvement of neurologic function at hospital discharge.10 The time course of oxidative stress after infarction onset and the concentration-dependent free-radicalescavenging effect of edaravone suggest that the timing of administration and the dosing regimen are 2 key elements determining the therapeutic outcome of edaravone. However, in clinical practice, most patients could not receive the IV infusion before their arrival at the hospital; hence, more attention has been paid to prehospital treatment in recent years. In the case of ALS, the chronic and progressive features of this disease warrant long-term use of potential pharmacotherapy. Moreover, the short elimination half-life of edaravone12 may increase the inconvenience of parenteral administration and weaken patients' compliance to the approved IV formulation of edaravone. A novel edaravone formulation, a sublingual (SL) tablet, was recently developed by a Chinese manufacturer. SL administration of the edaravone 30-mg SL tablet resulted in a 92% bioavailability of edaravone versus the IV infusion of the same dose over 30 min. The 90% CIs were 0.732e0.962 for Cmax, 0.868 to 0.974 for AUClast, and 0.870 to 0.974 for AUCinf.12 Since the SL route bypasses the swallowing process, it is even preferred over oral administration in patients with neurologic deficits of the CNS. In addition, the ease of use in both the prehospital setting in stroke patients and the outpatient setting in ALS patients adds value to this new formulation. The present study aimed to describe the pharmacokinetic (PK) profile of the edaravone SL tablet with an empirical compartmental model and to simulate the concentrationetime profiles of this drug following different dosing regimens, in comparison with the PK profiles of the clinically recommended IV dosage of edaravone. Other purposes were to find an optimal dose and dosing regimen of this new formulation and to support future clinical exploration of this drug in its approved indications and other therapeutic fields in development.
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MATERIALS AND METHODS The data used in this analysis were collected from a pilot bioavailability study that compared PK profiles between the edaravone SL tablet and the edaravone IV injection.12 The trial protocol was approved by the Ethics Committee of Beijing Tiantan Hospital of Capital Medical University (registration number KY 2018-043-02; Beijing, People's Republic of China). It was conducted in accordance with the ethics principles originating from the Declaration of Helsinki, as well as the Chinese Good Clinical Practices and applicable regulatory requirements. All subjects participating in the trial signed informed consent prior to any trial procedure.
Participants A total of 10 male subjects were enrolled into the study and received the investigational medicinal products in both study periods. The age of the subjects ranged from between 20 and 32 years; weight, 55e80 kg. The health status of each subject was determined with the collection of medical history, physical examinations, ECG examinations, and laboratory tests performed during the medical screening. Eligible subjects had no history or evidence of drug or alcohol abuse, no clinically significant abnormalities in medical history or laboratory tests, and no oral or buccal ulceration or related diseases. Eligible subjects had no smoking habit or smoked <5 cigarettes/d during the 3 months before the first study dose and were prohibited from smoking during the study period. They were required to refrain from prescribed and over-the-counter medications (including traditional Chinese medicines), excessive consumption of caffeine- or alcohol-containing beverages, and strenuous physical activity during the study.
Study Design The single-center, randomized, open-label, 2-waycrossover study was conducted in 10 healthy Chinese male volunteers. The subjects were randomly assigned in a 1:1 ratio to 1 of 2 dosing sequences: (1) the test treatment in the first period and the reference treatment in the second period, or (2) the other way around; the test treatment was edaravone 30-mg SL tablet, and the reference treatment was edaravone 30mg IV infusion for 30 min. As the mean half-life of edaravone is only 2e3 h,12 the washout period was set as 24 h to cover >5 half-lives.
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In each dosing period, blood samples (4 mL) for the bioassay of edaravone were taken with EDTA K2 tubes from an ulnar vein free from IV infusion at predose and 5, 10, 15, 30, and 45 min and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 h postdose. The plasma concentrations of edaravone were determined by a validated HPLC (Shimadzu, Kyoto, Japan) method with MS/MS (QTRAP 5500; AB Sciex Inc, Foster City, California).12
Model-building Process Model fitting was performed using a populationanalysis approach (Phoenix64 software version 8.1; Pharsight Corporation, Cary, North Carolina) with 1 integrated PK model for concentration data obtained both after the SL dose and after the IV dose, in which a model parameter of bioavailability (F) was estimated for the SL dosing period and the interperiod variability was explored. Diagnostic graphics and model simulation were performed using the same software. Data preparation and visualization were performed on the concentration measurements of each participant. Based on preliminary examination of the concentrationetime profiles, both 2- and 3-compartment mamillary models were assessed for their appropriateness in describing the PK data. For the SL-administered edaravone tablet, a first-order absorption with or without absorption lag time was assumed and incorporated into the PK model. Diagnostic goodness-of-fit plots, the values of Akaike information criterion (AIC) and objective function value, and relative SEs for parameter estimates were all considered for model selection. A decrease in the AIC or Bayesian information criterion (BIC) values between 2 nested models of >3.84 with 1 degree of freedom or of >5.99 with 2 degrees of freedom was considered a statistically significant model improvement on the basis of c2 test results. Thereafter, the covariate effects (ie, age [years] and weight [kg]) were explored for their ability to explain variability in the PK model parameters using stepwise forward selection and backward elimination. A likelihood ratio test was applied to investigate significant covariates with a significance level of P < 0.05 (decrease in AIC of >3.84 with 1 degree of freedom) for selection and P < 0.01 (decrease in AIC of >6.64) for elimination.13 In stepwise covariate
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Clinical Therapeutics modeling, both age and weight were evaluated for compartmental clearances and volumes of distribution, respectively. Model performance was assessed internally with visual predictive checks. The observed plasma concentrations with 90% prediction intervals were depicted with 1000 datasets simulated using the final PK parameters with significant covariates. Moreover, external model validation for IV infusion was performed by comparing the predicted PK parameters (ie, AUClast, Cmax, Tmax, t1/2), clearance [CL for IV edaravone or CL/F for SL edaravone], and volume of distribution [Vz for IV edaravone or Vz/F for SL edaravone] derived from noncompartmental analysis
Table I.
to those obtained from a previous PK study conducted in adult Chinese volunteers (Tables I and II).14
Model Application Finally, the model was applied to predict the PK profiles and PK parameters after single IV or SL dosing of edaravone 60 mg. The geometric SL/IV ratios derived from the model simulated PK parameters, together with the largest intrasubject variability observed in the previous bioavailability study,14 were used for estimating the sample size with an 80% power that is required for a bioavailability study bridging the SL use to the approved IV-administered edaravone for ALS.
Comparison of the demographic characteristics between the dataset for model fitting12 and the dataset for external validation.14
Characteristic Male sex, % Age, mean (range), y Weight, mean (range), kg BMI, mean (range), kg/m2
Table II.
Model Fitting (n ¼ 10)
External Validation (n ¼ 30)
100 26.4 (20e32) 62.2 (56.8e79.4) 23.0 (20.2e27.3)
50 31.4 (20e42) 59.7 (46e78) 21.6 (18.8e23.9)
Pharmacokinetic parameters derived from non-compartmental analysis (NCA) obtained based on model-simulated pharmacokinetic profiles after single intravenous administration of different doses of edaravone, compared to those reported in a published study conducted in Chinese healthy subjects. Data are given as mean (SD).14
Parameter
20 mg Literature Data*
AUClast, h mg/L AUCinf, h mg/L Cmax, mg/L CL, L/h V,z L t1/2, h
3.64 3.79 1.60 6.00 19.3 2.34
(1.37) (1.40) (0.38) (1.80) (7.3)* (0.69)
30 mg Simulated Datay 3.87 3.90 1.48 5.32 25.2 3.80
(0.78) (0.81) (0.24) (1.00) (6.74) (0.35)
Literature Data* 5.17 5.29 2.38 6.00 18.5 2.25
(0.93) (0.98) (0.32) (1.20) (2.6)* (0.42)
60 mg Simulated Datay 5.79 5.83 2.50 5.32 25.2 3.30
(1.05) (1.07) (0.44) (1.01) (6.74) (0.74)
Literature Data* 11.3 11.6 4.54 5.40 20.7 2.57
(3.42) (3.62) (0.90) (1.80) (6.5)* (0.32)
Simulated Datay 11.5 11.6 5.04 5.32 25.0 3.35
(2.10) (2.15) (0.89) (1.01) (6.68) (0.63)
* The y
NCA parameter results of the phase I clinical trial. The NCA parameter results of the model simulation. z The unit of V is corrected from L/kg to L based on the values of CL and t1/2, and the known relationship of these three parameters, ie, V ¼ CL $ t1/2/ln2.
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RESULTS
Evaluation of Model Performance
The PK analyses were based on 300 concentration measurements from 10 subjects (including 140 measurements from the IV period and 160 measurements from the SL period). The age of the subjects ranged from 20 to 32 years, and their body weights were between 56.8 and 79.4 kg.
Model-selection criteria suggested the appropriateness of the models. The attempts at using a 2-compartment linear disposition model were rejected by the comparison of 2 structural models, in which larger AIC and objective function values and higher parameter %CV were observed with the 2compartment model (3- vs 2-compartment model: AIC, −488.7 vs −486.0; Objective Function Value, −526.7 vs −516.0). The actual measurements versus individual predictions approximated the identity line; the same was also observed in population predictions (Figure 2). The residual plots (Figure 2) did not indicate skewness or a trend of the residuals versus the population predictions and time. The predictive performance of the final models was assessed by an evaluation of whether the distribution of the observed data was contained within the empirical distribution of the estimates predicted by the final model over a number of simulations. For this evaluation, 1000 datasets were simulated from the final model (and its uncertainty in parameter estimates) using the original dataset. Figure 3 shows the visual prediction checks as the time course of edaravone plasma concentrations with the 90% prediction intervals of each dosing route. Most of the observed data lay within the 5th and 95th percentiles of the simulations, and the observed and predicted percentiles were similar, indicating good model estimations. All of these results suggest that the final model prediction was reasonable for both the point estimates as well as the distributions.
Establishment of Pharmacokinetic Model The parameter estimates for the final model are summarized in Table III. Overall, the final model parameters were estimated with reasonable CIs. Neither age nor body weight was identified as a significant covariate in the PK models of edaravone. The plasma concentrationetime profile of edaravone was well described by the 3-compartment model with a parameter of F representing SL bioavailability and a first-order absorption model with an initial lag time assumed for the tablet dissolution (Table III and Figure 1).
Table III.
Parameter estimates of the final pharmacokinetic model.
Parameters Estimate %CV tvV, L tvCl, L/h tvKa, 1/h tvV2, L tvCl2, L/h tvTlag, h tvF tvV3, L tvCl3, L/h Stdev0
11.17 4.76 3.75 51.91 0.58 0.16 0.93 3.85 1.60 0.15
8.0 7.0 14.6 9.7 11.6 8.9 8.9 7.0 16.1 11.5
95% CI 9.41e12.93 4.10e5.42 2.67e4.82 42.01e61.81 0.45e0.71 0.13e0.19 0.77e1.09 3.32e4.38 1.09e2.10 0.11e0.18
IIV (%) 17.2 19.6 23.5 e e 24.7 19.5 e e e
CL ¼ clearance of central compartment; CL2 ¼ clearance of peripheral compartment 2; CL3 ¼ clearance of peripheral compartment 3; F ¼ bioavailability of sublingual administration; IIV ¼ inter-individual variability of the PK parameters (%CV); Ka ¼ absorption rate constant; Stdev0 ¼ intraindividual variability of the proportional residual model (SD); Tlag ¼ lag time after sublingual administration; V ¼ volume of distribution in the central compartment; V2 ¼ volume of distribution in the peripheral compartment 2; V3 ¼ volume of distribution in the peripheral compartment 3.
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External Model Validation External model validation was conducted by simulating the PK profiles of edaravone after IV doses from 20 to 60 mg and comparing the resultant PK parameters to those from the literature report.14 Table II presents the simulated PK parameters versus PK parameters reported in a published article. For each dose, the deviations of the simulated PK parameters from the corresponding observations were generally small, particularly in the estimates of Cmax and AUC. These results further confirm the good performance of the final disposition model of edaravone and justify its application in decision making and future study design.
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Clinical Therapeutics
Figure 1.
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Comparison of individual prediction (IPRED) versus independent variable (IVAR) (time) and observed concentration (DV, CObs) versus IVAR for 2 periods (30 mg IV for 30 min and 30 mg sublingual [SL]) per subject (1001e1010). The pink line and the red circles are the predicted concentration and the observed concentrations with IV administration, respectively; the green line and the blue circles present the predicted concentration and the observed concentration with SL administration, respectively.
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Figure 2.
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Goodness-of-fit plots and residual scatterplots of the IV final model. A, Population modelepredicted concentration versus observed concentration (DV, CObs). B, Population modelepredicted concentration versus DV. C, conditional weighted residuals (CWRES) versus independent variable (IVAR; time). D, CWRES versus model-predicted concentration. Blank hollow dot is the observed concentration. E, Quantile-Quantile plots of CWRES. F, histogram of CWRES. IPRED ¼ individual prediction; PRED ¼ population prediction.
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Clinical Therapeutics
Figure 3.
Visual predictive checks for the simulated pharmacokinetic (PK) profiles on the final PK model after IV infusion and after sublingual (SL) administration, respectively. In each panel, the pink-shaded area represents the 90% CI of the 50th percentile of the predicted concentrationetime profiles; the upper and lower blue-shaded areas represent the 90% CIs of the 5th and 95th percentiles of the predicted concentrationetime profiles, respectively.
Model Application The final PK models were used for simulating the PK profiles of edaravone after a dose of two 30-mg SL tablets and a 60-min IV infusion of 60-mg injections.
Table IV.
Pharmacokinetic parameters derived from noncompartmental analysis based on model-simulated pharmacokinetic profiles after the administration of a single dose of edaravone 60 mg IV injection (60-min infusion) or of edaravone 60 mg sublingual (SL) tablet.
Parameter
AUClast, h $ mg/L AUCinf, h $ mg/L Cmax, mg/L Tmax, h
SL
IV Injection
SL/IV Ratio, %*
10.98 11.06 4.16 0.83
11.57 11.66 4.41 1.04
94.90 94.85 94.33 NA
NA ¼ not applicable. * The ratio of the pharmacokinetic parameter after IV administration versus that after SL administration.
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Table IV provides the predicted PK parameters for both dosing routes. As is shown in the table, the ratios of SL PK exposure parameters versus the corresponding IV PK parameters ranged from 94.33% to 94.90%. According to the intrasubject %CV acquired in the pilot bioavailability study,12 the sample sizes of future bioavailability studies between a 60-min IV infusion of edaravone 60 mg and SL administration of 2 edaravone 30-mg tablets are estimated to be 14 and 4 for Cmax and for AUC, respectively. Given these estimations, it is feasible to design a bioavailability study for the dose of 60 mg between IV infusion and SL administration to support the marketing registration of SL edaravone for the indication of ALS.
DISCUSSION The present study established a mathematic model for describing the PK profile of edaravone administered in an IV injection or SL tablet, using data obtained from a bioavailability study.12 Although the concentration measurements were derived from the same subjects in 2 separate periods, the 2 dosing routes shared the same disposition kinetics in the model. Such a modelling approach not
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X. Chen et al. only enables us to perform partial model validation with external IV PK data but also intensifies the robustness of evidence for sample-size estimation regarding future 2-way crossover bioavailability studies as well. In fact, model validation with external data provides more confidence than do the validations with goodness-of-fit diagnostic graphs, residual scatterplots, and even visual predictive checks, because external validation could avoid datadriven bias in model construction. Given these advantages, the validity of our models was confirmed despite the small amount of source data. The final IV PK model reported in this article was different from that reported by Nakamaru et al15 in that the latter was a 3-compartment model with MichaeliseMenten plus linear elimination. The model reported by Nakamaru et al was more complicated than our current model. The nonlinear element of Nakamaru's model plays a dominant role only at the time that a little amount of edaravone was left in the central compartment. This finding implies that the nonlinear elimination property of edaravone has a minimal and therefore ignorable contribution to its total plasma exposure after administration. Moreover, the present linear PK model was also supported by the fact that the PK exposure of edaravone increased dose proportionally within the dose range of 20e60 mg.14,16,17 The population PK analysis of Nakamaru et al included 86 subjects derived from 5 studies in Japanese and white healthy volunteers.15 As in our study, age and weight were not identified as statistically significant covariates for the model. However, race was detected as a statistical covariate for 1 of the 2 peripheral volumes of distribution (V2), which demonstrated a 26% increase in white subjects versus Japanese subjects. However, on model simulation, such a covariate effect was translated to a difference in Ct of only 1 ng/mL after IV infusion. Hence the authors concluded that neither race, sex, weight, nor age is expected to introduce clinically relevant differences into the PK profiles of edaravone.15 In the PK model, a lag time of ~0.16 h was identified to describe the PK profile after SL dosing. This duration coincides with the median time required for the SL tablet to be dissolved,12 suggesting that tablet dissolution might be the underlying process for the value of Tlag. Adjusting the pharmaceutical characteristics of the SL tablet may lead to a
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modification in this model parameter. Compared to the observed PK results using the dataset for external validation, a relatively longer half-life and larger volume of distribution were seen in the simulated PK data. These observation deviations from the predictions might have been explained by the much shorter blood-sampling duration designed for that study, in which PK samples were collected for only 9 h postdose.14 In this study, the validated final model was used for predicting the PK differences between the SL and IV doses of 60-mg edaravone, namely, the test/reference ratios of Cmax and AUC, so as to evaluate the possibility of demonstrating PK bioequivalence between the 2 formulations and to support the regulatory approval of the novel SL tablet. The estimates seemed promising. On one hand, the test/ reference ratios were all close to 1.00; on the other hand, the small intrasubject variability obtained from the pilot bioavailability study12 further supports the feasibility of the PK bioequivalence study. Taken together, it is even plausible to waive the findings from the second bioavailability study based on the original bioavailability study and the subsequent modeling and simulation. The PK models obtained in the present study can be used even more extensively. For instance, the edaravone dosing regimen approved for the treatment of acute ischemic stroke is 30 mg IV BID for up to 14 days. However, mounting evidence has suggested that early administration and keeping a constant and effective concentration are 2 key points contributing to the clinical efficacy of edaravone in stroke patients.18 The half-life of edaravone is only 2e3 h. Assuming that the effective plasma level of edaravone is between 250 and 1000 ng/mL,19 a 30-mg dose with a 12-h IV dosing interval keeps the plasma drug concentration within the effective range for only 50% of the time within 24 h. The development of the SL edaravone tablet and its PK model also give us an opportunity to manage the therapeutic target concentration through a much more convenient and efficient approach for other potential indications.20,21 Last but not least, the dataset used for the present model development included only 10 Chinese male subjects aged between 20 and 32 years and weighing in the range of 55e80 kg. The small sample size of the dataset might explain the relatively large variability of the estimated model parameters for Ka,
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Clinical Therapeutics CL2, and CL3. Moreover, a population approach with such a homogeneous population may not be appropriate for covariate detection on PK parameters; hence, a larger dataset with a wider range of population characteristics should be considered in future modeling analyses.
CONCLUSIONS The present study developed a 3-compartment linear disposition model to describe the PK profile of edaravone after either IV infusion or SL administration. Additionally, a first-order absorption, bioavailability of SL administration, and an absorption lag time incorporated to the model fit the process of SL absorption. The validity of this model was proved by its goodness of fit, absence of residual trend, and comparability between predicted and observed values, as well as by the consistency of its predicted PK parameters with those reported by other research teams. The final model was used for supporting the assessment of PK bioequivalence between IV infusion and SL administration of 60-mg edaravone.
CONFLICTS OF INTEREST The authors have indicated that they have no other conflicts of interest with regard to the content of this article.
ACKNOWLEDGMENTS This study was supported by National Grant for New Drug Development 2017ZX09304018 and Chinese National Natural Fund grant 81671369. Xia Chen contributed writing, review, editing, model establishment and analysis. Zhuo Sun contributed writing the original draft model establishment and analysis. Jiaqing Wang contributed project administration. Wu Liang contributed model establishment and analysis. Xingquan Zhao contributed writing, review, and editing. Yilong Wang contributed writing, review, and editing. Yongjun Wang contributed writing, review, and editing.
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2. Tanaka M, Sugimura N, Fujisawa A, Yamamoto Y. Stabilizers of edaravone aqueous solution and their action mechanisms. 1. Sodium bisulfite. J Clin Biochem Nutr. 2017;61:159e163. 3. Shao F, Hu XL, Liu X, Shan MT. A novel LC-MS-MS method with an effective antioxidant for the determination of edaravone, a free-radical scavenger in dog plasma and its application to a pharmacokinetic study. J Chromatogr Sci. 2017;55:595e602. 4. Bhandari R, Kuhad A. Edaravone: a new hope for deadly amyotrophic lateral sclerosis. Drugs Today. 2018;54:349. 5. Hallenbeck JM. Inflammatory reactions at the bloodendothelial interface in acute stroke. Adv Neurol. 1996;71: 281e300. 6. Hall ED. Lazaroids: mechanisms of action and implications for disorders of the CNS. Neuroscientist. 1997;3:42e51. 7. Li Q, Barres BA. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol. 2018;18: 225e242. 8. Patel AR, Ritzel R, McCullough LD, Liu F. Microglia and ischemic stroke: a double-edged sword. Int J Physiol Pathophysiol Pharmacol. 2013;5:73e90. it 9. Z nanov a I, Siarnik P, Koll ar B, et al. Oxidative stress markers and their dynamic changes in patients after acute ischemic stroke. Oxid Med Cell Longev. 2016;2016: 9761697. 10. Uno M, Kitazato K-T, Suzue A, et al. Inhibition of brain damage by edaravone, a free radical scavenger, can be monitored by plasma biomarkers that detect oxidative and astrocyte damage in patients with acute cerebral infarction. Free Rad Biol Med. 2005;39:1109e1116. 11. Houkin K, Nakayama N, Kamada K, Noujou T, Abe H, Kashiwaba T. Neuroprotective effect of the free radical scavenger MCI-186 in patients with cerebral infarction: clinical evaluation using magnetic resonance imaging and spectroscopy. J Stroke Cerebrovasc Dis. 1998;7: 315e322. 12. Wang J, Chen X, Yuan B, et al. Bioavailability of edaravone sublingual tablet versus intravenous infusion in healthy male volunteers. Clin Ther. 2018;40:1683e1691. 13. Wahlby U, Jonsson EN, Karlsson MO. Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis. AAPS Pharm Sci. 2002;4:E27. 14. Li H, Xu K, Wang Y, et al. Phase I clinical study of edaravone in healthy Chinese volunteers: safety and pharmacokinetics of single or multiple intravenous infusions. Drugs Res Dev. 2012;12:65e70. 15. Nakamaru Y, Kinoshita S, Kawaguchi A, Takei K, Palumbo J, Suzuki M. Pharmacokinetic profile of edaravone: a comparison between Japanese and Caucasian populations. Amyotroph Lateral Scler Frontotemporal Degeneration. 2017;18(suppl 1):80e87.
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X. Chen et al. 16. Us Food and Drug Administration, Center for Drug Evaluation and Research. Application number 209176Orig1s000: summary review [FDA website]. Available at: https:// www.accessdata.fda.gov/ drugsatfda_docs/nda/2017/ 209176Orig1s000SumR.pdf. Accessed August 1, 2019. 17. Dash RP, Babu RJ, Srinivas NR. Two decades-long journey from riluzole to edaravone: revisiting the clinical pharmacokinetics of the only two amyotrophic lateral sclerosis therapeutics. Clin Pharmacokinet. 2018;57:1385e1398. 18. Markku K, Satoru Murayama GA, Ford DW, Dippel MR, Walters TT. For the MCI-186 Study Group. Safety, tolerability and pharmacokinetics of MCI-186 in patients with acute ischemic stroke: new formulation and dosing regimen. Cerebrovasc Dis. 2013;36: 196e204. 19. Shibata H, Arai S, Izawa M, et al. Phase I clinical study of MCI-186 (edaravone, 3-methyl1-phenyl-2pyrazolin-5-one) in healthy volunteers: safety and pharmacokinetics of single and multiple administrations. Jpn J Clin Pharmacol Ther. 1998;29:863e876. 20. Kikuchi K, Takeshige N, Miura N, et al. Beyond free radical scavenging: beneficial effects of edaravone (Radicut) in various diseases. Exp Ther Med. 2012;3:3e8. 21. Jiao SS, Yao XQ, Liu YH, et al. Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits. Proc Natl Acad Sci USA. 2015;112:5225e5230.
Address correspondence to: Xia Chen, MD, PhD, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, PR China. E-mail: connie_6096@126. com
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