Degradation pathway of a taxane derivative DS80100717 drug substance and drug product

Article abstract of DOI:10.1248/cpb.c20-00032

The degradation pathway of a taxane derivative and anticancer agent, DS80100717, was investigated. Several degradants were generated under acidic, basic, and oxidative stress conditions in solution. The chemical structures of eight degradants of DS80100717 were elucidated using MS and NMR. The major degradant of the DS80100717 drug substance derived by heating in solid-state was the N-oxide form via oxidation and C2′-epimer of the side chain via acid hydrolysis. We proposed previously unreported degradation pathways of DS80100717 with taxane derivatives such as paclitaxel, docetaxel, and cabazitaxel.

Full text of DOI:10.1248/cpb.c20-00032

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Chem. Pharm. Bull. 68, 392–397 (2020)
Vol. 68, No. 4
Regular Article
Degradation Pathway of a Taxane Derivative DS80100717 Drug
Substance and Drug Product
,a
,c
Kousuke Tamura,* Makoto Ono,b Takefumi Kawabe,a Motomu Ohara,a and Etsuo Yonemochi*
a Analytical and Quality Evaluation Research Laboratories, Daiichi Sankyo Co., Ltd.; 1–2–58 Hiromachi, Shinagawa-
b
ku, Tokyo 140–8710, Japan: Quality Assurance Department, Daiichi Sankyo Co., Ltd.; 3–5–1 Nihonbashi Honcho,
c
Chuo-ku, Tokyo 103–8426, Japan: and Graduate School of Pharmaceutical Sciences, Hoshi University; 2–4–41
Ebara, Shinagawa-ku, Tokyo 142–8501, Japan.
Received January 11, 2020; accepted January 30, 2020
The degradation pathway of a taxane derivative and anticancer agent, DS80100717, was investigated.
Several degradants were generated under acidic, basic, and oxidative stress conditions in solution. The chem-
ical structures of eight degradants of DS80100717 were elucidated using MS and NMR. The major degradant
of the DS80100717 drug substance derived by heating in solid-state was the N-oxide form via oxidation and
C2ꢀ-epimer of the side chain via acid hydrolysis. We proposed previously unreported degradation pathways
of DS80100717 with taxane derivatives such as paclitaxel, docetaxel, and cabazitaxel.
Key words forced degradation; chemical stability; structure elucidation; impurity; epimerization
Stress studies on taxane derivatives, including paclitaxel,12)
Introduction
Taxane derivatives, including paclitaxel, docetaxel, and docetaxel,13) and cabazitaxel,14) have been reported and used
cabazitaxel, are anticancer agents that bind along the inte- for pharmaceutical drug development and quality control.
rior surface of the microtubules and are well known for their
DS80100717 ((1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-
remarkable antitumor activities.1,2) Currently, these agents benzoyloxy-9,10-[(1S)-2-(dimethylamino)ethylidenedioxy]-
are utilized and evaluated in lung, breast, ovarian, and other 5,20-epoxy-1-hydroxytax-11-en-13-yl (2R,3S)-3-(tert-butoxy-
cancers. Various taxane derivatives are being researched and carbonylamino)-2-hydroxy-3-(3-methyloxetan-3-yl)propionate)
developed with the aim of improving the diverse medicinal was designed as a taxane derivative compound and was de-
properties and therapeutic effects including as a prodrug,3) veloped as an anticancer agent for injection.15) The chemical
albumin-bound,4) and encapsulated with liposome.5)
structure of DS80100717 is shown in Fig. 1. This study aimed
As a part of the pharmaceutical development, the stability to clarify the chemical stability and degradation pathway
of the drug and the identification of degradation products are of DS80100717, both drug substance and drug product (ly-
strictly required as quality control and safety considerations ophilized injection formulation), under various stress condi-
based on the International Conference on Harmonization tions. The degradation products were characterized by using
(ICH) guidelines.6–9) Stress studies are used to support the LC-MS, LC-MS/MS, online hydrogen-deuterium (H/D) ex-
development of stability-indicating analytical methods, to change LC-MS, and NMR spectral data.
understand the intrinsic stability of the drug substances and
products, and to estimate the degradation pathways.10) The
Experimental
studies are aligned with the ICH guidelines and exposed to
Materials DS80100717 drug substance was obtained
various conditions in both the solid-state and solution state.11) from Daiichi Sankyo Co., Ltd. (Tokyo, Japan). Hydrochloric
acid (HCl) and sodium hydroxide (NaOH) were as used for
volumetric analysis. Lactose monohydrate was of a special
grade, and hydrogen peroxide (H2O2) was of a special grade
from FUJIFILM Wako Pure Chemical Corporation (Osaka,
Japan). Lactic acid was of a special grade from Thermo
Fisher Scientific (Waltham, MA, U.S.A.). Britton-Robinson
buffer solutions (pH 2.0 to 12.0, ionic strength: 1.0) were of a
special grade from Nacalai Tesque, Inc. (Kyoto, Japan). Am-
monium formate was of special grade and methanol was of
HPLC grade from FUJIFILM Wako Pure Chemical Corpora-
tion. Acetonitrile of HPLC grade was purchased from Kanto
Chemical Co., Inc. (Tokyo, Japan). Acetonitrile-d3, methanol-
d4, and deuterium oxide were purchased from Cambridge Iso-
tope Labs (Andover, MA, U.S.A.). Purified water for LC/MS
was purchased from FUJIFILM Wako Pure Chemical Cor-
poration. All other chemicals and reagents were commercial
products of analytical grade.
Fig. 1. Chemical Structure of DS80100717
*To whom correspondence should be addressed. e-mail: tamura.kousuke.aa@daiichisankyo.co.jp; e-yonemochi@hoshi.ac.jp
© 2020 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.
393
Table 1. Components and Composition of DS80100717 Drug Product
Sample
Preparation
for
HPLC
Analysis The
DS80100717 drug substances, drug products, and its stressed
samples were separately prepared by mixing with water and
acetonitrile (4:6 (v/v)) at each concentration (0.5mg/mL).
Functions
Component
Recipe
10mg
Active pharmaceutical
ingredients
DS80100717
Bulking agent
pH adjusting agent
pH adjusting agent
pH adjusting agent
pH
Lactose monohydrate
Lactic acid
50mg
2.1mg
q.s.a)
Measurement
HPLC Analysis The Shimadzu Nexera X2 LC system
(Shimadzu Corporation, Kyoto, Japan) equipped with a pho-
todiode array (PDA) detector was used for HPLC analysis. A
YMC Triart C18 column (2.0mm i.d.×75mm, 1.9µm particle
size, YMC, Kyoto, Japan) was used as an analytical column.
The temperature of the column oven was set at 40°C. UV de-
tection was performed at 229nm, and the online PDA spectra
Hydrochloric acid
Sodium hydroxide
q.s.a)
4.0
Total volume
1.0mL, q.s.a)
a) Quantum sufficit.
Preparation of DS80100717 Lyophilized Samples The were collected between 200 and 400nm. The mobile phase
components and composition of the DS80100717 drug product A and B were 20mmol/L ammonium formate in water and
are described in Table 1. The samples were prepared as fol- acetonitrile/methanol (57:43 (v/v)), respectively. The flow rate
lows. The DS80100717 drug substance and additives (lactose was set at 0.5mL/min. Gradient elution conducted as follows:
monohydrate, lactic acid) were dissolved in purified water. the step gradient by changing the percentage of mobile phase
The pH of the solution was adjusted to 4.0 with 1mol/L hy- B at different times, T (min)/% mobile phase B=0/35, 2.3/50,
drochloric acid solution or 1mol/L sodium hydroxide solution. 4.1/66, 5.1/90, 10/90, 10.1/35, 14/35. The injection volume was
The total volume of the solutions was adjusted to the target 2mL. Empower 3 software (Waters Corporation, Milford,
volume with purified water and then filtered with a 0.2µm MA, U.S.A.) was used for data acquisition.
membrane filter (Millex-LG Hydrophilic polytetrafluoroeth-
Preparative LC Conditions Isolation of the degradation
ylene, Merck KGaA, Darmstadt, Germany). The bulk solu- products (Ac-5 and Ox-1) was undertaken using the Shimadzu
tion was filled into vials, and then the filled vials were half- Nexera X2 LC system (Shimadzu Corporation) and an Ex-
stopped with rubber stoppers. The samples were lyophilized plorer-220 solvent evaporator (Thermo Fisher Scientific). A
using a freeze dryer (VirTis AdVantage Plus, SP Scientific, Cadenza CD-C18 column (6.0mm i.d.×100mm, 3µm particle
Stone Ridge, NY, U.S.A.). The lyophilization program was as size, Imtakt Corporation, Kyoto, Japan) was used for prepara-
follows (the chamber pressure was not controlled during the tive isolation works. The mobile phase, the temperature of the
lyophilization process): Freezing: −40°C, 2h; Primary dry- column oven, and UV detection were the same as the ana-
ing: −20°C, 12h, Secondary drying: −5°C, 5h, Tertiary dry- lytical HPLC conditions described previously. Isocratic elution
ing: 5°C, 3h. After lyophilization, the samples were vacuum was conducted as the mobile phase A/B (40:60, (v/v)), and the
released with nitrogen. Next, the rubber stoppers were fully flow rate was 2mL/min. The injection volume was 50mL and
inserted into the vials with caps.
the run time was 12min. The degradation product fractions
Stress Study of DS80100717 Drug Substance in Solution were collected, and the solvent was removed using a solvent
The DS80100717 drug substance was subjected to various evaporator to obtain Ac-5 (HPLC purity: 94.2%) and Ox-1
stress conditions in solution at a DS80100717 concentration (HPLC purity: 94.0%) as a solid.
of 1mg/mL. Stress studies were performed under hydrolytic
LC-MS and MS/MS Analyses LC-MS and LC-MS/MS
conditions as follows: for acidic hydrolysis, a sample solution analyses were undertaken using a Shimadzu Nexera X2 LC
was mixed with a 0.1mol/L hydrochloric acid solution and ex- system equipped with an LTQ Orbitrap XL mass spectrometer
posed to 40°C for 1h; for basic hydrolysis, a sample solution (Thermo Fisher Scientific). The HPLC conditions were the
was mixed with the Britton-Robinson buffer solution (pH 10.0, same as the analytical HPLC conditions previously described.
ionic strength: 0.2) and exposed as such. A stress study under For online H/D exchange LC-MS analysis, deuterium oxide
an oxidative condition was performed as follows: A sample and methanol-d4 were used as solvents for the preparation of
solution was mixed with 0.3% hydrogen peroxide solution and mobile phase A and B. Electrospray ionization (ESI) was used
exposed to 25°C for 1h.
in the positive ion mode. The spray voltage was set at 4.0kV.
Stress Study of DS80100717 Drug Substance in Solid- The capillary temperature was set at 275°C. The sheath gas
State The DS80100717 drug substance was subjected to flow was set at 60 arb and the aux gas flow was set as 10 arb.
the various stress conditions in solid-state. A stress study The MS/MS measurement was performed by collision-induced
was performed under a heated condition: DS80100717 drug dissociation with a collision energy of 35%.
substance (100mg) in an open dish was stored in an oven at
NMR Analysis NMR experiments were conducted using
60°C for 4 weeks. Stress study under a humidity condition: an Avance 400MHz NMR spectrometer (Bruker BioSpin Cor-
DS80100717 drug substance (100mg) in an open dish was poration, Billerica, MA, U.S.A.) equipped with a broadband
stored under 75% relative humidity (RH) at 40°C for 4 weeks. observe 5mm probe. All spectra acquired from the isolated
Stress study under a photo-irradiation condition: DS80100717 samples (Ac-5 and Ox-1) were dissolved in acetonitrile-d3
and deuterium oxide (9:1 (v/v)). NMR experiments were
performed at 25°C. The chemical shifts were referenced to re-
sidual solvent peaks for acetonitrile-d3 (δ: 1.94ppm for proton
and 1.32ppm for carbon). The number of accumulations was
32 to 4096. NMR experiments (1D (1H-NMR, 13C-NMR) and
2D (1H–1H correlation spectroscopy, distortionless enhance-
drug substance (100mg) in an open dish was stored as per
ICH requirement (ICH Q1B option 1, D65 light source,
2000lx) at room temperature for 4 weeks (1344000lx·h).
Stress Study of DS80100717 Drug Product under Heat
Condition The DS80100717 drug products were exposed to
degrade at 25 and 40°C for 4 weeks, and at 60°C for 2 weeks.

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1
ment by polarization transfer, H–13C heteronuclear multiple products during long-term stability, as defined in the ICH
1
quantum correlation spectroscopy, H–13C heteronuclear multi- Q3A and Q3B guidelines, were reported as a subset of the po-
1
ple bond quantum correlation spectroscopy, and H–1H nuclear tential degradation products observed during stress studies.17)
Overhauser effect spectroscopy (NOESY))) were acquired in The chemical structures and degradation pathways of these
order to fully elucidate the isolated samples.
degradation products are shown in Fig. 3.
On exposure to heat in the solid-state, the DS80100717 drug
substance degraded via oxidation to form Ox-1 (0.32→0.48%)
Results and Discussion
Stability Study of DS80100717 Drug Substance and and via acid hydrolysis to form Ac-5 (0.03→0.09%). Alter-
Drug Product DS80100717 decomposed under acidic, basic, natively, the DS80100717 drug substance was stable under
and oxidative conditions in solution. The representative HPLC humidity and photo-irradiation (D65 light 2000lx). The results
chromatograms of the solution stability study of DS80100717 of the solid-state stability of DS80100717 drug substances
drug substances are shown in Fig. 2. We identified 8 degrada- under various conditions are shown in Table S1, Supplemen-
tion products (Ac-1, -2, -3, -4, -5, Ba-1, -2, and Ox-1). These tary Materials.
potential degradation products were defined at levels greater
The representative HPLC chromatograms of the solid-state
than 10% of the total degradation and were more than 25% stability of the DS80100717 drug products under heat condi-
of the largest individual degradant.16) The actual degradation tions are shown in Fig. 4. When exposed to heat, DS80100717
degraded via acid hydrolysis to form Ac-5 (0.10→2.39%) at
40°C for 4 weeks. On the other hand, the oxidation product
(Ox-1) was not increased under a heated condition owing to
the nitrogen atmosphere in the vial. The stability results of the
DS80100717 drug products under heat conditions are shown in
Table S2, Supplementary Materials.
Structure Elucidation of Degradation Products
Degradation Products in Acidic Condition
LC-MS analysis data of all degradation products are sum-
marized in Table 2. The ESI mass spectra of both Ac-1 and
-2 generated a protonated molecular ion at m/z 801, which is
56Da less than that of DS80100717 [M+H]+ at m/z 857. The
accurate mass spectra of Ac-1 and -2 showed a protonated
molecule [M+H]+ at m/z 801.3800 and 801.3804 (Calcd for
C41H57O14N2: 801.3810), respectively. Characteristic fragment
ions were observed at m/z 582, 313, and 295. These frag-
Fig. 2. Representative HPLC Chromatograms of the Solution Stability
ment ions indicated that Ac-1 and -2 retained a baccatin III
analogous moiety. Online H/D exchange LC-MS analysis of
Ac-1 and -2 indicated the presence of four labile hydrogen
Studies of DS80100717 Drug Substance
(a) Initial, (b) 0.1mol/LHCl at 40°C for 1h, (c) Britton–Robinson Buffer (ionic
Strength: 0.2, pH 10.0) at 40°C for 1h, (d) 0.3% H2O2 at 25°C for 1h.
Fig. 3. Chemical Structure of DS80100717 and Degradation Products

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Chem. Pharm. Bull.
395
atoms, which are one mass larger than the molecular mass of were significantly shifted to a low magnetic field. In addition,
DS80100717. Based on these results, Ac-1 and -2 were identi- the signals of Ac-5 at H22, H6′, and H7′ were significantly
fied as a C2′-epimer forms (2R, 3S and 2S, 3S), hydrolyzed at shifted to a high magnetic field. The same trend was observed
the tert-butoxy moiety of DS80100717.
and confirmed with the signals of 13C-NMR spectrum at C22,
The ESI mass spectra of Ac-3 and -4 demonstrated a proton- C2′, C3′, C4′, C5′, C6′, and C7.′ These shifts suggested that
ated molecular ion at m/z 757, which is 100Da less than that of the change in the stereochemistry at the C2′ position occurred
DS80100717 [M+H]+ at m/z 857. The accurate mass spectra (Tables S3 and S4, Supplementary Materials). The 1H-1H
of Ac-3 and -4 showed a protonated molecule [M+H]+ at NOESY experiment indicated that the signals of H2′, H3′, H6′,
m/z 757.3903 and 757.3898 (Calcd for C40H57O12N2: 757.3912), and H7′ correlated with the signal of H22, located in closer
respectively. Characteristic fragment ions were observed at positions as observed by the conformation of the paclitaxel
1
m/z 582, 313, and 295. These fragment ions indicated that molecule.18) In the H-NMR spectrum, the most important ob-
Ac-3 and -4 retained the baccatin III analogous moiety. Online servation was that the vicinal coupling constant of the signals
H/D exchange LC-MS analysis of Ac-3 and -4 indicated the of Ac-5 at δH2′ 4.76ppm (1H, d, J(2′-3′) =2.1Hz) were clearly
presence of four labile hydrogen atoms, one mass larger than different compared to DS80100717 at δH2′ 4.51ppm (1H, d,
the molecular mass of DS80100717. Based on these results, J(2′-3′) =6.0Hz) (Tables S3 and S4, Supplementary Materials).
Ac-3 and -4 were identified as C2′-epimer forms (2R, 3S This data suggested that the conformation between H2′ and
and 2S, 3S), hydrolyzed at the tert-butoxycarbonyl moiety of H3′ of Ac-5 demonstrated anti-conformation, in accordance
DS80100717.
with the Karplus equation.19) Based on these results, Ac-5 was
The ESI mass spectrum of Ac-5 demonstrated a protonated characterized as the C2′-epimer (2S, 3S) of the side chain.
molecular ion at m/z 857, which is the same as DS80100717
Degradation Product under Basic and Oxidative Conditions
The ESI mass spectrum of Ba-1 demonstrated a proton-
[M+H]+ at m/z 857. The accurate mass spectrum of Ac-5
showed a protonated molecule [M+H]+ at m/z 857.4422 ated molecular ion at m/z 220, which is 637Da less than
(Calcd for C45H65O14N2: 857.4436). The characteristic fragment that of DS80100717 [M+H]+ at m/z 857. The accurate mass
ions were m/z 839, 801, and 783. These fragment ions con- spectrum of Ba-1 showed a protonated molecule [M+H]+ at
firmed the same as DS80100717. Online H/D exchange LC-MS m/z 220.0819 (Calcd for C8H14O6N: 220.0821). Characteristic
analysis of Ac-5 and DS80100717 indicated no difference in fragment ions were observed at m/z 176, 174, 130, and 100.
the number of labile hydrogen atoms in each compound. Fig- These fragment ions were in accordance with the side chain of
1
ure 5 shows the H-NMR spectrum of the isolated Ac-5 sam- DS80100717 at the C13 position. Based on these results, Ba-1
ple. Compared to the H-NMR spectrum of DS80100717, the was identified as the side chain which was cleaved at the C13
1
signals of Ac-5 at H2′, H3′, and H5′ in the side chain moiety position of DS80100717.
The ESI mass spectrum of Ba-2 generated a protonated
molecular ion at m/z 600, which is 257Da less than that of
DS80100717 [M+H]+ at m/z 857. The accurate mass spec-
trum of Ba-2 showed a protonated molecule [M+H]+ at m/z
600.3162 (Calcd for C33H46O9N: 600.3173). Characteristic frag-
ment ions were observed at m/z 313 and 295. These fragment
ions indicated that Ba-2 retained the baccatin III analogous
moiety. Online H/D exchange LC-MS analysis of Ba-2 indi-
cated the presence of two labile hydrogen atoms, one mass
less than the molecular mass of DS80100717. Based on these
results, Ba-2 was identified as a baccatin III analogous moiety.
The ESI mass spectrum of Ox-1 demonstrated a protonated
molecular ion at m/z 873, which is 16Da more than that of
DS80100717 [M+H]+ at m/z 857. The accurate mass spec-
trum of Ox-1 showed a protonated molecule [M+H]+ at m/z
Fig. 4. Representative HPLC Chromatograms of DS80100717 Drug
Products
(a) Initial, (b) 40°C for 4 Weeks.
Table 2. Results of LC-MS Analysis
Relative retention
Mass data
(m/z)
Proposed molecular
Error
Product ions by MS/MS analysis
Number of labile
hydrogen atoms
Target
time (RRT) by
LC-MS analysis
formula ([M+H]+)
(mDa)a)
(m/z)
DS80100717
Ac-1
1.00
0.62
0.64
0.70
0.71
0.97
0.07
0.67
0.77
857.4425
801.3800
801.3804
757.3903
757.3898
857.4422
220.0819
600.3162
873.4361
C45H65O14N2
C41H57O14N2
C41H57O14N2
C40H57O12N2
C40H57O12N2
C45H65O14N2
C8H14O6N
−1.08
−0.95
−0.63
−0.87
−1.35
−1.34
−0.24
−1.03
−2.37
839, 801, 783, 661, 313, 295
783, 582, 564, 522, 400, 313, 295 277
783, 741, 582, 522, 400, 313, 295, 277
739, 670, 582, 313, 295
3
4
4
4
4
3
6
2
3
Ac-2
Ac-3
Ac-4
739, 670, 582, 313, 295
Ac-5
839, 801, 783
Ba-1
202, 176, 174, 158, 156, 130, 100
582, 564, 540, 522, 460, 331, 313, 295
817, 773
Ba-2
C33H46O9N
Ox-1
C45H65O15N2
a) Error (mDa)=(observed mass−calculated mass)×1000

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Fig. 5. Overlay of H-NMR Spectra of (a) DS80100717, (b) Ac-5, (c) Ox-1
a
b
c
Residual solvent (water), Residual solvent (acetonitrile), Contaminants.
Fig. 6. Summary of the Reactive Sites of DS80100717
873.4361 (Calcd for C45H65O15N2: 873.4385). The characteristic formed under various conditions. Chemical structures of the
fragment ion was m/z 817. This fragment ion was assigned degradants and estimated degradation pathways are shown
as an oxygen atom adducted to DS80100717. Online H/D in Fig. 3. Based on the elucidated chemical structures of the
exchange LC-MS analysis of Ox-1 and DS80100717 indicated degradants, the reactive sites within the DS80100717 molecule
no difference in the number of labile hydrogen atoms in each demonstrating susceptibility to degradation were estimated,
1
compound. The H-NMR spectrum of the isolated Ox-1 sam- as shown in Fig. 6. DS80100717 was susceptible to hydrolysis
1
ple is shown in Fig. 5. Compared to the H-NMR spectrum of (both acid and base) and peroxide-mediated oxidation in both
DS80100717, the signals of Ox-1 at H1″, H2″, H3″, and H4″ in solid-state and solution. The C13 side chain of taxane deriva-
the baccatin III analogous moiety were significantly shifted tives was commonly eliminated under basic conditions.12–14)
to a low magnetic field. The same trend was observed and Although taxane derivatives reportedly oxidize at the C1013)
confirmed with the signals of the 13C-NMR spectrum at C1″, and C3–C11 bridge,12,14) DS80100717 formed N-oxide at other
C2″, C3″, and C4″, which would be consistent with a change in positions as the major degradant. Furthermore, β-OH at C7 of
the third amine position in the baccatin III analogous moiety paclitaxel and docetaxel was easily epimerized into α-OH as
(Table S5, Supplementary Materials). Based on these results, the result of the retro-aldol reaction.12,13) On the other hand,
Ox-1 was characterized as an N-oxide form of DS80100717.
the C2′ side chain of DS80100717 was easily epimerized. The
Degradation Pathway of DS80100717 As the results of oxetane group on the side chain of DS80100717 was assumed
the stress testing of DS80100717, many degradation products to undergo epimerization at the C2′ position since it has less

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Chem. Pharm. Bull.
397
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Conclusion
The DS80100717 drug substance and drug product were
subjected to stress studies, and the degradation products were
evaluated. Eight degradation products were identified, iso-
lated, and characterized by various spectroscopic techniques
including MS and NMR. N-Oxide and C2′-epimer were ob-
served even in the solid-state. These degradation products are
likely to be formed in actual long-term stability studies. We
were able to examine these degradation products with appro-
priate stress studies. These degradation products are important
in pharmaceutical drug development and quality control of the
drug substance and drug product.
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Acknowledgments The authors thank Ms. Hisae Yuasa
(Daiichi Sankyo Co., Ltd.) for preparing lyophilized samples
and for HPLC analyses.
Conflict of Interest Kousuke Tamura, Makoto Ono, Take-
fumi Kawabe, and Motomu Ohara are currently employees of
Daiichi Sankyo Co., Ltd., respectively.
Supplementary Materials The online version of this ar-
ticle contains supplementary materials.
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