1 s2.0 S2405650218300315 Main
1 s2.0 S2405650218300315 Main
1 s2.0 S2405650218300315 Main
eNeurologicalSci
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A R T I C LE I N FO A B S T R A C T
Keywords: We conducted a phase I study investigating the efficacy, safety, and tolerability of ONO-2160, a newly developed
ONO-2160 levodopa pro-drug, and carbidopa compared with levodopa and carbidopa to stabilize levodopa plasma con-
Levodopa centration fluctuations in Japanese patients with Parkinson's disease. In an open-label two-period design, pa-
Parkinson's disease tients (n = 12) with Parkinson's disease received levodopa and carbidopa for 3 days before 7 days of treatment
Motor fluctuations
with ONO-2160 and carbidopa. Patients were primarily evaluated using the Unified Parkinson's Disease Rating
Scale Part III, a Parkinson's disease symptom diary, and analysis of adverse events. Pharmacokinetic analysis of
plasma levodopa concentration was also performed.
ONO-2160 and carbidopa therapy stabilized effective plasma levodopa concentration. No adverse events with
safety concerns were observed. The combination of ONO-2160 and carbidopa produced a prolonged and stable
plasma levodopa concentration with a reduction in Unified Parkinson's Disease Rating Scale Part III total scores.
The combination was well tolerated, with no safety concerns, when administered to Japanese patients with
Parkinson's disease.
Abbreviations: AE, adverse event; ADR, adverse drug reactions; CD, carbidopa; COMT, catechol-O-methyltransferase; DDCI, dopa-decarboxylase inhibitor; MMSE,
Mini-Mental State Examination; PD, Parkinson's disease; SD, standard deviation; SE, standard error; UPDRS, Unified Parkinson's Disease Rating Scale
⁎
Corresponding author at: Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
E-mail address: [email protected] (M. Nomoto).
https://doi.org/10.1016/j.ensci.2018.09.003
Received 10 September 2018; Accepted 15 September 2018
Available online 17 September 2018
2405-6502/ © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
M. Nomoto et al. eNeurologicalSci 13 (2018) 8–13
passively and slowly absorbed throughout the gastrointestinal tract into the previous 7 consecutive days; be receiving levodopa products (le-
the blood, where it is efficiently hydrolyzed by esterase enzymes into vodopa/CD) at a consistent dose and dosage frequency for the previous
levodopa before crossing the blood–brain barrier and conversion to 7 days before the start of the study; and be judged capable of accurately
dopamine in the brain (data not shown), increasing dopamine stores. recording symptom variations in a PD symptom diary.
This non-randomized, open-label phase I study aimed to evaluate the The key exclusion criteria included the presence of any of the fol-
safety, pharmacokinetic profile, and efficacy of ONO-2160 and carbi- lowing: parkinsonism other than PD; received or due to receive surgical
dopa (ONO-2160/CD) combination therapy, and to compare it against treatment for PD; psychiatric symptoms related to PD; concurrent angle
an active comparator, the immediate-release formulation of levodopa closure glaucoma; stomach or duodenum ulcers; diabetes mellitus;
and carbidopa (levodopa/CD) combination therapy, in Japanese pa- heart or lung disease; underwent ≥400-ml blood collection within
tients with PD. 90 days or ≥200-ml blood collection within 30 days; history of serious
drug or food allergies; alcohol or drug abuse; or judged ineligible to be a
2. Methods study subject by the investigators as a result of clinical observation,
laboratory test, physical examination, ECG, and ophthalmological ex-
2.1. Ethics amination.
This study complied with the ethical principles based on the 2.4. Pharmacokinetic analysis
Declaration of Helsinki, the standards stipulated in Article 14 -
Paragraph 3 and Article 80-2 of the Pharmaceutical Affairs Law (or the Pharmacokinetic analysis involved venous blood sampling
“Law on Securing Quality, Efficacy and Safety of Pharmaceuticals and throughout the study for evaluating plasma concentrations of levodopa
Medical devices” since November 25, 2014), and the “Ministerial as measured by the LC/MS/MS facility at Sumika Chemical Analysis
Ordinance on Good Clinical Practice (GCP)” (MHW Ordinance No. 28). Service, Ltd., Osaka, Japan.
The study protocol was approved by the institutional review board
of the Graduate School of Medicine at Ehime University. Trial regis- 2.5. Motor function evaluation
tration number: JapicCTI-142,702.
The Unified Parkinson's Disease Rating Scale (UPDRS) Part III
2.2. Study design and interventions (motor evaluation) was carried out on PD patients given a diagnosis of
motor fluctuations, before each dose and every hour for 10 h after each
This open-label, phase I study was carried out in Japanese patients dose.
with Parkinson's disease who exhibited motor fluctuations and who
were currently on levodopa therapy. The study started with a 3-day 2.6. Safety and tolerability
observation period (days 1–3) with patients remaining on their estab-
lished levodopa/CD dose followed by an equivalent ONO-2160/CD For adverse events (AEs) and adverse drug reactions (ADRs), in-
dosage (ONO-2160/CD 300/25 mg is approximately equal to levodopa/ cidences and number of events were calculated. A physical examination
CD at 100/10 mg; Fig. 1). The dose was then steadily increased to a (blood pressure, pulse rate, respiratory rate, body temperature, and
maximum dose of either ONO-2160/CD 600/50 mg (group 1) or ONO- body weight) was carried out at baseline and at regular time points
2160/CD 900/75 mg (group 2). The patients received the doses three throughout the study, and the changes over time were recorded.
times daily at 5-h intervals over 5 days (days 4–8). This was done by Quantitative analysis of common laboratory tests, including blood
increments of 150/12.5 mg until efficacy and pharmacokinetic analysis biochemistry, hematology, coagulation, and urinalysis, was carried out
on day 9 and day 10, respectively. at baseline and at regular time points throughout the study; the changes
over time were also recorded.
2.3. Patients
2.7. Statistical analysis
This open-label study involved 12 Japanese patients based on the
following key inclusion criteria: male or female patient aged ≥20 The analysis set for safety and pharmacodynamics included patients
to < 80 years and was given a diagnosis of PD on the basis of the who had received the study drug at least once. The motor function and
Clinical Diagnostic Criteria of the UK PD Society Brain Bank; a Modified pharmacokinetic analysis sets included patients who met the inclusion
Hoehn and Yahr Scale stage 1 to 3; and ≥24 points in Mini-Mental criteria and none of the exclusion criteria, who had received the study
State Examination (MMSE) at screening [15–17]. drug at least once and also had their data recorded at least once after
Patients also had to have ≥2 h of OFF-time per day on average in administration of the study drug in the ONO-2160/CD period. For drug
9
M. Nomoto et al. eNeurologicalSci 13 (2018) 8–13
3.1. Patients Levodopa/CD was administered 3–7 times daily for 3 days at the
same dosing frequency as the pre-hospital phase for each patient
Between May 2015 and October 2015, written informed consent (n = 12). To compare the pharmacokinetic parameters of ONO-2160/
was obtained from 12 patients who were enrolled and observed for CD and levodopa/CD precisely when administered the same dosing
≥3 days prior to hospitalization and assignment to ONO-2160/CD intervals, pharmacokinetic data from day 3 were expressed as mean
treatment based on the dose and dosage frequency of current levodopa ( ± SD) plasma levodopa concentrations for patients who were dosed
therapy. All 12 patients were screened against inclusion and exclusion three times daily (n = 8) (Fig. 2). Four patients receiving more than
criteria and treated with the study drug. There were no deviations from three doses a day were excluded from this analysis. Data from day 10
protocol and no patients were withdrawn from the study. The mean were expressed as mean ( ± SD) plasma levodopa concentration in each
( ± SD) age was 68.1 ± 6.0 years. group (Fig. 2).
Patients were evenly divided into two dose groups (group 1: ONO- ONO-2160/CD therapy resulted in a sustained plasma levodopa
2160/CD 600/50; and group 2: ONO-2160/CD 900/75 mg; n = 6 per concentration with smaller peak-to-trough fluctuations when compared
group) on the basis of their current levodopa therapy. The demographic with levodopa/CD therapy. This was evidenced when calculating the
and clinical characteristics of both groups were shown to be similar Cmax/Cmin ratio, which uses the highest peak and lowest trough of
(Table 1). In brief, group 1 patients had a mean MMSE score, Hoehn & plasma levodopa concentrations, to show stabilization of the active
Yahr Stage, and UPDRS Part III of 28.3 (range: 27–30), 2.5 (range: 2–3), drug. After levodopa/CD treatment, the mean ( ± SD) Cmax/Cmin was
and 28.0 (range: 13–51), respectively. Group 2 patients had a mean 14.27 ( ± 8.41) (data not shown), whereas the Cmax/Cmin of ONO-
MMSE score, Hoehn & Yahr Stage, and UPDRS Part III of 28.8 (range: 2160/CD 600/50 mg and ONO-2160/CD 900/75 mg treatments were
27–30), 2.9 (range: 2.5–3), and 30.3 (range: 22–41), respectively. 4.43 ( ± 3.71) and 2.98 ( ± 1.05), respectively (Table 2).
In both groups, the current mean levodopa daily dose and mean Pharmacokinetics of plasma levodopa were evaluated in patients
daily dosing frequency were recorded. Group 1 patients were on a mean who had initially received levodopa/CD for 3 days and 7 days of ONO-
daily dose of 491.7 mg (range: 300–650 mg) levodopa with a mean 2160/CD at either 600/50 mg or 900/75 mg (Table 2). The Cmax after
daily dosing frequency of 3.5 (range: 3–5). Group 2 patients were on a each dose on day 10 for patients receiving either ONO-2160/CD 600/
mean daily dose of 600.0 mg (range: 300–900 mg) levodopa with a 50 mg or ONO-2160/CD 900/75 mg was 906 ng/mL and 906 ng/mL
mean daily dosing frequency of 4.2 (range: 3–7). after the first dose, 1120 ng/mL and 1330 ng/mL after the second dose,
and 1170 ng/mL and 1220 ng/mL after the third dose, respectively
(Table 2). The AUC5h on day 10 after receiving ONO-2160/CD 600/
50 mg or ONO-2160/CD 900/75 mg was 2830 ng·h/mL and 2760 ng·h/
Table 1
mL after the first dose, and 4050 ng·h/mL and 4820 ng·h/mL after the
Demographic and clinical characteristics of the study population.
second dose, respectively. The AUC24h on day 10 was 13,700 ng·h/mL
Demographic or clinical Group 1 mean Group 2 mean (range) after three doses of ONO-2160/CD 600/50 mg and 15,000 ng·h/mL
characteristic (range)
after three doses of ONO-2160/CD 900/75 mg (Table 2).
Age, years 67.2 (57–73) 69.0 (63–79)
Sex: Male (n) 3 4
Sex: Female (n) 3 2 3.3. Motor function response
Duration of PD (months) 95.5 (34–186) 77.0 (40–139)
MMSE Score 28.3 (27–30) 28.8 (27–30)
The analysis set included all 12 patients for the levodopa/CD period
Hoehn & Yahr Stage (ON-time) 2.5 (2–3) 2.9 (2.5–3)
Levodopa daily dose 491.7 (300–650) 600.0 (300–900) and the ONO-2160/CD period (in which six patients had received 600/
Levodopa daily dosing frequency 3.5 (3–5) 4.2 (3–7) 50 mg and six patients had received 900/75 mg). Fig. 3A and B show
Off time (hours) 4.65 (2.0–8.1) 5.15 (1.9–8.9) the mean UPDRS Part III scores for the 10 h after dosing during each
UPDRS score: Part III 28.0 (13–51) 30.3 (22–41) period. For the total scores at each time point, summary statistics (ac-
UPDRS score: total, when ON 39.5 (18–69) 45.5 (30–59)
UPDRS score: total, when OFF 43.0 (23–75) 55.8 (39–72)
tual score, change from baseline, and change between predefined cor-
responding times in the levodopa/CD period and the ONO-2160/CD
MMSE, Mini-Mental State Examination; PD, Parkinson's disease; UPDRS, period) were calculated by treatment period. During ONO-2160/CD
Unified Parkinson's Disease Rating Scale. therapy, UPDRS Part III scores were maintained at a low level from
10
M. Nomoto et al. eNeurologicalSci 13 (2018) 8–13
Table 2
Summary of plasma levodopa pharmacokinetic parameters on day 10.
Group 1 Group 2
Day 10 First dose Day 10 Second dose Day 10 Third dose Day 10 First dose Day 10 Second dose Day 10 Third dose
Patient (n) 6 6 6 6 6 6
Cmax (ng/mL) 906 ± 621 1120 ± 502 1170 ± 243 906 ± 331 1330 ± 623 1220 ± 600
Tmax (h) 3.00 (2.00–4.00) 3.51 (1.00–4.00) 1.50 (0.00–4.00) 2.50 (2.00–4.00) 3.00 (2.00–4.00) 3.50 (0.00–4.08)
AUC5h (ng·h/mL) 2830 ± 1870 4050 ± 2120 – 2760 ± 1040 4820 ± 2380 –
AUC24h (ng·h/mL) 13,700 ± 6030 15,000 ± 6960
Cmax/Cmin 4.43 ± 3.71 2.98 ± 1.05
All values are means ± SD except for Tmax, which is the median (min - max).
Cmax, maximum plasma concentration; Tmax, time to maximum plasma concentration; AUC, area under the concentration–time curve; Cmax/Cmin, highest Cmax of the
day / lowest plasma concentration among those obtained from the Tmax after the first dose until the Tmax after the third dose. The dash indicates data not determined.
and no clinically relevant trends were seen in vital signs, clinical la-
boratory parameters, physical examinations, or electrocardiograms
(data not shown).
4. Discussion
11
M. Nomoto et al. eNeurologicalSci 13 (2018) 8–13
ONO-2160/CD treatment on day 9, suggesting that the time to max- financial support for investigator-initiated trials from Shionogi
imum plasma concentration (Tmax) of plasma levodopa with levodopa/ Pharmaceutical Co. Ltd. and Morinaga & Co. Ltd., and speaker honor-
CD treatment is short compared with that for ONO-2160/CD. aria from Sumitomo Dainippon Pharma Co. Ltd., Hisamitsu
This phase I study involved multiple dosing with ONO-2160/CD, Pharmaceutical Co. Inc., Ono Pharmaceutical Co. Ltd., and Kyowa
three times per day for 7 days. The ONO-2160/CD combination was Kirin. M. Nagai has received grants from Ono Pharmaceutical Co. Ltd.,
well tolerated at both doses investigated in Japanese PD patients. No consultancy fees from Takeda Pharmaceutical Co. Ltd., and honoraria
patients withdrew from the study and there were no clinically relevant from Novartis. N.N. has received research expenses from Kisyu
trends observed in vital signs, clinical laboratory parameters, physical Hosokawa. Y.K., K.Y., and S.S. are employees of Ono Pharmaceutical
examinations, or electrocardiograms. In comparison, a common Co., Ltd. A.T. has received consultancy fees from Ono Pharmaceutical
strategy in clinical practice to combat long-term motor complications of Co. Ltd., grants from Meiji Seika Pharma Co., Ltd., Hisamitsu
levodopa treatment is to begin adjuvant therapy that combines other Pharmaceutical Co., Inc., Pfizer Inc., Sumitomo Dainippon Pharma Co.,
classes of antiparkinsonian drugs, such as dopamine agonists, COMT Ltd., and Kyowa Hakko Kirin Co., Ltd., and honoraria from Sumitomo
inhibitors, or monoamine oxidase B inhibitors. A systematic review of Dainippon Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd., and AbbVie
the literature, including 45 clinical trials and nearly 9000 patients, GKR. R.A. has no conflict of interest to disclose.
showed that although adjuvant therapy significantly improves symp-
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