Keywords
cariprazine - schizophrenia - orodispersible - bioequivalence
Introduction
Cariprazine is an efficacious and well-tolerated third-generation, partial agonist
antipsychotic indicated for the treatment of schizophrenia (EU, US) [1], acute manic or mixed episodes, bipolar I
depression and major depression add-on (US) [2]. Consistent with the findings from large comparative clinical trials
and observational studies in schizophrenia, cariprazine has been found to be a
valuable treatment option, especially in treating negative symptoms of schizophrenia
[3]
[4]
[5] and dual schizophrenia
(co-occurrence of schizophrenia and substance abuse). In meta-analyses, it showed to
have comparable efficacy to other atypical antipsychotics concerning positive
symptoms and overall efficacy in schizophrenia [6]. Moreover, cariprazine has a favorable risk/benefit profile [7], which has led to its extensive utilization
worldwide. Cariprazine is available in an oral capsule formulation, covering the
dose range of 1.5, 3, 4.5, and 6 mg, to be taken once daily with or without food at
any time during the day [1]. An orodispersible
tablet formulation has been developed to optimize the utility of cariprazine in
patient groups with different needs and preferences.
Orodispersible tablets are solid dosage forms that quickly dissolve or disintegrate
in the mouth without requiring water or chewing [8]. Compared to conventional tablets/capsules, orodispersible tablets
have several benefits, such as easier administration and better patient adherence
[8]. Orodispersible tablets are
particularly suitable for pediatric, geriatric, and dysphagic patients who have
trouble swallowing conventional solid dosage forms [8]. Although liquid and injectable antipsychotics are alternatives to
standard tablets/capsules, in some clinical situations, they have limitations, as
patients may spit out the liquid or find injectable medication unacceptable [8]. Orodispersible tablet formulations may have
an advantage in patients who are very agitated or have medical conditions that make
swallowing difficult, or when there is a need for fluids to take the tablet/capsule,
which may not be available and may draw unwanted attention to the condition of the
patients [8].
One of the main challenges in treating patients with mental illnesses such as
schizophrenia is treatment non-adherence. Here, the average for poor adherence to
antipsychotic medication is around 50% but ranges between 20% and 90% [9]
[10]
[11]. Non-adherence is more
common when patients disagree with treatment, medication regimens are difficult, and
when side effects are unacceptable [11]
[12]
[13]
[14]. Up to 80% of patients with
schizophrenia are at least partially nonadherent to antipsychotic treatment at some
point during their illness, which, in turn, can lead to treatment failure, relapse,
and hospitalization [8]. Furthermore, since
many patients have poor insight into their illness, any measures that can improve
the acceptance of the medication can help them stick to their treatment and improve
their long-term outcomes [8]. As oral
treatments are less invasive than injections, using oral formulations can help build
a good initial therapeutic relationship that predicts a positive attitude towards
medication, which in turn predicts adherence [8].
A recent study on patient’s acceptance of medication formulations for acute agitation
found that there was a clear preference for oral formulations over intramuscular or
inhaled formulations [15]. This finding is
particularly important, as treatment guidelines now recommend that patient
preferences are considered in treatment choices (shared decision-making or informed
choice) [15]. A survey of hospitalized
patients with schizophrenia in 2010 showed that 42% wanted to be involved in
treatment decisions [15]. Patients involved in
their treatment decisions had a better therapeutic relationship, more positive
attitudes towards their medication, and better insight than patients who were not
involved [15]. So, although some doctors may
prefer injectable formulations for adherence, patients still prefer oral
formulations. Hence, having various oral formulations (e. g., tablet, capsule,
orodispersible tablet, liquid) to treat mental disorders still has value in
psychiatric treatment.
The purpose of this article is to present the outcome of a bioequivalence study
comparing a newly developed cariprazine orodispersible tablet formulation (1.5 mg)
to the standard cariprazine capsule 1.5 mg. The primary objective was the assessment
of bioequivalence between these two formulations in healthy adult volunteers after a
single dose administration under fasting conditions in a cross-over design.
Methods
Study design and participants
This was a phase I open-label, randomized, single-dose bioequivalence study. It
was conducted at one clinical study center in Germany. Only healthy Caucasian
males and females of non-childbearing potential (permanently sterile or
postmenopausal) aged 18 to 55 years (inclusive) were enrolled in the clinical
trial. Participants had to be healthy non-smokers with a body mass index (BMI)
between 18.5 and 30 kg/m2 (inclusive). Regular treatment with any
systemically available medication and intake of strong or moderate CYP3A4
inhibitors or inducers, or strong or moderate CYP2D6 inhibitors within 30 days
prior to treatment administration was excluded.
A schematic diagram of the trial is presented in [Fig. 1]. This trial was performed in a
2-period, 2-sequence, cross-over design, where each subject was planned to
receive one test and one reference product in a randomized sequence, separated
by a wash-out period of 55 days to avoid any carry-over effects. This type of
design makes it possible to have an intra-individual comparison between
treatments and is the standard design for bioequivalence studies [16].
Fig. 1 Schematic presentation of the trial.
The study consisted of a 3-week screening period, during which the volunteers
were assessed if they fulfilled all inclusion criteria and none of the exclusion
criteria. Eligible subjects were then hospitalized from 24 h before study drug
administration (Day 1 and Day 56) until 72 h post dose (last PK sampling). An
end-of-study examination was performed within 14 to 21 days after the last
administration of treatment, followed by a follow-up call at 6 weeks
post-dose.
Blood sampling was performed over 72 h post-dose to characterize pharmacokinetic
parameters. A truncated approach was considered adequate in accordance with the
Guideline on the Investigation of Bioequivalence [16] for substances with a long half-life
and administered as immediate release formulations [16]. Blood samples were withdrawn at the
following time points: pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6,
7, 8, 9, 10, 12, 16, 24, 36, 48, 60, 72 h post-dose (23 samples per subject and
period).
Treatments
This trial was performed with the lowest dose strength of cariprazine (1.5 mg).
The EMEA BE guideline [16] allows for the
selection of lower strengths if the highest strength cannot be administered to
healthy volunteers for safety/tolerability reasons. As shown previously, healthy
volunteers do not tolerate cariprazine doses higher than 1.5 mg [1]. Moreover, cariprazine has linear
pharmacokinetics in the dose-range of 1.5–6 mg, so what is seen for 1.5 mg is
also valid for higher doses.
The subjects were randomly assigned to one of the two possible sequences, TR or
RT, where the test compound (T) was the cariprazine 1.5 mg orodispersible
tablet, and the reference compound (R) was cariprazine 1.5 mg hard capsule, both
developed and manufactured by Gedeon Richter Plc.
The investigational products were administered at the trial site under the
supervision of the study team. Both treatments were followed by an inspection of
the oral cavity and of the hands. In case of T, subjects wetted their mouth by
swallowing 20 mL of water (room temperature) prior to administration.
Afterwards, one orodispersible tablet was taken orally without further fluid
intake in an upright position by placing it on the tongue, where it
disintegrated. The orodispersible tablet was not chewed or swallowed whole.
Subjects were instructed to let the orodispersible tablet disintegrate in their
mouth. Once the tablet was dispersed or the latest up to 90 s after being placed
on the tongue, in case some residues were not dispersed completely, the subjects
swallowed the saliva. In the case of R, one hard capsule was taken orally with
240 mL water (room temperature) in an upright position.
Analytical methods
Cariprazine concentrations in plasma samples were analyzed using a validated
HPLC-MS/MS method developed by Gedeon Richter Plc. (LLOQ for cariprazine was
10 pg/mL). Metabolite concentrations of desmethyl-cariprazine (DCAR) and
didesmethyl-cariprazine (DDCAR) in plasma samples were analyzed by the same
validated HPLC-MS/MS method (LLOQ for DCAR and DDCAR was 20 pg/mL) and were
presented in the bioanalytical report as supportive data only. No PK parameters
were calculated for the metabolites as the chosen study design does not allow
accurate determination of metabolite PK parameters.
Pharmacokinetic and statistical analysis
Pharmacokinetic parameters for cariprazine were derived by non-compartmental
analysis. In accordance with the requirements of the EMEA BE Guideline [16], AUC0–72h and
Cmax of cariprazine were considered as primary variables and
decision criteria for bioequivalence assessment. Analysis of variance (ANOVA)
was performed on ln-transformed AUC0–72h and Cmax at the
alpha level of 0.05. Fixed factors incorporated in the model included Sequence,
Subject (Sequence), Period, and Formulation. The ratio of means (T/R) and 90%
confidence interval for the ratio of geometric means, based on least-squares
means from the ANOVA of the ln-transformed data, were calculated. Acceptance
limits of 80.00% – 125.00% were applied for AUC0–72h and
Cmax 90% confidence intervals. Tmax of cariprazine was
a secondary variable evaluated descriptively.
Analysis populations
For the current clinical trial, two populations were analyzed: full analysis set
(FAS) and per-protocol set (PPS). The per-protocol set, defined as all
randomized subjects who finished the clinical trial without any major protocol
deviations, was used to assess cariprazine pharmacokinetics. Descriptive
statistics were used for the plasma concentrations and pharmacokinetic
parameters of cariprazine. The full analysis set comprised all subjects
randomized. The incidence of adverse events (AEs), adverse drug reactions
(ADRs), and serious adverse events (SAEs) were calculated for each treatment
group. All safety measures were analyzed using descriptive statistics.
Monitoring and ethics
Monitoring in the clinical trial was performed in accordance with the
requirements of the GCP guideline [17] and
based on the monitoring plan. Source data verification was performed for 100% of
data obtained during the clinical trial on-site. This study was performed in
compliance with European Union Directive 2001/20/EC, applicable national
statutory requirements, the Declaration of Helsinki, and ICH Good Clinical
Practice (GCP), including the archiving of essential documents and the
requirements of the German Medicinal Product Act (Arzneimittelgesetz, AMG). The
clinical trial was only initiated after receiving positive opinion from the
Independent Ethics Committee and approval from the national health authority
(BfArM) was received for clinical trial protocol, subject information, including
the ICF, as well as any subsequent amendments.
Informed consent was obtained from all subjects involved in the study, prior to
the first measures and activities. Every subject had the right to refuse further
participation in the clinical trial at any time and without giving reasons.
Subjects were informed in the ICF that they would not receive any medical
benefit from their participation since they were healthy and did not need
treatment with this medical substance.
Results
Subject disposition and demographic characteristics
Fifty-four healthy male and female subjects of non-childbearing potential were
randomized and included in the FAS, while 53 subjects received the
investigational compound at least once. One subject who was randomized but did
not receive the investigational compound was still included in the FAS following
the protocol.
Ten subjects dropped out before completion of PK blood sampling: two subjects
withdrew their consents, five subjects were withdrawn due to vomiting, and three
subjects were withdrawn due to other AEs (see [Table 3]). In addition, one subject was excluded from PPS due to
minimal exposure under the reference product (AUC<5% mean AUCR);
thus, the PPS consisted of 43 subjects.
Table 3 Treatment-Emergent Adverse Events with at least 5%
occurrence.
|
Period 1
|
Period 2
|
|
Test
|
Reference
|
Test
|
Reference
|
|
Death
|
0
|
0
|
0
|
0
|
|
SAE
|
0
|
0
|
0
|
0
|
|
ADO
|
4 (+1 PTAE)
|
1
|
1
|
1
|
|
TEAE
|
32
|
20
|
22
|
24
|
|
from this:
|
|
Fatigue
|
6
|
3
|
2
|
7
|
|
Nausea
|
5
|
3
|
3
|
2
|
|
Headache
|
3
|
3
|
3
|
3
|
|
Abdominal discomfort
|
1
|
0
|
0
|
2
|
|
Blood pressure increased
|
4
|
1
|
2
|
2
|
|
Nasopharyngitis
|
0
|
2
|
1
|
0
|
|
Dizziness
|
3
|
1
|
2
|
0
|
|
Myalgia
|
1
|
1
|
1
|
0
|
|
Presyncope
|
0
|
2
|
1
|
0
|
ADO=Adverse Events Leading to Drop-Out, SAE=Serious Adverse Events,
PTAE=Pre-Treatment Adverse Events, TEAE=Treatment-Emergent Adverse
Events.
Out of the 43 subjects included in the PPS 1 was female and 42 were male.
Subjects were aged 20 to 55 years with a BMI between 18.7 and 29.9 kg/m². All
subjects were Caucasian as given in the inclusion criteria of the trial.
Pharmacokinetic analyses
[Fig. 2] presents the mean plasma
concentration vs. time profiles of cariprazine after single oral administration
of cariprazine 1.5 mg orodispersible tablet (T) and cariprazine 1.5 mg capsules,
hard (R) under fasting conditions to subjects of the PPS.
Fig. 2 Mean plasma concentration vs. time profiles of cariprazine
after single oral administration of Cariprazine 1.5 mg orodispersible
tablets (T) and Cariprazine 1.5 mg capsules, hard (R) under fasting
conditions.
The mean curves of cariprazine obtained after a single oral administration of
cariprazine 1.5 mg orodispersible tablets (T) and cariprazine 1.5 mg capsules,
hard (R) increased without any lag-time, reaching their comparable maximum
values of about 800 pg/mL at 3 h post-dose.
In the present clinical trial, pre-dose values in period II were observed in 9
cases in a range of 11.1 to 15.9 pg/mL (LLOQ: 10 pg/mL) despite the already long
wash-out phase of 55 days, with 6 cases prior to administration of T and 3 cases
prior to the administration of R. Overall, these values were below 5% of the
respective Cmax value in all cases, so subject’s data were included
in pharmacokinetic measurements and calculations without any adjustments.
Pharmacokinetic parameters obtained after administration of the two formulations
are summarized in [Table 1]. Parametric
point estimates and 90% confidence intervals determined for the primary
pharmacokinetic parameters of cariprazine; comparison of Test vs. Reference
(T/R) are shown in [Table 2].
Table 1 Geometric mean (GeoCV%) pharmacokinetic parameters
of cariprazine after single oral administration of (T) and (R) under
fasting conditions, n=43.
|
PK parameter
|
ODT (test)
|
Capsule (reference)
|
|
AUC0–72h (h·pg/mL)
|
23800 (33.22)
|
20200 (43.44)
|
|
Cmax (pg/mL)
|
890 (38.23)
|
882 (49.93)
|
|
tmax *(h)
|
3.50 (1.00–6.00)
|
3.50 (1.52–8.02)
|
*For tmax median (min-max) is presented,
ODT=orodispersible tablet.
Table 2 Point estimates and 90% confidence intervals of
pharmacokinetic parameters of cariprazine: comparison of Test vs.
Reference (T/R).
|
Parameter
|
Point Estimate [%]
|
Lower Limit CI [%]
|
Upper Limit CI [%]
|
CVintra [%]
|
|
AUC0–72h
|
117.76
|
111.86
|
123.96
|
14.22
|
|
Cmax
|
100.88
|
93.33
|
109.04
|
21.67
|
CI=confidence interval.
For the primary pharmacokinetic parameter AUC0–72h of cariprazine, a
point estimate of 117.76% with an affiliated 90% confidence interval of 111.86%
– 123.96% was calculated, representing a result within the pre-defined
acceptance limits for demonstration of bioequivalence of the Test and Reference
product [16]. For the primary
pharmacokinetic parameter Cmax of cariprazine, a point estimate of
100.88% with an affiliated 90% confidence interval of 93.33% – 109.04% was
calculated. The confidence interval was completely within the pre-defined
acceptance limits of 80.00% – 125.00%. Thus, the bioequivalence of Test and
Reference products was clearly demonstrated for both PK parameters of
cariprazine.
Safety and tolerability outcomes
Safety data is summarized in [Table 3].
Fifty-three subjects received the investigational products at least once. In
total, 98 treatment-emergent adverse events (TEAEs) were reported by 41
subjects. Fifty-four TEAEs in 29 subjects occurred after Test treatment and 44
TEAEs in 26 subjects after Reference treatment. Therefore, the number of
subjects who experienced TEAEs after Test treatment was nearly similar to the
number of subjects who experienced TEAEs after Reference treatment.
The most frequently reported TEAEs were: fatigue (n=18), nausea (n=13) and
headache (n=12). In total, 83 TEAEs were classified as study drug-related (Test:
45, Reference: 38) and 15 TEAEs were classified as not related to the drug
(Test: 9, Reference: 6).
Discussion
The primary objective of this study was to evaluate the bioequivalence of a newly
developed orodispersible tablet containing 1.5 mg cariprazine in comparison to
cariprazine 1.5 mg hard capsules and to show that the new formulation is just as
safe and tolerable as the original hard capsule formulation. Both trial objectives
were met: bioequivalence of the Test and the Reference product was demonstrated
based on AUC0-72h and Cmax values of cariprazine. Data on
safety and tolerability showed a comparable risk profile for both formulations and a
tolerability in line with the SmPC of cariprazine as well as the substance class of
atypical antipsychotics.
With this positive clinical trial, another opportunity opens up for dosing of
patients treated with cariprazine: dosing with the new cariprazine formulation, the
cariprazine orodispersible tablet. It disperses quickly in the mouth, has a pleasant
taste, and can be used without any liquid. With its advantages, the cariprazine
orodispersible tablet is an awaited treatment formulation.
Disclosure
Author Contributions
All authors participated in the writing, editing, and critical revision of
intellectual content, and approved the final version of this manuscript.
Specific roles: Viktória Meszár (Clinical Project Manager and manuscript first
draft), Gabriella Magyar (Pharmacokineticist), Gabriella Pásztor Mészáros
(Principal Analyst), Krisztina Péter (study design), Balázs Szatmári (data
interpretation), Lívia Marton (Clinical Project Manager), Zsófia Dombi (writing
assistance), Ágota Barabássy (data interpretation and writing assistance).
Data Availability Statement
Data Availability Statement
The study data is owned by Gedeon Richter Plc (Budapest, Hungary). Parts of data can
be made available upon request.
Previous communication
Data of this study was not published previously.
