Lack of Clinically Meaningful Effect of Cariprazine on the Pharmacokinetics of a Combined Oral Contraceptive.

Introduction: Cariprazine (CAR) is a potent dopamine receptor partial agonist antipsychotic approved by the EMA and the FDA. To address the uncertainty regarding the effectiveness of hormonal contraceptives during CAR co-administration and whether a second barrier method is necessary, a drug-drug interaction study with an oral contraceptive was conducted post-approval.

Methods: The phase I, fixed-sequence multicenter study involved two periods with 24 patients with schizophrenia, aiming to evaluate the effect of CAR on the pharmacokinetics (PK) of a combined oral contraceptive (COC) containing 30 μg ethinylestradiol (EE) and 150 μg levonorgestrel (LNG).

Population Pharmacokinetics of Cariprazine and its Major Metabolites.

Background And Objectives: Cariprazine, a dopamine D-preferring D/D receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5-6 mg/day) and manic/mixed (3-6 mg/day) episodes associated with bipolar I disorder. This population pharmacokinetic analysis describes the concentration-time profiles of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR).

Relationship Between Plasma Concentrations and Clinical Effects of Cariprazine in Patients With Schizophrenia or Bipolar Mania.

Population pharmacokinetic/pharmacodynamic modeling (via NONMEM) was used to describe longitudinal exposure-response relationships for total cariprazine (sum of cariprazine and its major active metabolites) in 2,558 patients with schizophrenia or bipolar mania. Drug exposure metrics were explored for potential relationships with efficacy and safety end points. Total cariprazine exposures were significantly related to reductions in Positive and Negative Syndrome Scale (PANSS) or Young Mania Rating Scale (YMRS) total scores in schizophrenia or bipolar mania, respectively, via a maximum effect (E )-type relationship.

[Cariprazine, a new type - dopamine D₃ receptor preferring - partial agonist atypical antipsychotic for the treatment of schizophrenia and the primary negative symptoms].

Dopamine D₂ receptor partial agonists represent a new generation of atypical antipsychotics. Cariprazine, which has received centralized market authorization from the European Medicines Agency in 2017 for the treatment of adult patients with schizophrenia (including those with predominant negative symptoms of schizophrenia) differs from the other two partial agonist antipsychotics aripiprazole and brexpiprazole due to its unique features. Cariprazine is a dopamine D₃ preferring D₃/D₂ partial agonist with very similar dopamine receptor subtype selectivity as dopamine.

Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(+)-PHNO.

Rationale: Second-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior.

Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment).

Purpose: Cariprazine is a potent dopamine D3-preferring D3/D2 receptor partial agonist in development for the treatment of schizophrenia, bipolar mania, and depression. Pharmacokinetics of cariprazine and the two clinically relevant metabolites (desmethyl- and didesmethyl-cariprazine) was evaluated in a clinical pharmacology study.

Methods: This was a multicenter, randomized, open-label, parallel-group, fixed-dose (3, 6, or 9 mg/day) study of 28-week duration (≤4-week observation, 12-week open-label treatment, and 12-week follow-up).

Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors.

Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile.

Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents.

We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N',N'-dimethyl-urea), a D(3)/D(2) dopamine receptor partial agonist with ∼10-fold preference for the D(3) receptor. Oral bioavailability of cariprazine at a dose of 1mg/kg in rats was 52% with peak plasma concentrations of 91ng/mL. Cariprazine 10mg/kg had good blood-brain barrier penetration, with a brain/plasma AUC ratio of 7.

Occupancy of dopamine D₂ and D₃ and serotonin 5-HT₁A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography.

Rationale: Cariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D(3) and D(2) receptors and moderate affinity to serotonin 5-HT(1A) receptors. Targeting receptors other than D(2) may provide a therapeutic benefit for both positive and negative symptoms associated with schizophrenia. Positron emission tomography (PET) can be used as a tool in drug development to assess the in vivo distribution and pharmacological properties of a drug.

Physico-chemical characterization of a novel group of dopamine D(3)/D(2) receptor ligands, potential atypical antipsychotic agents.

The fundamental physico-chemical properties such as ionization and lipophilicity of twelve alkyl-aryl-piperidine and aryl-piperazine derivatives have been determined. Compounds are members of a recently identified, new class of potent dopamine D(3)/D(2) receptor ligands as potential atypical antipsychotic agents and were used in the development of a promising drug candidate (RGH-188) being present currently in clinical phase II investigations. The ionization constant (pK(a)) and the partition coefficient in octanol/water (logP(oct)) and cyclohexane/water systems (logP(ch)) were measured by validated analytical methods.

Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: II. behavioural characterisation of RG-15.

RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl -phenyl) -piperazine -1 -yl] -ethyl] -cyclohexyl] -3 -pyridinesulfonic amide dihydro-chloride), is a highly selective dopamine D3/D2 receptor antagonist with subnanomolar affinity for the D3 receptor and nanomolar affinity for the D2 receptor. We found that RG-15 showed a good oral bioavailability (54%) and high brain levels (approx. 900 ng/g) in rats and demonstrated antipsychotic efficacy in amphetamine-induced hyperactivity and conditioned avoidance response tests in rats, yielding ED50 (median effective dose) values of 8.

Sensitive LC-MS/MS methods for the quantification of RGH-188 and its active metabolites, desmethyl- and didesmethyl-RGH-188 in human plasma and urine.

Selective and sensitive LC-MS/MS methods have been developed and validated for simultaneous determination of RGH-188, a novel atypical antipsychotic, and its two active metabolites, desmethyl- and didesmethyl-RGH-188 in human plasma and urine. Deuterated analytes, [2H6]-RGH-188, [2H3]-desmethyl-RGH-188 and [2H8]-didesmethyl-RGH-188 were used as internal standards (IS). The compounds were isolated from the alkalized biological matrix using liquid-liquid extraction (LLE) and the extracts were analysed by reversed-phase HPLC with MS/MS detection.

Effects of RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide], an orally active, selective dopamine D(3) receptor partial agonist in animal models of cocaine abuse.

Dopamine D(3) receptor partial agonism has been suggested as a potential therapeutic intervention in cocaine addiction. RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide] was identified as a novel selective dopamine D(3) receptor partial agonist and used for testing this hypothesis in animal models. The compound showed nanomolar affinity to human (K(i) = 6.

An HPLC/UV method for the determination of RGH-1756 in dog and rat plasma.

RGH-1756 (1-(2-methoxy-phenyl)-4-(4-[4-(6-imidazo[2,1-b]-thiazolyl)-phenoxy]-butyl)-piperazine dimethansulphonate) is a novel atypical antipsychotic candidate of Gedeon Richter Ltd. A new HPLC method has been developed and validated for the quantitative determination of RGH-1756 in dog and rat plasma. The compound and the internal standard are extracted from the biological samples by a simple and fast liquid--liquid extraction method, using 1-chlorobutane.

Application of LC-MS analysis to the characterisation of the in vitro and in vivo metabolite profiles of RGH-1756 in the rat.

RGH-1756, 1-(2-methoxy-phenyl)-4-(4-[4-(6-imidazol[2,1-b] thiazolyl)-phenoxy]-butyl-4-(14)C)-piperazine dimethane is a novel atypical antipsychotic drug candidate of Gedeon Richter Ltd. The metabolic pathways of the compound have been investigated by profiling the metabolites present in plasma, bile, and faeces samples of rats treated with (14)C-RGH-1756. The metabolites formed in vitro by rat liver microsomes have also been analysed.

Role of sodium channel inhibition in neuroprotection: effect of vinpocetine.

Vinpocetine (ethyl apovincaminate) discovered during the late 1960s has successfully been used in the treatment of central nervous system disorders of cerebrovascular origin for decades. The increase in the regional cerebral blood flow in response to vinpocetine administration is well established and strengthened by new diagnostical techniques (transcranial Doppler, near infrared spectroscopy, positron emission tomography). The latest in vitro studies have revealed the effect of the compound on Ca(2+)/calmodulin dependent cyclic guanosine monophosphate-phosphodiesterase 1, voltage-operated Ca(2+) channels, glutamate receptors and voltage dependent Na(+)-channels; the latest being especially relevant to the neuroprotective action of vinpocetine.

High-performance liquid chromatographic method for the determination of RGH-5002 in human, rabbit and rat plasma.

A sensitive, accurate and reproducible high performance liquid chromatography (HPLC) procedure for the analysis of RGH-5002 in biological fluids was developed. After a single step liquid-liquid extraction at pH 9 using n-hexane, RGH-5002 and internal standard were eluted from a Hypersil Si column with 5 mM ammonium acetate-methanol-acetonitrile (0.5:45:50 v/v/v) at 28 degrees C.

Distribution and elimination of RGH-5002 in rats.

In the present study distribution and elimination of RGH-5002--a new centrally acting muscle relaxant--were investigated in rats by using 14C-labelled compound. Whole-body autoradiography and quantitative determination of the radioactivity in various organs following single and repeated oral administration of [14C]RGH-5002 demonstrated extensive distribution of the drug with high levels in the gastrointestinal tract, kidneys, liver, endocrine and exocrine glands and lungs. Minimal accumulation was observed after repeated (8 days) administration.

In vitro degradation of thymopoietin32-35 in human, dog and rat plasma.

TP4 (Arg-Lys-Asp-Val) is a synthetic immunomodulatory tetrapeptide of Chemical Works of Gedeon Richter Ltd. The aim of this study was to give comparative data on the in vitro degradation of 14C-TP4 in plasma of different species at two TP4 concentrations to allow suitable extrapolation of preclinical data to human system. The results show that the degradation was very fast in each plasma and varied by the species and concentrations studied.

Pharmacokinetic study of bisaramil in man.

Six healthy volunteers received an oral dose of 100 mg and an intravenous dose of 35 mg of bisaramil in a cross over study. Plasma concentrations were measured by HPLC. Bisaramil was eliminated from the plasma with a half life of 8.

Effects of a non-absorbable osmotic load on drug absorption in healthy volunteers.

1. We have studied the effects of a non-absorbable osmotic load on the absorption of a multicomponent solution of frusemide, atenolol, hydrochlorothiazide and salicylic acid in six healthy volunteers. 2.

The influence of gastrointestinal transit on drug absorption in healthy volunteers.

1. The effect of variability of gastric emptying and oro-caecal transit on the absorption of a multicomponent solution of frusemide, atenolol, hydrochlorthiazide and salicylic acid has been studied in six healthy subjects. Each subject was studied on five separate occasions: three times under basal conditions, once following metoclopramide and once following codeine pretreatment in an attempt to speed and slow transit respectively.

High-performance liquid chromatographic method for the determination of RGH-5702 in plasma samples.

A quick and selective high-performance liquid chromatographic method has been developed for the determination of RGH-5702 in plasma samples. A simple one-step extraction is used followed by reversed-phase chromatography and UV detection. This method allowed the separation of the compound and internal standard within 7 minutes.