Cariprazine

Absorption

The most clinically relevant drug concentration equates to the combined systemic concentration of cariprazine plus desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), the two main pharmacologically active metabolites of cariprazine. After single dose administration of cariprazine, the peak plasma cariprazine concentration occurred in approximately three to six hours. In healthy volunteers, the Tmax following oral administration was 3.6 hours for cariprazine, 6.5 hours for DCAR, and 18.1 hours for DDCAR. The steady-state was reached dose-proportionally within three weeks for cariprazine, DCAR, and DDCAR in patients with schizophrenia.
Administration of a single dose of 1.5 mg cariprazine capsule with a high-fat meal did not significantly affect the Cmax and AUC of cariprazine or its metabolite, desmethyl cariprazine (DCAR).

Toxicity

In pre-marketing clinical trials, an accidental acute overdosage (48 mg/day) was reported in one patient who experienced orthostasis and sedation. The patient fully recovered the same day. As there are no specific antidotes for cariprazine, supportive care, including close medical supervision and monitoring, is advised to manage overdose. The possibility of multiple drug involvement should also be considered.

The Uses of Cariprazine

Cariprazine is an orally active D2/D3 dopamine receptor antagonist. Cariprazine is an antipsychotic drug candidate for the potential treatment of schizophrenia, bipolar mania and depression

The Uses of Cariprazine

Cariprazine is an orally active D2/D3 dopamine receptor antagonist (1,2,3). Cariprazine is an antipsychotic drug candidate for the potential treatment of schizophrenia, bipolar mania and depression.

Indications

Cariprazine is indicated for the treatment of schizophrenia in adults to manage both positive and negative symptoms. It is also indicated to monotherapy for acute management of manic or mixed episodes associated with bipolar I disorder (bipolar mania) in adults, and acute management of depressive episodes associated with bipolar I disorder (bipolar depression) in adults.

Background

Cariprazine is an atypical antipsychotic agent and a piperazine derivative that was first developed in Hungary. It works as a partial agonist at central dopamine D2, dopamine D3, and serotonin 5-HT1A receptors and as an antagonist at serotonin 5-HT2A receptors. Cariprazine has been investigated in a variety of psychiatric disorders, including schizophrenia, bipolar disorders, and major depressive disorder. Cariprazine gained its first global approval in the US in September 2015 and was later approved by Health Canada in April 2022. It is currently used to treat schizophrenia, and manic or mixed episodes and depressive episodes associated with bipolar I disorder.

Definition

ChEBI: An N-alkylpiperazine that is N,N-dimethyl-N'-{trans-4-[2-(piperazin-1-yl)ethyl]cyclohexyl}urea substituted at position 4 on the piperazine ring by a 2,3-dichloroph nyl group. Used (as the hydrochloride salt) for treatment of schizophrenia and bipolar disorder.

Pharmacokinetics

Cariprazine is an antipsychotic agent. In clinical trials, it reduced positive and negative symptoms in patients with schizophrenia and acute mania in patients with bipolar I disorder. In animal models, cariprazine showed therapeutic benefits against cognitive deficits, mania, and catalepsy. In a meta-analysis study, cariprazine was shown to improve anxiety and depressed mood in patients with psychosis.
As cariprazine is a partial agonist at dopamine D2 and D3 receptors, it produces an apparent lower blockade level than other antipsychotic agents that block dopamine receptors. This receptor binding profile is advantageous as dopamine receptor blockade is associated with extrapyramidal symptoms as side effects. Partial agonism would allow the dopamine receptor to be stimulated even at maximal receptor occupancy by the drug. Antagonism at 5-HT1A and 5-HT2A receptors by cariprazine can increase dopaminergic neurotransmission in the nigrostriatal pathway, thereby further reducing the risk of extrapyramidal symptoms. However, cariprazine is still associated with a risk of akathisia, extrapyramidal disorder, restlessness, and tremor.

Metabolism

Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to form two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). DCAR and DDCAR are pharmacologically active metabolites with in vitro receptor binding profiles similar to the parent drug. DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR can be metabolized by CYP3A4 to form a hydroxylated metabolite.