Long-acting injectable antipsychotics (LAIs) hold an important place in the therapeutic management of patients with schizophrenia and other psychoses. They offer advantages, such as knowledge of whether patients follow the medical advice that is given, stable pharmacokinetics and better correlation between the administered dose and the plasma levels of the drug, regular follow-up and reduced risk of overdose. Knowledge of the best way to administer LAIs is important in clinical practice because it maximizes the efficacy of the drug and minimizes the side-effects. This knowledge is facilitated through understanding both the pharmacokinetics and the pharmaceutical forms of these drugs because it provides necessary information concerning their mode of action. Currently in Greece, two first-generation (haloperidol and zuclopenthixol) and four newer LAIs (risperidone, olanzapine, paliperidone and aripiprazole) are in circulation. Their pharmaceutical form facilitates the delayed delivery of the drug during a period of weeks, thus increasing the time interval needed for the drug administration in order to maintain plasma therapeutic concentrations under stable state conditions. This is achieved by creating an extravascular drug reservoir (depot) in the skeletal muscles from which the drug is slowly released into the systemic circulation. The rate of removal of LAIs is regulated by the slow rate of absorption in the site of injection and the phenomenon of their increased half-life is called flip-flop pharmacokinetics. Their rate of absorption from skeletal muscles depends on factors, such as the injection technique, the pharmaceutical form of the drug, the distribution of fat tissue and the blood supply of the muscle. First-generation LAIs are characterized chemically by an esterified drug molecule that is dissolved in oil vehicle. The esterified drug is then hydrolyzed rapidly by plasma esterases allowing the entrance of the drug into the brain. On the contrary, newer LAIs are aqueous- based formulations characterized by various pharmaceutical forms: microspheres (risperidone), pamoic acid crystal (olanzapine), nanocrystals (paliperidone), dry drug- suspension with water (aripiprazole). Among newer drugs, risperidone and aripiprazole must be administered orally concurrently with the LAI for an initial time period. Furthermore, risperidone is the only LAI administered every 2 weeks and 3-monthly paliperidone is the only one administered every 3 months. All the other LAIs (1st generation and atypical) are usually administered every 4 weeks. This paper reviews the pharmacokinetic and pharmaceutical characteristics of these drugs. It also provides information concerning basic elements of LAI pharmacokinetics in order to understand these characteristics better.

KEYWORDS: long acting injectable antipsychotics, pharmaceutical characteristics, pharmacokinetics, psychosis, depot

Theocharis Chr. Kyziridis


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