What are the pharmacokinetics of all atypical antipsychotics, including half-life and metabolism?

Pharmacokinetics of Atypical Antipsychotics

Overview of Absorption and Bioavailability

Atypical antipsychotics are highly lipophilic compounds that cross lipoidal membranes freely and are well absorbed when administered orally, but undergo substantial first-pass metabolism resulting in bioavailability ranging from 10-70%. 1

• All atypical antipsychotics are highly bound to plasma proteins (75-99%) and tissues, with extensive distribution volumes typically ranging from 100-1000 L 1
• The high lipophilicity allows these agents to readily cross the blood-brain barrier and distribute widely throughout body tissues 1

Metabolism and Elimination Pathways

Primary Metabolic Routes

The primary route of elimination for most atypical antipsychotics is hepatic metabolism and biotransformation, which produces pharmacologically active metabolites. 1

• Clozapine is metabolized primarily by CYP1A2, with significant influence from smoking status, age, and sex on plasma concentrations 2
• Risperidone is metabolized by CYP2D6 to 9-hydroxyrisperidone (paliperidone), an active metabolite with equivalent pharmacological activity 2
• Olanzapine undergoes metabolism via multiple pathways including CYP1A2 and CYP2D6, with significant interindividual variability 2
• Quetiapine is extensively metabolized with a short half-life, though its clinical effects may persist longer than plasma concentrations suggest 2
• Aripiprazole is metabolized by CYP2D6 and CYP3A4, with CYP2D6 metabolizer status significantly influencing pharmacokinetics 3

Active Metabolites

• Risperidone's clinical effects depend on the combined plasma concentrations of risperidone plus 9-hydroxyrisperidone (the "active moiety"), making monitoring of the parent compound alone potentially misleading 2
• There is no linear relationship between parent compound and metabolite concentrations, and the clinical relevance of pharmacologically active metabolites remains incompletely understood 1

Half-Life Characteristics

Atypical antipsychotics demonstrate wide variability in elimination half-lives, which directly impacts dosing frequency and steady-state achievement. 1, 4

• Long-acting injectable (LAI) formulations have substantially different pharmacokinetic profiles than oral formulations due to sustained-release characteristics 3
• LAI risperidone, paliperidone, and aripiprazole show influence of body weight and administration site on pharmacokinetics according to population pharmacokinetic models 3

Interindividual Variability and Genetic Factors

CYP2D6 Polymorphisms

CYP2D6 metabolizer status creates substantial interindividual variability in plasma concentrations, resulting in large differences in steady-state levels on identical dose regimens. 1

• CYP2D6 metabolizer status definitively influences LAI aripiprazole pharmacokinetics, though this relationship remains debated for LAI risperidone and paliperidone 3
• Poor metabolizers of CYP2D6 may experience significantly higher plasma concentrations and increased risk of dose-dependent adverse effects 4
• Ultra-rapid metabolizers may achieve subtherapeutic concentrations at standard doses 4

Clinical Implications of Variability

• Wide interindividual pharmacokinetic variability, combined with problems of noncompliance and drug interactions, provides rationale for therapeutic drug monitoring (TDM) in conjunction with clinical assessment 1
• The combination of pharmacogenetics and pharmacokinetics (including population PK models) enables personalized antipsychotic therapy 3

Therapeutic Drug Monitoring and Concentration Ranges

Clozapine

Clozapine demonstrates a clear positive relationship between plasma concentrations and clinical response, with a therapeutic threshold of 350-420 ng/mL associated with good clinical outcomes. 2

• TDM for clozapine is well-established because high plasma concentrations increase risk of epileptic seizures 2
• Plasma clozapine concentrations are influenced by CYP1A2 activity, age, sex, and smoking status 2

Olanzapine

Studies strongly indicate a relationship between olanzapine plasma concentrations and clinical outcomes, with a therapeutic range of 20-50 ng/mL established. 2

• Olanzapine TDM is considered very useful for assessing therapeutic efficacy and controlling adverse events 2

Risperidone

• Despite large variability and lack of fixed-dosage studies, monitoring plasma concentrations of the active moiety (risperidone plus 9-hydroxyrisperidone) may be useful 2
• A plasma threshold concentration of 74 ng/mL for the active moiety has been associated with parkinsonian side effects 2
• TDM is particularly valuable when switching between oral and long-acting injectable formulations 2

Amisulpride

• Preliminary data suggest a therapeutic plasma concentration of 367 ng/mL is associated with clinical improvement 2
• A therapeutic range of 100-400 ng/mL is proposed from non-systematic clinical experience 2

Quetiapine

There is little evidence supporting a relationship between plasma quetiapine concentrations and clinical response, and no optimal therapeutic range has been identified. 2

• PET studies show discrepancy between time course of receptor occupancy and plasma quetiapine concentrations 2
• The value of quetiapine plasma concentration monitoring in clinical practice remains controversial 2

Agents Without Established Ranges

• No direct evidence exists concerning optimal plasma concentration ranges for ziprasidone, aripiprazole (oral), or sertindole 2

Clinical Indications for Therapeutic Drug Monitoring

TDM should be utilized when patients lack response to therapeutic doses, demonstrate noncompliance, develop toxicity, or when drug interactions occur with coadministered medications. 1

• The delayed onset of clinical response relative to treatment initiation, combined with pronounced interindividual kinetic variability, supports TDM use 1
• Growing evidence indicates TDM can improve efficacy, especially when patients fail to respond to therapeutic doses or develop adverse effects 2
• Optimization through combined pharmacogenetics and pharmacokinetics improves the benefit-risk balance and patients' quality of life 3

Common Pitfalls to Avoid

• Monitoring risperidone parent compound alone without measuring 9-hydroxyrisperidone leads to erroneous interpretations of therapeutic adequacy 2
• Assuming linear relationships between parent compounds and metabolites can result in dosing errors, as no such linear relationship exists 1
• Failing to account for CYP2D6 metabolizer status when dosing aripiprazole or risperidone may result in subtherapeutic or toxic concentrations 3, 4
• Ignoring the influence of smoking status on clozapine metabolism can lead to unexpected concentration changes when patients alter smoking habits 2