Summary

Ritonavir significantly increases aripiprazole plasma concentrations through CYP3A4 inhibition, requiring dose reduction of aripiprazole to prevent toxicity. This interaction is clinically significant and requires careful monitoring and dose adjustment.

Introduction

Aripiprazole is an atypical antipsychotic medication primarily used to treat schizophrenia, bipolar disorder, and major depressive disorder as adjunctive therapy. It belongs to the quinolinone class of antipsychotics and works as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors. Ritonavir is a protease inhibitor originally developed for HIV treatment but now commonly used as a pharmacokinetic enhancer (booster) for other protease inhibitors due to its potent inhibition of cytochrome P450 enzymes, particularly CYP3A4.

Mechanism of Interaction

The interaction between aripiprazole and ritonavir occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Aripiprazole is primarily metabolized by CYP3A4 and CYP2D6 enzymes to form its active metabolite, dehydro-aripiprazole. Ritonavir is a potent inhibitor of CYP3A4, which significantly reduces the clearance of aripiprazole from the body. This inhibition leads to increased plasma concentrations of both aripiprazole and its active metabolite, potentially doubling or tripling exposure levels. The interaction is dose-dependent and begins within days of concurrent administration.

Risks and Symptoms

The primary clinical risk of this interaction is aripiprazole toxicity due to elevated plasma concentrations. Patients may experience increased side effects including extrapyramidal symptoms (tremor, rigidity, dystonia), sedation, orthostatic hypotension, and metabolic effects such as weight gain and hyperglycemia. Severe cases may lead to tardive dyskinesia, neuroleptic malignant syndrome, or cardiac arrhythmias due to QT prolongation. The interaction is considered clinically significant (major) and requires proactive management to prevent adverse outcomes.

Management and Precautions

When aripiprazole and ritonavir must be used concurrently, reduce the aripiprazole dose by 50% and monitor closely for signs of toxicity. For patients taking ritonavir-boosted regimens, consider reducing aripiprazole to 25% of the usual dose. Monitor for extrapyramidal symptoms, sedation, metabolic changes, and cardiovascular effects. Regular assessment of therapeutic response and side effects is essential. Consider therapeutic drug monitoring if available. When discontinuing ritonavir, gradually increase aripiprazole back to the original dose over 1-2 weeks while monitoring for loss of efficacy. Alternative antipsychotic medications with less CYP3A4 dependence may be considered in some cases.

Aripiprazole interactions with food and lifestyle

Alcohol: Aripiprazole may enhance the sedative effects of alcohol. Patients should avoid or limit alcohol consumption while taking aripiprazole as it can increase drowsiness, dizziness, and impair cognitive function. Grapefruit juice: May increase aripiprazole blood levels by inhibiting CYP3A4 metabolism, though this interaction is generally considered minor and not routinely contraindicated in clinical practice.

Ritonavir interactions with food and lifestyle

Ritonavir should be taken with food to improve absorption and reduce gastrointestinal side effects. Taking ritonavir on an empty stomach may result in decreased drug levels and reduced effectiveness. Alcohol consumption should be avoided or limited while taking ritonavir, as both can cause liver toxicity and the combination may increase the risk of hepatic adverse effects. Patients should also avoid grapefruit juice, as it may affect the metabolism of ritonavir through CYP3A4 inhibition, potentially leading to increased drug levels and toxicity. St. John's wort should be strictly avoided as it significantly reduces ritonavir levels by inducing CYP3A4, which can lead to treatment failure and development of drug resistance.