Aripiprazole Lauroxil

Aripiprazole lauroxil is a prodrug: it has no effect until the body turns it into aripiprazole. After an injection into muscle, enzymes break it down by hydrolysis, first to N-hydroxymethyl aripiprazole and then to aripiprazole. CYP2D6 is not involved in this activation step. It matters afterwards, because the liver clears aripiprazole through CYP3A4 and CYP2D6 [1].

Aripiprazole is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at 5-HT2A receptors; the label says its mechanism in schizophrenia is unknown. Aripiprazole starts to appear in the blood 5 to 6 days after an injection and keeps being released for another 36 days. Levels build with each dose and reach steady state about 4 months after treatment starts. The aripiprazole half-life after Aristada is 54 to 57 days, compared with about 75 hours for aripiprazole tablets [1].

Aristada comes in four doses: 441 mg, 662 mg or 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 2 months. These contain 300, 450, 600 and 724 mg of aripiprazole. Because the first injection takes days to release drug, treatment starts either with 21 days of aripiprazole tablets or with one Aristada Initio injection (675 mg) plus a single 30 mg tablet [1].

CYP2D6 is a liver enzyme with many inherited variants. People with two non-working copies are poor metabolizers. CPIC estimates that about 6.5% of people of European ancestry are poor metabolizers, compared with about 2% to 3% in most other groups and under 1% of people of East Asian or Oceanian ancestry [3].

The Aristada label recommends dose adjustment in known poor metabolizers "due to high aripiprazole concentrations" [1]. The label does not give exposure figures for poor metabolizers on Aristada itself, and the studies that measured the effect used aripiprazole tablets or other aripiprazole injections. A 2021 meta-analysis found that poor metabolizers taking aripiprazole had 1.51 times the dose-adjusted levels of aripiprazole plus its active metabolite seen in normal metabolizers, and intermediate metabolizers 1.47 times [4]. The aripiprazole page covers that evidence in more detail.

The FDA labels handle poor metabolizers at three points [1] [2]:

• During a 21-day start with tablets, the oral aripiprazole label applies. That label halves the usual tablet dose for known poor metabolizers.
• Aristada Initio comes in a single strength, so its label says to avoid it in known poor metabolizers and in people taking strong CYP2D6 inhibitors, strong CYP3A4 inhibitors or strong CYP3A4 inducers.
• Once a person is stable on Aristada, the label's interaction table applies when another drug is added for more than 2 weeks. For a poor metabolizer who starts a strong CYP3A4 inhibitor, the dose drops to 441 mg from any higher dose. For a poor metabolizer who starts a strong CYP2D6 inhibitor, no change is needed, because the enzyme is already inactive.

The Aristada dose is chosen from the tablet dose a person was stable on: 10 mg a day corresponds to 441 mg monthly, 15 mg a day to 662 mg monthly, 882 mg every 6 weeks or 1064 mg every 2 months, and 20 mg or more to 882 mg monthly [1]. Apart from the interaction rows above, the label gives no separate Aristada dose table for poor metabolizers.

The FDA's Table of Pharmacogenetic Associations lists aripiprazole lauroxil and CYP2D6 in its first section, where the data support therapeutic management recommendations [5]. A Gene2Rx report shows that statement for your CYP2D6 result.

CPIC has not published a guideline for this drug, and its gene-drug list gives the pair a provisional level of B/C [6]. The DPWG's 2024 antipsychotic guideline covers aripiprazole but not aripiprazole lauroxil [7].

The result is most useful before treatment starts, when your prescriber chooses between a tablet lead-in and Aristada Initio and picks the first Aristada dose. Bring the report and a full list of your medicines, including over-the-counter products and supplements.

Other medicines matter as much as genes here. Strong CYP2D6 inhibitors such as fluoxetine, paroxetine, bupropion and quinidine, and strong CYP3A4 inhibitors such as clarithromycin, itraconazole and ketoconazole, are on the FDA's list of interacting drugs [8]. Someone with normal CYP2D6 genes who takes a strong CYP2D6 inhibitor can clear aripiprazole like a poor metabolizer, an effect called phenoconversion. The Aristada label lowers the dose by one strength for either type of strong inhibitor and avoids the higher doses when both are taken together. Strong CYP3A4 inducers such as carbamazepine and rifampin lower levels; the label raises the 441 mg dose to 662 mg with them [1].

Because each injection lasts weeks, a change takes a long time to reach steady levels, in either direction. Do not start, stop or change aripiprazole lauroxil or any other medicine because of a genetic result without talking to your prescriber.

Consumer arrays (23andMe, AncestryDNA, MyHeritage) are not clinical-grade tests, and their raw data is labeled not for medical use. They read fixed positions, and Gene2Rx uses imputation to infer some variants that were not measured directly. A normal result means none of the assessed variants was found among the positions your data covers; it cannot rule out a variant at a position the data does not cover. If a clinical test (GeneSight, Genomind or another lab) has already reported your CYP2D6 genotype, those results can be entered for a Panel Report.

A genotype does not predict whether the drug will control symptoms or which side effects you will have. Response to antipsychotics depends on much more than drug levels.

Does CYP2D6 activate Aristada?

No. Enzyme hydrolysis turns aripiprazole lauroxil into aripiprazole. CYP2D6 helps clear aripiprazole afterwards, which is why poor metabolizers have higher levels [1].

I am a poor metabolizer. Can I still get Aristada?

The label does not rule it out. It advises against Aristada Initio and adjusts the dose, as described in What the FDA label recommends.

1. Aristada (aripiprazole lauroxil) extended-release injectable suspension: prescribing information (Alkermes). DailyMed. Doses, activation, pharmacokinetics and CYP2D6 and interaction adjustments.
2. Aristada Initio (aripiprazole lauroxil) extended-release injectable suspension: prescribing information (Alkermes). DailyMed. Avoid in known CYP2D6 poor metabolizers.
3. CPIC. CYP2D6 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographic group.
4. Milosavljevic F et al. Association of CYP2C19 and CYP2D6 poor and intermediate metabolizer status with antidepressant and antipsychotic exposure: a systematic review and meta-analysis. JAMA Psychiatry (2021). Pooled aripiprazole exposure by CYP2D6 group.
5. US Food and Drug Administration. Table of Pharmacogenetic Associations. The FDA statement for aripiprazole lauroxil and CYP2D6 poor metabolizers.
6. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). Provisional level B/C for CYP2D6 and aripiprazole lauroxil.
7. Beunk L et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. Eur J Hum Genet (2024). The drugs the DPWG antipsychotic guideline covers.
8. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong CYP2D6 and CYP3A4 inhibitors and inducers.