Treatment of Tardive Dyskinesia: Considerations Regarding Metabolic Pathways and Drug-Drug Interactions

The CYP450 enzymes also display genetic diversity, which can affect their rate of metabolizing activity.¹² In this case, the amount of enzyme stays constant, but the activity level is lower or higher.⁹ A patient with diminished activity is described as a "poor metabolizer," and those with excessive activity are called "ultra" or "rapid metabolizers."

CYP3A4/5 and CYP2D6 are the three most common metabolic pathways within the CYP450 enzyme family, with 50% of drugs being metabolized through CYP3A4/5 pathways and 25% through CYP2D6.¹³

CYP3A4 is the most predominant metabolic pathway of the commonly prescribed medications,⁷ and it is highly expressed in the liver and intestine.¹¹ Induction of the CYP3A4 enzyme increases the rate of metabolism of victim compounds, causing lower plasma drug levels.¹⁴ This may result in subtherapeutic levels of drugs, or supratherapeutic levels of a drug administered as a prodrug.¹² Inducers include phenobarbital, phenytoin, St. John's Wort, and glucocorticoids.¹⁵

CYP3A4 inhibitors include macrolide antibiotics, azole antifungals, calcium-channel blockers, goldenseal, and grapefruit.¹⁵ Inhibition by these agents can result in higher levels of the substrate compound, and, in the case of a prodrug, lower levels of active compound are produced while the enzyme activity is inhibited.^12,14

CYP2D6 is another enzyme commonly implicated in drug metabolism.⁹ CYP2D6 also shows broad substrate specificity but is not highly inducible. CYP2D6 is subject to inhibition by various drugs, including some opiate analogs and some selective serotonin reuptake inhibitors.^9,16 CYP2D6 exhibits high genetic variability, which modifies the level of synthesis and the level of enzymatic activity, which can affect individual patients' responses.⁹ With its wide genetic variation, the degree of enzyme activity can vary greatly between patients, but is usually described in terms of patients being poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers.¹⁶

Transporters are membrane-bound proteins that help guide the movement of substrates across biological membranes.¹⁷ They are widely distributed in the body, including in the liver, intestine, kidney, and organs with barrier functions. Transporter proteins affect absorption, distribution, and elimination of drugs throughout the body, and altered transporter activity also affects plasma levels of drugs.

As with CYP450 enzyme pathways, a drug may be a substrate of one or many transport proteins, and can be an inducer or inhibitor of transport proteins.⁷ P-glycoprotein (P-gp) is a well-known efflux transporter. Transport proteins are regulated in similar way to CYP450 enzymes: through constitutive expression and by induction via exogenous compounds.¹⁸ In fact, P-gp and CYP3A4 share the same induction pathways, and transporter proteins can also be inhibited through interaction with a perpetrator molecule. Contributions of P-gp competition/induction on DDIs, therefore, are difficult to untangle from processes involved in other metabolic DDIs because the transport proteins and CYP enzymes are frequently co-affected.¹⁹

A recent study determined that transporter information is unavailable for 58% of the drugs approved between 2005 and 2016, and for 69% of drugs already established.⁷ Studies have shown, however, that aripiprazole, paliperidone, and risperidone are substrates of P-gp.²⁰

An estimated 43 million Americans suffer from schizophrenia, bipolar disorder, and/or major depressive disorder, for which APDs are standard of care.^1-7 While APDs help manage these disorders, their use is associated with the development of tardive dyskinesia (TD), a condition characterized by involuntary movements of the orofacial region, trunk, and extremities, and which are often irreversible.^8,9 Discontinuing or reducing the APD dose to reduce or eliminate TD movements is often not an option in psychiatric patients, as doing so can compromise the patient's underlying mental health condition.^10,11

The TD patient population is diverse; patients with TD may have an underlying mental health disorder, and they are also likely to have comorbid conditions, including diabetes, obesity, and cardiovascular and lipid disorders, which require additional medications for management.^5-7,12 As such, polypharmacy is especially prevalent in this patient population (Table 2.1).¹³ In fact, in one retrospective review more than 50% of patients visiting outpatient psychiatry departments were reported to be taking three or more psychotropic drugs, and more than half of patients (53%) reported also taking medications for nonpsychiatric conditions.¹⁴ Polypharmacy is associated with several concerns, including the increased risk of AEs, drug interactions, medication error, patient nonadherence, and medical comorbidities. Therefore, treatment considerations for TD must take into account the patients' concomitant medications for psychiatric and nonpsychiatric conditions, to help reduce the risk of DDIs.^15,16

Overall, approximately 20% to 30% of adverse reactions are the result of DDIs, and the risk for DDIs increases to about 84% when the number of concomitant drugs rises from 2 to 6 agents.¹⁶ Therefore, identifying the metabolic pathways involved in the absorption, metabolism, and excretion of each medicine that a patient is taking is essential to minimize DDIs and adverse reactions.

Drugs that serve as substrates, inhibitors, or inducers can have pharmacokinetic interactions with other medications, as well as with foods, beverages, and herbal supplements.¹⁶ When drug substrates are metabolized through the cytochrome P450 (CYP450) pathway, CYP inducers cause increased enzyme activity, resulting in reduced drug activity.¹⁷ Conversely, CYP inhibitors simultaneously block activity, causing increased plasma levels of drugs or other substrates, sometimes necessitating dosage reductions.

When reviewing patients' medications, it's important to know how each medication will affect the body's handling of concomitant drugs. A so-called "perpetrator" inhibits or induces metabolic enzymes or transporters that affect the plasma levels of a substrate drug, termed the "victim."¹⁸ Many inducers and inhibitors are also substrates of the enzymes they affect.¹⁹

In addition, the majority of the CYP genes are polymorphic; variation in CYP content and activities can substantially impact the metabolism of drugs, resulting in differences in drug response and adverse drug effects.²⁰

The CYP3A4/5 pathway metabolizes many medications used to manage components of metabolic syndrome, such as antihypertensives, antidiabetics, and statins, which could interact with APDs or medicines used to treat TD (Table 2.2).^21-24 Some of the common substrates of the CYP2D6 pathway are beta blockers, APDs, antiarrhythmics, antiemetics, antidepressants, and opioids (Table 2.3).^{20,21,23,24,26}

To minimize or prevent DDIs in patients receiving APD therapy, clinicians should identify concomitant medications that are metabolized by CYP3A4/5 or CYP2D6 (see Tables 2.2 and 2.3), those with a narrow therapeutic index, or those requiring stable serum concentrations, such as anticoagulants, anticonvulsants, anti-infectives, cardiovascular therapeutics, oral contraceptives, glucocorticoids, antiretroviral agents, and other psychotropics.¹⁶

Membrane-bound proteins called transporters also play a role in the metabolism of drugs, although less is known about their role in DDIs.^27,28 Found in the liver, intestine, kidney, and organs with barrier functions, transporter proteins enable the translocation of substrate molecules across the biological membranes.²⁷ In doing so, they affect absorption, distribution, and drug elimination.²⁹ Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp)/multidrug resistance-associated protein (MDR)-1 are well known efflux transporters, and their inhibition results in decreased efflux of substrate drugs; further, their induction leads to increased efflux of substrate drugs.²⁸ Many drugs that are CYP3A4 substrates, inhibitors, and inducers are also inhibitors or inducers of P-gp.³⁰ As such, many drug interactions involve effects of both CYP3A4 and P-gp.

Managing TD in patients taking concomitant medications for other conditions requires that clinicians are aware of all medications a patient is taking, for both psychiatric and nonpsychiatric conditions, as these can have important safety and therapeutic consequences, as well as can affect adherence.¹⁶

Consideration of DDIs is especially important in elderly patients, as this population has a significantly higher risk for TD and is often polymedicated.^5,33 Furthermore, elderly patients are more vulnerable to certain AEs (eg, orthostatic hypertension, urinary retention, and constipation), which may require additional medications for management.⁵ Managing these AEs with new medications, in turn, may compound the risk of additional AEs and DDIs.

The 2021 American Psychiatric Association practice guidelines recommend the use of a vesicular monoamine transporter 2 (VMAT2) inhibitor for the treatment of TD that has an impact on the patient.³⁴ VMAT2 inhibitors are the only FDA-approved drugs for the treatment of TD in adults.^31,35 When choosing a VMAT2 inhibitor, it is important to consider the patient's overall treatment plan, and to identify drug metabolic pathways that may be involved in DDIs.

TD is a potentially disabling, often irreversible, movement disorder that results from chronic exposure to typical or atypical antipsychotic drugs (APDs).^1-3 TD classically presents as involuntary, repetitive movements throughout the body, most often seen in the mouth, tongue, and jaw.^1,2,4 TD of any severity can have a substantial impact on a patient's functioning, quality of life, and underlying psychiatric stability.^2,5-10 Therefore, timely recognition of TD movements is imperative for appropriate management and treatment.¹¹

The American Psychiatric Association practice guidelines recommend vesicular monoamine transporter 2 (VMAT2) inhibitors for the treatment of TD that has an impact on the patient.¹¹ Typically, patients with TD have multiple underlying health conditions, requiring a range of medications. In order to limit drug-drug interactions, it is important to consider pharmacokinetics and metabolic pathways when choosing a VMAT2 inhibitor to treat TD.^12-14

AUSTEDO XR is a VMAT2 inhibitor indicated for the treatment of TD in adults.¹⁴ The precise mechanism of action of AUSTEDO XR is unknown, but it is believed to be related to its effect as a reversible depletor of monoamines, including dopamine, from nerve terminals. AUSTEDO XR inhibits the uptake of dopamine into synaptic vesicles by binding to VMAT2 on the vesicle in the presynaptic neuron.^14,15 Dopamine molecules collect outside the blocked VMAT2 and are degraded by monoamine oxidase. Reducing dopamine levels in the presynaptic neuron results in less dopamine signaling to the postsynaptic neuron, which may lead to fewer abnormal involuntary movements.

AUSTEDO XR was FDA approved based on 3 phase 1 studies in healthy volunteers; a steady-state bioequivalence testing study, a dose-proportionality study, and a single-dose relative bioavailability and food effects study.¹⁶ The characteristics of each study are shown below:

Bioequivalence of once-daily AUSTEDO XR was established with AUSTEDO BID, using pharmacokinetic profile studies. When studies show a drug to be bioequivalent, they can be considered therapeutically equivalent. Data illustrating the bioequivalence of AUSTEDO BID and AUSTEDO XR are shown below (Figure 3.1).¹⁶

The pivotal trials of AUSTEDO include two randomized, placebo-controlled 12-week clinical trials (Aim to Reduce Movements in Tardive Dyskinesia [ARM-TD] and Addressing Involuntary Movements in Tardive Dyskinesia [AIM-TD]).^12-14 Patients who completed ARM-TD or AIM-TD were eligible to enroll in the Reducing Involuntary Movements in Participants With Tardive Dyskinesia (RIM-TD) clinical trial, an open-label study to evaluate long-term maintenance therapy with AUSTEDO for adult patients with TD.¹⁷ RIM-TD is the longest TD study to date, with data spanning 688 patient-years through Week 158.¹⁶

Patients in the ARM-TD and AIM-TD clinical trials received the AUSTEDO twice-daily (BID) formulation. ARM-TD was a flexible-dose trial in which patients with TD received AUSTEDO titrated to individualized doses that reduced abnormal movements and was tolerated (up to 48 mg/day; mean dose was 38.3 mg/day).^12,14 AIM-TD was a fixed-dose trial in which adults with TD were randomized to receive AUSTEDO at doses of 12 mg/day, 24 mg/day, 36 mg/day, or placebo.^13,14 The primary endpoint of both studies was the change in Abnormal Involuntary Movement Scale (AIMS) total score from baseline to Week 12.^12,13

After completing ARM-TD or AIM-TD, patients in the RIM-TD trial discontinued the study drug for at least 1 week and began AUSTEDO at a dose of 12 mg/day, which was titrated for up to 6 weeks to identify a dose that adequately controlled dyskinesia and was tolerated.¹⁷ The dose was adjusted weekly, in increments of 6 mg/day to identify a dose that adequately controlled dyskinesia and was tolerable.¹⁷

In the ARM-TD study, AIMS total score for patients receiving AUSTEDO demonstrated statistically significant improvement, by 3.0 points from baseline to endpoint (Week 12), compared with 1.6 points for the placebo group (P=0.019, treatment effect of −1.4 points) (Figure 3.2).¹²

In the AIM-TD study, AUSTEDO significantly reduced AIMS total score from baseline to Week 12 by 3.3 points in the 36 mg/day group (P=0.001, treatment difference of −1.9 points), by 3.2 points in the 24 mg/day group (P=0.003, treatment difference of −1.8 points), and by 2.1 points in the 12 mg/day group (P=0.217, treatment difference of −0.7 points) compared with a reduction of 1.4 points in the placebo group (Figure 3.3).¹³

In the RIM-TD trial, patients on AUSTEDO experienced a gradual reduction in AIMS total scores over time (Figure 3.4), with 67% and 42% of patients achieving ≥50% and ≥70% improvement in AIMS total score, respectively, by Week 145.¹⁷

Across both placebo-controlled studies in patients with TD, adverse reactions reported in ≥2% of patients treated with AUSTEDO are shown in Table 3.1.^14,18 Across both studies, 4% of patients required dose reduction of AUSTEDO due to adverse events (AEs) versus 2% of patients taking placebo.¹⁴ At baseline, 56% of patients treated with AUSTEDO across both studies were taking concomitant antidepressant therapy.¹⁸

Adverse reactions with AUSTEDO XR are expected to be similar to AUSTEDO.

In the RIM-TD trial, tolerability was maintained through Week 158, suggesting that long-term treatment with AUSTEDO has demonstrated tolerability in patients with TD, including those who are concomitantly taking APDs.¹⁷

The TD patient population is diverse, comprising patients with myriad comorbid conditions that require various and varied medications.^12,13 Polypharmacy and pathways of drug metabolism are important considerations when choosing a treatment for TD, as drug-drug interactions can become a concern for patients taking concomitant medications.¹⁴

Clinical trials of AUSTEDO included patients with a broad range of primary conditions, including gastrointestinal disorders, depression, bipolar disorder, schizophrenia, and schizoaffective disorder.^12,13,18 Overall, approximately 98% of patients enrolled in AIM-TD and ARM-TD had an underlying psychiatric comorbidity for which they were receiving concomitant medications, including, but not limited to, antidepressants, APDs, anxiolytics, antiepileptics, hypnotics and sedatives, and opioids. Notably, 64% of patients were receiving concomitant atypical APDs and 12% were receiving concomitant typical or combination APDs.¹⁴

These patients also had multiple comorbid conditions, including a range of cardiovascular disorders, such as arrythmia, hypertensive heart disease, atrial fibrillation, coronary artery disease, and myocardial ischemia.¹⁸ In addition, patients had a history of metabolism and lipid disorders, including diabetes, dyslipidemia, hypercholesterolemia, and hyperlipidemia. Patients were taking a variety of medications to treat these comorbidities, including angiotensin-converting enzyme (ACE) inhibitors, beta blockers, antiarrhythmic drugs, blood-glucose lowering drugs, and lipid-modifying agents.

Approximately half of all medications overall are metabolized through the CYP3A4 pathway.¹⁹ Another 30% of medications are metabolized through the CYP2D6 pathway. AUSTEDO XR is metabolized primarily through CYP2D6, with minor contribution from CYP3A4/5 and other enzymes, but AUSTEDO XR is neither an inducer nor inhibitor for these enzyme pathways.^14,20 Because AUSTEDO XR is principally metabolized through the CYP2D6 pathway, the maximum daily dose of AUSTEDO XR should not exceed 36 mg in patients taking strong CYP2D6 inducers or in those who are poor CYP2D6 metabolizers (Table 3.2).

AUSTEDO XR is the only FDA-approved VMAT2 inhibitor with no recommendations against concomitant use with CYP3A4 inducers or inhibitors; as such, AUSTEDO XR should be considered for patients with TD who are receiving strong CYP3A4 inducers or inhibitors for underlying conditions (Table 3.2).^14,20.21

AUSTEDO XR is a VMAT2 inhibitor indicated for the treatment of adult patients with TD.¹⁴ AUSTEDO XR has no recommendations against concomitant use with CYP3A4 inhibitors or inducers, and therefore, should be considered for patients taking those medications.