Psychosomatics 46:262-273, June 2005
© 2005 The Academy of Psychosomatic Medicine
The Dosing of Atypical Antipsychotics
Jose de Leon, M.D.,
Scott C. Armstrong, M.D., and
Kelly L. Cozza, M.D.
Dr. de Leon is the Medical Director of the University of Kentucky Mental Health Research Center, Eastern State Hospital, Lexington; and Associate Professor of Psychiatry, College of Medicine, University of Kentucky, Lexington. Dr. Armstrong is the Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, Ore., and Associate Clinical Professor of Psychiatry, Oregon Health Sciences University, Portland, Ore. Dr. Cozza is a staff psychiatrist for the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, D.C., and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, Md. Drs. Armstrong and Cozza are co-authors, along with Dr. Jessica R. Oesterheld, of the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-glycoproteins, 2nd edition (American Psychiatric Publishing, Inc., 2003). Address correspondence and reprint requests to Dr. de Leon, Mental Health Research Center at Eastern State Hospital, 627 West Fourth St., Lexington, KY 40508; jdeleon{at}uky.edu (e-mail).
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
|
ABSTRACT
|
Drug-drug interactions or genetic variability may require using doses different from those recommended for atypical antipsychotics. Dosage alterations of olanzapine and clozapine, dependent on cytochrome P450 1A2 (CYP1A2) for clearance, and quetiapine, dependent on cytochrome P450 3A (CYP3A), may be necessary when used with other drugs that inhibit or induce their metabolic enzymes. Smoking cessation can significantly increase clozapine, and perhaps olanzapine, levels. Ziprasidone pharmacokinetic drug-drug interactions are not likely to be important. Genetic variations of cytochrome P450 2D6 (CYP2D6) and drug-drug interactions causing inhibition (CYP2D6 and/or CYP3A) or induction (CYP3A) may be important for risperidone, and perhaps for aripiprazole, dosing. Adding inhibitors may cause side effects more easily in drugs with a narrow therapeutic window, such as clozapine or risperidone, than in those with a wide therapeutic window, such as olanzapine or aripiprazole. Adding inducers may be associated with a gradual development of lost efficacy.
|
INTRODUCTION
|
The two main types of drug-drug interactions are classified as either pharmacodynamic or pharmacokinetic. Atypical antipsychotic pharmacodynamic drug-drug interactions occur at the receptor level. They generally are intuitive and are well described in general psychiatry textbooks. This review focuses on pharmacokinetic drug interactions, which are associated with drug concentration changes and can be explained by changes in absorption, distribution, biotransformation, and excretion. Increasing detailed knowledge in biotransformation by metabolic enzymes has led the Food and Drug Administration (FDA) to request pharmaceutical companies to study drug metabolic enzymes before new drugs are approved for release. The most important metabolic enzymes are the cytochrome P450 (CYP) enzymes. The less well understood uridine 5'-diphosphate glucuronosyltransferases (UGTs)1 and other enzymes will only be briefly mentioned here.
The three most important CYPs involved in atypical antipsychotic metabolism are CYP3A, CYP2D6, and CYP1A2. CYP3A is the most abundant CYP subfamily and metabolizes many nonpsychiatric medications. CYP2D6 is the main metabolic pathway for many old drugs, such as typical antipsychotics, tricyclic antidepressants, and some new drugs. CYP1A2 appears to be an important metabolic pathway for clozapine and olanzapine. CYP3A, CYP2D6, and CYP1A2 can be inhibited. CYP3A and CYP1A2 can be induced, while CYP2D6 induction is controversial, but it appears likely not to be clinically relevant. For an excellent and highly educative description of possible drug-drug interaction patterns with metabolic inhibitors and inducers, see a prior update.2 The chronology of inhibition and induction differs. Inhibition reaches its maximum effect when the inhibitor has reached a steady state, while inducers usually take up to 3–4 weeks to reach a maximum effect, which is dependent on the synthesis of new enzymes. The different mechanisms also explain the different chronology after the discontinuation of inhibitors and inducers.
The dosing recommendations provided by all drug package labels, including those of atypical antipsychotics, are generated by "average subject" dose response in double-blind studies that forbid most co-prescriptions. Therefore, these dosing recommendations may be appropriate for the "average subject" taking only atypical antipsychotics. In the real world, most patients taking atypical antipsychotics take other drugs (psychiatric or nonpsychiatric). Moreover, polypharmacy is often the norm in the consultation/liaison, med-psych setting. The use of multiple medications increases the possibility that clinically relevant drug-drug interactions are likely to occur, necessitating dose corrections for atypical antipsychotics.
A linear relationship exists between most or all usual atypical antipsychotic doses and concentrations, particularly within the same subject. The concentration-dose ratio (C/D), a simple formula, can assist in appreciating this relationship.3 For example, it is believed that plasma clozapine concentrations exceeding 350 ng/ml are therapeutic and that most patients require 300–600 mg/day to reach these levels.4–6 If one assumes that 300 mg/day is needed to reach 350 ng/ml, this provides a C/D of 1.2 (or 350/300). Conversely, if one assumes that a 600-mg/day dose is needed to reach 350 ng/ml, this provides a C/D of 0.6 (or 350/600). Therefore, the average patient taking clozapine has a C/D of 0.6–1.2. Adding an inhibitor increases the C/D, while adding an inducer will lead to a decrease of the C/D ratio. A factor of 2 change in the C/D is probably meaningful from the clinician’s point of view.3 An inhibitor increasing the C/D by 2 may require halving the atypical antipsychotic dose (a correction factor of 0.5). An inducer decreasing the C/D by half may require doubling an atypical antipsychotic dose (a correction factor of 2 in the tables). Small C/D changes are unlikely to be detected above the "noise" when measuring plasma levels in the clinical environment.7,8
|
PSYCHIATRIC DRUGS THAT ARE INHIBITORS OR INDUCERS
|
Psychiatric drugs have the potential to cause drug-drug interactions with atypical antipsychotics. Many antidepressants are metabolic inhibitors, and several anticonvulsants or mood stabilizers are inducers. Inhibition and/or induction profiles of psychiatric drugs are well published. However, researchers and reviewers do not always agree in regard to the potency of inhibition or induction or to their clinical significance. Nevertheless, we believe that sufficient information suggests that paroxetine, fluoxetine, and bupropion are major CYP2D6 inhibitors.9–13 Fluvoxamine inhibits CYP1A2. Nefazodone is the most powerful CYP3A inhibitor among antidepressants but the list of clinically significant CYP3A inhibitors includes fluoxetine (particularly its metabolite, norfluoxetine) and fluvoxamine. There is less agreement about sertraline, which may inhibit several CYPs, including CYP2D6, in high doses.9–13 Citalopram and escitalopram are generally considered mild CYP inhibitors but may have the potential to cause some CYP2D6 inhibition.12,13 The limited published information suggests that citalopram causes no clinically significant changes in clozapine14,15 or risperidone14 levels. Therefore, citalopram and escitalopram are not described again in this review. More studies are needed to definitively establish that mild CYP inhibition by citalopram and escitalopram has limited clinical relevance.
Anticonvulsants and/or mood stabilizers, such as carbamazepine and phenytoin, are powerful inducers of several CYP, including CYP3A and UGTs.3,16 Phenobarbital and primidone are less frequently used in psychiatric patients but are also powerful metabolic inducers. Valproic acid is not an inducer; however, it inhibits UGTs and some CYPs (particularly CYP2C9). Gabapentin, levetiracetam, and tiagabine are neither metabolic inducers nor inhibitors. Three other anticonvulsants that are usually considered weak inducers are topiramate, lamotrigine, and oxcarbazepine.3,16 Topiramate may mildly induce CYP3A. Lamotrigine is probably a weak UGT inducer. In a recent review,3 one of us (J.d.L.) described oxcarbazepine as a weak inducer that is unlikely to cause clinically significant induction. However, new publications17 and new clinical experience appear to indicate that oxcarbazepine has the potential to be an inducer of CYP3A and UGTs.
|
CLINICAL RELEVANCE OF DRUG-DRUG INTERACTIONS
|
Co-administration of atypical antipsychotics with other medications that could either induce or inhibit the metabolism of the atypical antipsychotic appears to be a common practice. Two separate studies,18,19 with a total group size of more than 500 risperidone-treated patients, indicated that up to 33% were prescribed paroxetine or fluoxetine, both potent inhibitors of 2D6, one of two enzymes that metabolize risperidone. These same studies showed that up to 30% of the patients were concomitantly prescribed carbamazepine, a potent inducer of 3A4, the other enzyme involved in risperidone metabolism. These percentages suggest that co-prescribing atypical antipsychotics with inducers and inhibitors may be frequent. Moreover, in consultation-liaison settings, nonpsychiatric drug inducers and inhibitors can further complicate the situation.
Not all patients treated with polypharmacy may have clinically significant drug-drug interactions, but they are at risk. The atypical antipsychotic dose, other co-medications, the dose and potency of the inhibitor or /inducer, and the specific metabolic pathways involved may be important. The pharmacological concept of the therapeutic window is necessary to understand the clinical relevance of drug-drug interactions.20 The therapeutic window determines the plasma level’s clinical significance, particularly after the addition of inhibitors. Two atypical antipsychotics, clozapine and olanzapine, are dependent on CYP1A2 for their oxidative metabolism. Compared to olanzapine, clozapine has a much narrower therapeutic index; therefore, adding an inhibitor to clozapine is potentially more serious than adding it to olanzapine. Similarly, risperidone and aripiprazole probably have relatively similar metabolic pathways that are dependent primarily on CYP2D6 and CYP3A. Although studies of plasma aripiprazole level have not been published, this drug probably has a wider therapeutic window than risperidone, with less inhibitor problem potential. Adding inducers can be problematic for all atypical antipsychotics, but quetiapine, which is mainly dependent on CYP3A, may have levels that are lowered more dramatically when a CYP3A inducer is co-administered.
The medical literature can be influenced by drug company openness and by the chronology of changes in FDA requirements. In the last 5 years, after several drugs were withdrawn because of associated drug-drug interactions, the FDA began asking companies to conduct pharmacokinetic studies before marketing new drugs. More recently marketed drugs, such as olanzapine, quetiapine, ziprasidone, and aripiprazole, have been progressively subjected to better-controlled pharmacokinetic studies with inhibitors and inducers. When compared with industry pharmacokinetic studies, clinician-published naturalistic studies and case reports measuring drug levels are less controlled but important; they reflect the real world and are less biased. Many atypical antipsychotic pharmacokinetic studies conducted by pharmaceutical companies are limited because they used single doses of the atypical antipsychotic instead of multiple doses. Other studies were too brief, a major problem for inducers that require several weeks to reach maximum effects. Until clinicians begin publishing their experience with co-prescription and drug levels, establishing whether pharmaceutical company studies reflect the real world can be difficult. Therefore, we recommend caution: if the potential for a particular drug-drug interaction is not yet well studied or proven, it does not imply that it cannot occur. The absence of evidence is not evidence of absence. Many potential drug-drug interactions may occur in "real world" situations and can be predictable based on our pharmacokinetic knowledge.
Individual genetic variability may also be important. Some subjects, because of genetic reasons, may not be "average." Subjects with little to no enzymatic activity are phenotypically described as poor metabolizers. Subjects with increased enzyme activity are called ultrarapid metabolizers, and some appear to have repeated (more than two) active gene copies.21,22 There is limited understanding and experience of drug-drug interactions in these extreme patients.
CLOZAPINE AND OLANZAPINE
CYP1A2 explains 70% of clozapine’s metabolism.23 Other CYPs (CYP2D6, CYP2C9, CYP2C19, and CYP3A) may be involved in minor clozapine pathways but are probably not relevant for clinicians. In vitro studies suggest that clozapine is metabolized by CYP3A;24 clinical studies with several powerful CYP3A inhibitors suggest that drug interactions with CYP3A inhibitors may not be important for clozapine in typical doses.25–27 Other metabolic pathways may include the flavin-containing monoxygenase system and UGTs (possibly UGT1A3 and UT1A4).1
Phenotypical population studies have not shown clear cases of poor CYP1A2 metabolizers or ultrarapid metabolizers but suggest that females tend to have lower CYP1A2 activity than males. CYP1A2 metabolizes some female sexual hormones; the resulting competition may explain lower female activity. Moreover, pregnant women probably have even lower CYP1A2 activity28 particularly close to delivery; thus, it is likely that clozapine and olanzapine levels may increase in pregnant women.
The CYP1A2 gene is located in the long arm of chromosome 15; a few genetic variations have been described. Two polymorphisms influencing inducer response were described in Japanese and Caucasians.22 However, a recent study described that the Caucasian variation failed to affect clozapine levels in the clinical environment.29 One French patient with a high clozapine C/D of 4.3 (compared to the average C/D of 0.6–1.2), suggesting a poor CYP1A2 metabolizer status, had a heterozygous CYP1A2 mutation.30 A few cases of patients who appear to quickly metabolize clozapine have been published, but the underlying genetic variations are unknown. One of these patients, thought to have a high metabolic capacity to destroy clozapine,31 had a C/D <0.17. In summary, genetic variations should explain only rare cases (<1%) of patients needing very high or very low clozapine doses to reach therapeutic levels.
CYP1A2 is the most important CYP for olanzapine metabolism.32 Although the literature does not provide good estimations of the overall importance of CYP1A2 in olanzapine metabolism, small clinical studies33,34 have found correlations of 0.7 to 0.8 between olanzapine levels and CYP1A2 activity indexes; these correlations suggest that CYP1A2 may explain approximately 50%–60% of olanzapine’s metabolism. Other minor oxidation enzymes are CYP2D6 and flavin-containing monoxygenase. More importantly, UGTs, possibly UGT1A4, appear to play an important role in olanzapine’s metabolism.1,35
Compared to olanzapine, clozapine’s therapeutic index is much narrower. Several of clozapine’s side effects are dose related, and levels higher than 1,000 ng/ml have been associated with toxicity, including risk of seizure and severe sedation.36 Measuring plasma clozapine levels is advisable when inhibitors or inducers need to be added or discontinued in clozapine patients. Certainly, drugs with similar pharmacodynamic properties that lack metabolic inhibitory or inductive properties may be preferred in clozapine patients because of clozapine toxicity.
Inducers
Environmental influences on clozapine and olanzapine metabolism are much more relevant for clinicians than rare CYP1A2 genetic variants. Inducers can increase clozapine and olanzapine metabolism by increasing CYP1A2 and UGT activity (Table 1). Polycyclic aromatic hydrocarbons in tobacco smoke induce clozapine and olanzapine metabolism.20 Thus, if a clozapine or olanzapine patient smokes, smoking cessation would probably cause an average patient’s drug blood level to increase by an average of 1.5 (Table 1) 2–4 weeks later.20
View this table:
[in this window]
[in a new window]
|
TABLE 1. Inhibitors and Inducers of Clozapine and Olanzapine, With Recommendations and Correction Factors (please be aware that correction factors are average estimations based on current available literature)
|
Clinicians should be aware of the roles smoking and gender play in clozapine metabolism. An average female nonsmoker requires low clozapine doses (around 300 mg/day) to reach therapeutic levels, while an average heavy male smoker may require high doses (around 600 mg/day). Male nonsmokers and female smokers fall in between.4–6,20 Obviously, these average results may not apply to all individuals. In the future, it is hoped that genetics may help us individualize clozapine doses.
In a large naturalistic olanzapine study, neither gender nor smoking predicted olanzapine mean or high doses.47 The reason for this is that olanzapine may be less dependent than clozapine on CYP1A2 metabolism and UGT1A4 may have a major role.35,47 Naturalistic studies of clozapine (or caffeine, another typical CYP1A2 substrate) easily demonstrate gender and smoking effects.
Some anticonvulsants, particularly phenytoin and carbamazepine, induce the metabolism of clozapine and olanzapine.3 Carbamazepine’s effects on olanzapine metabolism have been studied and seem to be mediated mainly by increasing UGT activity.35 Similarly, anticonvulsants may induce clozapine’s metabolism by increasing UGT activity. Carbamazepine, however, should not be prescribed in the United States with clozapine because of the concern of an increased risk of agranulocytosis. Olanzapine or large clozapine doses may be needed when one of these powerful anticonvulsant inducers is co-prescribed (Table 1). It is too soon to know if lamotrigine’s mild UGT inductive properties are relevant for patients taking clozapine and olanzapine.1 Most valproic acid studies in clozapine or olanzapine patients suggest no effect or small variations that may not be clinically relevant and hard to detect above the "noise" of measuring clozapine levels in "the real world."
Inhibitors
Most people in the United States may have detectable plasma caffeine levels from consuming caffeinated beverages or some foods.48 Caffeine is highly dependent (>90%) on CYP1A2 for its metabolism.48 It can competitively inhibit clozapine and olanzapine metabolism and cause clinically significant drug-drug interactions.20 Steady caffeine doses in a stabilized clozapine or olanzapine patient should not concern clinicians. However, clozapine and olanzapine patients should be warned to avoid "dramatic" changes (up or down) in caffeine intake. Changes (increases or decreases) of daily caffeine intake by >1 cup of coffee (or two cans of caffeinated soda) in nonsmokers or changes of >3 cups (or six caffeinated cans of soda) in smokers may be relevant.20
Other clinically relevant clozapine and olanzapine inhibitors are fluvoxamine and cimetidine (Table 1). The fluroquinolones, particularly ciprofloxacin and norfloxacin, are powerful CYP1A2 inhibitors45 and can cause increased levels of clozapine and olanzapine. Other fluroquinolones, including gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and trovafloxacin, do not appear to inhibit CYP1A245 and can be safely prescribed for clozapine and olanzapine patients (Table 1). Macrolides,45,49 such as erythromycin and clarithromycin, are powerful CYP3A inhibitors. Although the clinical data are inconclusive, high erythromycin doses may also inhibit CYP1A2, varying from patient to patient.49 Generally, macrolides co-prescribed with clozapine, and probably with olanzapine, may be relatively free of drug-drug interactions, but close monitoring is recommended.
A complicating factor in patients taking antimicrobial agents is that serious respiratory infections (pneumonias and upper respiratory infections with fever) release cytokines, which in turn inhibit CYP1A2 activity and synthesis.7,25 The available published information urges clinicians treating clozapine patients to be careful if patients develop serious respiratory infections with fever and to pay particular attention to any signs suggesting clozapine toxicity (severe sedation, myoclonus, or even seizures). The clozapine dose should be reduced at least by half (correction factor of 0.5, see Table 1) if clozapine toxicity signs are present until the patient has recovered from the infection.25 Other serious infections, such as appendicitis, may also have similar effects.46 The same recommendation may also apply to olanzapine.7,25 However, compared to clozapine, since olanzapine has a wider therapeutic range and less bothersome adverse drug reactions, this may be less of an issue with olanzapine.
|
QUETIAPINE
|
In vitro studies suggest that although CYP2D6 and CYP2C9 may contribute to quetiapine’s metabolism, CYP3A4 is the major metabolic pathway for quetiapine.50 The CYP3A enzyme subfamily genes are located in chromosome 7 and include CYP3A5, an auxiliary enzyme, and CYP3A4, the main enzyme. CYP3A5 shares a high homology with CYP3A4 and appears to metabolize the same substrates.22 CYP3A5 is deficient in approximately 80% of Caucasians and 20% of African Americans.19 The clinical relevance of the CYP3A5 polymorphism is unclear. The literature has not identified any subjects lacking CYP3A4 expression. As with CYP1A2 substrates, environmental influences on CYP3A are more likely to explain unusual quetiapine C/D cases than genetic variations.
The p-glycoprotein is a xenobiotic pump controlled by a gene called MDR1 that is also located on chromosome 7. The p-glycoprotein is located in the enterocyte near CYP3A4 and shares its substrates, inhibitors, and inducers. At the enterocyte, CYPA4 and the p-glycoprotein work jointly to decrease substrate bioavailability. A CYP3A4 drug will be destroyed by CYP3A4 and transported back to the lumen by the p-glycoprotein.
Inducers
Anticonvulsant inducers have dramatic effects in quetiapine metabolism (Table 2). They should be avoided unless the clinician is willing to dramatically increase the dose (by a factor of 5).51 Because of quetiapine metabolism’s high sensitivity to induction, mild inducers, such as topiromate and oxacarbazepine, may have clinically important effects.
View this table:
[in this window]
[in a new window]
|
TABLE 2. Inhibitors and Inducers of Quetiapine, With Recommendations and Correction Factors (please be aware that correction factors are average estimations based on current available literature)
|
Inhibitors
Protease inhibitors can inhibit CYP3A39 and, therefore, quetiapine metabolism. Ritonavir is by far the most potent CYP3A inhibitor, followed by indinavir and atazanavir. Amprenavir, lopinavir, nelfinavir, amprenavir, and saquinavir are less potent CYP3A inhibitors.39
Antifungal agents (ketoconazole), macrolides (clarithromycin and erythromycin), and nefazadone are also powerful CYP3A inhibitors.45 Fluvoxamine, fluoxetine, and high sertraline doses may cause lower but clinically relevant CYP3A inhibition.9–13
|
ZIPRASIDONE
|
The cytosolic aldehyde oxidase metabolizes approximately two-thirds of ziprasidone. CYP3A has a relatively minor metabolic role.55 A study that was well designed by a pharmaceutical company but was too short in length to mimic clinical practice suggested that the effects of a CYP3A inducer (carbamazepine) on ziprasidone C/D may not be clinically relevant56 and will require a minor dose change (multiply the ziprasidone dose by 1.5). We recommend close clinical follow-up for 3–4 weeks after adding a potent CYP3A inducer (Table 2) to the regimen of a ziprasidone patient to avoid losing prior ziprasidone response. More important, discontinuing a CYP3A inducer needs to be followed by a follow-up in 2–3 weeks to assess new ziprasidone adverse drug reactions.
To avoid liability, clinicians should avoid co-prescribing potent CYP3A inhibitors (Table 2) with ziprasidone. If co-administration is necessary, we recommend documenting discussing with the patient the increased QTc risk and/or checking an ECG before and after adding the CYP3A inhibitor. A pharmaceutical company study57 reported that adding a powerful CYP3A inhibitor, ketoconazole, and suggested a small plasma ziprasidone level increase, implying a low pharmacological risk for drug-drug interactions with inhibitors.
|
RISPERIDONE AND ARIPIPRAZOLE
|
The CYP2D6 enzyme activity varies due to over 50 CYP2D6 gene alleles (chromosome 22).21,22 The poor metabolizer is the most clinically significant phenotype and is associated with lack of the enzyme.19 In Caucasians, 7% are poor metabolizers and 1–7% are ultrarapid metabolizers. The proportion of poor metabolizers in other races is 1% to 3%. The proportion of ultrarapid metabolizers may be higher (approximately 25%) in North African and Middle Eastern populations.22
CYP2D6 is a major metabolic pathway for risperidone, whose main active metabolite is 9-hydroxyrisperidone. Studies from risperidone’s marketer suggest that 9-hydroxyrisperidone and risperidone have similar pharmacodynamic activity. A small study in 11 volunteers suggested that two poor CYP2D6 metabolizers and nine extensive metabolizers have similar total plasma concentrations of the total risperidone moiety (the sum of risperidone and 9-hydroxyrisperidone).58 Thus, risperidone’s marketer proposed that CYP2D6 polymorphisms are therapeutically unimportant for risperidone.58 One of us (J.d.L.) has studied more than 40 psychiatric patients who were poor CYP2D6 metabolizers.19,59 After we corrected for confounding variables, poor CYP2D6 metabolizers had over three times the risk (odds ratio of 3.4) of significant risperidone adverse drug reactions and six times more risk of discontinuing risperidone (odds ratio of 6.0) because of adverse drug reactions (versus other reasons).19 The effects of a CYP2D6 poor metabolizer phenotype were consistent, powerful, and important for the individual. The main way to avoid risperidone’s adverse drug reactions in CYP2D6 poor metabolizers may be to prescribe small doses. Case reports suggest that CYP2D6 ultrarapid metabolizers may need high risperidone doses.60,61
A drug-drug interaction with carbamazepine led to the hypothesis that risperidone may also be metabolized by CYP3A.62 An in vitro study verified that CYP3A further metabolizes risperidone and 9-hydroxyrisperidone.63 Known genetic variants in CYP3A519 and MDR119,64 do not appear to influence adverse drug reactions19 or levels.64
Plasma risperidone and 9-hydroxyrisperidone concentrations can be used to interpret risperidone drug interactions.59 Clinicians need to understand two plasma ratios (the C/D and the risperidone/9-hydroxyrisperidone concentrations). By adding plasma risperidone and 9-hydroxyrisperidone concentrations (total risperidone concentration), one calculates the concentration for C/D. In a patient taking 6 mg/day, one should expect a plasma risperidone concentration of 9 ng/ml and a plasma 9-hydroxyrisperidone concentration of 33 ng/ml. This provides a total risperidone concentration (C) of 42 ng/ml. Thus, the C/D is 7 (42/6). Typical risperidone doses provide a C/D of approximately 7.65 A C/D change by a factor of 2 is probably meaningful from the clinician’s point of view.3 If this patient’s total blood level exceeds 84 ng/ml, a genetic and/or environmental factor causing the patient to metabolize risperidone two times slower than the average patient should be suspected. This level (84 ng/ml) is equivalent to the blood level of an average patient taking 12 mg/day of risperidone. Similarly, if a patient takes 6 mg/day and his or her blood level is 21 ng/ml, one should suspect a lack of risperidone compliance or some genetic and/or environmental factor that causes the patient to metabolize risperidone two times faster than the average patient. This level (21 ng/ml) is equivalent to the blood level of an average patient taking 3 mg/day of risperidone.65 CYP3A inducers decrease the C/D ratio, and CYP3A inhibitors increase the C/D ratio.
The risperidone/9-hydroxyrisperidone concentration is an index of CYP2D6 activity.19,59,66 The normal plasma risperidone/9-hydroxyrisperidone is<1 (approximately 0.2). A typical risperidone patient taking 4 mg/day may have a respective plasma concentration of 5 ng/ml for risperidone and 23 ng/ml for 9-hydroxyrisperidone. Therefore, the risperidone/9-hydroxyrisperidone concentration will be 0.2 (5/23). A plasma inverted ratio>1 (risperidone concentration greater than 9-hydroxyrisperidone concentration) indicates a CYP2D6 poor metabolizer or the presence of a powerful CYP2D6 inhibitor.19,59,66
Similarly, aripiprazole appears to depend on CYP2D6 and CYP3A for its metabolism.67 Because pharmacokinetic studies of this recently marketed drug have yet to be published, the limited available drug-drug interactions come from the package insert. Similarly, CYP2D6 genetic studies of aripiprazole response are unpublished. Because of limited aripiprazole adverse drug reactions and a likely wide therapeutic window, being a CYP2D6 poor metabolizer may be less important than with risperidone treatment, but CYP2D6 ultrarapid metabolizers may not respond to usual aripiprazole doses.
Inducers
Adding carbamazepine to risperidone or aripiprazole will decrease their plasma levels. One should consider a progressive doubling of the dose (Table 3) to maintain adequate plasma levels. It would be wiser to consider the same strategy after adding other CYP3A inducers, including phenytoin, phenobarbital, or primidone. Adding oxcarbazepine may also require risperidone or aripiprazole dose increases, but there are no published data, to our knowledge, to estimate a correction factor.
View this table:
[in this window]
[in a new window]
|
TABLE 3. Inhibitors and Inducers of Risperidone and Aripiprazole, With Recommendations and Correction Factors (please be aware that correction factors are average estimations based on current available literature)
|
Inhibitors
Adding CYP2D6 inhibitors, such as paroxetine or bupropion, can invert risperidone/9-hydroxyrisperidone and increase risperidone’s risk of adverse drug reactions. They should be avoided or associated with close monitoring and lower risperidone doses.19,59 Adding CYP3A inhibitors decreases the C/D and may also increase risperidone’s adverse drug reactions. Fluoxetine, which can inhibit both CYP2D6 and CYP3A, may be accompanied by increased risperidone C/D ratios by a factor of 3–4,59 the inversion of risperidone/9-hydroxyrisperidone, and side effects. Similarly, another CYP3A and CYP2D6 inhibitor, ritonavir, can cause serious risperidone toxicity.39 The aripiprazole package insert recommends decreasing aripiprazole by half when adding a CYP2D6 inhibitor and indicates that a low dose of a powerful CYP3A inhibitor, ketoconazole, will increase levels requiring a decrease in half of the dose (correction factor, 0.5; Table 3).
|
EFFECTS OF ATYPICAL ANTIPSYCOTICS ON OTHER DRUGS
|
Prior sections have focused on the effects of other drugs on the different atypical antipsychotics and did not describe the atypical antipsychotic’s potential to change other compound plasma concentrations. Atypical antipsychotics appear to be neither significant inhibitors nor inducers of metabolic enzymes. Their package inserts describe that atypical antipsychotics are unlikely to cause drug-drug interactions. However, in unusual polypharmacy situations where patients take drugs with a narrow therapeutic window, adding an atypical antipsychotic may be the straw that breaks the camel’s back through competitive inhibition of multiple drugs vying for particular metabolic enzymes. Several case reports suggest that atypical antipsychotics may potentially cause drug-drug interactions. Clozapine may compete with tricyclic antidepressants that are partially metabolized by CYP1A2, increasing their levels and toxicity potential.43 In two cases, adding quetiapine to carbamazepine caused increases of carbamazepine 10,11-epoxido because of CYP3A4 inhibition that lead to neurological toxicity in one patient.53
|
CONCLUSION
|
In conclusion, consulation-liaison psychiatrists need to remember that patients may require higher or lower usual doses of atypical antipsychotics because of genetic variability and/or drug-drug interactions. Low or high C/Ds can frequently occur, respectively, because of inducers or inhibitors on patients taking olanzapine and clozapine (dependent on CYP1A2 for clearance) and quetiapine (dependent on CYP3A). The starting, or more important, the cessation of smoking can later change clozapine levels significantly, and perhaps, to some degree, olanzapine levels. Pharmacokinetic drug-drug interactions are not likely to be important for ziprasidone (CYP3A minor pathway), but independent studies by clinicians are needed. The CYP2D6 polymorphism (poor metabolizers and ultrarapid metabolizers) and drug-drug interactions at CYP2D6 (inhibition) and at CYP3A (inhibition or induction) may be important for risperidone dosing and perhaps for aripiprazole dosing. Adding inhibitors may cause side effects more easily in drugs with a narrow therapeutic window (clozapine or risperidone) than in those with a wide therapeutic window (olanzapine or aripiprazole). Adding inducers may be associated with a lack of response. Clinicians need to remember that drug-drug interactions are highly individualized problems that are probably influenced by individual factors, such as genetics and the co-occurrence of other factors, such as other co-medications.
|
ACKNOWLEDGMENTS
|
During the last 2 years, Dr. de Leon had researcher-initiated proposals funded by Eli Lilly Research Foundation and Roche Molecular Systems. He was on the advisory board of Astra-Zeneca and Bristol-Myers-Squibb and lectured once supported by Eli Lilly.
Dr. de Leon wants to acknowledge his past mentor, George M. Simpson, M.D., for his current interest and encouragement in Dr. de Leon’s quest for deeper knowledge of atypical antipsychotic pharmacokinetics. Miranda van der Molen-Eijgenraam, Pharm.D., was kind to translate her article on clozapine and infections into English and provide details to Dr. de Leon.
|
REFERENCES
|
- de Leon J: Glucuronidation enzyme genes and psychiatry. Int J Neuropsychopharmacol 2003; 6:57–72[CrossRef][Medline]
- Armstrong SC, Cozza KL, Sandson NB: Six patterns of drug-drug interactions. Psychosomatics 2003; 44:255–258[Abstract/Free Full Text]
- de Leon J: Psychopharmacology. atypical antipsychotic dosing: the effect of co-medication with anticonvulsants. Psychiatr Serv 2004; 55:125–128[Free Full Text]
- Perry PJ, Bever KA, Arndt S, Combs MD: Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram. Biol Psychiatry 1998; 44:733–738[CrossRef][Medline]
- Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ: Influence of dose, cigarette smoking, age, sex and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol 2004; 24:70–78[CrossRef][Medline]
- Simpson GM, Josiassen RC, Stanilla JK, de Leon J, Nair C, Abraham G, Odom-White A, Turner RM: Double-blind study of clozapine dose response in chronic schizophrenia. Am J Psychiatry 1999; 156:1744–1750[Abstract/Free Full Text]
- de Leon J, Diaz FJ: Serious respiratory infections can increase clozapine levels and contribute to side effects. Prog Neuro-Psychopharmacol Biol Psychiatry 2003; 27:1059–1063[CrossRef][Medline]
- Diaz FJ, de Leon J, Josiassen RC, Cooper TB, Simpson GM: Plasma clozapine concentration coefficients of variation in a long-term study. Schizophr Res 2005; 72:131–135[CrossRef][Medline]
- Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI: Drug interactions with newer antidepressants: Role of human cytochromes P450. J Clin Psychiatry 59(suppl 15):19–27, 1998
- Preskorn SH: Outpatient Management of Depression. 2nd Ed. Caddo, OK, Professional Communications, Inc., 1999
- Lacy CF, Goldman MP, Lance LL: Drug Information Handbook Pocket 2004–2005. Hudson, OH, Lexi-Comp Inc, 2004
- Brosen K: Some aspects of genetic polymorphism in the biotransformation of antidepressants. Therapie 2004; 59:5–12[Medline]
- Jeppsen U, Gram LF, Vistisen K, Loft S, Poulsen HE, Brosen K: Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 1996; 51:73–78[CrossRef][Medline]
- Taylor D, Ellison Z, Shaw LE, Wickham H, Murray R: Co-administration of citalopram and clozapine: effects on plasma clozapine levels. Int Clin Psychopharmcol 1998; 13:19–21
- Avenoso A, Facciola G, Scordo MG, Gitto C, Ferrante GD, Media AG, Spina E: No effect of citalopram on plasma levels of clozapine, risperidone and their active metabolites in patients with chronic schizophrenia. Clin Drug Invest 1998; 16:393–398[CrossRef]
- Anderson GD: A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 1998; 32:554–563[Abstract]
- Baird P: Beware of cytochrome P450 inducers. Curr Psychiatry 2002; 1:11–16
- Martin K, Begaud B, Verdoux H, Lechevallier N, Latry P, Moore N: Patterns of risperidone prescription: a utilization study in south-west France. Acta Psychiatr Scand 2004; 109:202–206[CrossRef][Medline]
- de Leon J, Susce MT, Pan RM, Fairchild M, Koch W, Wedlund PJ: The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry 2005; 66:15–27[Medline]
- de Leon J: Psychopharmacology. atypical antipsychotic dosing: the effect of smoking and caffeine. Psychiatr Serv 2004; 55:491–493[Free Full Text]
- Ingelmann-Sundberg M: Human drug metabolizing cytochrome P450 enzymes: properties and polymorphism. Naunyn-Schmiedeberg’s Arch Pharmacol 2004; 369:89–104[CrossRef][Medline]
- Dahl ML: Cytochrome P450 phenotyping/genotyping in patients receiving antipsychotics. useful aid to prescribing. Clin Pharmacokinet 2002; 41:453–470[CrossRef][Medline]
- Bertilsson L, Carrillo JA, Dahl ML, Llerena A, Alm C, Bondesson U, Lindstrom L, de la Rubia I, Ramos S, Benitez J: Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. Br J Clin Pharmacol 1994; 38:471–473[Medline]
- Linnet K, Olesen OV: Metabolising of clozapine by cDNA-expressed human cytochrome P450 enzymes. Drug Met Disposition 1997; 25:1379–1382
- de Leon J: Respiratory infections rather than antibiotics may increase clozapine levels: a critical review of the literature (letter). J Clin Psychiatry 2004; 65:1144–1145[Medline]
- Hagg S, Spigset O, Mjorndal T, Granberg K, Persbo-Lunqvist G, Dahlqvst R: Absence of interaction between erythromycin and a single dose of clozapine. Eur J Clin Pharmacol 1999; 55:221–226[CrossRef][Medline]
- Raaska K, Neuvonen PJ: Serum concentration of clozapine and N-desmethylclozapine are unaffected by the potent CYP3A4 inhibitor itraconazole. Eur J Clin Pharmacol 1998; 54:167–170[CrossRef][Medline]
- Knutti R, Rothweiller H, Schlatter C: The effects of pregnancy on the pharmacokinetics of caffeine. Arch Toxicol 1982; 5 Suppl:187–192
- Van der Weide J, Steijns LS, van Weelden MJ: The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics 2003; 13:169–172[CrossRef][Medline]
- Allorge D, Chevalier D, Lo-Guidice JM, Cauffiez C, Suard F, Baumann P, Eap CB, Broly F: Identification of a novel splice-site mutation in the CYP1A2 gene. Br J Clin Pharmacol 2003; 56:341–344[CrossRef][Medline]
- Bender S, Eap CB: Very high cytochrome P4501A2 activity and non-response to clozapine (letter). Arch Gen Psychiatry 1998; 35:1048–1050[CrossRef]
- Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM: Olanzapine. pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 1999; 37:177–193[CrossRef][Medline]
- Carrillo JA, Herraiz AG, Ramos SI, Gervasini G, Vizcaino S, Benitez J: Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003; 23:119–127[CrossRef][Medline]
- Shirley KL, Hon YY, Penzak SR, Lam YW, Spratlin V, Jann MW: Correlation of cytochrome P450 (CYP) 1A2 activity using caffeine phenotyping and olanzapine disposition in healthy volunteers. Neuropsychopharmacology 2003; 28:961–966[Medline]
- Linnet K, Olesen OV: Free and glucuronidated olanzapine serum concentrations in psychiatric patients: influence of carbamazepine co-medication. Ther Drug Monitor 2002; 24:512–517[CrossRef][Medline]
- Simpson GM, Cooper TA: Clozapine plasma levels and convulsions. Am J Psychiatry 1978; 135:99–100[Abstract/Free Full Text]
- Mookhaek EJ, Loonen AJM: Retrospective evaluation of the effect of omeprazole on clozapine metabolism. Pharm World Sci 2004; 26:180–182[CrossRef][Medline]
- Joos AA, Frank UG, Kaschka WP: Pharmacokinetic interaction of clozapine and rifampicin in a forensic patient with an atypical mycobacterial infection. J Clin Psychopharmacol 1998; 18:83–85[CrossRef][Medline]
- Wynn GH, Zapor MJ, Smith BH, Wortmann G, Oesterheld JR, Armstrong SC, Cozza KL: Antirretrovirals, part I: overview, history and focus on protease inhibitors. Psychosom 2004; 45:262–270
- Penzak SR, Hon YY, Lawhorn WD, Shirley KL, Spratlin V, Jann MW: Influence of ritonavir on olanzapine pharmacokinetics in healthy volunteers. J Clin Psychopharmacol 2002; 22:366–370[CrossRef][Medline]
- Pinninti NR, de Leon J: Interaction of sertraline with clozapine (letter). J Clin Psychopharmacol 1997; 17:119–120[CrossRef][Medline]
- Markowitz JS, Gill HS, Devane LS, Mintzer JE: Fluroquinolone inhibition of clozapine metabolism (letter). Am J Psychiatry 1997; 153:881
- Smith T, Riskin J: The effects of clozapine on plasma nortriptyline concentration. Pharmacopsychiatr 1994; 27:41–42
- Cooke C, de Leon J: Adding other antipsychotics to clozapine (letter). J Clin Psychiatry 1999; 60:710[Medline]
- Pea F, Furlanut M: Pharmacokinetic aspects of treating infections in the intensive care unit. Clin Pharmacokinet 2001; 40:833–868[CrossRef][Medline]
- van der Molen-Eijgenraam M, Blanken-Meijs JT, Heeringa M, van Grootheest AC: Delirium due to increase in clozapine level during an inflammatory reaction. Ned Tijdschr Geneeskd 2001; 145:427–430[Medline]
- Botts S, Littrell R, de Leon J: Variables associated with high olanzapine dosing in a state hospital. J Clin Psychiatry 2004; 65:1138–1143[Medline]
- de Leon J, Diaz FJ, Rogers T, Browne D, Dinsmore L, Ghosheh O, Dwoskin LP, Crooks P: A pilot study of plasma caffeine concentrations in a US sample of smokers and non-smoker volunteers. Prog Neuro-Psychopharmacol Biol Psychiatry 2003; 27:165–171[CrossRef][Medline]
- Westphal JF: Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol 2000; 50:285–295[CrossRef][Medline]
- Gunasekara NS, Spencer CM: Quetiapine. a review of its use in schizophrenia. CNS Drugs 1998; 9:325–340[CrossRef]
- Wong YW, Yeh C, Thyrum PT: The effects of concomitant phenytoin administration on the steady-state pharmacokinetics of quetiapine. J Clin Psychopharm 2001; 21:89–93[CrossRef][Medline]
- Zapor MJ, Cozza KL, Wynn GH, Wortmann GW, Armstrong SC: Antirretrovirals, part II: focus on non-protease inhibitor antriretrovirales (NRTIs, NNRTIs and fusion inhibitors). Psychosomatics 2004; 45:524–526[Abstract/Free Full Text]
- Fitzgerald B, Okos A: Elevation of carbamazepine-10, 11-epoxide by quetiapine. Pharmacotherapy 2002; 22:1500–1503[CrossRef][Medline]
- Potkin SG, Thyrum PT, Alva G, Carreon D, Yeh C, Kalali A, Arvanatis LA, the pharmacokinetic group: effects of fluoxetine and imipramine on the pharmacokinetics and tolerability of the antipsychotic quetiapine. J Clin Psychopharmacol 2002; 22:174–182[CrossRef][Medline]
- Beedham C, Miceli JJ, Obach RS: Ziprasidone metabolism, aldehyde oxidase, and clinical implications. J Clin Psychopharmacol 2003; 23:229–232[CrossRef][Medline]
- Miceli JJ, Anziano RJ, Robarge L, Hansen RA, Laurant A: The effects of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteers. Br J Clin Pharmacol 2000; 49(suppl 1):65S-70S
- Miceli JJ, Smith M, Robarge L, Morse T, Laurent A: The effects of ketoconazole on ziprasidone pharmacokinetics: a placebo-controlled crossover study in healthy volunteers. Br J Clin Pharmacol 2000; 49(suppl 1):71S-76S
- Huang M, Van Peer A, Woestenborghs R, De Coster RD, Heykants J, Jansen AAI, Zylic Z, Visscher HW, Jonkman JHG: Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54:257–268[Medline]
- Bork J, Rogers T, Wedlund P, de Leon J: A pilot study of risperidone metabolism: the role of cytochrome P450 2D6 and 3A. J Clin Psychiatry 1999; 60:469–476[Medline]
- Guzey C, Aamo T, Spigset O: Risperidone metabolism and the impact of being a cytochrome P450 2D6 ultrarapid metabolizer (letter). J Clin Psychiatry 2000; 61:600–601
- Albrecht A, Morena PG, Baumann P, Eap CB: High dose of depot risperidone in a nonresponder schizophrenic patient. J Clin Psychopharm 2004; 24:673–674[CrossRef][Medline]
- de Leon J, Bork JA: Risperidone and the cytochrome P4503A (letter). J Clin Psychiatry 1997; 58:450
- Fang J, Bourin M, Baker GB: Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol 1999; 359:147–151[CrossRef][Medline]
- Yasui-Fururoki N, Mihara K, Takahata T, Suzuki A, Nakagami T, De Vries R, Tateishi T, Kondo T, Kaneko S: Effect of various factors on steady-plasma concentration of risperidone and 9-hydroxyrisperidone: lack of impact of MDR-1 genotypes. Br J Clin Pharmacol 2003; 57:569–575
- Anderson CB, True JE, Ereshefsky L, Miller AL, Peters BL, Velligan DI: Risperidone dose, plasma levels and response. 1993 New Research Program and Abstracts. American Psychiatric Association Annual Meeting, San Francisco, May 1993 (NR 217), p 113
- Ereshefsky L: Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry 57(suppl 11):12–25, 1996
- Harrison TS, Perry CM: Aripiprazole. a review of its use in schizophrenia and schizoaffective disorder. Drugs 2004; 64:1715–1736[CrossRef][Medline]
- Shad MU, Preskorn SH: A possible bupropion and imipramine interaction. J Clin Psychopharm 1997; 17:118–119[CrossRef][Medline]
- Kennedy SH, McCann SM, Masellis M, McIntyre RS, Raskin J, McKay G, Baker GB: Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine. J Clin Psychiatry 2002; 63:181–186[Medline]
This article has been cited by other articles:
|
|
|
|
 
M. J. Arranz and S. Kapur
Pharmacogenetics in Psychiatry: Are We Ready for Widespread Clinical Use?
Schizophr Bull,
November 1, 2008;
34(6):
1130 - 1144.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. de Leon, N. B. Sandson, and K. L. Cozza
A Preliminary Attempt to Personalize Risperidone Dosing Using Drug-Drug Interactions and Genetics: Part II
Psychosomatics,
July 1, 2008;
49(4):
347 - 361.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. de Leon, S. C. Armstrong, and K. L. Cozza
Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19.
Psychosomatics,
January 1, 2006;
47(1):
75 - 85.
[Abstract]
[Full Text]
[PDF]
|
|
|
Get information about faster international access.
Privacy Policy
Copyright © 2005
Academy of Psychosomatic Medicine.
All rights reserved.
Home
| Search
| Current Issue
| Past Issues
| Subscribe
| All APPI Journals
| Help
| Contact Us
|
TOP
ABSTRACT
INTRODUCTION
