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Journal of Psychiatric Practice:
doi: 10.1097/01.pra.0000415076.28497.8e
COLUMNS: Psychopharmacology

Clinically Important Differences in the Pharmacokinetics of the Ten Newer “Atypical” Antipsychotics: Part 1


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SHELDON H. PRESKORN, MD, is Professor, Department of Psychiatry, University of Kansas School of Medicine-Wichita, and Chief Science Officer and Medical Direc tor, Kansas University-Wichita Clinical Trials Unit (KU-W CTU), Wichita, Kansas.

He has more than 35 years of drug development research experience at all levels (i.e., preclinical through Phase IV) and has been a principal investigator on over 300 clinical trials including every antidepressant marketed in the United States over a period of 25 years. Dr. Preskorn maintains a website at where readers can access previous columns and other publications.

Disclosure statement: During a career of over 30 years in clinical psychopharmacology, Dr. Preskorn has worked with over 85 pharmaceutical companies in the United States and throughout the world. Over the past year, Dr. Preskorn has received grants/research support from or has served as a consultant for, on the advisory board, or on the speakers bureau for the following: Abbott, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Cyberonics, Dey Pharma, Eisai, Johnson & Johnson, Lundbeck, Merck, National Institute of Mental Health, Naurex, Orexigen, Pierre Fabre, Pfizer, Stanley Medical Research Institute, Sunovion, and the U.S. Food and Drug Administration. Of special relevance to this series, Dr. Preskorn has over his career been an investigator on either industry and/or federally sponsored studies of every antipsychotic mentioned in this series.

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The “atypical” antipsychotics are grouped together by what they are not (i.e., not dopamine2 selective antagonists like haloperidol). While sharing that characteristic, these agents differ substantially in pharmacokinetics and pharmacodynamics. This column, the first in a series on these agents, reviews the bioavailability and half-life of the 10 newer “atypical” antipsychotics, including the most recently marketed members of this class (asenapine, iloperidone, and lurasidone). Drugs with high oral bioavailability are generally less susceptible to diet or drug-drug interactions affecting first pass metabolism. The converse is true for drugs with lower oral bioavailability (e.g., they may have a food effect in which oral bioavailability is decreased in the fasted versus fed state). The half-life of an antipsychotic agent in large measure determines whether it can be safely and effectively administered once a day, at least in an immediate release formulation. Pharmacokinetic differences among atypical antipsychotics can explain why some individuals may not respond to the usually effective dose of a drug, while others may be especially sensitive to its dose-dependent adverse effects. An understanding of pharmacokinetic differences among the atypical antipsychotics can help clinicians optimize drug selection and dose for specific patients under specific treatment conditions. Subsequent columns in this series on atypical antipsychotics will discuss their metabolism, including the principal enzyme(s) mediating each drug’s clearance, effects of co-administration of substantial CYP enzyme inhibitors, effect of hepatic and renal impairment, and the substantial and clinically important pharmacodynamic differences among these agents. (Journal of Psychiatric Practice 2012;18:199–204)

So called “atypical” antipsychotic medications are grouped together more by virtue of what they are not (i.e., not a dopamine-2 or D2 selective receptor antagonist such as haloperidol) rather than what they are. For this reason, there is considerable variability among these drugs in terms of their pharmacodynamics (i.e., what they do to the body) and pharmacokinetics (i.e., what the body does to them). This series of columns will focus on the some of the clinically significant differences among these drugs, including the three most recently approved antipsychotic agents (asenapine, iloperidone, and lurasidone), in the following pharmacokinetic parameters:

1. The bioavailability of the drug,

2. The half-life of the drug.

3. The enzyme(s), if any, principally responsible for the biotransformation of the drug prior to elimination from the body,

Although this column focuses on pharmacokinetic differences, I will begin with a few comments about pharmacodynamics because they are central to the concept of “atypicality.” Historically, this concept arose from the contrast between the clinical pharmacology of clozapine and that of haloperidol and other conventional antipsychotics (also termed neuroleptics). The five characteristics that generally distinguish clozapine from haloperidol are shown in Table 1.1–3 The greater affinity for serotonin (5hydroxytryptophan, 5-HT) 2A than D2 is generally thought to account for the lower risk of acute and chronic extrapyramidal side effects (EPS) and prolactin elevation seen with clozapine versus haloperidol. The greater affinity for the 5-HT2A versus the D2 receptor was a core concept in the discovery efforts that produced all of the current “atypical” antipsychotics. The exception to this general statement is aripiprazole, which is a partial D2 agonist in contrast to haloperidol, which is a full D2 antagonist.4 As discussed in an earlier column, chlorpromazine and other early “low potency” antipsychotics could also be classified as atypical antipsychotics based on the criteria listed in Table 1.1

Table 1
Table 1
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With these few comments for context, this column will focus on clinically meaningful differences in pharmacokinetics among the “atypical” antipsychotics. While these drugs share some pharmacodynamic properties, many of them differ substantially in their pharmacokinetic profiles. In an earlier column, I discussed the four ways in which drugs are generally classified: (1) structure, (2) pharmacodynamics, (3) pharmacokinetics, and 4) therapeutic use.5 While therapeutic use is the most common way in which prescribers think about drugs, it is of little value when it comes to psychiatric medications. Instead, classification based on pharmacodynamics and pharmacokinetics is much more clinically useful. Parenthetically, both of these characteristics stem from the drug’s structure (i.e, its molecular makeup). Equation 1, which is familiar to readers of this column, summarizes the relationships between the pharmacodynamics and pharmacokinetics of a drug and the biological variance that exists among patients.

Equation (Uncited)
Equation (Uncited)
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Table 2 summarizes pharmacokinetic characteristics of each of the newer “atypical” antipsychotics. The following sections discuss clinically meaningful differences among these medications in their bioavailability and half lives. The next column in this series will discuss the other information shown in Table 2 in more detail. Note that the pharmacokinetic values listed in the table are taken from the prescribing information for each drug and thus represent the shared assessment of the U.S. Food and Drug Administration and the manufacturer of each drug.

Table 2
Table 2
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This measure refers to the fraction of an orally administered drug that makes it into the systemic circulation and eventually to the target of interest (e.g., a specific receptor or other regulatory protein in the brain). The bioavailability of some drugs (e.g., iloperidone) is high, so that almost 100% of the orally administered drug is absorbed from the gastrointestinal (GI) tract into the systemic circulation; however, the opposite is true for other drugs (e.g., when asenapine is administered orally, only 2/100 mg [i.e., 2%] of the agent is absorbed into the body from the GI tract). Drugs with a high oral bioavailability are generally less susceptible to diet or drug interactions, whereas the converse is true for drugs with low oral bioavailability. For example, before the development of asenapine could move forward, an orally disintegrating tablet had to be developed to allow for clinically meaningful absorption of the drug. If this tablet is swallowed rather than being allowed to disintegrate into the oral cavity, the drug will not generate a clinically meaningful drug concentration in the central compartment (i.e., blood) nor at the target (i.e., the D2 receptor in the mesolimbic system) presumed to mediate the desired clinical action of the drug (i.e., antipsychotic efficacy).

In the case of some drugs (e.g., asenapine), their low bioavailability is principally due to their physiochemical properties, including dissolution and lipophilicity characteristics. In the case of other drugs (e.g., lurasidone), their low bioavailability is in part the result of extensive metabolism in the gut wall by the cytochrome P450 enzyme (CYP) 3A4 prior to absorption into the systemic circulation or the process of being actively pumped out of the mucosal cells lining the gut back into the bowel by a transport protein such a p-glycoprotein. For other drugs (e.g., ziprasidone), low bioavailability is due to a combination of these factors.

Absolute bioavailability has not been established for all drugs or at least that information is not in the public domain. An example is quetiapine.13,16 Only the “relative” bioavailability of the immediate release oral formulation in comparison to an oral solution is given in the prescribing information and the literature, and it is reported to be the same.

Parenthetically, a number of drugs that are metabolized via CYP 3A4, of which quetiapine is one, undergo substantial first pass metabolism, which can lower their effective absolute bioavailability.

Drugs with relatively low oral bioavailability are at increased risk for having a food effect, meaning that the oral bioavailability is decreased in the fasted versus the fed state, as is the case with lurasidone and ziprasidone.17 This issue is not germane to asenapine because its delivery system (i.e., the disintegrating tablet) is designed to permit absorption across the oral mucosa. However, that is also why the drug’s labeling recommends that patients not eat or drink anything for 10 minutes after taking asenapine; otherwise, a portion of the drug would be absorbed into the food and pass into the GI tract where its absorption is low.

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This term generally refers to the time necessary to clear half of the remaining drug from the plasma compartment. Given that central nervous system drugs such as antipsychotics generally have high lipophilicity and a large volume of distribution, they accumulate in the brain, the target organ. For the same reason, their clearance from the brain and hence from their receptor targets takes longer than their clearance from the plasma. For this reason, drugs with half-lives longer than 12 but less than 24 hours can often be administered once a day with reasonable efficacy and tolerability. That is why the immediate release formulations of most of the drugs shown in Table 2 can be administered once daily. The exceptions are quetiapine and ziprasidone, because their half-lives are appreciably shorter than 12 hours. However, quetiapine is now available in a sustained release formulation that allows for once a day administration. A once daily formulation of ziprasidone has not been produced, most likely due to reduced bioavailability as it passes down the GI tract. Risperidone may initially appear to be an exception to the rule that a half-life greater than 12 hours is necessary for a drug to be effective and safe when administered once a day. However, risperidone is biotransformed into the active metabolite, 9hydroxyrisperidone or paliperidone, which has an average half-life of 18 hours. In fact, the plasma concentration of this metabolite is the predominant circulating moiety in most patients. The exception is individuals who are either deficient in CYP 2D6 or have very low activity due to genetic variation (i.e., CYP 2D6 poor metabolizers and some intermediate metabolizers) or CYP 2D6 extensive metabolizers who are taking a substantial CYP 2D6 inhibitor (e.g., paroxetine, 20 mg/day or more).

The half-lives of the drugs in Table 2 are dependent on whether and how they undergo phase I and II metabolism. In the case of those drugs whose biotransformation is dependent on a CYP enzyme that can be induced or inhibited, their half-lives will change as a function of such induction or inhibition. In addition, clearance of a drug that is dependent principally on a polymorphic CYP enzyme will be different in individuals who are intact or deficient in that CYP enzyme. This illustrates the concept of personalized medicine based on genetic differences among patients. For example, the half-life of iloperidone is 18 hours in individuals with normal CYP 2D6 and 3A4 activity, but 33 hours in individuals who are genetically deficient in CYP 2D6. The same would also be true for individuals who are receiving a concomitant substantial CYP 2D6 inhibitor in addition to iloperidone.

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While a group of drugs may belong to the same therapeutic class and even share some pharmacodynamic characteristics, they can differ in clinically important ways in their pharmacokinetics. This column reviewed differences among atypical antipsychotics in two pharmacokinetic parameters, bioavailability and half-life. Subsequent columns will focus on other pharmacokinetic parameters, including effects of oxidative versus non-oxidative drug metabolism and the enzyme(s), if any, principally responsible for the biotransformation of the drug prior to elimination from the body, as well as clinical considerations that arise in using these agents in patients with impaired renal and/or hepatic function. In addition to the pharmacokinetic differences among the atypical antipsychotics, they also differ in clinically important ways in their pharmacodynamics. That aspect will also be discussed in a subsequent column.

By understanding the general principles presented in this series of columns, the prescriber will be better able to optimize drug selection and dose for a specific patient under specific conditions.

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1. Preskorn SH. The evolution of antipsychotic drug therapy; Reserpine, chlorpromazine, and haloperidol. J Psychiatr Pract. 2007;13:253–60

2. Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther. 1989;251:238–46

3. Meltzer HY, Matsubara S, Lee JC. The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs. Psychopharmacol Bull. 1989;25:390–2

4. Tadori Y, Forbes RA, McQuade RD, et al. In vitro pharmacology of aripiprazole, its metabolite and experimental dopamine partial agonists at human dopamine D2 and D3 receptors. Eur J Pharmacol. 2011;668:355–65

5. Preskorn SH. Drugs are an acquired source of biological variance among patients. J Psychiatr Pract. 2006;12:391–6

6. Abilify (aripiprazole) prescribing information, February 2012, Bristo-Meyers Squibb and Otsuka Pharmaceutical (available at, accessed May 4, 2012).
7. Saphris (asenapine) prescribing information, October 2011, Merck and Company (available at /asenapine/saphris/hcp/default.jsp, accessed May 4, 2012).
8. Clozaril (clozapine) prescribing information, October 2011, Novartis Pharmaceuticals (available at, accessed May 4, 2012).
9. Fanapt (iloperidone) prescribing information, January 2012, Novartis Pharmaceuticals (available at, accessed May 4, 2012)
10. Latuda [lurasidone] prescribing information, April 2012, Sunovion Pharmaceuticals (available at /LatudaPrescribingInformation.pdf, accessed May 3, 2012).
11. Zyprexa (olanzapine) prescribing information, June 2011, Eli Lilly (available at, accessed May 4, 2012).
12. Invega (paliperidone) prescribing information, September 2011, Janssen Pharmaceuticals (available at, accessed May 4, 2012).
13. Seroquel (quetiapine) prescribing information, February 2012, AstraZeneca Pharmaceuticals (available at, accessed May 4, 2012).

14. Risperdol (risperidone) prescribing information, Septem ber 2011, Janssen Pharmaceuticals (available at, accessed May 4, 2012)
15. Geodon (ziprasidone) prescribing information, December 2010, Pfizer (available at, accessed May 4, 2012).
16. DeVane CL, Nemeroff CB. Clinical pharmacokinetics of quetiapine: An atypical antipsychotic. Clin Pharmacokinet. 2001;40:509–22

17. Lincoln J, Stewart ME, Preskorn SH. How sequential studies inform drug development: Evaluating the effect of food intake on optimal bioavailability of ziprasidone. J Psychiatr Pract. 2010;16:103–14


atypical antipsychotics; pharmacokinetics; bioavailability; half-life; cytochrome P450 enzymes

© 2012 Lippincott Williams & Wilkins, Inc.


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