As noted in the first two columns in this series, medications are generally classified in one of four ways: 1) structure, 2) pharmacodynamics, 3) pharmacokinetics, and 4) therapeutic use.1,2 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 organic chemistry). 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.
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). The first two columns in this series focused on clinically significant differences among the atypical antipsychotics in bioavailability, half life, and metabolism. This third column in the series discusses the effect hepatic and renal impairment has on the clearance and hence dosing recommendations for these agents. Note that the pharmacokinetic values listed in the table on page 434 are taken from the product label for each drug and thus represent the shared assessment of the U.S. Food and Drug Administration (FDA) and the manufacturer of each drug.
SCOPE OF THE PROBLEM
As noted in the second column in this series, clinicians frequently encounter patients who have an unusual response to a given dose of a medication. For this discussion, “usual” refers to the dose-response data reflected in the product label (i.e., the doses that are efficacious, safe, and well tolerated). However, the patients in most registration efficacy trials are a narrow subset of all patients due to the often extensive inclusion and exclusion criteria that are part of such protocols. Thus, patients in clinical trials are often not the “usual” patient treated by clinicians. Patients who do not respond in a manner consistent with the clinical trial data summarized in the product label are commonly referred to in practice as being “sensitive” or “resistant” to the effects of the medication in question. The FDA approaches this issue of outliers on the usual dose-response curve found in registration clinical trials by using the concept of “special populations,” with dose adjustments for these populations reflected in the product label. Two of the special populations that are usually included in product labels are patients with renal or hepatic impairment.
Of note, all of the medications reviewed in this column have a labeled indication for the treatment of patients with schizophrenia and several also have a labeled indication for the treatment of patients with bipolar disorders and/or major depression. Patients with these psychiatric conditions in turn have an increased likelihood of suffering from a variety of general medical conditions, including obesity, hypertension, diabetes, and atherosclerosis. They also have an increased likelihood of suffering from alcohol and other substance abuse and dependence. These conditions in turn increase the risk that these patients will also be suffering from renal and/or hepatic impairment. For these reasons, the information reviewed in this column is of particular relevance when choosing among the drugs reviewed here and selecting the most appropriate doses for treating such patients.
SPECIAL POPULATIONS WITH RENAL AND HEPATIC IMPAIRMENT
Table 1 presents the standard definitions that are commonly accepted in general medicine and hence by the U.S. FDA to quantify the degree of hepatic or renal impairment. Thus, these are the terms that are generally used in the sections on dosing and special populations in FDA-approved product labels. The Child-Pugh Score was originally developed by Child and Turcotte in 1964.3 It was subsequently modified by Pugh and colleagues in 1973.4 The degree of hepatic impairment is graded on a point system of 1 to 3 for each of five measures: 1) total bilirubin, 2) serum albumin, 3) prothrombin time, 4) ascites, and 5) hepatic encephalopathy. The score is predictive of 1 and 2 year survival rates: 100% and 85% for mild, 81% and 57% for moderate, and 45% and 35% for severe. Readers interested in more details on how to calculate a patient’s Child-Pugh Score are referred to en.wikipedia.org/wiki/Child-Pugh_score and depts.washington.edu/uwhep/calculations/childspugh.htm.
As part of a new drug’s development,5–7 separate singleor multiple-dose studies are done in individuals with varying degrees of renal or hepatic impairment to determine whether the pharmacokinetics of the drug are altered to a clinically meaningful degree by such impairment. Based on these results, guidance is provided in the product label for using the drug in patients with such impairment (Table 2). Although these studies would meet the criteria for phase I clinical trials, in which the emphasis is on safety, tolerability, and pharmacokinetics rather than efficacy, they are typically conducted during phase III. That is because the decision to proceed with these studies is contingent upon availability of sufficient phase II and III evidence of efficacy relative to any safety or tolerability concerns to conclude that the drug will likely be marketed. Without such evidence, there would be no reason to expose these special populations to the drug or to incur the expense of such studies.
The information in the following sections is based on the product labeling for the various agents.8–17
In a single dose study of 15▒mg of aripiprazole, the Cmax of aripiprazole and dehydro-aripiprazole was increased by 36% and 53%, respectively, in individuals with severe renal impairment compared with normal controls, but aripiprazole exposure (area under the curve [AUC]) was 15% lower for aripiprazole and 7% higher for dehydro-aripiprazole. Given that renal excretion of both unchanged aripiprazole and dehydro-aripiprazole is less than 1% of the dose, no dosage adjustment is required for patients with renal impairment.
In a single dose study of 15▒mg of aripiprazole, the AUC of aripiprazole was increased by 31% and 8%, and decreased by 20% in individuals with mild, moderate, and severe hepatic impairment, respectively, compared with normal controls. Based on these results, no dose adjustment is required in individuals with hepatic impairment.
In a single dose study of 5▒mg of asenapine, asenapine exposure (i.e., AUC) was similar in individuals with varying degrees of renal impairment compared with normal controls. Hence, no dose adjustment is required for renal impairment.
In a single dose study of 5▒mg of asenapine, asenapine exposure (i.e., AUC) was 7 times higher in individuals with severe hepatic impairment compared with normal controls. Thus, asenapine is not recommended for use in patients with severe hepatic impairment.
The history of clozapine is important in understanding its product label. Clozapine is the oldest of the “atypical” antipsychotics discussed in this series, and it was, in fact, the blueprint for the development of these newer antipsychotics. It was first synthesized in the late 1950s and it was available in some European countries for more than 25 years before it was approved in the United States. In fact, the manufacturer had to be encouraged by the FDA and academic psychiatrists to develop it for the U.S. market. It is unique among all antipsychotics in being approved based on its efficacy in patients with otherwise treatment-resistant schizophrenia. It was approved in this way because of its significant toxicity, including a relatively high, dose-dependent risk of seizures and a non-dose-dependent risk of agranulocytosis.
Clozapine’s history probably accounts for the fact that no renal and hepatic impairment studies were done with this agent. Most likely such studies were not required in its submission package—despite the fact that clozapine is extensively metabolized by the liver into numerous metabolites the clinical pharmacology of which has not been extensively studied or at least not published in the public domain. For all of these reasons, the product label for clozapine recommends that caution should be exercised when treating individuals with renal and/or hepatic impairment.
In a single dose study of 3▒mg of iloperidone, the AUCs of iloperidone and its two major metabolites, P88 and P95, were, on average, increased by 24%, decreased by 6%, and increased by 52%, respectively, in individuals with severe renal impairment compared with normal controls. The Cmax values for iloperidone and its two metabolies were minimally changed. Given these data and the fact that iloperidone is extensively metabolized with less than 1% of the drug excreted unchanged, no dosage adjustment is recommended when using this drug in individuals with renal impairment.
A study in individuals with hepatic impairment was apparently not submitted in the new drug application for iloperidone. Given the absence of these data coupled with the extensive hepatic metabolism of iloperidone mentioned above, iloperidone is not recommended for use in patients with hepatic impairment.
Dose adjustment is recommended in individuals with moderate and severe renal or hepatic impairment. The recommended starting dose in such individuals is 20▒mg/day. The maximum recommended dose is 80▒mg/day in individuals with moderate or severe renal impairment or moderate hepatic impairment and 40▒mg/day in individuals with severe hepatic impairment.
The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment or mild to moderate hepatic impairment compared with normal controls. The results in individuals with renal impairment are consistent with the fact that olanzapine is extensively metabolized before excretion, so that only 7% of a dose is excreted as olanzapine. Of note, olanzapine is not removed by dialysis. Given the extensive pre-clearance hepatic metabolism of olanzapine and the absence of data, olanzapine should be dosed cautiously in individuals with severe hepatic impairment.
In a single dose study of 3▒mg of paliperidone (also known as 9-hydroxyrisperidone), elimination decreased with decreasing estimated renal function. Total clearance of paliperidone was reduced by 32%, 64%, and 71% in individuals with mild, moderate, and severe renal impairment, respectively. That decrease in clearance corresponded to an average increase in exposure (AUC) of 1.5 fold, 2.6 fold, and 4.8 fold, respectively, compared with exposure in normal controls. There was also an increase in half-life from 23 hours in normal controls to 24, 40, and 51 hours in individuals with mild, moderate, and severe renal impairment, respectively.
Based on these results, dosing of paliperidone should be individualized according to the patient’s renal function. For patients with mild renal impairment, the recommended initial dose of paliperidone is 3 mg once a day and the recommended maximum dose is 6▒mg once a day depending on efficacy and tolerability. For patients with moderate to severe renal impairment, the recommended initial dose of paliperidone is 1.5▒mg once a day and the recommend maximum dose is 3▒mg once a day depending on efficacy and tolerability. Paliperidone has not been studied in individuals with estimated creatinine clearance below 10▒ml/min and hence its use is not recommended in such patients.
A similar pharmacokinetic study found no difference in plasma concentrations of free paliperidone in individuals with moderate hepatic impairment compared with normal individuals, even though there was a decrease in total (bound and free) paliperidone exposure in individuals with moderate hepatic impairment due to a decrease in total protein binding. Based on these results, no dosage adjustment of paliperidone is recommended for patients with mild or moderate hepatic impairment.
Mean oral clearance of quetiapine was 25% lower in individuals with severe renal impairment compared with normal individuals. However, the plasma concentrations of quetiapine were in the same ranges in individuals with renal insufficiency as in individuals with normal renal function. Based on these results, dosage adjustment of quetiapine is not recommended when treating individuals with renal insufficiency.
Individuals with hepatic impairment (N = 8) had a 30% lower mean clearance of quetiapine than individuals with normal hepatic function. In two of these individuals, the AUC and Cmax were 3 times higher than those observed in normal subjects given the same dose. Based on these results and the fact that quetiapine is extensively metabolized in the liver, dose adjustment downward may be needed when treating individuals with varying degrees of hepatic impairment.
Clearance of risperidone and its active metabolite, paliperidone (also known as 9-hydroxyripseridone), was decreased 60% in individuals with moderate to severe renal impairment compared with individuals with normal renal function. Hence, care should be taken when treating patients with renal impairment with risperidone and monitoring renal function may be useful.
The pharmacokinetics of the total (i.e., free plus bound) concentration of risperidone was comparable in individuals with hepatic impairment and normal controls. However, the mean free fraction of risperidone in plasma was increased because of diminished concentration of both albumin and alpha-1 acid glycoprotein. For this reason, dose reduction of risperidone is recommended in patients with hepatic impairment.
In a study in which 20▒mg was administered twice a day for 8 days, the pharmacokinetics of ziprasidone was comparable in individuals with varying degrees of renal impairment and in individuals with normal renal function. Those results, coupled with the fact that ziprasidone is highly metabolized so that less than 1% is excreted unchanged, support the conclusion that dosage adjustment of the oral formulation of ziprasidone is not needed in such patients. Of note, ziprasidone is not removed by hemodialysis.
In a study in which 20▒mg of ziprasidone was administered twice a day for 5 days, the AUCs of ziprasidone increased by 13% and 34% in individuals with mild and moderate hepatic impairment, respectively, compared with individuals with normal hepatic function. As expected, the mean half-life of ziprasidone was longer in individuals with mild to moderate hepatic impairment versus normal controls (7.1▒h vs. 4.8▒h). These findings are consistent with the fact that hepatic metabolism plays a substantial role in the clearance of ziprasidone. Nevertheless, the magnitude of these changes did not result in a recommendation for ziprasidone dosage adjustment in the presence of hepatic impairment.
Studies with the acute intramuscular (IM) form of ziprasidone have not been done in individuals with renal or hepatic impairment. Since the cyclodextrin excipient used in the IM preparation is cleared by renal filtration, IM ziprasidone should be administered with caution in patients with renal impairment.
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 from a pharmacokinetic perspective. Such is the case with the newer “atypical” antipsychotics discussed in this series of columns. That is why some individuals may not respond to the usually effective dose of a drug, while others are especially sensitive to dose-dependent adverse effects. This column, the third in this series, focused on the effect of renal or hepatic impairment on the pharmacokinetics of each of the newer “atypical” antipsychotics and reviewed the dose adjustments for such impairment contained in the product labels for each drug. In addition to the pharmacokinetic differences among these drugs, the newer atypical antipsychotics also differ in clinically important ways in their pharmacodynamics, a topic that will be discussed in a subsequent column. By understanding the general principles presented here, prescribers will be better able to optimize drug selection and dosing for a specific patient under specific conditions and understand the reasons behind the need for individualizing the dose for that specific patient.
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2. Preskorn SH. Clinically important differences in the pharmacokinetics of the ten newer “atypical” antipsychotics: Part 2. Metabolism and elimination. J Psychiatr Pract. 2012;18:361–8
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4. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646–9
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7. Macaluso M, Krams M, Preskorn SH. Phase I trials: From traditional to newer approaches part II. J Psychiatr Pract. 2011;17:277–84
8. Abilify (aripiprazole) prescribing information, February 2012, Bristol-Meyers Squibb and Otsuka Pharmaceutical (available at www.abilify.com
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9. Saphris (asenapine) prescribing information, October 2011, Merck and Company (available at hcp.saphris.com/asenapine/saphris/hcp/default.jsp
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10. Clozaril (clozapine) prescribing information, October 2011, Novartis Pharmaceuticals (available at www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf
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11. Fanapt (iloperidone) prescribing information, January 2012, Novartis Pharmaceuticals (available at www.pharma.us.novartis.com/product/pi/pdf/fanapt.pdf
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12. Latuda [lurasidone] prescribing information, April 2012, Sunovion Pharmaceuticals (available at www.latuda.com/LatudaPrescribingInformation.pdf
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13. Zyprexa (olanzapine) prescribing information, June 2011, Eli Lilly (available at pi.lilly.com/us/zyprexa-pi.pdf
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14. Invega (paliperidone) prescribing information, September 2011, Janssen Pharmaceuticals (available at www.invegasustenna.com/important-product-information
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15. Seroquel (quetiapine) prescribing information, February 2012, AstraZeneca Pharmaceuticals (available at www1.astrazeneca-us.com/pi/Seroquel.pdf
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16. Risperdol (risperidone) prescribing information, September 2011, Janssen Pharmaceuticals (available at www.risperdal.com/prescribing.html
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17. Geodon (ziprasidone) prescribing information, December 2010, Pfizer (available at labeling.pfizer.com/ShowLabeling.aspx?id=584
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