Journal of Clinical Psychopharmacology
&
Volume 35, Number 1, February 2015
7. Muscatello MR, Bruno A, Pandolfo G, et al. Effect of aripiprazole augmentation of serotonin reuptake inhibitors or clomipramine in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2011;31:174Y179. 8. Connor KM, Payne VM, Gadde KM, et al. The use of aripiprazole in obsessive-compulsive disorder: preliminary observations in 8 patients. J Clin Psychiatry. 2005;66:49Y51. 9. Murotani T, Ishizuka T, Isogawa Y, et al. Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system. Neuropharmacology. 2011;61:228Y233. 10. Yoshimatsu H. Hypothalamic neuronal histamine regulates body weight through the modulation of diurnal feeding rhythm. Nutrition. 2008;24:27Y31. 11. He M, Deng C, Huang XF. The role of hypothalamic H1 receptor antagonism in antipsychotic-induced weight gain. CNS Drugs. 2013;27:423Y434. 12. DeLeon A, Patel NC, Crismon ML. Aripiprazole: a comprehensive review of its pharmacology, clinical efficacy, and tolerability. Clin Ther. 2004;26:649Y666.
Prolonged Elimination of Paliperidone After Administration of Paliperidone Palmitate Depot Injections To the Editors: aliperidone (9-hydroxy-risperidone), which is the pharmacologically active main metabolite of risperidone, has recently been approved for use as an antipsychotic agent on its own, both for oral (Invega) and intramuscular depot (Invega Sustenna, Xeplion) administration. In the depot formulation, paliperidone is bound to palmitic acid, resulting in high lipid solubility. After intramuscular administration, the drug is slowly dissolved and hydrolyzed to active paliperidone by a first-order process, after which it is absorbed into the circulation.1 The apparent elimination half-life is determined by the absorption rate from the administration site and is approximately 1 month (25Y49 days), allowing for once-monthly administration.1,2 To rapidly achieve therapeutic serum concentrations, higher and more frequent dosing is recommended initially. If a procedure with loading doses is not followed, steady state may not be reached until 4 to 5 months after treatment initiation. Correspondingly, after withdrawal of treatment, pharmacologically active serum concentrations should be expected to linger for as long as 4 to 5 months.
P
In the treatment of chronic psychotic disorders such as schizophrenia, intramuscular depot antipsychotics may offer an advantage over oral antipsychotics in terms of treatment adherence and thus improve outcomes, especially in patients with limited insight into their own condition and the necessity of treatment. The protracted elimination of depot injections provides long-term protection against psychotic breaks, even beyond the designated dosing intervals, thus providing a more robust pharmacological treatment and giving health care personnel more leeway time in cases of nonadherence.2 However, the long elimination time may also have some drawbacks, such as protracted adverse effects (eg, metabolic disturbances) or drug interactions (eg, with other QT-prolonging medications). Clinicians may not be aware that clinically significant plasma concentrations may be present several months after the end of intramuscular therapy. We present a patient with an exceptionally long detection time of paliperidone in serum after the cessation of intramuscular administration. Possible explanations to the prolonged elimination are discussed.
CASE REPORT A 31-year-old obese man with schizophrenia (body weight, 125 kg; body mass index [BMI], 36.1 kg/m2) who had been involuntarily committed to a mental health facility was given a total of 6 intramuscular injections of paliperidone palmitate (total dose in paliperidone equivalents 850 mg) in the gluteal area (alternating sides) during a 129-day (4.3-month) period. The initial dose was 150 mg paliperidone (equal to 234 mg paliperidone palmitate), followed by 100 mg 1 week later. Thereafter, the patient was administered 4 injections of 150 mg approximately once monthly until the medication was stopped. All injections were administered by a trained staff experienced in delivering intramuscular depot injections. Prior to paliperidone treatment, the patient had been administered a total of 5 depot injections of risperidone 37.5 mg with 2 weeks’ intervals. Paliperidone was stopped mainly because of lack of effect despite relatively high doses, and the patient was switched first to perphenazine depot injections, then 4 months later to zuclopenthixole depot injections. His other medications during and after paliperidone therapy were valproic acid 1800 mg/d, clonazepam 0.5 to 1 mg/d as needed, and biperidene 2 to 4 mg as needed. The serum concentration of paliperidone was followed for a total of 19 months after cessation of therapy and was analyzed
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editors
with a liquid chromatographyYmass spectrometry method developed and validated at our laboratory. In brief, 1 mL serum was mixed with 50 KL internal standard (CH3risperidone 4 Kmol/L), 200 KL Na2CO3 (1 mol/L), and 4 mL n-hexane:butanol: acetonitrile (93:5:2) solution. After centrifugation, the organic phase was evaporated to dryness under air, dissolved in 50 KL methanol, and transferred to vials. Samples were then inserted into an Agilent1100 MSD liquid chromatographyYmass spectrometry system (Agilent Hewlett Packard, Santa Clara, Calif). Separation was performed on a Zorbax SB-C18 high-performance liquid chromatography column 4.6 30 mm with methanol:ammonium acetate 50 mmol/L (65:35) mobile phase. Paliperidone was monitored at m/z 427.0, and the internal standard at m/z 421.0. The limit of quantification was 2.5 nmol/L (approximately 1.0 ng/mL). Linearity was achieved over the calibration range of 2.5 to 1000 nmol/L (1.0Y425 ng/mL). The interassay coefficient of variation calculated from quality control samples at 10, 100, and 250 nmol/L (4.3, 43, and 107 ng/mL) was lower than 10%. The conversion factor from ng/mL to nmol/L is 2.34. During treatment, the serum concentration of paliperidone varied between 17 and 24 ng/mL (therapeutic range, 20Y60 ng/mL3), with a slowly increasing trend and the highest value measured at the time of cessation. Subsequently, the paliperidone serum concentration was measured at regular intervals and fell very slowly, until a concentration of 1.3 ng/mL was measured 19 months after cessation (Fig. 1). The apparent elimination half-life was estimated to 142 days, that is, approximately 20 weeks or 4.5 months.
DISCUSSION The patient had a lower than expected serum concentration of paliperidone during treatment with depot injections. In comparison, a prospective study of the pharmacokinetics of intramuscular paliperidone 150 mg monthly showed mean plasma concentrations of 35 and 40 ng/mL after the second and eighth injections, respectively.4 He also showed a considerably longer elimination time after cessation of therapy than expected from the known pharmacokinetic characteristics of the drug. Paliperidone is mainly eliminated unchanged in the urine; hence, impaired renal function may decrease clearance of the drug. Our patient had a normal kidney function (serum creatinine concentration, 0.81 mg/dL). Obesity is associated with lower plasma concentrations of paliperidone,1 which could have contributed to the lower than expected serum concentration during therapy, but www.psychopharmacology.com
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
95
Journal of Clinical Psychopharmacology
Letters to the Editors
&
Volume 35, Number 1, February 2015
Arne Helland, MD Department of Clinical Pharmacology St Olav University Hospital Trondheim, Norway [email protected]
Vigdis Elin Giæver Syrstad, MD Division of Mental Health Care St Olav University Hospital Trondheim, Norway
Olav Spigset, MD, PhD Department of Laboratory Medicine Children’s and Women’s Health Norwegian University of Science and Technology Trondheim, Norway
REFERENCES
FIGURE 1. Semilogarithmic time/concentration plot of paliperidone following the cessation of intramuscular depot injections. The elimination curve shows a high degree of linearity (r = 0.97, P < 0.001). The elimination rate constant was 0.0049 dayj1, which corresponds to an apparent elimination half-life of 142 days.
can hardly explain the prolonged elimination. Drugs that inhibit the P-glycoprotein efflux pump may reduce the clearance of paliperidone.5 However, none of the drugs administered to our patient significantly affect P-glycoprotein. To our knowledge, there have been no reports describing aberrantly long elimination times of paliperidone. A case report described lack of effect of intramuscular injections of haloperidol decanoate in a young, adipose female with schizophrenia. The effect improved significantly after switching from 1.5-inch (38.1-mm) to 2-inch (50.8-mm) injection needles. The authors hypothesized that unintended injection into poorly vascularized subcutaneous fat could have led to delayed and/or erratic absorption of the drug.6 The actual site of drug delivery by intended intramuscular injections in the gluteal area has been investigated by means of computed tomography. The study showed that only 32% of injections with a 30-mm (1.2-inch) needle were actually intramuscular, whereas the rest were subcutaneous. Patients with subcutaneous injections had a thicker subcutaneous fat layer and a thinner muscle layer than those with successful intramuscular injections. In males, BMI correlated significantly to subcutaneous fat thickness.7 As a group, patients with schizophrenia have higher BMI,8 a higher fat percentage, and a lower muscle mass9 than the general population. Our patient was obese, with a BMI of 36.1 kg/m2, and was reported to have an excess of subcutaneous fat. Thus, it seems likely that he had excessive adipose
96
www.psychopharmacology.com
tissue in the area of injection. Needles provided by the manufacturer of Xeplion and Invega Sustenna are 1 inch (25.4 mm) for deltoid injections in patients less than 90 kg and 1.5 inches (38.1 mm) for deltoid injections in patients greater than 90 kg and for gluteal injections. We suspect that this length may be too short for patients with excessive subcutaneous fat. In light of this, erroneous injection into fat tissue seems likely in this case. Delayed absorption from the site of administration may possibly explain both the lower serum concentration than expected during therapy, as well as the excessively long elimination time observed in this case. In conclusion, this case illustrates the possibility of clinically significant blood levels of paliperidone remaining up to a year after cessation of therapy, with trace amounts of the drug being detectable for at least a year and a half. The apparent elimination half-life was 142 days. We hypothesize that erroneous injection into subcutaneous fat may lead to delayed release from fat tissue, resulting in lower than expected blood levels during therapy and prolonged elimination when therapy is stopped. Clinicians should be aware of this pitfall and consider using a longer needle than those provided by the manufacturer in patients with excessive adipose tissue in the area of administration, to ensure proper intramuscular administration. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest.
1. Samtani MN, Vermeulen A, Stuyckens K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic. Clin Pharmacokinet. 2009;48:585Y600. 2. Park EJ, Amatya S, Kim MS, et al. Long-acting injectable formulations of antipsychotic drugs for the treatment of schizophrenia. Arch Pharm Res. 2013;36:651Y659. 3. Hiemke C, Baumann P, Bergemann N, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44:195Y235. 4. Coppola D, Liu Y, Gopal S, et al. A one-year prospective study of the safety, tolerability and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia. BMC Psychiatry. 2012;12:26. 5. Nakagami T, Yasui-Furukori N, Saito M, et al. Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone: in vivo evidence of involvement of P-glycoprotein in risperidone disposition. Clin Pharmacol Ther. 2005;78:43Y51. 6. Brahm NC, Washington NB. Case report: increased patient response to intramuscular haloperidol decanoate following a change in needle length. J Pharm Pract. 2011;24:561Y563. 7. Chan VO, Colville J, Persaud T, et al. Intramuscular injections into the buttocks: are they truly intramuscular? Eur J Radiol. 2006;58:480Y484. 8. Homel P, Casey D, Allison DB. Changes in body mass index for individuals with and without schizophrenia, 1987Y1996. Schizophr Res. 2002;55:277Y284. 9. Saarni SE, Saarni SI, Fogelholm M, et al. Body composition in psychotic disorders: a general population survey. Psychol Med. 2009;39:801Y810.
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
&
Volume 35, Number 1, February 2015
7. Muscatello MR, Bruno A, Pandolfo G, et al. Effect of aripiprazole augmentation of serotonin reuptake inhibitors or clomipramine in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2011;31:174Y179. 8. Connor KM, Payne VM, Gadde KM, et al. The use of aripiprazole in obsessive-compulsive disorder: preliminary observations in 8 patients. J Clin Psychiatry. 2005;66:49Y51. 9. Murotani T, Ishizuka T, Isogawa Y, et al. Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system. Neuropharmacology. 2011;61:228Y233. 10. Yoshimatsu H. Hypothalamic neuronal histamine regulates body weight through the modulation of diurnal feeding rhythm. Nutrition. 2008;24:27Y31. 11. He M, Deng C, Huang XF. The role of hypothalamic H1 receptor antagonism in antipsychotic-induced weight gain. CNS Drugs. 2013;27:423Y434. 12. DeLeon A, Patel NC, Crismon ML. Aripiprazole: a comprehensive review of its pharmacology, clinical efficacy, and tolerability. Clin Ther. 2004;26:649Y666.
Prolonged Elimination of Paliperidone After Administration of Paliperidone Palmitate Depot Injections To the Editors: aliperidone (9-hydroxy-risperidone), which is the pharmacologically active main metabolite of risperidone, has recently been approved for use as an antipsychotic agent on its own, both for oral (Invega) and intramuscular depot (Invega Sustenna, Xeplion) administration. In the depot formulation, paliperidone is bound to palmitic acid, resulting in high lipid solubility. After intramuscular administration, the drug is slowly dissolved and hydrolyzed to active paliperidone by a first-order process, after which it is absorbed into the circulation.1 The apparent elimination half-life is determined by the absorption rate from the administration site and is approximately 1 month (25Y49 days), allowing for once-monthly administration.1,2 To rapidly achieve therapeutic serum concentrations, higher and more frequent dosing is recommended initially. If a procedure with loading doses is not followed, steady state may not be reached until 4 to 5 months after treatment initiation. Correspondingly, after withdrawal of treatment, pharmacologically active serum concentrations should be expected to linger for as long as 4 to 5 months.
P
In the treatment of chronic psychotic disorders such as schizophrenia, intramuscular depot antipsychotics may offer an advantage over oral antipsychotics in terms of treatment adherence and thus improve outcomes, especially in patients with limited insight into their own condition and the necessity of treatment. The protracted elimination of depot injections provides long-term protection against psychotic breaks, even beyond the designated dosing intervals, thus providing a more robust pharmacological treatment and giving health care personnel more leeway time in cases of nonadherence.2 However, the long elimination time may also have some drawbacks, such as protracted adverse effects (eg, metabolic disturbances) or drug interactions (eg, with other QT-prolonging medications). Clinicians may not be aware that clinically significant plasma concentrations may be present several months after the end of intramuscular therapy. We present a patient with an exceptionally long detection time of paliperidone in serum after the cessation of intramuscular administration. Possible explanations to the prolonged elimination are discussed.
CASE REPORT A 31-year-old obese man with schizophrenia (body weight, 125 kg; body mass index [BMI], 36.1 kg/m2) who had been involuntarily committed to a mental health facility was given a total of 6 intramuscular injections of paliperidone palmitate (total dose in paliperidone equivalents 850 mg) in the gluteal area (alternating sides) during a 129-day (4.3-month) period. The initial dose was 150 mg paliperidone (equal to 234 mg paliperidone palmitate), followed by 100 mg 1 week later. Thereafter, the patient was administered 4 injections of 150 mg approximately once monthly until the medication was stopped. All injections were administered by a trained staff experienced in delivering intramuscular depot injections. Prior to paliperidone treatment, the patient had been administered a total of 5 depot injections of risperidone 37.5 mg with 2 weeks’ intervals. Paliperidone was stopped mainly because of lack of effect despite relatively high doses, and the patient was switched first to perphenazine depot injections, then 4 months later to zuclopenthixole depot injections. His other medications during and after paliperidone therapy were valproic acid 1800 mg/d, clonazepam 0.5 to 1 mg/d as needed, and biperidene 2 to 4 mg as needed. The serum concentration of paliperidone was followed for a total of 19 months after cessation of therapy and was analyzed
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editors
with a liquid chromatographyYmass spectrometry method developed and validated at our laboratory. In brief, 1 mL serum was mixed with 50 KL internal standard (CH3risperidone 4 Kmol/L), 200 KL Na2CO3 (1 mol/L), and 4 mL n-hexane:butanol: acetonitrile (93:5:2) solution. After centrifugation, the organic phase was evaporated to dryness under air, dissolved in 50 KL methanol, and transferred to vials. Samples were then inserted into an Agilent1100 MSD liquid chromatographyYmass spectrometry system (Agilent Hewlett Packard, Santa Clara, Calif). Separation was performed on a Zorbax SB-C18 high-performance liquid chromatography column 4.6 30 mm with methanol:ammonium acetate 50 mmol/L (65:35) mobile phase. Paliperidone was monitored at m/z 427.0, and the internal standard at m/z 421.0. The limit of quantification was 2.5 nmol/L (approximately 1.0 ng/mL). Linearity was achieved over the calibration range of 2.5 to 1000 nmol/L (1.0Y425 ng/mL). The interassay coefficient of variation calculated from quality control samples at 10, 100, and 250 nmol/L (4.3, 43, and 107 ng/mL) was lower than 10%. The conversion factor from ng/mL to nmol/L is 2.34. During treatment, the serum concentration of paliperidone varied between 17 and 24 ng/mL (therapeutic range, 20Y60 ng/mL3), with a slowly increasing trend and the highest value measured at the time of cessation. Subsequently, the paliperidone serum concentration was measured at regular intervals and fell very slowly, until a concentration of 1.3 ng/mL was measured 19 months after cessation (Fig. 1). The apparent elimination half-life was estimated to 142 days, that is, approximately 20 weeks or 4.5 months.
DISCUSSION The patient had a lower than expected serum concentration of paliperidone during treatment with depot injections. In comparison, a prospective study of the pharmacokinetics of intramuscular paliperidone 150 mg monthly showed mean plasma concentrations of 35 and 40 ng/mL after the second and eighth injections, respectively.4 He also showed a considerably longer elimination time after cessation of therapy than expected from the known pharmacokinetic characteristics of the drug. Paliperidone is mainly eliminated unchanged in the urine; hence, impaired renal function may decrease clearance of the drug. Our patient had a normal kidney function (serum creatinine concentration, 0.81 mg/dL). Obesity is associated with lower plasma concentrations of paliperidone,1 which could have contributed to the lower than expected serum concentration during therapy, but www.psychopharmacology.com
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
95
Journal of Clinical Psychopharmacology
Letters to the Editors
&
Volume 35, Number 1, February 2015
Arne Helland, MD Department of Clinical Pharmacology St Olav University Hospital Trondheim, Norway [email protected]
Vigdis Elin Giæver Syrstad, MD Division of Mental Health Care St Olav University Hospital Trondheim, Norway
Olav Spigset, MD, PhD Department of Laboratory Medicine Children’s and Women’s Health Norwegian University of Science and Technology Trondheim, Norway
REFERENCES
FIGURE 1. Semilogarithmic time/concentration plot of paliperidone following the cessation of intramuscular depot injections. The elimination curve shows a high degree of linearity (r = 0.97, P < 0.001). The elimination rate constant was 0.0049 dayj1, which corresponds to an apparent elimination half-life of 142 days.
can hardly explain the prolonged elimination. Drugs that inhibit the P-glycoprotein efflux pump may reduce the clearance of paliperidone.5 However, none of the drugs administered to our patient significantly affect P-glycoprotein. To our knowledge, there have been no reports describing aberrantly long elimination times of paliperidone. A case report described lack of effect of intramuscular injections of haloperidol decanoate in a young, adipose female with schizophrenia. The effect improved significantly after switching from 1.5-inch (38.1-mm) to 2-inch (50.8-mm) injection needles. The authors hypothesized that unintended injection into poorly vascularized subcutaneous fat could have led to delayed and/or erratic absorption of the drug.6 The actual site of drug delivery by intended intramuscular injections in the gluteal area has been investigated by means of computed tomography. The study showed that only 32% of injections with a 30-mm (1.2-inch) needle were actually intramuscular, whereas the rest were subcutaneous. Patients with subcutaneous injections had a thicker subcutaneous fat layer and a thinner muscle layer than those with successful intramuscular injections. In males, BMI correlated significantly to subcutaneous fat thickness.7 As a group, patients with schizophrenia have higher BMI,8 a higher fat percentage, and a lower muscle mass9 than the general population. Our patient was obese, with a BMI of 36.1 kg/m2, and was reported to have an excess of subcutaneous fat. Thus, it seems likely that he had excessive adipose
96
www.psychopharmacology.com
tissue in the area of injection. Needles provided by the manufacturer of Xeplion and Invega Sustenna are 1 inch (25.4 mm) for deltoid injections in patients less than 90 kg and 1.5 inches (38.1 mm) for deltoid injections in patients greater than 90 kg and for gluteal injections. We suspect that this length may be too short for patients with excessive subcutaneous fat. In light of this, erroneous injection into fat tissue seems likely in this case. Delayed absorption from the site of administration may possibly explain both the lower serum concentration than expected during therapy, as well as the excessively long elimination time observed in this case. In conclusion, this case illustrates the possibility of clinically significant blood levels of paliperidone remaining up to a year after cessation of therapy, with trace amounts of the drug being detectable for at least a year and a half. The apparent elimination half-life was 142 days. We hypothesize that erroneous injection into subcutaneous fat may lead to delayed release from fat tissue, resulting in lower than expected blood levels during therapy and prolonged elimination when therapy is stopped. Clinicians should be aware of this pitfall and consider using a longer needle than those provided by the manufacturer in patients with excessive adipose tissue in the area of administration, to ensure proper intramuscular administration. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest.
1. Samtani MN, Vermeulen A, Stuyckens K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic. Clin Pharmacokinet. 2009;48:585Y600. 2. Park EJ, Amatya S, Kim MS, et al. Long-acting injectable formulations of antipsychotic drugs for the treatment of schizophrenia. Arch Pharm Res. 2013;36:651Y659. 3. Hiemke C, Baumann P, Bergemann N, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44:195Y235. 4. Coppola D, Liu Y, Gopal S, et al. A one-year prospective study of the safety, tolerability and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia. BMC Psychiatry. 2012;12:26. 5. Nakagami T, Yasui-Furukori N, Saito M, et al. Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone: in vivo evidence of involvement of P-glycoprotein in risperidone disposition. Clin Pharmacol Ther. 2005;78:43Y51. 6. Brahm NC, Washington NB. Case report: increased patient response to intramuscular haloperidol decanoate following a change in needle length. J Pharm Pract. 2011;24:561Y563. 7. Chan VO, Colville J, Persaud T, et al. Intramuscular injections into the buttocks: are they truly intramuscular? Eur J Radiol. 2006;58:480Y484. 8. Homel P, Casey D, Allison DB. Changes in body mass index for individuals with and without schizophrenia, 1987Y1996. Schizophr Res. 2002;55:277Y284. 9. Saarni SE, Saarni SI, Fogelholm M, et al. Body composition in psychotic disorders: a general population survey. Psychol Med. 2009;39:801Y810.
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
