Medical Hypotheses 82 (2014) 225–228
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Clozapine administered once versus twice daily: Does it make a difference? Ric M. Procyshyn a,b,⇑, Fidel Vila-Rodriguez a,b, William G. Honer a,b, Alasdair M. Barr a,c a
British Columbia Mental Health and Addictions Research Institute, 938 W 28th Avenue, Vancouver, B.C. V5Z 4H4, Canada Department of Psychiatry, University of British Columbia, Vancouver V6T 1Z3, Canada c Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada b
a r t i c l e
i n f o
Article history: Received 5 August 2013 Accepted 30 November 2013
a b s t r a c t Clozapine, generally considered to be the most effective antipsychotic, is the gold standard for treatmentresistant schizophrenia. With a relatively short half-life of 12 h and a very quick dissociation rate from the dopamine D2 receptor, pharmacokinetic and pharmacodynamics principles would dictate that clozapine be administered twice daily. However, due to clozapine’s side effects (e.g., sedation), it is often prescribe once daily at bedtime. Even if the patient develops tolerance to the side effects, it is still often prescribed once daily to simplify medication regimens in hopes of increasing adherence. Unfortunately, good intentions and convenience do not always make for optimal pharmacotherapy. Based upon clozapine’s pharmacokinetic and pharmacodynamic profiles, we hypothesize that optimal treatment with clozapine requires it be given twice daily rather than once daily. We present here some pharmacokinetic simulations and published data to support our hypothesis. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction
Pharmacokinetic simulations
Clozapine is the only antipsychotic indicated for treatmentresistant schizophrenia and thus it is important that clinicians do everything possible to optimize its use. To our knowledge, there are no published studies evaluating whether once daily administration of clozapine is better than giving it twice daily in terms of effectiveness and tolerability. Although this may seem trivial at first, when one considers that clozapine has a relatively short half-life and dissociates quickly from the dopamine D2 receptor, it justifies further consideration. It takes on even more significance knowing that the established threshold clozapine plasma concentration for therapeutic response (i.e., 350–420 ng/mL) was determined using steady-state trough plasma samples (i.e., approximately 12 h after the evening dose) in patients administered clozapine twice rather than once daily [1–3]. The following pharmacokinetic simulations put into perspective how dosage interval may influence the effectiveness and tolerability of clozapine treatment.
Simulation A: Clozapine 200 mg administered twice daily
⇑ Corresponding author at: British Columbia Mental Health and Addictions Research Institute, A3-938 W 28th Avenue, Vancouver, B.C. V5Z 4H4, Canada. Tel.: +1 604 875 2000x4722; fax: +1 604 875 3871. E-mail address: [email protected] (R.M. Procyshyn). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.11.043
Using a multi-dose pharmacokinetic simulator we illustrate what is predicted in a 70 Kg patient receiving clozapine 200 mg twice daily (e.g., 9 AM and 9 PM). Consistent with the threshold reference value mentioned above, we force our model to have a steady-state trough plasma concentration (just prior to the 9 AM dose) of 350 ng/mL. We accomplish this by entering the following population-based pharmacokinetic parameters into the model (volume of distribution = 4.6 L/kg; absorption half-life = 0.5 h; terminal elimination half-life = 12 h; oral bioavailability = 0.55). The patient’s clozapine plasma concentration is predicted to range from a trough of 350 ng/mL to a peak of 610 ng/mL (Fig. 1).
Simulation B: Clozapine 400 mg administered once daily Now let us consider what will happen if the same patient receives clozapine 400 mg once daily at 9 PM, keeping all other pharmacokinetic variables constant. Assuming that blood is drawn at 9 AM at steady state, the predicted clozapine plasma concentration would be 470 ng/mL. This is 1.3-fold greater than the previous simulation but does not reflect the true trough value. The model also predicts that the patient’s clozapine level will fall below the therapeutic threshold of 350 ng/mL by 2 PM and that the true
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R.M. Procyshyn et al. / Medical Hypotheses 82 (2014) 225–228
Fig. 1. Pharmocokinetic simulation of clozapine administered twice daily (red) and once daily (purple). (Pharmacokinetic simulator from http://home.fuse.net/clymer/ graphs/pkplot.html). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
trough value (just prior to the 9 PM dose) will be 235 ng/mL. The peak concentration will be 800 ng/mL (Fig. 1). Dopamine D2 receptor occupancy Consistent with the dopamine hypothesis of schizophrenia, antipsychotics are believed to exert their main therapeutic effect by antagonizing dopamine D2 receptors. Using positron emission tomography (PET), investigators have shown that most antipsychotics, under steady state conditions and therapeutic doses, occupy greater than 70% of striatal dopamine D2 receptors [4–6]. However, clozapine is an exception with PET studies showing less than 63% striatal dopamine D2 receptor occupancy at therapeutic doses [5–7]. We were able to find a case study in which a patient had taken 400 mg of clozapine (i.e., 200 mg at 8 AM and 200 mg at 11 AM) with PET scans measuring extrastriatal dopamine D2 receptor occupancy at 1, 6 and 25 h following the second dose [8]. Extrastriatal dopamine D2 receptor occupancy was reported to be 43% at 6 h and 17% at 25 h; the latter representing the trough plasma concentration. According to Pilowski et al., this trough level would extrapolate to even lower striatal dopamine D2 occupancy and thus would be significantly below that believed necessary for antipsychotic effect [9]. Incidentally, the plasma concentrations of clozapine were also measured in this case study and were in good agreement with our pharmacokinetic simulation above depicting 400 mg once daily. Discussion and clinical implications Dose-related side effects attributed to clozapine include, but are not limited to, postural hypotension, hypersalivation, drowsiness,
and sedation [10]. In some instances, these side effects may be so bothersome that clozapine has to be discontinued. In the case of orthostatic hypotension and sedation, physicians will often try to reduce the side effect burden by prescribing clozapine once daily at bedtime. Although done with good intention, prescribing the entire daily dose at bedtime will produce much higher clozapine concentrations throughout the night and into the morning relative to twice daily administration. Consequently, this may increase or worsen the risk of adverse events occurring throughout the night (e.g., enuresis, hypersalivation) and early morning (e.g., sedation). A strategy often used to mitigate clozapine-associated side effects is to administer it twice daily with a greater proportion of the daily dose given at bedtime. Apart from reducing side effect burden, this approach will also produce higher trough plasma concentrations than had the total daily dose been administered once daily. Another less often used strategy is to augment clozapine with low dose fluvoxamine; an inhibitor of cytochrome P4501A2. This approach decreases the biotransformation of clozapine to norclozapine and has been shown to mitigate clozapine-associated metabolic side effects that include weight gain, as well as elevated fasting glucose and triglycerides [11]. In addition, this intentional and therapeutic drug–drug interaction reduces the clearance of clozapine, which in turn increases clozapine’s elimination half-life. Although requiring further study, it is possible that this increase in half-life would allow for once daily administration of clozapine that results in trough plasma concentrations that are above the established threshold for therapeutic response. Finally, the development of an extended release formulation to be given once daily may also reduce side effect burden, as was the case with quetiapine XR where a lower intensity of self-reported sedation compared to the IR formulation was reported [12]. As illustrated by simulation A, when clozapine is given twice daily, the plasma concentration did not fall below the threshold
R.M. Procyshyn et al. / Medical Hypotheses 82 (2014) 225–228
clozapine plasma concentration for therapeutic response (i.e., 350 ng/mL). On the other hand, giving clozapine once daily at bedtime is predicted to result in the patient’s clozapine plasma concentration to fall below the therapeutic threshold plasma concentration of 350 ng/mL by 2 PM. If this were to happen clinically, one might expect to see manifestations of break-through symptoms in the late afternoon and evening possibly requiring ‘‘as needed’’ (PRN) medications that may include either a benzodiazepine or even another antipsychotic. This in itself becomes problematic as PRN medications increase the risk of medication errors and frequency of drug-related adverse events [13]. One may challenge the clinical significance of low clozapine trough plasma concentrations using recent data that compared once daily administration of quetiapine immediate release (IR) and extended release (XR) formulations [14]. At a daily dose of 300 mg for either formulation, no significant difference was noted in trough D2 receptor occupancy at steady state conditions (7 ± 7% vs. 8 ± 6% for the IR vs. XR, respectively). On first impression, one may surmise that if the XR formulation, which is clinically effective when administered once daily, has negligible trough D2 receptor occupancy, then by inference negligible trough D2 occupancy for an IR formulation given once daily would also be clinically effective. However, this reasoning is flawed on at least two accounts. Firstly, examination of the time curves of D2 receptor occupancy for these formulations show very different profiles. For example, D2 receptor occupancy of the IR, compared to the XR formulation, peaks much quicker (1.7 vs. 5 h, respectively) and has higher peak D2 receptor occupancy (50 ± 4% vs. 32 ± 11%, respectively). Perhaps more significant is that D2 receptor occupancy of the IR formulation decreases appreciably within the first 10 h after administration whereas a much more sustained D2 receptor occupancy is observed for the XR formulation. This difference in D2 receptor occupancy over time would equate to differences in pharmacodynamics that could certainly translate into differences in clinical effect. Secondly, this study used a daily dose of 300 mg, which is at the lower end of the recommended maintenance dose for the treatment of schizophrenia (i.e., 300–600 mg for the IR formulation and 400–800 mg for the XR formulation). In this regard, trough D2 receptor occupancies for a dose of 400 mg twice daily of the IR formulation or 800 mg once daily of the XR formulation was reported to be 24 ± 8.8% vs. 17.9 ± 15.2, respectively [15]. Therapeutic drug monitoring is a valuable tool that enables clinicians to tailor the dosage of a medication to an individual’s requirements. In general, therapeutic drug monitoring uses drug plasma concentrations to titrate the dose such that the plasma concentration is associated with the highest probability of response and tolerability and low risk of toxicity [16]. In the case of clozapine where fluctuation of plasma levels are predictive of relapse [17,18] and rehospitalizations, [19] therapeutic drug monitoring has a significant role to play. Contrary to this view, NÖrdstrom et al., have questioned the utility of therapeutic drug monitoring for clozapine, as they were unable to predict D2 receptor occupancy with clozapine plasma concentrations [20]. However, the relationship between receptor occupancy and clozapine plasma concentration in this study was based on the assumption that there is a linear relationship between free clozapine concentration in the brain and total (i.e., protein bound and unbound) clozapine plasma concentration. This assumption is faulty since it is only the unbound (free) fraction of clozapine in the plasma that determines clozapine concentration in the brain. This likely takes on even more significance when one considers that clozapine is highly protein bound (95–97%). Furthermore, this study attempts to correlate plasma concentrations with receptor occupancy by performing PET 3–6 h after the administration of clozapine. For a drug that has been well fitted using a triexponential (two-compartment, first-order absorption) linear model [21], this time
227
period would coincide with the post peak distribution phase (a phase); a period of time where concentration equilibrium has not likely been established between the central compartment and the more poorly perfused peripheral compartment. On the other hand, therapeutic drug monitoring of clozapine measures trough plasma concentration, which coincides with the post distribution phase (b phase). During this phase, concentration equilibrium between the central and peripheral compartment will have been established and the loss of clozapine from the central compartment will follow a first-order process. Taken together, trough plasma concentrations show far less variability compared to plasma concentrations taken during the post peak distribution phase. The full benefits of therapeutic drug monitoring can only be realized if the acquisition of blood for interpretation with respect to an established therapeutic reference range is collected in accordance to the published literature. In this regard, the established threshold clozapine plasma concentration for therapeutic response was determined using steady-state trough plasma samples (i.e., approximately 12 h after the evening dose) in patients administered clozapine twice daily, not once daily [1–3]. Thus, using clozapine plasma concentrations to guide therapy in a patient that is taking clozapine once daily may lead to erroneous treatment decisions. Clinicians must be aware of the fact that the 12-h post-dose plasma concentration will be higher in a patient taking clozapine once daily compared to had the patient been taking the same daily dose of clozapine divided twice daily. Similarly, clinicians must keep in mind that in those patients taking clozapine once daily, the plasma concentration might fall below the therapeutic threshold for response several hours prior to their next scheduled dose. In conclusion, clinicians should be mindful of how important the dosage interval is for medications that have relatively short half-lives. In this particular case, we suggest that if a patient is not responding adequately or is experiencing intolerable side effects while taking clozapine once daily, it may be worthwhile to administer it twice daily. In the least, this will optimized the use of clozapine in accordance to its pharmacokinetic/pharmacodynamics profiles. What’s more, this may improve therapeutic outcomes. [Note: Conversion factor from ng/mL to nmol/L is 3.06]. Conflicts of interest Dr. Procyshyn is a paid consultant for and is on the speaker’s bureau for AstraZeneca, Bristol-Myers Squibb, Janssen, Otsuka, Pfizer, and Sunovion. He also has funding from the Canadian Institute of Health Research. Dr. Honer has received consulting fees or sat on paid advisory boards for: MDH Consulting, In Silico (no honorarium), Novartis, Roche, Otsuka, and Lundbeck; received honoraria from Rush University, the Korean Society for Schizophrenia Research, the Centre for Addiction and mental Health (Toronto), the BC Schizophrenia Society, the Fraser, Vancouver Coastal and the Providence Health Authorities, and the Canadian Agency for Drugs and Technology in Health; provided expert testimony for Fasken Martineau DuMoulin, Cave and Company, and Hartshorne & Mehl; and received grants from the Canadian Institute of Health Research. Dr. Barr has received grants from Bristol-Myers Squibb and the Canadian Institute of Health Research. Dr. Vila-Rodriguez has nothing to declare. Sources of Funding Canadian Institutes of Health Research, and the BC Mental Health and Addictions Services.
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References [1] Hasegawa M, Gutierrez-Esteinou G, Way L, et al. Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: effect of smoking. J Clin Psychopharmacol 1993;13:383–90. [2] Kronig MH, Munne RA, Szymanski S, et al. Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 1995;152:179–82. [3] Spina E, Avenoso A, Facciolà G, et al. Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics. Psychopharmacology 2000;148:83–9. [4] Farde L, Wiesel F-A, Halldin C, et al. Central d2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 1988;45:71–8. [5] Farde L, Nordström AL, Wiesel FA, et al. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 1992;49:538–44. [6] Kapur S, Ziprusky RB, Remington G. Clinical and theoretical implications of 5HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999;156:286–93. [7] Nordström AL, Farde L, Nyberg S, et al. D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a pet study of schizophrenic patients. Am J Psychiatry 1995;152:1444–9. [8] Takano A, Suhara T, Kusumi I, et al. Time course of dopamine D2 receptor occupancy by clozapine with medium and high plasma concentrations. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:75–81. [9] Pilowski LS, Mulligan RS, Acton PD, et al. Limbic selectivity of clozapine (letter). Lancet 1997;350:490–1. [10] Flanagan RJ. Side-effects of clozapine and some other psychoactive drugs. Curr Drug Safety 2008;3:115–22.
[11] Lu M-L, Lane H-Y, Lin S-K, et al. Adjunctive fluvoxamine inhibits clozapinerelated weight gain and metabolic disturbances. J Clin Psychiatry 2004;65:766–71. [12] Datto C, Berggre L, Patel JB, et al. Self-reported sedation profile of immediaterelease quetiapine fumarate compared with extended-release quetiapine fumarate during dose initiation: a randomized, double-blind, crossover study in health adult subjects. Clin Ther 2009;31:492–502. [13] Procyshyn RM, Barr AM, Brickell T, et al. Medication errors in psychiatry. A comprehensive review. CNS Drugs 2010;24:595–609. [14] Nord M, Nyberg S, Brogren J, et al. Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarte immediate-release and extended-release formulations in health subjects. Int J Neuropsychopharmacol 2011;14:1357–66. [15] Mamo DC, Uchida HU, Vitcu I, et al. Quetiapine extended-release versus immediate-release formulation: a positron emission tomography study. J Clin Psychiatry 2008;69:1–86. [16] Hiemke C, Baumann P, Bergemann N, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 2011;44:195–235. [17] Gaertner I, Gaertner HJ, Vonthein R, et al. Therapeutic drug monitoring of clozapine in relapse prevention: a five-year prospective study. J Clin Psychopharmacol 2001;21:305–10. [18] Ulrich S, Baumann B, Wolf R, et al. Therapeutic drug monitoring of clozapine and relapse – a retrospective study of routine clinical data. Int J Clin Pharmacol Ther 2003;41:2–13. [19] Stieffenhofer V, Saglam H, Schmidtmann I, et al. Clozapine plasma level monitoring for prediction of rehospitalization schizophrenic outpatients. Pharmacopsychiatry 2011;44:55–9. [20] NordstrÖm A-L, Farde L, Nyber S, et al. D1, D2, and 5HTs receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 1995;152:1444–9. [21] Choc MG, Lehr RG, Hsuan F, et al. Multiple-dose pharmacokinetics of clozapine in patients. Pharm Res 1987;4:402–5.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Clozapine administered once versus twice daily: Does it make a difference? Ric M. Procyshyn a,b,⇑, Fidel Vila-Rodriguez a,b, William G. Honer a,b, Alasdair M. Barr a,c a
British Columbia Mental Health and Addictions Research Institute, 938 W 28th Avenue, Vancouver, B.C. V5Z 4H4, Canada Department of Psychiatry, University of British Columbia, Vancouver V6T 1Z3, Canada c Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada b
a r t i c l e
i n f o
Article history: Received 5 August 2013 Accepted 30 November 2013
a b s t r a c t Clozapine, generally considered to be the most effective antipsychotic, is the gold standard for treatmentresistant schizophrenia. With a relatively short half-life of 12 h and a very quick dissociation rate from the dopamine D2 receptor, pharmacokinetic and pharmacodynamics principles would dictate that clozapine be administered twice daily. However, due to clozapine’s side effects (e.g., sedation), it is often prescribe once daily at bedtime. Even if the patient develops tolerance to the side effects, it is still often prescribed once daily to simplify medication regimens in hopes of increasing adherence. Unfortunately, good intentions and convenience do not always make for optimal pharmacotherapy. Based upon clozapine’s pharmacokinetic and pharmacodynamic profiles, we hypothesize that optimal treatment with clozapine requires it be given twice daily rather than once daily. We present here some pharmacokinetic simulations and published data to support our hypothesis. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction
Pharmacokinetic simulations
Clozapine is the only antipsychotic indicated for treatmentresistant schizophrenia and thus it is important that clinicians do everything possible to optimize its use. To our knowledge, there are no published studies evaluating whether once daily administration of clozapine is better than giving it twice daily in terms of effectiveness and tolerability. Although this may seem trivial at first, when one considers that clozapine has a relatively short half-life and dissociates quickly from the dopamine D2 receptor, it justifies further consideration. It takes on even more significance knowing that the established threshold clozapine plasma concentration for therapeutic response (i.e., 350–420 ng/mL) was determined using steady-state trough plasma samples (i.e., approximately 12 h after the evening dose) in patients administered clozapine twice rather than once daily [1–3]. The following pharmacokinetic simulations put into perspective how dosage interval may influence the effectiveness and tolerability of clozapine treatment.
Simulation A: Clozapine 200 mg administered twice daily
⇑ Corresponding author at: British Columbia Mental Health and Addictions Research Institute, A3-938 W 28th Avenue, Vancouver, B.C. V5Z 4H4, Canada. Tel.: +1 604 875 2000x4722; fax: +1 604 875 3871. E-mail address: [email protected] (R.M. Procyshyn). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.11.043
Using a multi-dose pharmacokinetic simulator we illustrate what is predicted in a 70 Kg patient receiving clozapine 200 mg twice daily (e.g., 9 AM and 9 PM). Consistent with the threshold reference value mentioned above, we force our model to have a steady-state trough plasma concentration (just prior to the 9 AM dose) of 350 ng/mL. We accomplish this by entering the following population-based pharmacokinetic parameters into the model (volume of distribution = 4.6 L/kg; absorption half-life = 0.5 h; terminal elimination half-life = 12 h; oral bioavailability = 0.55). The patient’s clozapine plasma concentration is predicted to range from a trough of 350 ng/mL to a peak of 610 ng/mL (Fig. 1).
Simulation B: Clozapine 400 mg administered once daily Now let us consider what will happen if the same patient receives clozapine 400 mg once daily at 9 PM, keeping all other pharmacokinetic variables constant. Assuming that blood is drawn at 9 AM at steady state, the predicted clozapine plasma concentration would be 470 ng/mL. This is 1.3-fold greater than the previous simulation but does not reflect the true trough value. The model also predicts that the patient’s clozapine level will fall below the therapeutic threshold of 350 ng/mL by 2 PM and that the true
226
R.M. Procyshyn et al. / Medical Hypotheses 82 (2014) 225–228
Fig. 1. Pharmocokinetic simulation of clozapine administered twice daily (red) and once daily (purple). (Pharmacokinetic simulator from http://home.fuse.net/clymer/ graphs/pkplot.html). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
trough value (just prior to the 9 PM dose) will be 235 ng/mL. The peak concentration will be 800 ng/mL (Fig. 1). Dopamine D2 receptor occupancy Consistent with the dopamine hypothesis of schizophrenia, antipsychotics are believed to exert their main therapeutic effect by antagonizing dopamine D2 receptors. Using positron emission tomography (PET), investigators have shown that most antipsychotics, under steady state conditions and therapeutic doses, occupy greater than 70% of striatal dopamine D2 receptors [4–6]. However, clozapine is an exception with PET studies showing less than 63% striatal dopamine D2 receptor occupancy at therapeutic doses [5–7]. We were able to find a case study in which a patient had taken 400 mg of clozapine (i.e., 200 mg at 8 AM and 200 mg at 11 AM) with PET scans measuring extrastriatal dopamine D2 receptor occupancy at 1, 6 and 25 h following the second dose [8]. Extrastriatal dopamine D2 receptor occupancy was reported to be 43% at 6 h and 17% at 25 h; the latter representing the trough plasma concentration. According to Pilowski et al., this trough level would extrapolate to even lower striatal dopamine D2 occupancy and thus would be significantly below that believed necessary for antipsychotic effect [9]. Incidentally, the plasma concentrations of clozapine were also measured in this case study and were in good agreement with our pharmacokinetic simulation above depicting 400 mg once daily. Discussion and clinical implications Dose-related side effects attributed to clozapine include, but are not limited to, postural hypotension, hypersalivation, drowsiness,
and sedation [10]. In some instances, these side effects may be so bothersome that clozapine has to be discontinued. In the case of orthostatic hypotension and sedation, physicians will often try to reduce the side effect burden by prescribing clozapine once daily at bedtime. Although done with good intention, prescribing the entire daily dose at bedtime will produce much higher clozapine concentrations throughout the night and into the morning relative to twice daily administration. Consequently, this may increase or worsen the risk of adverse events occurring throughout the night (e.g., enuresis, hypersalivation) and early morning (e.g., sedation). A strategy often used to mitigate clozapine-associated side effects is to administer it twice daily with a greater proportion of the daily dose given at bedtime. Apart from reducing side effect burden, this approach will also produce higher trough plasma concentrations than had the total daily dose been administered once daily. Another less often used strategy is to augment clozapine with low dose fluvoxamine; an inhibitor of cytochrome P4501A2. This approach decreases the biotransformation of clozapine to norclozapine and has been shown to mitigate clozapine-associated metabolic side effects that include weight gain, as well as elevated fasting glucose and triglycerides [11]. In addition, this intentional and therapeutic drug–drug interaction reduces the clearance of clozapine, which in turn increases clozapine’s elimination half-life. Although requiring further study, it is possible that this increase in half-life would allow for once daily administration of clozapine that results in trough plasma concentrations that are above the established threshold for therapeutic response. Finally, the development of an extended release formulation to be given once daily may also reduce side effect burden, as was the case with quetiapine XR where a lower intensity of self-reported sedation compared to the IR formulation was reported [12]. As illustrated by simulation A, when clozapine is given twice daily, the plasma concentration did not fall below the threshold
R.M. Procyshyn et al. / Medical Hypotheses 82 (2014) 225–228
clozapine plasma concentration for therapeutic response (i.e., 350 ng/mL). On the other hand, giving clozapine once daily at bedtime is predicted to result in the patient’s clozapine plasma concentration to fall below the therapeutic threshold plasma concentration of 350 ng/mL by 2 PM. If this were to happen clinically, one might expect to see manifestations of break-through symptoms in the late afternoon and evening possibly requiring ‘‘as needed’’ (PRN) medications that may include either a benzodiazepine or even another antipsychotic. This in itself becomes problematic as PRN medications increase the risk of medication errors and frequency of drug-related adverse events [13]. One may challenge the clinical significance of low clozapine trough plasma concentrations using recent data that compared once daily administration of quetiapine immediate release (IR) and extended release (XR) formulations [14]. At a daily dose of 300 mg for either formulation, no significant difference was noted in trough D2 receptor occupancy at steady state conditions (7 ± 7% vs. 8 ± 6% for the IR vs. XR, respectively). On first impression, one may surmise that if the XR formulation, which is clinically effective when administered once daily, has negligible trough D2 receptor occupancy, then by inference negligible trough D2 occupancy for an IR formulation given once daily would also be clinically effective. However, this reasoning is flawed on at least two accounts. Firstly, examination of the time curves of D2 receptor occupancy for these formulations show very different profiles. For example, D2 receptor occupancy of the IR, compared to the XR formulation, peaks much quicker (1.7 vs. 5 h, respectively) and has higher peak D2 receptor occupancy (50 ± 4% vs. 32 ± 11%, respectively). Perhaps more significant is that D2 receptor occupancy of the IR formulation decreases appreciably within the first 10 h after administration whereas a much more sustained D2 receptor occupancy is observed for the XR formulation. This difference in D2 receptor occupancy over time would equate to differences in pharmacodynamics that could certainly translate into differences in clinical effect. Secondly, this study used a daily dose of 300 mg, which is at the lower end of the recommended maintenance dose for the treatment of schizophrenia (i.e., 300–600 mg for the IR formulation and 400–800 mg for the XR formulation). In this regard, trough D2 receptor occupancies for a dose of 400 mg twice daily of the IR formulation or 800 mg once daily of the XR formulation was reported to be 24 ± 8.8% vs. 17.9 ± 15.2, respectively [15]. Therapeutic drug monitoring is a valuable tool that enables clinicians to tailor the dosage of a medication to an individual’s requirements. In general, therapeutic drug monitoring uses drug plasma concentrations to titrate the dose such that the plasma concentration is associated with the highest probability of response and tolerability and low risk of toxicity [16]. In the case of clozapine where fluctuation of plasma levels are predictive of relapse [17,18] and rehospitalizations, [19] therapeutic drug monitoring has a significant role to play. Contrary to this view, NÖrdstrom et al., have questioned the utility of therapeutic drug monitoring for clozapine, as they were unable to predict D2 receptor occupancy with clozapine plasma concentrations [20]. However, the relationship between receptor occupancy and clozapine plasma concentration in this study was based on the assumption that there is a linear relationship between free clozapine concentration in the brain and total (i.e., protein bound and unbound) clozapine plasma concentration. This assumption is faulty since it is only the unbound (free) fraction of clozapine in the plasma that determines clozapine concentration in the brain. This likely takes on even more significance when one considers that clozapine is highly protein bound (95–97%). Furthermore, this study attempts to correlate plasma concentrations with receptor occupancy by performing PET 3–6 h after the administration of clozapine. For a drug that has been well fitted using a triexponential (two-compartment, first-order absorption) linear model [21], this time
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period would coincide with the post peak distribution phase (a phase); a period of time where concentration equilibrium has not likely been established between the central compartment and the more poorly perfused peripheral compartment. On the other hand, therapeutic drug monitoring of clozapine measures trough plasma concentration, which coincides with the post distribution phase (b phase). During this phase, concentration equilibrium between the central and peripheral compartment will have been established and the loss of clozapine from the central compartment will follow a first-order process. Taken together, trough plasma concentrations show far less variability compared to plasma concentrations taken during the post peak distribution phase. The full benefits of therapeutic drug monitoring can only be realized if the acquisition of blood for interpretation with respect to an established therapeutic reference range is collected in accordance to the published literature. In this regard, the established threshold clozapine plasma concentration for therapeutic response was determined using steady-state trough plasma samples (i.e., approximately 12 h after the evening dose) in patients administered clozapine twice daily, not once daily [1–3]. Thus, using clozapine plasma concentrations to guide therapy in a patient that is taking clozapine once daily may lead to erroneous treatment decisions. Clinicians must be aware of the fact that the 12-h post-dose plasma concentration will be higher in a patient taking clozapine once daily compared to had the patient been taking the same daily dose of clozapine divided twice daily. Similarly, clinicians must keep in mind that in those patients taking clozapine once daily, the plasma concentration might fall below the therapeutic threshold for response several hours prior to their next scheduled dose. In conclusion, clinicians should be mindful of how important the dosage interval is for medications that have relatively short half-lives. In this particular case, we suggest that if a patient is not responding adequately or is experiencing intolerable side effects while taking clozapine once daily, it may be worthwhile to administer it twice daily. In the least, this will optimized the use of clozapine in accordance to its pharmacokinetic/pharmacodynamics profiles. What’s more, this may improve therapeutic outcomes. [Note: Conversion factor from ng/mL to nmol/L is 3.06]. Conflicts of interest Dr. Procyshyn is a paid consultant for and is on the speaker’s bureau for AstraZeneca, Bristol-Myers Squibb, Janssen, Otsuka, Pfizer, and Sunovion. He also has funding from the Canadian Institute of Health Research. Dr. Honer has received consulting fees or sat on paid advisory boards for: MDH Consulting, In Silico (no honorarium), Novartis, Roche, Otsuka, and Lundbeck; received honoraria from Rush University, the Korean Society for Schizophrenia Research, the Centre for Addiction and mental Health (Toronto), the BC Schizophrenia Society, the Fraser, Vancouver Coastal and the Providence Health Authorities, and the Canadian Agency for Drugs and Technology in Health; provided expert testimony for Fasken Martineau DuMoulin, Cave and Company, and Hartshorne & Mehl; and received grants from the Canadian Institute of Health Research. Dr. Barr has received grants from Bristol-Myers Squibb and the Canadian Institute of Health Research. Dr. Vila-Rodriguez has nothing to declare. Sources of Funding Canadian Institutes of Health Research, and the BC Mental Health and Addictions Services.
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