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International Clinical Psychopharmacology:
doi: 10.1097/YIC.0b013e32834093d1
Original Articles

Dose correspondence between olanzapine long-acting injection and oral olanzapine: recommendations for switching

Detke, Holland C.; Zhao, Fangyi; Garhyan, Parag; Carlson, Janice; McDonnell, David

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Author Information

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA

Correspondence to Holland C. Detke, PhD, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA Tel: +1 317 651 9043; fax: +1 317 277 0490; e-mail: detkehc@lilly.com

Received April 6, 2010

Accepted September 15, 2010

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Abstract

Oral-to-depot dose correspondence was explored in a 24-week study of olanzapine long-acting injection (LAI). Patients with schizophrenia stabilized on oral olanzapine of 10, 15, or 20 mg/day (n=1065) were randomized to continue their oral treatment or switch directly to a fixed dose of olanzapine LAI [(mg/weeks) 45/4, 150/2, 405/4, or 300/2] without oral supplementation. Six-month relapse rates for each LAI-dose group stratified by earlier oral dose were analyzed using a Cox proportional hazard model assessing risk of relapse relative to each oral dose. Relapse rates for the therapeutic LAI doses (≥150 mg) varied depending on earlier oral dose, ranging from 1.5% (patients switched from 10 mg/day to 300 mg/2 weeks) to 18.8% (patients switched from 20 mg/day to 150 mg/2 weeks). Switching from 10 mg/day to 405 mg/4 weeks produced a comparable risk of relapse as remaining on that oral dose [Hazard ratio (HR)=1.03]. Switching from 15 or 20 mg/day to 300 mg/2 weeks produced comparable risk of relapse as remaining on those oral doses (HR=0.68 and 1.13, respectively). Pharmacokinetic modeling was conducted to evaluate the resulting dosing recommendations. Findings suggest that patients can be switched directly from oral to olanzapine LAI without the need for oral supplementation and with a low risk of relapse when initiated on an appropriate LAI dose.

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Introduction

Depot antipsychotics are useful treatment options for patients with schizophrenia who have difficulty with oral treatment adherence (Wistedt and Ranta, 1983; Soni et al., 1992; Wei et al., 1996; Adams et al., 2001; Ereshefsky and Mascarenas, 2003; Kane et al., 2003; Kissling et al., 2005). However, it is often not always clear how best to switch these patients to a depot antipsychotic formulation (Lambert et al., 2003). One of the clinical challenges is selection of the appropriate starting dose. Dosing higher than necessary could result in tolerability issues that could lead to treatment discontinuation, whereas dosing lower than necessary could result in destabilization of the patient or an increased risk of relapse. Given that it can sometimes be difficult to convince a patient to begin a long-acting injectable antipsychotic, once the choice has finally been made, it is important not to jeopardize the commitment to and/or success of that choice. Thus, it is useful to have a very clear understanding of dose correspondence for the long-acting formulation relative to some standard (such as the oral formulation, if one exists).

Olanzapine long-acting injection (LAI) is a depot formulation of the atypical antipsychotic olanzapine. Steady-state dose correspondence to oral olanzapine can be estimated by dividing the dose (in mg) by the number of days in the prescribed injection interval. Therefore, 300 mg/2 weeks corresponds to oral olanzapine of approximately 20 mg/day; 405 mg/4 weeks corresponds to oral olanzapine of approximately 15 mg/day; and 150 mg/2 weeks corresponds to oral olanzapine of approximately 10 mg/day. However, it takes approximately 3 months to achieve steady-state concentrations (Zypadhera European Public Assessment Report, 2008; Kane et al., 2010), thus leaving some question as to the dose correspondence to oral olanzapine before the achievement of steady state.

In an acute, 8-week, placebo-controlled study (N=404; Lauriello et al., 2008), symptomatic patients with schizophrenia were switched directly from their earlier antipsychotic to a fixed dose of olanzapine LAI (210 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks), without oral antipsychotic supplementation. Despite the fact that patients had not yet had the time to achieve steady-state concentrations of olanzapine, results indicated an early onset of effect comparable with that seen with oral olanzapine in earlier oral studies using a similar patient population (Beasley et al., 1996a, 1996b, 1997; Lauriello et al., 2008). Patients treated with olanzapine LAI had statistically significant improvement compared with those treated with placebo by week 1 of treatment and with improvement continuing throughout the 8 weeks (Lauriello et al., 2008). Although this study provided important information about efficacy and early onset of action of olanzapine LAI, it did not provide information about dose correspondence or how to select a specific dose.

To address this question of dose selection when switching to olanzapine LAI, we analyzed data from a randomized, double-blind, oral olanzapine-controlled study (Kane et al., 2010). In that study, clinically stable patients with schizophrenia were switched to oral olanzapine and established on a stable oral maintenance dose before being randomized to either stay on that stabilized oral dose or switch directly to one of several fixed doses of olanzapine LAI. Overall results reported by Kane et al. (2010) showed the effectiveness of the standard olanzapine LAI doses at maintaining patients' clinical stability. In these analyses, we stratified the relapse rates from the study by Kane et al. (2010) by patients' earlier stabilized oral dose. By taking patients' dosing needs into account as reflected by this stabilized oral dose, we attempted to identify starting olanzapine LAI doses which seemed best to correspond to the different oral doses as measured by relapse rates which were most similar to the specific oral dose. For example, for patients switched from a stable dose of oral olanzapine of 10 mg/day, we evaluated which olanzapine LAI dose seemed to provide the most similar performance to the oral dose of 10 mg/day. We utilized these clinical findings in combination with the known depot-to-oral dose correspondence at steady state (Kane et al., 2010) to develop dosing guidelines for switching patients to olanzapine LAI. We then used existing olanzapine plasma concentration data to conduct post-hoc pharmacokinetic simulations to evaluate the olanzapine concentrations which would be achieved when using these specific dosing recommendations.

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Methods

This was a post-hoc analysis based on data from a 24-week double-blind, randomized, multicenter study conducted from July 2004 to September 2006, at 112 sites in 26 countries (F1D-MC-HGKA; for a complete description of the study methods, see Kane et al., 2010). The study protocol was approved by institutional review boards at each site. All patients and/or their authorized legal representative provided written informed consent before participation.

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Description of patients and study design

The participants, who met Diagnostic and Statistical Manual Fourth Revision or the Diagnostic and Statistical Manual- Fourth Text Revision criteria for schizophrenia, were between the ages of 18 and 75 years, had outpatient status for at least 4 weeks before study entry, and were judged to be clinically stable, with a Brief Psychiatric Rating Scale (BPRS; Overall, 1972) score of less than or equal to 4 (1–7 range) on each of the following items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content.

The patients were tapered off their earlier antipsychotic medication and switched to oral olanzapine over a 2-week period. They then had to show maintenance of clinical stability on oral olanzapine monotherapy (10, 15, or 20 mg/day) to be eligible for randomization into the double-blind period of the study. Dosing was at the discretion of the investigator. Clinical stability was defined as no change in dose for at least 4 weeks, a Clinical Global Impressions Improvement of Illness (Guy, 1976) score less than or equal to 4, and BPRS score less than or equal to 4 on the same four positive symptom items used in the study entry criteria.

The patients who showed clinical stability on a fixed dose of oral olanzapine for 4 consecutive weeks were randomized to double-blind treatment for up to 24 weeks with a fixed dose of olanzapine LAI or continued treatment with their oral olanzapine dose. The patients were randomized in a 1 : 1 : 2 : 1 : 2 ratio to very low (45 mg/4 weeks), low (150 mg/2 weeks), medium (405 mg/4 weeks), or high (300 mg/2 weeks) fixed doses of olanzapine LAI, or to remain on their fixed stabilized dose of oral olanzapine of 10, 15, or 20 mg/day. No oral antipsychotic supplementation was allowed at any time.

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Outcome measures

The protocol-defined primary outcome measures for the study were time to relapse and rate of relapse, with relapse defined as (i) an increase on any of the BPRS positive items to a score more than 4, with an absolute increase of more than or equal to 2 on that specific item since randomization; (ii) an increase of any of the BPRS positive items to a score more than 4, with an absolute increase of more than or equal to 4 on the BPRS positive subscale since randomization; or (iii) hospitalization because of worsening of positive psychotic symptoms.

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Statistical methods

All analyses were carried out on an intent-to-treat basis. Six-month cumulative relapse rates were tabulated for each treatment group stratified by earlier stabilized oral olanzapine dose. Within each stratum (10, 15, or 20 mg/day earlier oral dose), the risk of relapse for each olanzapine LAI arm was calculated relative to that of the oral arm using a Cox proportional hazard model with treatment group as independent effect and geographic region as a stratification factor. Hazard ratios (HR) and 95% confidence intervals (CIs) are reported. P values were calculated using the Wald test.

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Selection of optimal starting olanzapine long-acting injection dose

The stratified relapse rates and HRs were evaluated to develop recommendations for optimal dose initiation of olanzapine LAI from specific stabilized oral doses. The goal was to determine which dose groups achieved an HR closest to a value of 1 relative to remaining on a specific dose of oral olanzapine. The olanzapine LAI dose with the HR closest to 1 would represent the dose that would best approximate the efficacy of the oral dose in question. This would then be considered the corresponding starting dose when switching from that particular oral olanzapine dose.

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Pharmacokinetic simulations

Clinical recommendations for dose initiation were subsequently evaluated using pharmacokinetic simulations. Pharmacokinetic and demographic data from four studies were used to create a combined meta-dataset [(F1D-EW-LOBS, 2006), F1D-MC-HGJZ (Lauriello et al., 2008), F1D-MC-HGKA (Kane et al., 2010), and F1D-MC-HGKB (McDonnell et al., 2009)] for the development of a population pharmacokinetic model to describe the disposition of olanzapine. This meta-dataset consisted of 8638 observations in 786 unique patients. Timing of plasma sampling varied across studies, with the final meta-dataset including sampling both within and between injection intervals.

A one-compartment population pharmacokinetic model with combined zero order and first order absorption processes for olanzapine LAI and first order absorption for oral olanzapine adequately described the olanzapine pharmacokinetics in these study populations (Garhyan et al., 2008). The model incorporated interpatient variability on apparent clearance and the relative oral bioavailability. Interoccasion (within-patient) variability in the apparent clearance between periods spanning 6 months of treatment was also incorporated into the model. A combined additive/proportional residual error model was used. Two covariates were incorporated into the final model: smoking status and sex (Carrillo et al., 2003; Bigos et al., 2008). The final population model incorporated the effects of smoking status on the apparent clearance and apparent volume. Sex was incorporated into the final population model as an effect on the first-order depot absorption rate constant.

This population pharmacokinetic model was used to simulate plasma olanzapine concentration profiles for various oral-to-LAI olanzapine-switching scenarios. Parameters of the simulation created a ‘typical’ patient on whom to assess the pharmacokinetic profile of the dosing regimens. Although the average patient with schizophrenia is typically a male smoker, we selected a female nonsmoker for the prototype in these simulations because female nonsmokers tend to have higher olanzapine concentrations than male nonsmokers, and we were more concerned with checking the upper limits of probable concentrations to ensure that any dose loading strategy did not result in higher than intended concentrations of olanzapine. The qualitative interpretation of the simulated olanzapine profiles for different regimens will be similar even if a different representative patient (e.g. male smoker) was used for simulation. Average olanzapine plasma concentrations within an olanzapine LAI dosing interval were calculated by dividing the area under the simulated olanzapine profile over a dosing interval by the duration of dosing interval.

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Results

A total of 1065 patients were randomized to double-blind treatment. The patients were predominantly male (65%) and Caucasian (72%), with a mean age of 39 years. Average age of onset of schizophrenia was 25.6 years. Approximately 37% of patients had experienced two or more episodes or psychotic exacerbations in the past 24 months. At time of randomization, mean Positive and Negative Syndrome Scale score was 55.9 (SD=15.6), and mean Clinical Global Impressions Severity was 3.1 (SD=0.9), consistent with a stabilized population. Additional information on patient demographics and baseline characteristics and primary efficacy and safety data are presented elsewhere (Kane et al., 2010).

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Rates of relapse

Of the 1065 randomized patients, 475 had been stabilized on oral olanzapine of 10 mg/day , 236 had been stabilized on oral olanzapine of 15 mg/day, and 353 had been stabilized on oral olanzapine of 20 mg/day. Six-month cumulative relapse rates for each of the randomized treatment groups stratified by earlier oral dose are presented in Table 1. For patients stabilized on oral olanzapine of 10 mg/day, rate of relapse was lowest for the patients randomized to the highest dose of olanzapine LAI (300 mg/2 weeks, 1.5%); however, the rate most similar to that of remaining on oral olanzapine of 10 mg/day (6.3%) was the rate observed for those patients randomized to 405 mg/4 weeks (5.7%). For patients stabilized on oral olanzapine of 15 mg/day, there was no single dose of olanzapine LAI which most closely reflected the relapse rate seen in patients remaining on oral olanzapine of 15 mg/day (5.0%), which fell between the rates seen with 300 mg/2 weeks (3.3%) and 405 mg/4 weeks (6.6%). For patients stabilized on oral olanzapine of 20 mg/day, the relapse rates were most similar for olanzapine LAI of 300 mg/2 weeks (8.7%) and remaining on the dose of 20 mg/day (8.2%).

Table 1
Table 1
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Relative risk of relapse

Table 2 presents the relative risk of relapse for the olanzapine LAI groups relative to the oral group for each of the earlier stabilized oral dose strata. For the group stabilized on oral olanzapine of 10 mg/day, the relative risk of relapse was most similar between patients who remained on oral therapy and patients randomized to receive olanzapine LAI of 405 mg/4 weeks (HR=1.03; 95% CI=0.40–2.67; P=0.954). The relative risk of relapse was highest and statistically significant for patients randomized to receive olanzapine LAI of 45 mg/4 weeks (HR=2.78; 95% CI=1.13–6.84; P=0.027). The patients randomized to receive olanzapine LAI of 150 mg/2 weeks (approximately 10 mg/day at steady state) had twice the risk of relapse compared with those who remained on oral therapy (HR=2.08; 95% CI=0.77–5.59; P=0.147), although the difference was not statistically significant.

Table 2
Table 2
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For the group stabilized on oral olanzapine of 15 mg/day, the relative risk of relapse was most similar between patients who remained on oral therapy and those randomized to receive olanzapine LAI of 300 mg/2 weeks (HR=0.68; 95% CI=0.08–6.08; P=0.727). The relative risk of relapse was highest and statistically significant for patients randomized to receive olanzapine LAI of 45 mg/4 weeks (HR=5.59; 95% CI=1.68–18.59; P=0.005). The patients who were randomized to receive olanzapine LAI of 405 mg/4 weeks (approximately oral olanzapine of 15 mg/day) had an almost 50% greater risk of relapse compared with those who remained on oral therapy (HR=1.44; 95% CI=0.36–5.79; P=0.606; Table 2), although the difference was not statistically significant.

For the group stabilized on oral olanzapine of 20 mg/day, the relative risk of relapse was most similar between patients who remained on oral therapy and those randomized to receive olanzapine LAI of 300 mg/2 weeks (HR=1.13; 95% CI=0.34–3.75; P=0.843). The relative risk of relapse was highest and statistically significant for patients randomized to receive olanzapine LAI of 45 mg/4 weeks (HR=8.00; 95% CI=3.53–18.14; P<0.001; Table 2).

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Clinical recommendations

On the basis of these clinical findings, patients taking oral olanzapine of 20 mg/day seem to be able to switch directly to a target olanzapine LAI maintenance dose of 300 mg/2 weeks with no greater risk of relapse than if they had remained on their optimized oral dose. However, for patients taking oral olanzapine of 10 or 15 mg/day, clinical findings indicated that to achieve a smooth transition to olanzapine LAI without increasing the risk of relapse, it would be necessary to switch to the next higher dose level than the target maintenance dose. Table 3 presents these dosing recommendations. An 8-week time frame for the loading dose was chosen based on the known pharmacokinetic profile of olanzapine LAI (Kane et al., 2010), which produces therapeutic plasma concentrations of olanzapine immediately after the first injection but takes at least 12 weeks to achieve steady-state concentrations (target maintenance dose levels), with the most notable dip in plasma concentrations observed during the first 8 weeks of treatment.

Table 3
Table 3
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Pharmacokinetic simulations

Figures 1–3 present pharmacokinetic simulations of various dosing regimens over 24 weeks, with and without the use of different potential loading doses during the first 8 weeks of treatment with olanzapine LAI. These simulations provide a comparative display of olanzapine concentration profiles achieved with each regimen. As expected, olanzapine concentrations in regimens without a loading dose were lower during the first 8 weeks of treatment than those observed with a loading dose regimen.

Fig. 1
Fig. 1
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Fig. 2
Fig. 2
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Fig. 3
Fig. 3
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Plasma olanzapine concentrations in the regimens without loading doses were not subtherapeutic as concentrations were within the range associated with oral doses of 5–20 mg/day (10th percentile of 5 mg/day=5.19 ng/ml; 90th percentile of 20 mg/day=68.8 ng/ml: Study F1D-MC-HGAJ, 1995). However, the starting dose of olanzapine LAI of either 150 mg/2 weeks (Fig. 1) or 300 mg/4 weeks (Fig. 2) (approximately olanzapine of 10 mg/day at steady state) provides lower olanzapine concentrations during the first 8 weeks. In contrast, a loading dose of 300 mg/2 weeks exceeds the target maintenance concentration starting at week 4 and results in high concentrations, exceeding the target even after beginning the lower maintenance dose of 150 mg/2 weeks or 300 mg/4 weeks.

Similarly, simulated olanzapine plasma concentrations showed that a direct switch from oral olanzapine of 15 mg/day to olanzapine LAI of either 210 mg/2 weeks or 405 mg/4 weeks (approximately 15 mg/day at steady state) required more time to reach steady state than if using a starting dose of olanzapine LAI of 300 mg/2 weeks during the first 8 weeks of treatment (Fig. 3), thus providing less olanzapine coverage during the first 8 weeks. A loading dose of 300 mg/2 weeks results in higher olanzapine concentrations during this period and provides near steady-state concentrations that would have been achieved without this loading dose. A maintenance dose of olanzapine LAI of either 210 mg/2 weeks or 405 mg/4 weeks thereafter continued to maintain olanzapine plasma concentrations in the desired range for a patient with a target oral dose of 15 mg/day.

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Discussion

The 6-month rates of relapse for patients randomized to a therapeutic dose of olanzapine LAI (150 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) were low, ranging from approximately 2 to 19%, but varied depending on earlier oral olanzapine dose. The majority of patients who relapsed were those who had switched to an olanzapine LAI dose lower than their corresponding oral stabilizing dose, with patients showing the least increase in risk of relapse when switched to an olanzapine LAI dose equivalent to or higher than their stabilized oral dose. Rates of relapse for the patients who remained on oral olanzapine, representing the control groups for these analyses, were comparable with those earlier reported with oral olanzapine treatment (Dellva et al., 1997; Beasley et al., 2003).

For the patients stabilized on oral olanzapine of 10 mg/day, switching directly to the corresponding steady-state dose of olanzapine LAI (150 mg/2 weeks) led to numerically higher rates of relapse compared with remaining on oral treatment or compared with switching to a higher olanzapine LAI dose. Those 150 mg/2-week-treated patients showed twice as many relapses (approximately 12%) as those remaining on 10 mg/day oral (approximately 6%) at 6 months. Although this relative risk was not found to be statistically significant, the doubling of such risk may be clinically relevant and should be considered when selecting the appropriate starting dose for these patients. For these patients, a starting dose of 405 mg/4 weeks produced a 6-month relapse rate of approximately 6%, similar to the relapse rate when no switch had occurred but the patient remained on their optimized oral dose. Although switching to the highest dose of olanzapine LAI (300 mg/2 weeks) more than halved the rate of relapse for these patients, which is certainly desirable from an efficacy perspective, it is important to note that there could be tolerability issues, which might increase the risk of treatment discontinuation. For instance, although patients treated with the highest dose (300 mg/2 weeks) had the lowest risk of relapse of all randomized treatments, patients treated with this dose also experienced greater mean weight gain (1.70 kg for 300 mg/2 weeks vs. 0.89 kg for 405 mg/4 weeks; P=0.06), a mean increase in prolactin (+3.57 μg/l for 300 mg/2 weeks vs. −2.76 μg/l for 405 mg/4 weeks; P=0.02), higher incidence of change from normal to high triglyceride levels (24.5% for 300 mg/2 weeks vs. 9.8% for 405 mg/4 weeks; P=0.02), and a higher rate of injection-site irritation (2.1% for 300 mg/2 weeks vs. 0% for 405 mg/4 weeks; P=0.03). Therefore, use of the dose of 405 mg/4 weeks (or dose of 210 mg/2 weeks) is recommended as the optimal starting dose for patients switching from oral olanzapine of 10 mg/day.

For the patients stabilized on oral olanzapine of 15 mg/day, the relapse rate after switching to a dose of 405 mg/4 weeks was somewhat higher than the rate seen for patients who remained on the oral dose of 15 mg/day, whereas the rate for patients switched to the dose of 300 mg/2 weeks was somewhat lower than that of the patients remaining on the oral dose of 15 mg/day. The HR analysis also indicated that the closest corresponding starting dose (with a HR close to 1 relative to oral olanzapine of 15 mg/day) would seem to be somewhere between these two doses. However, if one uses the criterion of having no greater risk of relapse than would be seen with the stable oral dose, then the recommended starting dose for 15-mg patients would be 300 mg/2 weeks.

For the patients stabilized on oral olanzapine of 20 mg/day, those switched to 300 mg/2 weeks had a relapse rate most similar to that of the oral dose of 20 mg/day, and risk of relapse was almost identical. Therefore, although this dose represents the corresponding maintenance dose, which presumably does not reach steady-state concentrations of olanzapine for at least 3 months, this dose nevertheless seemed to maintain patients' clinical stability sufficiently such that no loading dose was required, and patients did not show any significant increase in risk of relapse from a direct switch to this maintenance dose.

Pharmacokinetic simulations of olanzapine concentrations confirmed these clinical recommendations in that the use of a higher starting dose than the corresponding steady-state maintenance dose did indeed reduce the time to achieve the desired olanzapine plasma concentrations. Use of the loading dose did also provide greater olanzapine levels during this early period of treatment to potentially minimize any noticeable decrease in therapeutic coverage during the initial switch. However, to avoid surpassing the desired target concentration, the simulations show that use of the loading dose regimen should be followed by a decrease to the known corresponding maintenance dose. Switching to too high a dose during that initial period (for example, switching from oral olanzapine of 10 mg/day to olanzapine LAI of 300 mg/2 weeks for the first 8 weeks) produced plasma concentrations higher than desired for a period of time, even after decreasing to the target 150 mg/2-week maintenance dose of olanzapine LAI.

Therefore, based on these data, we recommend using a loading dose strategy for those patients stabilized on oral olanzapine of 10 or 15 mg/day. For patients stabilized on oral olanzapine of 10 mg/day, olanzapine LAI treatment should begin with 405 mg/4 weeks or 210 mg/2 weeks (a comparable dose of 405 mg/4 weeks) for the first 8 weeks of treatment. Those patients can then be switched to the olanzapine LAI dose of 150 mg/2 weeks or 300 mg/4 weeks (approximately oral olanzapine of 10 mg/day) as their regular maintenance dose thereafter. For patients stabilized on oral olanzapine 15 mg/day, the optimal recommended starting olanzapine LAI dose would be 300 mg/2 weeks for the first 8 weeks of treatment before being switched to olanzapine LAI of 405 mg/4 weeks or 210 mg/2 weeks (approximately oral olanzapine of 15 mg/day) as their regular maintenance dose. As olanzapine LAI of 300 mg/2 weeks is the highest dose of olanzapine LAI available, a loading dose is neither possible nor required for those patients stabilized on oral olanzapine of 20 mg/day.

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Limitations

One limitation of this analysis is that the resulting recommendations are based on clinical significance, not statistical significance. As this was a secondary analysis dependent on the number of patients who were stabilized at each of the oral doses at the discretion of the investigator, the study was not powered to detect differences in risk of relapse for each stratum of oral stabilizing dose. Likewise, relatively few patients experienced relapse (with the exception of those randomized to receive very low doses of olanzapine LAI). Therefore, it could also be reasonably argued that a loading dose may not be necessary for many patients, and, as seen in the study by Lauriello et al. (2008), a direct switch produced therapeutic results within the first week of treatment regardless of earlier or randomized dose. However, it should be noted that the study by Lauriello et al. (2008) did not include the low dose of 150 mg/2 weeks, and results from these analyses suggest that a direct switch to that low dose may provide insufficient coverage for some patients if no loading dose is used. For patients who are already stable, newly stable, or in the process of being stabilized, there may be less willingness on the part of the treating physician to risk destabilization through insufficient dosing during the transition to a new treatment.

It is also important to note that there are many other effective methods for switching patients from an oral to a long-acting regimen. Use of a crosstaper of earlier antipsychotic medication, use of a loading dose, or use of oral antipsychotic supplementation are all possible solutions to compensate for any potential decrease in coverage during this sensitive initial period in the patient's treatment with a long-acting formulation. Number and duration of loading doses and the size of the dose itself also can vary. However, given that patients for whom a depot is typically prescribed tend to be patients who have difficulty adhering to oral medication regimens, it would seem logical to try to avoid switching methods which rely on the use of oral supplementation to maximize the likelihood of a successful switch in this patient population and minimize the risk of jeopardizing either the patient's clinical stability or the patient–physician treatment alliance.

Along these same lines, it is important to remember that these analyses were based on data from a randomized, controlled trial in which the patients were generally adherent to their oral olanzapine regimen before being switched to olanzapine LAI. Thus, their prescribed dose was also generally their dose taken. However, for patients who are less adherent, prescribed dose may not correspond to dose taken, making it more difficult to estimate actual effective oral dose. Thus, in actual clinical practice, it is possible that some patients who are receiving high oral doses may not require doses of the same magnitude when switching to a LAI formulation. The clinician should be aware that when using the dosing guidance for olanzapine LAI in Table 3, ‘target oral dose’ refers to the assumed effective dose, which may be different than the actual prescribed dose taken earlier.

It is also important to note that the current dosage recommendations (loading and maintenance doses) are primarily based on the HR assessment of the potential for relapse during the first 6 months of olanzapine LAI treatment. The pharmacokinetic simulations were developed to illustrate the advantages and different patterns of olanzapine exposures that are achievable using the recommended loading/maintenance doses. Prospective target concentrations to aid selection of each of the simulated regimens could not be defined; olanzapine concentrations typically exhibit wide interindividual variability and do not have a well-defined exposure–response relationship. Nevertheless, simulated pharmacokinetic profiles show that using the proposed loading regimens, olanzapine concentrations would be higher than those achieved without loading and the increased therapeutic coverage may reduce the risk of relapse after switching to olanzapine LAI from oral olanzapine.

Finally, these analyses do not specifically address the question of choice of injection frequency, and only 2-week and 4-week injection intervals were evaluated here. One issue to consider, however, is that increasing the frequency of injections does increase the number of opportunities for the patient potentially to experience a post-injection delirium/sedation syndrome event (Detke et al., 2010; McDonnell et al., 2010). Although the risk is the same at each injection, more opportunities for an event (i.e. more frequent injections) result in a slightly higher cumulative risk per patient over time (Eli Lilly and Company, 2008). Ultimately though, the dose and the frequency of the injection should be determined by the individual patient's treatment needs, also taking into consideration issues of convenience and ability to comply with the mandatory 3-h post-injection observation period.

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Conclusion

Although there are multiple methods available for switching patients to a LAI antipsychotic, selection of a method that does not rely on oral supplementation may be desirable in patients who have a tendency toward nonadherence to oral regimens. For olanzapine LAI, these analyses indicated that patients could be switched directly from oral to LAI olanzapine with minimal to no greater risk in relapse if an appropriate dose correspondence strategy was used. Patients switching from oral olanzapine of 10 or 15 mg/day should be initiated on a higher loading dose regimen for the first 8 weeks of treatment before being decreased to their target maintenance dose. Patients switching from oral olanzapine of 20 mg/day can be switched directly to their target maintenance dose of olanzapine LAI of 300 mg/2 weeks without a need for a loading dose.

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Acknowledgement

This study was funded by Eli Lilly and Company.

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olanzapine; olanzapine long-acting injection; olanzapine pamoate; pharmacokinetics; relapse; switching

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