Abstract
Background
This study aimed to determine the effects of dosage forms on the steady-state dose-corrected (C/D) concentrations of quetiapine and N-desalkylquetiapine in patients.
Methods
This was a retrospective cohort study that included 831 therapeutic drug monitoring samples derived from 512 patients. Multiple linear regression analysis was used to identify independent factors that affected the C/D values for quetiapine and N-desalkylquetiapine. Moreover, we compared the C/D values of quetiapine and N-desalkylquetiapine between the two groups and conducted subgroup analyses based on daily dose, sex, and age.
Results
The C/D ratio of quetiapine in the extended-release (XR) group was 1.7-fold higher compared with that in the immediate-release (IR) group (P < 0.001); however, no statistically significant difference was observed in the C/D ratio of N-desalkylquetiapine between the two subgroups (P > 0.05). In the subgroups stratified by daily dose, sex, and age group, the C/D ratios of quetiapine in the XR group were 1.31–2.65-fold higher compared with that in the IR group (all P < 0.001). No significant differences were observed in the C/D ratio of N-desalkylquetiapine among the subgroups (P > 0.05).
Conclusion
Dosage form significantly affects the steady-state C/D ratio of quetiapine; however, it does not significantly affect the C/D ratio of N-desalkylquetiapine.
Keywords: quetiapine, n-desalkylquetiapine, dosage form, dose-corrected blood concentration, therapeutic drug monitoring
Introduction
Psychiatric disorders affect between 18.1% and 36.1% of adults worldwide, with severe mental illnesses, such as schizophrenia, bipolar disorder, and depression, affecting 0.8%–6.8% of the global population.1,2 Psychotropic medications are currently the cornerstone treatment for psychotic disorders, and include antipsychotic medications, mood stabilizers, and antidepressants.3 Quetiapine is a dibenzothiazepine derivative that is widely used as an atypical antipsychotic. It is available in two different pharmaceutical forms: immediate-release (IR) and extended-release (XR). It exhibits a wide range of pharmacological effects and shows affinity for the dopamine D2 and 5-HT receptors, as well as the alpha-1 and histamine H1 receptors.4,5 Currently, it is used for the treatment of schizophrenia and bipolar disorder.5–7 In addition, it serves as an adjunctive therapy for major depressive disorder.8 Following its oral administration, quetiapine is predominantly metabolized in the body by cytochrome P450 (CYP450) 3A4, which produces the pharmacologically active metabolite N-desalkylquetiapine.9
Quetiapine IR was introduced in 1997. At doses within the recommended therapeutic range, it exhibits linear pharmacokinetics, with an elimination half-life (t½) of approximately 6 to 11 hours.10 Its active metabolite, N-desalkylquetiapine, has a half-life ranging from 10 to 13 hours.10 The recommended dosing frequency is 2–3 times daily, with a maximum daily dose not to exceed 800 mg.4 In patients diagnosed with schizophrenia or schizoaffective disorder, the frequency of daily dosing is a significant predictor of nonadherence to antipsychotic medication.9 Inconsistent adherence to prescribed antipsychotic regimens can result in treatment failure, relapse, and severe outcomes, such as hospitalization and an increased risk of suicide. Consequently, the development of quetiapine XR, which is designed for once-daily administration, may assist patients in complying with their treatment regimen to achieve optimal long-term outcomes.
Quetiapine XR is a once-daily formulation developed by AstraZeneca that received FDA marketing approval in 2007. This formulation was established to control drug release more effectively. Several clinical trials demonstrated that it is effective and well-tolerated in patients with acute schizophrenia, as well as in those receiving quetiapine XR as maintenance treatment for schizophrenia;11,12 however, alteration of dosage forms inevitably leads to changes in the drug’s in vivo processes. The pharmacokinetic profiles of quetiapine’s XR and IR differ significantly following single-dose administration. Specifically, the time to peak concentration (Tmax) for quetiapine XR is approximately 5 hours compared with 1–2 hours for quetiapine IR.4 Moreover, the peak concentration (Cmax) of quetiapine XR is approximately 13% lower compared with that of quetiapine IR when administered at equivalent doses;13 however, the ratio of the 24-hour area under the curve (AUC0-24h) for the two formulations approaches 1.04, which indicates comparable overall bioavailability.13
With ongoing innovation and advancement in precision medical testing, therapeutic drug monitoring (TDM) has emerged as an important element in the management of individualized medication for patients with mental disorders. It significantly enhances clinical efficacy and reduces adverse drug reactions, thus ensuring the safety and effectiveness of treatment.14 The consensus guidelines issued by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) recommend a therapeutic reference concentration of quetiapine ranging from 100 to 500 ng/mL, with a laboratory alert level set at 1000 ng/mL. For N-desalkylquetiapine, the recommended therapeutic concentration is between 100 and 250 ng/mL, with a recommendation grade of Level II.14 However, quetiapine exhibits significant interindividual pharmacokinetic variability among different patient populations. In real-world TDM settings, the dose-adjusted plasma concentrations (C/D) of quetiapine and its metabolites may vary by approximately 10 to 26-fold between individuals.15 Previous studies have indicated that factors such as patient age, sex, and CYP 450 gene polymorphisms significantly contribute to individual variations in drug concentrations.16 Additionally, the dosage form is a critical factor that should not be overlooked, as it can also influence the plasma concentrations of quetiapine and its metabolites.15 Currently, there is limited information regarding the effect of dosage forms on quetiapine C/D. Moreover, the effect of dosage forms on the C/D of N-desalkylquetiapine has not been fully established. To address these limitations, we conducted a retrospective cohort study of patients with mental disorders, using data from TDM extracted from a medical record-based database. We determined the effect of dosage forms on the C/D of quetiapine and N-desalkylquetiapine. The results provide clinical evidence to enhance our understanding of the pharmacokinetics associated with the two dosage forms of quetiapine.
Methods and Materials
Study Population and Design
This study used routine TDM data from patients treated at the Xi’an Mental Health Center between January and December 2022. Plasma concentrations of quetiapine and its metabolite, N-desalkylquetiapine, were measured. Demographic information, including age, sex, and weight, along with prescription details, such as daily dosage and dosage form, were collected from the electronic medical record system and the laboratory information system. In addition, liver and kidney function indicators, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine (Crea), were collected. The inclusion criteria were as follows: (1) Patients must be diagnosed with schizophrenia, bipolar disorder, or depression according to the ICD-10 criteria; (2) Hospitalized patients received quetiapine IR tablets administered twice daily (morning and evening) or quetiapine XR tablets administered once daily at bedtime, with TDM performed for quetiapine and N-desalkylquetiapine; (3) Subjects treated with a fixed dose of quetiapine for a minimum of 3 days to ensure that steady-state blood concentrations of quetiapine (half-life: 6–11 hours) and N-desalkylquetiapine (half-life: 10–13 hours) were achieved;10 (4) Patients were included in the study only if the time interval between the last drug intake and the sampling was between 10 to 12 hours for quetiapine IR tablets, and between 12 to 16 hours for quetiapine XR tablets.17 As previously reported, studies have shown that serum concentrations of quetiapine XR remain stable between 12 and 16 hours following the last dose.13,17 (5) For cases in which patients received the same dosage of quetiapine and multiple TDM results were available, only the most recent monitoring result was included. The exclusion criteria were as follows: (1) absence of a recorded daily dosage or administration of a non-therapeutic dosage, defined as a daily dose <150 mg or >800 mg; (2) undetectable blood concentrations of quetiapine and N-desalkylquetiapine, or concentrations below the quantitative detection limit, which may indicate potential issues with medication compliance; (3) patients <18 years of age; and (4) patients with incomplete clinical data. This was a retrospective analysis of anonymized data collected during routine clinical testing, which received a waiver of individual informed consent. Our study complies with the Declaration of Helsinki principles. The ethics committee of the Xi’an Mental Health Center approved the study (XAJWKY-2026002).
Bioanalytical Methods
Blood concentrations of quetiapine and N-desalkylquetiapine were quantified using the LC-MS/MS method (LC-MS/MS 8050 CL, Shimadzu, Japan), which was developed and validated in the TDM laboratory. This method has been used for the routine TDM of quetiapine and N-desalkylquetiapine. Patients who were administered quetiapine, either in IR or XR tablet, received a fixed dosage for a minimum duration of 3 days.18 The blood samples were centrifuged to obtain plasma, which was subsequently treated with MARG-1 protein precipitation reagent (Hunan Demite Instrument Co, Ltd.) to remove proteins. The pretreated samples were quantitatively analyzed using an LC-MS/MS 8050 CL mass spectrometer in positive ion mode. Quetiapine and N-desalkylquetiapine plasma calibrators, along with low, medium, and high plasma quality control samples, were obtained from Hunan Demite Instrument Co., Ltd. and were confirmed to be within their validity period. The intra- and interday imprecision and inaccuracy were <15%, thus meeting the requirements for bioanalytical sample testing.
Analyzed Parameters and Statistical Analysis
The study outcome measures included the C/D ratio of quetiapine and N-desalkylquetiapine, which were assessed relative to age (grouped as older [ie, >44 years] against younger [ie, ≤44 years]) and sex. All statistical analyses were conducted using SPSS version 27.0 software (IBM SPSS Statistics, Armonk, NY, USA). For graphical presentations, GraphPad version 4 was used (GraphPad Software, San Diego, CA, USA). Continuous variables conforming to a normal distribution are presented as the mean ± standard deviation (Mean ± SD), whereas nonnormally distributed continuous variables are described using the median and interquartile range, and denoted as M (Q1-Q3). Categorical variables are expressed as counts (n) or percentages (%). For the comparison of continuous variables between two subgroups, independent sample t-tests were used for data following a normal distribution, or the Mann–Whitney U-test for nonnormally distributed data. When comparing continuous variables across multiple groups, a one-way ANOVA was applied to normally distributed data, whereas the Kruskal–Wallis H-test was used for nonnormally distributed data. For categorical variable comparisons between two subgroups, the chi-square (χ2) test was performed. Multiple linear regression analysis was used to identify independent factors that influence the C/D ratio of quetiapine and N-desalkylquetiapine. A P-value ≤0.05 was considered statistically significant.
Results
Demographic Characteristics
The demographic characteristics of the patients are listed in Table 1. Based on the inclusion and exclusion criteria, a total of 512 hospitalized patients undergoing quetiapine treatment were included, which resulted in 831 TDM measurements for quetiapine and N-desalkylquetiapine. Among these, there were 405 samples from patients diagnosed with schizophrenia, 104 samples from patients with bipolar disorder, and 322 samples from patients with depression. Of the patients studied, 206 received quetiapine IR treatment, resulting in a total of 326 blood concentration measurements. In contrast, 306 patients were treated with quetiapine XR, which resulted in 505 blood concentration measurements. Patients received a median daily dose of quetiapine of 400 mg/day (200–400 mg), which resulted in median plasma concentrations of quetiapine and N-desalkylquetiapine of 252.80 ng/mL (147.98–407) and 107.10 ng/mL (72.50–158.80), respectively. The median C/D ratios for quetiapine and N-desalkylquetiapine were 0.78 ng/mL/mg/day (0.47–1.15) and 0.33 ng/mL/mg/day (0.24–0.42), respectively. The median patient age was 38 years (26.0–54), with males accounting for 51.02% of the total cases. The median height and weight were 165 cm (160–174.75) and 66 kg (58.0–75), respectively, whereas the median body mass index (BMI) was 24.09 kg/m2 (21.48–26.08). Combination therapy primarily consisted of other antipsychotic medications (14.92%), mood stabilizers (81.11%), antidepressants (12.03%), and sedative-hypnotics (40.43%). The indicators of liver and kidney function are listed in Table 1.
Table 1.
Patient Demographic and Clinical Characteristics
| Characteristics | Samples, n | Range | M (Q1-Q3) |
|---|---|---|---|
| Age, year | |||
| ≤ 44 | 504 | 18–44 | 29.0 (23.0–34.5) |
| > 44 | 327 | 45–85 | 57.0 (50.0–64.0) |
| Gender | |||
| Male | 424 | ||
| Female | 407 | ||
| BMI (kg/m2) | 13.56–36.11 | 24.09 (21.48–26.08) | |
| Diagnosis | |||
| Schizophrenia | 405 | ||
| Bipolar disorder | 104 | ||
| Depression | 322 | ||
| Daily dose (mg/day) | 150–800 | 400 (200–400) | |
| Dosage form | |||
| Immediate-release tablet | 326 | ||
| Extended-release tablet | 505 | ||
| Plasma concentration (ng/mL) | |||
| Quetiapine | 5.60–1270.50 | 252.80 (147.98–407.0) | |
| N-desalkylquetiapine | 7.0–492.04 | 107.10 (72.50–158.80) | |
| C/D ratio (ng/mL/mg/day) | |||
| Quetiapine | 0.028–3.18 | 0.78 (0.47–1.15) | |
| N-desalkylquetiapine | 0.034–0.91 | 0.33 (0.24–0.42) | |
| Concomitant medications | |||
| Aripiprazole | 39 | ||
| Clozapine | 21 | ||
| Risperidone | 16 | ||
| Paliperidone | 34 | ||
| Amisulpride | 14 | ||
| Lithium | 163 | ||
| Valproate | 511 | ||
| Paroxetine | 12 | ||
| Sertraline | 7 | ||
| Fluoxetine | 8 | ||
| Citalopram | 51 | ||
| Venlafaxine | 12 | ||
| Mirtazapine | 10 | ||
| Zopiclone | 119 | ||
| Alprazolam | 36 | ||
| Lorazepam | 118 | ||
| Oxazepam | 50 | ||
| Clonazepam | 13 | ||
| Liver function indicators | |||
| AST (U/L) | 7.0–68.0 | 16.0 (13.0–21.0) | |
| ALT (U/L) | 3.0–102.0 | 15.0 (10.0–24.0) | |
| Renal function indicators | |||
| BUN (mmol/L) | 1.3–11.2 | 4.1 (3.3–4.9) | |
| Crea (μmol/L) | 7.2–110.0 | 62.0 (53.0–69.0) |
Abbreviations: BMI, Body Mass Index; ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; BUN, Blood Urea Nitrogen; Crea, Creatinine; C/D, Concentration-to-dose ratio.
The Differences in Baseline Characteristics Between Patients in the Quetiapine IR and Quetiapine XR Groups
A comparison of the baseline characteristics for the different subgroups is shown in Table 2. Significant differences in age, gender, and disease diagnosis were observed between the two dosage form subgroups (P < 0.001); however, no statistically significant difference was evident for BMI (P > 0.05). In addition, significant differences were observed in the proportions of the combined use of lithium carbonate, valproate, citalopram, mirtazapine, and zopiclone between the two subgroups, with all differences achieving statistical significance (P < 0.05). Considerable differences were also observed in ALT, BUN, and Crea levels between the two subgroups (P < 0.01).
Table 2.
Baseline Characteristics Comparison Between the Immediate-Release Group and the Extended-Release Group
| Immediate-Release Group (n=326) | Extended-Release Group (n=505) | z/χ2 | P | |
|---|---|---|---|---|
| Age, year | 46.0 (30.0–63.0) | 33.0 (24.0–49.0) | −7.295 | < 0.001 |
| Gender | ||||
| Male | 125 | 299 | 34.47 | < 0.001 |
| Female | 201 | 206 | ||
| BMI (kg/m2) | 24.24 (22.04–26.04) | 23.88 (21.30–26.08) | −1.918 | 0.0552 |
| Diagnosis | ||||
| Schizophrenia | 204 | 201 | 41.893 | < 0.001 |
| Bipolar disorder | 26 | 78 | ||
| Depression | 96 | 226 | ||
| Concomitant medications | ||||
| Aripiprazole | ||||
| Yes | 11 | 28 | 2.084 | 0.1489 |
| No | 315 | 477 | ||
| Clozapine | ||||
| Yes | 5 | 16 | 2.146 | 0.1429 |
| No | 321 | 489 | ||
| Risperidone | ||||
| Yes | 7 | 9 | 0.14 | 0.7086 |
| No | 319 | 496 | ||
| Paliperidone | ||||
| Yes | 15 | 19 | 0.355 | 0.5514 |
| No | 311 | 486 | ||
| Amisulpride | ||||
| Yes | 5 | 9 | 0.0737 | 0.786 |
| No | 321 | 496 | ||
| Lithium | ||||
| Yes | 44 | 119 | 12.719 | < 0.001 |
| No | 282 | 386 | ||
| Valproate | ||||
| Yes | 219 | 292 | 7.315 | 0.0068 |
| No | 107 | 213 | ||
| Paroxetine | ||||
| Yes | 6 | 6 | 0.592 | 0.4418 |
| No | 320 | 499 | ||
| Sertraline | ||||
| Yes | 3 | 4 | 0.0389 | 0.8436 |
| No | 323 | 501 | ||
| Fluoxetine | ||||
| Yes | 1 | 7 | 2.418 | 0.1199 |
| No | 325 | 498 | ||
| Citalopram | ||||
| Yes | 27 | 24 | 4.28 | 0.0386 |
| No | 299 | 481 | ||
| Venlafaxine | ||||
| Yes | 5 | 7 | 0.0303 | 0.8618 |
| No | 321 | 498 | ||
| Mirtazapine | ||||
| Yes | 7 | 3 | 4.015 | 0.0451 |
| No | 319 | 502 | ||
| Zopiclone | ||||
| Yes | 64 | 55 | 12.322 | < 0.001 |
| No | 262 | 450 | ||
| Alprazolam | ||||
| Yes | 13 | 23 | 0.153 | 0.6954 |
| No | 313 | 482 | ||
| Lorazepam | ||||
| Yes | 52 | 66 | 1.349 | 0.2455 |
| No | 274 | 439 | ||
| Oxazepam | ||||
| Yes | 20 | 30 | 0.0132 | 0.9085 |
| No | 306 | 475 | ||
| Clonazepam | ||||
| Yes | 8 | 5 | 2.754 | 0.097 |
| No | 318 | 500 | ||
| Liver function indicators | ||||
| AST (U/L) | 16.0 (13.0–20.0) | 16.0 (13.0–21.0) | −0.42 | 0.6742 |
| ALT (U/L) | 13.5 (10.0–21.0) | 16.0 (10.0–25.3) | −2.722 | 0.0065 |
| Renal function indicators | ||||
| BUN (mmol/L) | 4.3 (3.4–5.3) | 4.0 (3.3–4.8) | −3.447 | < 0.001 |
| Crea (μmol/L) | 60.0 (51.0–67.0) | 63.0 (55.0–70.0) | −3.91 | < 0.001 |
Abbreviations: BMI, Body Mass Index; ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; BUN, Blood Urea Nitrogen; Crea, Creatinine.
Multiple Linear Regression Analysis
For multiple linear regression analysis, the dosage form was treated as the independent variable, whereas the quetiapine C/D ratio served as the dependent variable. The factors that showed significant differences in the univariate analysis, such as age, sex, disease diagnosis, concomitant medications, and liver and kidney function indicators, were included as covariates. In Model 1, which did not adjust for other covariates, patients in the quetiapine IR group had lower quetiapine C/D values compared with those in the quetiapine XR group (B = −0.341, 95% CI: −0.407 to −0.275, P < 0.001). The model exhibited an adjusted R2 of 0.110, with an F-statistic of 103.063 (P < 0.01). After adjusting for covariates, Model 2 (B = −0.371, 95% CI: −0.442 to −0.301, P < 0.001) indicated that dosage form is an independent factor significantly associated with the quetiapine C/D ratio. However, the effect size is limited, as evidenced by an adjusted R2 of 0.157 and an F statistic of 13.902 (P < 0.01). The detailed results are listed in Figure 1.
Figure 1.
Forest plot of multiple linear regression results for factors influencing quetiapine dose-corrected concentration.
Multiple linear regression analysis revealed that in Model 1, which was not adjusted for other covariates, no significant difference in the N-desalkylquetiapine C/D ratio was observed between the quetiapine XR and quetiapine IR groups (P > 0.05, Figure 2). The adjusted R2 value was −0.001, with an F-statistic of 0.000 and a corresponding p-value of 0.985. After adjusting for covariates, Model 2 (adjusted R2 = 0.134, F = 11.718, P < 0.01) indicated that the dosage form was not an independent factor influencing the C/D ratio of N-desalkylquetiapine (P > 0.05, Figure 2).
Figure 2.
Forest plot of multiple linear regression results for factors influencing N-desalkylquetiapine dose-corrected concentration.
The Effect of Dosage Form on the C/D Ratio of Quetiapine and N-Desalkylquetiapine
The results of the Mann–Whitney U-test indicated that the C/D value of quetiapine XR was 1.70-fold greater than that of quetiapine IR (Table 3), with a statistically significant difference (P < 0.001). In contrast, there was no statistically significant difference in the C/D value of N-desalkylquetiapine between the two subgroups (P > 0.05).
Table 3.
Comparison of C/D Ratio of Quetiapine and N-Desalkylquetiapine Between the Immediate-Release Group and the Extended-Release Group
| Subgroup | n | Daily Dose (mg/day) | Plasma Concentration (ng/mL) | C/D (ng/mL/mg/day) | ||
|---|---|---|---|---|---|---|
| Quetiapine | N-Desalkylquetiapine | Quetiapine | N-desalkylquetiapine | |||
| Immediate-release group | 326 | 300 (200–500) | 174.90 (105.50–273.60) | 101.15 (70.80–144.60) | 0.54 (0.32–0.88) | 0.33 (0.23–0.42) |
| Extended-release group | 505 | 400 (200–400) | 330.50 (196.08–493.73) | 114.70 (74.04–164.40) | 0.92 (0.64–1.30) | 0.33 (0.24–0.41) |
| z | −3.251 | −11.692 | −2.506 | −10.605 | −0.0534 | |
| P | 0.0011 | < 0.001 | 0.0122 | < 0.001 | 0.9574 | |
Abbreviation: C/D, Concentration-to-dose ratio.
The effect of dosage form on the C/D ratio of quetiapine and N-desalkylquetiapine among the different dose groups is listed in Table 4. In the low-dose (χ ≤ 200 mg), medium-dose (200 mg < χ≤ 400 mg), and high-dose (400 mg < χ ≤ 800 mg) quetiapine groups, the Mann–Whitney U-test indicated that the C/D ratio of quetiapine XR was between 1.38- and 2.65-fold greater than that of quetiapine IR, with a statistically significant difference (P < 0.001). In contrast, no statistically significant difference was evident for the N-desalkylquetiapine C/D ratio between the two subgroups among different dose groups (P >0.05).
Table 4.
Comparison of C/D Ratio of Quetiapine and N-Desalkylquetiapine Across Different Daily Dose Subgroups
| Daily dose (mg/day) | Subgroup | n | Plasma Concentration (ng/mL) | C/D (ng/mL/mg/day) | ||
|---|---|---|---|---|---|---|
| Quetiapine | N-desalkylquetiapine | Quetiapine | N-desalkylquetiapine | |||
| χ ≤ 200 | Immediate-release group | 116 | 126.55 (71.05–202.34) | 71.05 (46.70–89.35) | 0.68 (0.36–1.01) | 0.37 (0.27–0.46) |
| Extended-release group | 166 | 188.80 (130.70–279.0) | 69.60 (52.30–91.0) | 0.94 (0.65–1.40) | 0.35 (0.26–0.46) | |
| z | −5.054 | −0.0304 | −4.715 | −0.68 | ||
| P | < 0.001 | 0.9757 | < 0.001 | 0.4963 | ||
| 200 < χ ≤ 400 | Immediate-release group | 127 | 191.30 (134.58–276.88) | 105.20 (84.10–140.33) | 0.59 (0.38–0.88) | 0.33 (0.25–0.40) |
| Extended-release group | 226 | 362.10 (245.50–507.50) | 126.65 (91.60–161.90) | 0.91 (0.61–1.27) | 0.32 (0.23–0.40) | |
| z | −8.498 | −3.059 | −6.188 | 0.76 | ||
| P | < 0.001 | 0.0022 | < 0.001 | 0.4475 | ||
| 400 < χ ≤ 800 | Immediate-release group | 83 | 209.30 (133.45–323.38) | 165.90 (122.40–217.20) | 0.34 (0.21–0.55) | 0.28 (0.21–0.38) |
| Extended-release group | 113 | 547.50 (390.95–722.48) | 188.13 (142.30–246.68) | 0.90 (0.65–1.20) | 0.31 (0.24–0.40) | |
| z | −8.583 | −2.285 | −8.098 | −1.757 | ||
| P | < 0.001 | 0.0223 | < 0.001 | 0.0789 | ||
Abbreviation: C/D, Concentration-to-dose ratio.
Subgroup Analysis by Sex and Age Group
The results of the Mann–Whitney U-test indicated that, within the male subgroup, the C/D ratio for quetiapine XR was 1.31-fold higher compared with that for quetiapine IR, and the difference was significant (P < 0.001, Table 5). In contrast, no significant difference was observed in the C/D ratio of N-desalkylquetiapine between the two subgroups in the male subgroup (P > 0.05, Table 5). The Mann–Whitney U-test indicated that the C/D value of quetiapine XR was twice that of quetiapine IR in the female subgroup, and the difference was significant (P < 0.001, Table 5). In contrast, a significant difference was not observed in the C/D value of N-desalkylquetiapine between the two subgroups in the female subgroup (P >0.05; see Table 5).
Table 5.
Comparison of C/D Ratio of Quetiapine and N-Desalkylquetiapine Between the Immediate-Release Group and the Extended-Release Group Among Patients with Different Genders and Ages
| Subgroup | n | Daily dose (mg/day) | Plasma concentration (ng/mL) | C/D (ng/mL/mg/day) | ||
|---|---|---|---|---|---|---|
| Quetiapine | N-desalkylquetiapine | Quetiapine | N-desalkylquetiapine | |||
| Male | ||||||
| Immediate-release group | 125 | 300 (200–400) | 218.90 (137.96–314.08) | 104.0 (76.68–145.23) | 0.71 (0.44–1.01) | 0.33 (0.25–0.42) |
| Extended-release group | 299 | 400 (200–600) | 348.50 (204.98–545.45) | 109.50 (75.73–164.03) | 0.93 (0.69–1.30) | 0.32 (0.25–0.40) |
| z | −2.645 | −6.145 | −1.405 | −5.003 | −0.896 | |
| P | 0.0082 | < 0.001 | 0.1599 | < 0.001 | 0.3704 | |
| Female | ||||||
| Immediate-release group | 201 | 300 (200–500) | 153.20 (88.88–237.43) | 96.70 (68.28–143.96) | 0.45 (0.29–0.76) | 0.33 (0.23–0.41) |
| Extended-release group | 206 | 400 (200–400) | 294.75 (190.60–448.70) | 116.20 (70.40–169.40) | 0.90 (0.57–1.30) | 0.34 (0.24–0.44) |
| z | −1.615 | −9.102 | −1.867 | −8.31 | −0.99 | |
| P | 0.1063 | < 0.001 | 0.0619 | < 0.001 | 0.322 | |
| ≤ 44 | ||||||
| Immediate-release group | 155 | 300 (200–600) | 151.30 (89.73–247.83) | 104.0 (70.13–151.0) | 0.44 (0.26–0.70) | 0.31 (0.23–0.40) |
| Extended-release group | 349 | 400 (200–400) | 335.49 (201.18–490.27) | 116.80 (79.13–163.68) | 0.89 (0.63–1.26) | 0.31 (0.23–0.41) |
| z | −1.51 | −9.964 | −1.853 | −9.886 | −0.543 | |
| P | 0.131 | < 0.001 | 0.0638 | < 0.001 | 0.5873 | |
| > 44 | ||||||
| Immediate-release group | 171 | 300 (200–400) | 194.60 (127.65–293.68) | 97.70 (75.15–137.40) | 0.64 (0.40–0.96) | 0.35 (0.25–0.44) |
| Extended-release group | 156 | 400 (200–400) | 300.95 (184.55–504.65) | 103.70 (69.45–175.85) | 1.02 (0.67–1.34) | 0.35 (0.27–0.44) |
| z | −1.275 | 5.973 | 1.068 | −5.769 | 0.524 | |
| P | 0.2025 | < 0.001 | 0.2855 | < 0.001 | 0.6002 | |
Abbreviation: C/D, Concentration-to-dose ratio.
The results of the Mann–Whitney U-test revealed that the C/D values of quetiapine XR were significantly higher compared with those of quetiapine IR in the ≤44 years and >44 years subgroups, and the differences were significant (P < 0.001 for both subgroups; see Table 5). In contrast, no significant differences were observed in the C/D values of N-desalkylquetiapine between the two subgroups, in the ≤44 years and >44 years subgroups (P > 0.05 for both subgroups; see Table 5).
Discussion
In this study, we compared the clinical data of patients in the quetiapine IR group with those in the quetiapine XR group. Significant differences were observed between the two subgroups in terms of gender, age, diagnosis, and the proportion of patients coadministered with lithium carbonate, valproate, citalopram, mirtazapine, and zopiclone, as well as indicators of liver and kidney function. Multiple linear regression analyses were conducted to determine whether dosage forms act as independent factors for the C/D values of quetiapine and N-desalkylquetiapine. Dosage form was used as the independent variable, whereas the factors identified through univariate screening were treated as covariates. The results indicated that, in both unadjusted and covariate-adjusted models, the dosage form was an independent factor that influenced the quetiapine C/D ratio; however, despite being statistically significant, its effect size remains limited; It did not significantly affect the N-desalkylquetiapine C/D ratio.
Our results are consistent with those of previous studies. One study indicated that, in patients treated with quetiapine, the C/D ratio of quetiapine XR at steady-state plasma concentration, was often significantly higher (by 43.75%) compared with that of quetiapine IR. This is consistent with the results of the present study.15 Our results are also consistent with those of Fisher et al,19 as no significant differences were observed in the C/D ratios of N-desalkylquetiapine between the subgroups of quetiapine XR and IR. These results are consistent across subgroup analyses based on different daily doses as well as gender and age categories. They indicate that the C/D ratio of quetiapine XR is significantly higher compared with that of IR; however, no significant difference was observed for the C/D ratio of N-desalkylquetiapine.
The effect of dosage form factors on the pharmacokinetics of quetiapine primarily occurs from variations in release characteristics and absorption rates. The estimated absorption rates for the two dosage forms are 1.46 and 0.10 h−1, respectively.20 Following oral administration, quetiapine IR rapidly disintegrates and releases its contents into the gastrointestinal tract, reaching peak plasma concentrations within 1–1.5 hours.21 In contrast, quetiapine XR releases the drug slowly and continuously, requiring 4–5 hours to achieve peak plasma concentrations.21 Because of the design characteristics of the dosage form, the plasma concentration of quetiapine IR may decrease to a relatively low level by the end of the dosing interval. In contrast, quetiapine XR is continuously released and absorbed at a relatively constant rate throughout the dosing period, thus providing sustained counteraction against the rapid elimination of the drug. Therefore, quetiapine XR maintains the drug concentration at a relatively high level at the same dosage for a longer time.13
The steady-state plasma concentration of N-desalkylquetiapine is primarily affected by the total exposure to the parent drug, quetiapine, as well as the processes of its formation and elimination. Figueroa et al found that the least squares mean ratio of the AUC between quetiapine XR and IR during the 0–24 hour dosing interval was 1.04 (0.92–1.19), indicating similar bioavailability between the two formulations of quetiapine.13 Therefore, although the two formulations show different absorption rates, the overall exposure to quetiapine remains comparable, resulting in similar quantities of quetiapine metabolized by hepatic CYP 3A4. There is no significant difference in the plasma concentration of N-desalkylquetiapine between the two formulations. In a word, once its plasma concentration attains a steady state, the plasma concentration of N-desalkylquetiapine will not vary because of differences in dosage forms, provided that the AUC of the parent drug quetiapine is comparable and its clearance rate remains constant.
Although our study yielded meaningful results, several limitations should be considered. The low explanatory variance of the multiple regression model indicates that the covariates included in this analysis account for only a limited proportion of the total variability in quetiapine exposure. Although the dosage form is an independent factor influencing the C/D ratio of quetiapine, its effect is limited. Numerous prior studies have demonstrated that polymorphisms in the hepatic drug-metabolizing enzymes, CYP 3A4, and 2D6, significantly affect the steady-state plasma concentration or the C/D ratio of quetiapine and N-desalkylquetiapine.16,22 However, because of the constraints of this study, the effect of CYP450 liver enzyme gene polymorphisms on the pharmacokinetics of quetiapine was not determined. Second, this study is retrospective in nature, and as such, it poses significant challenges in effectively controlling for putative confounding variables that may influence the C/D ratios of quetiapine and N-desalkylquetiapine. There were significant differences between the two subgroups with varying dosage forms in terms of age, sex, diagnosis, and the proportion of concomitant use of lithium carbonate, valproate, citalopram, mirtazapine, and zopiclone, along with indicators of liver and kidney function. These differences may affect the results of the study. Nevertheless, the multiple linear regression analysis revealed that dosage form is a significant independent variable influencing the quetiapine C/D ratio; however, it does not significantly affect the N-desalkylquetiapine C/D ratio. Third, this study analyzed 831 TDM observations collected from 512 patients, with several patients contributing multiple TDM results. The failure to adjust for non-independent observations resulting from clustering may result in inflated statistical significance and an increased type I error rate. Fourth, in our retrospective dataset, we were unable to clearly ascertain the reasons behind the prescribing deviations related to the choice of quetiapine formulation. In the future, we will conduct prospective studies aimed at eliminating the differences in individual characteristic parameters between the two subgroups. This approach will further validate the effect of dosage forms on the C/D ratios of quetiapine and N-desalkylquetiapine.
Conclusion
In summary, our study and those of others indicate that once a steady-state blood concentration of quetiapine and N-desalkylquetiapine is achieved, the dosage form may potentially affects the C/D ratio of quetiapine; however, its effect is limited. Consequently, this finding should be interpreted with caution in clinical practice. However, it does not affect the C/D ratio of N-desalkylquetiapine. Given the inherent limitations of this retrospective study, we will conduct a prospective cohort study to further investigate the potential impact of dosage form on the steady-state plasma concentrations of quetiapine and its active metabolite, N-desalkylquetiapine. Furthermore, we will investigate the relationship between these concentrations and both the clinical efficacy and the adverse drug reactions in patients with mental disorders who are receiving different formulations of quetiapine.
Funding Statement
There is no funding to report.
Data Sharing Statement
Data will be made available on request. The clinical and laboratory data supporting this study’s findings are available from the corresponding author upon special request.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data will be made available on request. The clinical and laboratory data supporting this study’s findings are available from the corresponding author upon special request.