Population Pharmacokinetic Modeling of Risperidone and 9-Hydroxyrisperidone to Estimate CYP2D6 Subpopulations in Children and Adolescents

AIM:: The study aims were to characterize risperidone and (±)-9-hydroxyrisperidone pharmacokinetic (PK) variability in children and adolescents and to evaluate covariate effects on PK parameters. METHODS:: Steady-state samples were drawn at predose, 1, 2, 4, and 7 hours postdose; cytochrome P450 2D6 (CYP2D6) genotypes were available for 28 subjects. A nonlinear mixed-effects model (NONMEM) modeled the PKs of risperidone and (±)-9-hydroxyrisperidone; covariates included age, weight, sex, and CYP2D6 phenotype. The model included 497 observations [risperidone (n = 163), (+) and (-)-9-hydroxyrisperidone (n = 334)] from 45 subjects aged 3-18.3 (mean 9.6 ± 3.7) years, weighing 16.8-110 (43 ± 20.2) kg. RESULTS:: A 1-compartment mixture model described risperidone and (±)-9-hydroxyrisperidone clearances for 3 CYP2D6 metabolizer subpopulations: extensive, intermediate, and poor. Weight significantly affected (±)-9-hydroxyrisperidone clearance. Clearance estimates in the mixture model were poor metabolizer 9.38 L/h, intermediate metabolizer 29.2 L/h, and extensive metabolizer 37.4 L/h. CONCLUSION:: Active moiety [risperidone plus (±)-9-hydroxyrisperidone] PK variability and the covariate effects were better explained with the addition of metabolite PK parameters. This model may aid the development of individualized risperidone dosing regimens in children and adolescents.     

Effect of venlafaxine on the pharmacokinetics of risperidone

An open-label study evaluated the effect of steady-state venlafaxine on the single-dose pharmacokinetic profile of risperidone, a CYP2D6 substrate; its active metabolite, 9-hydroxyrisperidone; and the total active moiety (risperidone plus 9-hydroxyrisperidone). Thirty healthy subjects received a 1 mg oral dose of risperidone before and after venlafaxine dosing to steady state. No significant changes occurred between treatments in the area under the concentration-time curve (AUC) for 9-hydroxyrisperidone or the total active moiety. However, venlafaxine weakly altered the pharmacokinetics of risperidone. Oral clearance decreased 38%, and the volume of distribution decreased 17%, resulting in a 32% increase in the AUC for risperidone. Renal clearance of 9-hydroxyrisperidone also decreased by 20% in the presence of venlafaxine. Safety profiles of both drugs were not altered. This study demonstrated that venlafaxine did not affect the pharmacokinetic profile of 9-hydroxyrisperidone or the total active moiety, although it weakly inhibited the metabolism of risperidone. These results show that venlafaxine is unlikely to be involved in a pharmacokinetic interaction with concomitant risperidone.     

Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1

This study estimated the population pharmacokinetics of risperidone and its active metabolite, 9-hydroxyrisperidone, according to genetic polymorphisms in the metabolizing enzyme (CYP2D6) and transporter (ABCB1) genes in healthy subjects. Eighty healthy subjects who received a single oral dose of 2?mg risperidone participated in this study. However, eight subjects with rare genotype variants in CYP2D6 alleles were excluded from the final model built in this study. We conducted the population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone using a nonlinear mixed effects modeling (NONMEM) method and explored the possible influence of genetic polymorphisms in CYP2D6 alleles and ABCB1 (2677G>T/A and 3435C>T) on the population pharmacokinetics of risperidone and 9-hydroxyrisperidone. A two-compartment model with a first-order absorption and lag time fitted well to serum concentration-time curve for risperidone. 9-hydroxyrisperidone was well described by a one-compartment model as an extension of the parent drug (risperidone) model with first-order elimination and absorption partially from the depot. Significant covariates for risperidone clearance were genetic polymorphisms of CYP2D6*10, including CYP2D6*1/*10 (27.5?% decrease) and CYP2D6*10/*10 (63.8?% decrease). There was significant difference in the absorption rate constant (k ( a )) of risperidone among the CYP2D6*10 genotype groups. In addition, combined ABCB1 3435C>T and CYP2D6*10 genotypes had a significant (P?T as covariates was successfully constructed. The estimated contribution of genetic polymorphisms in CYP2D6*10 and ABCB1 3435C>T to population pharmacokinetics of risperidone and 9-hydroxyrisperidone suggests the interplay of CYP2D6 and ABCB1 on the pharmacokinetics of risperidone and 9-hydroxyrisperidone according to genetic polymorphisms.     

Plasma concentrations of risperidone and 9-hydroxyrisperidone: effect of comedication with carbamazepine or valproate

To evaluate the pharmacokinetic interaction between risperidone and the mood-stabilizing agents carbamazepine and valproic acid, steady state plasma concentrations of risperidone and 9-hydroxyrisperidone (9-OH-risperidone) were compared in patients treated with risperidone alone (controls, n = 23) and in patients comedicated with carbamazepine (n = 11) or sodium valproate (n = 10). The three groups were matched for sex, age, body weight, and antipsychotic dosage. Plasma concentrations of risperidone and 9-OH-risperidone did not differ between valproate-comedicated patients and controls. By contrast, the concentrations of both compounds were lower in patients taking carbamazepine, although the difference reached statistical significance only for the metabolite (p < 0.001). The sum of the concentrations of risperidone and 9-OH-risperidone in patients receiving carbamazepine (median 44 nmol/L) was also significantly lower than in patients receiving valproate (168 nmol/L) and in controls (150 nmol/L). In five patients assessed with and without carbamazepine comedication, dose-normalized plasma risperidone and 9-OH-risperidone concentrations were significantly lower when the patients received combination therapy than when they received risperidone alone. In three patients assessed with and without valproate, no major changes in the levels of risperidone and its metabolite were observed. These findings demonstrate that carbamazepine markedly decreases the plasma concentrations of risperidone and its active 9-OH-metabolite, probably by inducing CYP3A4-mediated metabolism. This interaction is likely to be clinically significant. Conversely, valproic acid does not cause any major change in plasma antipsychotic levels.     

Effect of cyamemazine on the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone: a preliminary retrospective study

Administration of cyamemazine, an antipsychotic drug with anxiolytic properties, together with other antipsychotic agents is common in patients with schizophrenia. This retrospective study investigated the effects of cyamemazine on the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone in 47 patients treated with 1 to 12 mg/day of risperidone. Of these 47 patients, 24 were receiving cyamemazine comedication ("cyamemazine" group) and 23 patients were treated with risperidone alone ("control" group). Plasma concentrations were measured using a high-performance liquid chromatographic method with photodiode-array ultraviolet detection. The median plasma concentration of risperidone was significantly higher in the cyamemazine group (31.5 ng/mL) than in the control group (5.0 ng/mL), whereas the 9-hydroxyrisperidone median concentration was significantly lower in the cyamemazine group (16.5 ng/mL versus 39.0 ng/mL in the control group). However, the sum of risperidone plus 9-hydroxyrisperidone (active moiety) plasma concentration was not significantly affected by cyamemazine comedication. A combination with cyamemazine resulted in an inverted metabolic ratio (risperidone/9-hydroxyrisperidone). These findings suggest that cyamemazine inhibits the 9-hydroxylation of risperidone and is probably an inhibitor of cytochrome P450 2D6 as are many other phenothiazine drugs.     

Significant pharmacokinetic interaction between risperidone and carbamazepine: its relationship with CYP2D6 genotypes

The effects of carbamazepine coadministration (400 mg/day for 1 week) on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone were studied in 11 schizophrenic inpatients treated with 6 mg/day risperidone. Blood samplings were performed before and during carbamazepine coadministration, and 1 week after its discontinuation. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-mass spectrometry-mass spectrometry. CYP2D6 genotypes were determined using the polymerase chain reaction method. Plasma concentrations of risperidone and 9-hydroxyrisperidone during carbamazepine coadministration (2.5+/-3.6 ng/ml and 19.4+/-4.1 ng/ml) were significantly ( P<0.01) lower than those before carbamazepine coadministration (5.0+/-7.9 ng/ml and 34.6+/-9.8 ng/ml). The changes in risperidone concentrations were positively correlated to the concentration ratios of risperidone/9-hydroxyrisperidone (r(s)=0.90, P<0.01), which were closely associated with CYP2D6 genotypes. The present study suggests that carbamazepine induces the metabolism of risperidone and 9-hydroxyrisperidone, and that the decrease in risperidone concentration is dependent on the CYP2D6 activity.     

ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety

Risperidone is metabolized to its active metabolite, 9-hydroxyrisperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4. Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination. The aim of the present study was to evaluate the influence of polymorphisms in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account. Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively. Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme. The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds. The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients. Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes. In conclusion, our results confirmed the significant effect of CYP2D6 genotype on the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisms have a moderate effect on those of 9-hydroxyrisperidone and the active moiety.     

Interpreting serum risperidone concentrations

Risperidone is an atypical antipsychotic commonly used for treatment of schizophrenia and other psychotic disorders. Although therapeutic drug monitoring is not routine for any of the atypical antipsychotics, serum antipsychotic concentrations are measured routinely to assess treatment nonadherence. In humans, risperidone is metabolized by cytochrome P450 2D6 to 9-hydroxyrisperidone; together these constitute the active moiety. Dose-proportional increases in serum concentrations have not been reported for the parent drug, but have been reported for 9-hydroxyrisperidone and the active moiety (i.e., the combined concentrations of risperidone and 9-hydroxyrisperidone). We describe a 34-year-old Caucasian man of Sicilian descent with a history of schizophrenia, disorganized type. He was suspected to be noncompliant with his risperidone therapy. Initially, active moiety risperidone concentrations increased linearly with prescribed dosage increases. However, with continued increases, active moiety concentrations adjusted downward and remained 17-36% below anticipated levels. We propose a method for estimating target active moiety concentrations of risperidone based on dosage-a method that may be used to guide clinicians in assessing nonadherence to risperidone treatment.     

Pharmacokinetic and safety assessments of galantamine and risperidone after the two drugs are administered alone and together

To explore the steady-state pharmacokinetic profile after coadministration of galantamine and risperidone, an open-label, randomized, single-center, two-way crossover drug-drug interaction study was conducted in 16 healthy elderly subjects, ages 60 years and older. The results showed that risperidone, when administered with galantamine, did not change the bioavailability of galantamine at steady state. In addition, systemic exposure of risperidone active moiety (risperidone plus 9-hydroxyrisperidone), the most clinically relevant component of risperidone treatment, was not affected by galantamine coadministration, while systemic exposure was increased by approximately 10% for risperidone and decreased by about 10% for 9-hydroxyrisperidone (active metabolite of risperidone). Galantamine and risperidone were both safe and well tolerated administered either alone or together. Thus, no dose adjustment for either risperidone orgalantamine is necessary when these two drugs are administered together in the dose range evaluated.     

Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone,in Japanese patients with schizophrenia

The effects of various CYP2D6 genotypes on the steady-state plasma concentrations (Css) of risperidone and its active metabolite, 9-hydroxyrisperidone, were studied in 85 Japanese schizophrenic patients (27 men and 58 women) treated with 6 mg/d risperidone for at least 2 weeks. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-tandem mass spectrometry. The patients had the following CYP2D6 genotypes: wild-type (wt)/wt (40 patients), CYP2D6*10 (*10)/wt ( 28), CYP2D6*5 (*5)/wt ( 8), *10/*10 ( 5), *5/*10 ( 3), and CYP2D6*4/CYP2D6*14 ( 1), respectively. The Css values of risperidone and 9-hydroxyrisperidone were corrected to the median body weight of 58 kg. The medians (ranges) of the Css of risperidone in the aforementioned genotype groups were 2.2 (0.37-35.7), 6.4 (2.1-26.5), 12.3 (4.7-39.5), 19.4 (13.4-26.4), 64.0 (41.6-68.8), and 91.8 nmol/L. Those values for risperidone-to-9-hydroxyrisperidone ratio were 0.03 (0.01-0.33), 0.06 (0.03-0.19), 0.14 (0.07-0.29), 0.28 (0.25-0.38), 0.48 (0.38-0.58), and 2.35, respectively. The Css of risperidone was significantly (P < 0.05 or P < 0.001) different among the four genotype groups (wt/wt, *10/wt, *5/wt, and *10/*10), except between the *5/wt and *10/*10 groups. Also, the risperidone-to-9-hydroxyrisperidone ratio significantly (P < 0.005 or P < 0.001) differed among these genotype groups. No significant differences were found in the Css of 9-hydroxyrisperidone and the active moiety (the Css of risperidone plus 9-hydroxyrisperidone) among these genotype groups. This study confirms previous findings that the CYP2D6 status affects the Css of risperidone via its strong regulation of 9-hydroxylation of risperidone. However, similar active moiety of risperidone among different genotype groups suggests that the determination of the CYP2D6 genotype has little importance for clinical situations.     

利培酮与9-羟利培酮对精神分裂症患者血药浓度与剂量的关系

目的:探讨口服利培酮的精神分裂症患者利培酮、9-羟利培酮血药浓度、利培酮与9-羟利培酮血药浓度之和及比值与剂量的关系.方法:采用液-质联用法测定利培酮和9-羟利培酮血药浓度;计算利培酮、9-羟利培酮血药浓度及两者之和与剂量的相关系数.结果:利培酮、9-羟利培酮及两者之和与剂量相关系数分别0.766 8,0.980 0和0.979 8.36.6%患者9-羟利培酮血药浓度高于利培酮.结论:9-羟利培酮血药浓度及两者之和比利培酮血药浓度与剂量有更好相关性,9-羟利培酮在精神分裂症治疗中有重要作用.     

Serum prolactin levels, plasma risperidone levels, polymorphism of cytochrome P450 2D6 and clinical response in patients with schizophrenia

The object of this study is to assess 1) the relationship between plasma antipsychotic drug concentration, serum prolactin levels and the clinical efficacy of risperidone, 2) the relationship between the CYP2D6 polymorphisms and metabolizing of risperidone and 3) the role of 9-hydroxyrisperidone in elevating prolactin levels. One-hundred and eighteen Chinese schizophrenia patients (40 males, 78 females, age 15-60 years) were given risperidone at dosages ranging from 2-8 mg/day for 8 weeks. Clinical efficacy was determined using the Brief Psychiatric Rating Scores (BPRS). Serum prolactin levels were assayed before and after the 8 week treatment and plasma risperidone and 9-hydroxyrisperidone levels were also measured at the end of the 8-week treatment. The results showed there was no significant correlation between the concentration of active moiety and clinical response. Risperidone treatment significantly increased serum prolactin levels. Furthermore, changes of prolactin levels were not correlated with the clinical response. For the risperidone/ 9-hydroxyrisperidone ratio, there was a statistically significant difference among the CYP2D6*1/*1, *1/*10, *10/*10 genotypes (Kruskal-Wallis test, p = 0.012). No significant differences were found in the concentration of 9-hydroxyrisperidone and active moiety among the genotypes. In addition, the concentration of 9-hydroxyrisperidone was not significantly correlated with the increase of serum prolactin. In conclusion, our study has, for the first time, produced evidence that in Chinese schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6. Neither changes in serum prolactin levels nor plasma concentration of active moiety were significantly correlated with clinical efficacy of risperidone. 9-hydroxyrisperidone may not play a predominant role in elevating serum prolactin level.     

Effect of rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics of risperidone

The authors studied the effect of rifampin, a dual inducer of CYP3A and P-glycoprotein, on the pharmacokinetics and pharmacodynamics of risperidone in humans. Ten healthy male subjects were treated daily for 7 days with 600 mg rifampin or with placebo. On day 6, a single dose of 1 mg risperidone was administered. Plasma risperidone and 9-hydroxyrisperidone concentrations were measured. Rifampin significantly decreased the mean area under the plasma concentration-time curve by 51% for risperidone, by 43% for 9-hydroxyrisperidone, and by 45% for the active moieties (risperidone + 9-hydroxyrisperidone). Rifampin also decreased the peak plasma concentration of risperidone by 38%, 9-hydroxyrisperidone by 46%, and the active moieties by 41%. The apparent oral clearance of risperidone approximately doubled after rifampin treatment. Thus, rifampin reduced the exposure to risperidone, probably because of a decrease in its bioavailability through the induction of CYP3A and probably P-glycoprotein.     

利培酮和其主要活性代谢产物9-羟基利培酮代谢动力学模型的建立和鉴别

建立利培酮(RIP)和其活性代谢物9-羟基利培酮代谢动力学模型，并考察其在健康男性志愿者中的药动学特征。22名健康男性志愿者单剂量口服利培酮2 mg，在服药前及服药后96 h内的不同时间点取血。HPLC-MS法测定RIP和9-羟基利培酮的血药浓度；依据RIP和9-羟基利培酮的T_1/2确定志愿者中CYP2D6快代谢(EM)、中代谢(IM)和慢代谢(PM)型的分布，相似转换法(similarity transformation)进行模型结构鉴别，依据鉴别结果进行模型修正；加权最小二乘法进行模型参数估算；以Monte Carlo法产生的模拟数据进行模型验证，评估模型参数求算的准确性。22名健康男性志愿者中EM型18名，IM型4名；模型鉴别结果提示假设模型不可整体鉴别，当获知RIP代谢为9-羟基利培酮的转换分数时，模型参数均可求算；模型对于EM型和IM型RIP和9-羟基利培酮血药浓度经时过程和主要药动学参数AUC_0-T，C_max和T_max预测效果均较好。RIP代谢为9-羟基利培酮的转换速率常数EM型为(0.12±0.08) h^-1，IM型为(0.014±0.007) h^-1，RIP的消除速率常数EM型为(0.25±0.18) h^-1，IM型为(0.05±0.23) h^-1。模型验证结果提示：参数估算值的均值与实际值较为接近；大多数参数的平均预测误差均在±15%内。模型具有代表性，不同CYP2D6表型者RIP代谢药动学参数差异较大，可为RIP进一步临床研究打下基础。同时模型结构鉴别可为复杂药动学模型的参数求算和实验设计提供有力的帮助。     

Pharmacokinetics and bioequivalence evaluation of risperidone in healthy male subjects with different CYP2D6 genotypes

The aim of this study was to evaluate the bioequivalence of risperidone in healthy male subjects representing different CYP2D6 genotypes with respect to risperidone, 9-hydroxyrisperidone (9-OH-risperidone), and active moiety. A total of 506 Korean subjects were genotyped for CYP2D6*10 by means of allele-specific polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Based on the genotype analysis, 24 subjects, 7 homozygous for CYP2D6*1, 10 for *10, and 7 heterozygous for *10, were recruited and received a single oral dose of 2 mg risperidone tablet in this study. Serum concentrations of risperidone and 9-OHrisperidone up to 48 h were simultaneously determined. There were no significant differences of the active moiety, risperidone, and 9-OH-risperidone between the two preparations in AUC0-proportinal to, and Cmax. The 90% confidence intervals (CIs) for the ratio of means of the log-transformed AUC0-proportional to. and Cmax for the active moiety, risperidone, and 9-OH-risperidone were all within the bioequivalence acceptance criteria of 0.80-1.25. The CYP2D6*10 allele particularly was associated with higher serum concentrations of risperidone and the risperidone/9-OH-risperidone ratio compared with the CYP2D6*1 allele. The results demonstrate that the two preparations of risperidone are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice. Furthermore, the pharmacokinetic parameters of risperidone and the risperidone/9-OH-risperidone ratio are highly dependent on the CYP2D6 genotypes.     

Multiple dose pharmacokinetics of risperidone and 9-hydroxyrisperidone in Chinese female patients with schizophrenia

AIM: To study the multiple dose clinical pharmacokinetics of risperidone and its main active metabolite, 9-hydroxyrisperidone, in Chinese female patients with schizophrenia. METHODS: The subjects were 23 Chinese female inpatients aged 18-65 years who met the CCMD-III (third revision of the Chinese Criteria of Mental Disorders) criteria for schizophrenia. Subjects were tested after 17 d of treatment with 2 mg risperidone twice daily. Plasma concentrations of risperidone and 9-hydroxy-risperidone were assayed by using validated high performance liquid chromatography-mass spectrometry (HPLC-MS) methods. RESULTS: Risperidone was rapidly absorbed (Tmax was 1.6 h) and its T1/2 in plasma was short (3.2 h). 9-hydroxy-risperidone was quickly metabolized from the parent drug with a mean Tmax of 2.5 h. It had a long half-life of 24.7 h. The C(ss)(av) of risperidone and 9-hydroxy-risperidone were 36.9+/-33.1 and 110.6+/-30.5 microg x h x L(-1), respectively, and the AUC(ss)0-12 were 443.2+/- 397.4 and 1327.2+/- 402.3 microg x h x L(-1), respectively. CL/F and V/F of risperidone were 8.7+/- 6.2 L/h and 34.1+/- 24.3 L, respectively. Interindividual variations for pharmacokinetic parameters were quite large for risperidone. All 23 subjects experienced high prolactin levels when treated with risperidone. However there was no correlation between prolactin level and the concentration of risperidone, 9-hydroxy-risperidone, or the active moiety. CONCLUSION: Risperidone showed large interindividual variations in pharmacokinetics. Administration of risperidone resulted in high serum prolactin levels. The results indicate that systemic exposure to risperidone and 9-hydroxy-risperidone in female Chinese schizophrenic patients is higher relative to published data for white Caucasian patients. Larger studies regarding the PK/PD relationship may be required to develop a reasonable clinical dosage regimen for Chinese female patients.     

Preclinical study of a potent P-glycoprotein and cytochrome P450 enzyme inducer rifampicin changing pharmacokinetic parameters of risperidone and its metabolite, 9-hydroxyrisperidone, using a rat model

The objective of the present investigation is to examine the effects of rifampicin, which is a P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4 inducer, on the pharmacokinetics of risperidone and its active metabolite, 9-hydroxyrisperidone, in rats. To determine the plasma levels of risperidone and 9-hydroxyrisperidone in rats, a high performance liquid chromatographic method was developed using a liquid?Cliquid acid back extraction. After pretreated with rifampicin (600?mg/kg) for 6?days, the mean C_max and AUC_0?C10 values of risperidone were significantly decreased and the Cl_t of the drug was significantly increased compared with control (p?<?0.01, <0.05, and <0.05, respectively). The C_max and AUC_0?C424 of 9-hydroxyrisperidone were also significantly decreased compared with control (p?<?0.01, respectively). Thus, the relative bioavailability of risperidone and 9-hydroxyrisperidone once pretreated with rifampicin (600?mg/kg) was 42.5 and 32.5?%, respectively. The exposure of rifampicin significantly decreased oral bioavailability and affected the pharmacokinetics of risperidone and its active metabolite, 9-hydroxyrisperidone, by the induction of P-gp and CYP3A4 as well.     

Risperidone: Effects of Formulations on Oral Bioavailability

The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover study comparing a 1-mg tablet with a 1-mg/ml oral solution. Both formulations were administered as a single 1-mg dose with a 10-day washout period between treatments. Of 26 healthy men who entered the study, 23 completed both treatment periods. Plasma concentrations of risperidone and the active moiety (risperidone plus its active metabolite, 9-hydroxyrisperidone) were determined by radioimmunoassays. For key pharmacokinetic values (C_max, AUC), the 90% CIs on the relative bioequivalence of risperidone, 9-hydroxyrisperidone, and the active moiety were contained within the equivalence range of 80–120% (80–125% for log-transformed data). The results demonstrate that the 1-mg/ml oral solution and the 1-mg tablet are bioequivalent.     

Pharmacokinetic and safety assessments of concurrent administration of risperidone and donepezil

Treatment of Alzheimer's disease sometimes uses combinations of drugs because dementia is frequently associated with behavioral symptoms. Risperidone and donepezil are both metabolized through cytochrome P450 2D6 and 3A4, raising the possibility of drug interactions with combination therapy. The objective of this study was to determine whether significant drug interactions occur with concomitant administration of donepezil and risperidone. In an open-label, three-way crossover study, 24 healthy men were randomly assigned to receive 0.5 mg of risperidone twice daily, 5 mg of donepezil once daily, or both drugs for 14 consecutive days, followed by a 21-day washout period. The treatment ratios of AUC and associated 90% confidence intervals (CIs) for risperidone active moiety, defined as risperidone plus 9-hydroxyrisperidone (ratio = 110.2%; 90% CI = 103.7-117.2), and for donepezil (ratio = 97.1%; 90% CI = 90.0-103.6) were within the 80% to 125% of bioequivalence range. The treatment ratios of Cmax and associated 90% CIs for risperidone active moiety (ratio = 114.6%; 90% CI = 107.0-122.8) and for donepezil (ratio = 96.1%; 90% CI = 90.0-102.6) were also within the bioequivalence range. Therefore, no significant pharmacokinetic differences occurred in either risperidone active moiety or donepezil when given alone or in combination. Adverse events (predominantly headache, nervousness, and somnolence) were minor and comparable for all treatment groups. The results indicate that no clinically meaningful drug interactions occurred between risperidone 1 mg daily and donepezil 5 mg daily at steady state, and therefore no dosage adjustment is required when both drugs are combined with the dosage regimen studied. Additional investigations are warranted to determine the potential for interactions in elderly patients with dementia who may eliminate risperidone and donepezil more slowly and thus be more vulnerable to clinical drug interactions than the young healthy subjects examined in this study.     

Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors

Because of the enormous gap between premarketing studies in physically healthy subjects and clinical practice in patients, the present study reconsidered interindividual variability factors affecting risperidone concentrations under routine therapeutic drug monitoring conditions. The study included 92 patients, 27% of whom were 70 years or older. The patients received risperidone orally (dose range, 0.5-11 mg per day) and had concentrations of risperidone and the active metabolite 9-hydroxyrisperidone measured at steady state by a new, rapid, and sensitive method of high-performance liquid chromatography (HPLC). After normalization to a dose of 4 mg/day, median concentrations were 2.9 ng/ml (80% range, 0.9-27.9 ng/ml) for the parent compound and 24.1 ng/ml (80% range, 12.0-57.6 ng/ml) for the metabolite. When considering linear regression models, age was identified as a major source of interindividual variability, with expected increases of 340% and 220% for concentrations of parent compound and metabolite, with age increasing from 20 to 80 years. Body weight provided an additional significant contribution to the variability of 9-hydroxyrisperidone concentration, a 20-kg higher body weight associated with a concentration decrease of 23%. Serotonin-specific reuptake inhibitor (SSRI) comedication (fluoxetine, two patients; citalopram, two patients; paroxetine, one patient; fluvoxamine, one patient) was significantly associated with 4.6-fold higher concentrations of parent compound, in keeping with an inhibitory action on CYP2D6 enzyme. Significantly higher concentrations of 9-hydroxy-risperidone (+ 29%) were also observed in the 17 patients with biperiden comedication. Therapeutic drug monitoring data, collected in patients representative of the population for which the drug was intended, allowed us to quantify the dose reduction needed in elderly patients and thus provided valuable information in addition to the one collected during premarketing studies performed with strict inclusion and exclusion criteria.