Total Active Moiety Research Articles

Exploratory focused pharmacogenetic testing reveals novel markers associated with risperidone pharmacokinetics in Saudi children with autism.

Background: Autism spectrum disorders (ASDs) encompass a broad range of phenotypes characterized by diverse neurological alterations. Genomic studies have revealed considerable overlap between the molecular mechanisms implicated in the etiology of ASD and genes involved in the pharmacokinetic (PK) and pharmacodynamic (PD) pathways of antipsychotic drugs employed in ASD management. Given the conflicting data originating from candidate PK or PD gene association studies in diverse ethnogeographic ASD populations, dosage individualization based on "actionable" pharmacogenetic (PGx) markers has limited application in clinical practice. Additionally, off-label use of different antipsychotics is an ongoing practice, which is justified given the shortage of approved cures, despite the lack of satisfactory evidence for its safety according to precision medicine. This exploratory study aimed to identify PGx markers predictive of risperidone (RIS) exposure in autistic Saudi children. Methods: This prospective cohort study enrolled 89 Saudi children with ASD treated with RIS-based antipsychotic therapy. Plasma levels of RIS and 9-OH-RIS were measured using a liquid chromatography-tandem mass spectrometry system. To enable focused exploratory testing, genotyping was performed with the Axiom PharmacoFocus Array, which included a collection of probe sets targeting PK/PD genes. A total of 720 PGx markers were included in the association analysis. Results: A total of 27 PGx variants were found to have a prominent impact on various RIS PK parameters; most were not located within the genes involved in the classical RIS PK pathway. Specifically, 8 markers in 7 genes were identified as the PGx markers with the strongest impact on RIS levels (p < 0.01). Four PGx variants in 3 genes were strongly associated with 9-OH-RIS levels, while 5 markers in 5 different genes explained the interindividual variability in the total active moiety. Notably, 6 CYP2D6 variants exhibited strong linkage disequilibrium; however, they significantly influenced only the metabolic ratio and had no considerable effects on the individual estimates of RIS, 9-OH-RIS, or the total active moiety. After correction for multiple testing, rs78998153 in UGT2B17 (which is highly expressed in the brain) remained the most significant PGx marker positively adjusting the metabolic ratio. For the first time, certain human leukocyte antigen (HLA) markers were found to enhance various RIS exposure parameters, which reinforces the gut-brain axis theory of ASD etiology and its suggested inflammatory impacts on drug bioavailability through modulation of the brain, gastrointestinal tract and/or hepatic expression of metabolizing enzymes and transporters. Conclusion: Our hypothesis-generating approach identified a broad spectrum of PGx markers that interactively influence RIS exposure in ASD children, which indicated the need for further validation in population PK modeling studies to define polygenic scores for antipsychotic efficacy and safety, which could facilitate personalized therapeutic decision-making in this complex neurodevelopmental condition.

The Frequency of CYP2D6 and CYP3A4/5 Genotypes and The Impact of Their Allele Translation and Phenoconversion-Predicted Enzyme Activity on Risperidone Pharmacokinetics in Saudi Children with Autism.

Data on the role of CYP2D6 and CYP3A4/5 polymorphisms in relation to risperidone (RIS) pharmacokinetics (PK) in children are relatively limited and inconsistent. This is partially attributable to the limited coverage of CYP2D6 and CYP3A4/5 metabolizer phenotypes, particularly those of poor and ultrarapid metabolizers (PMs and UMs), which has led to calls for studies of populations with a non-European background that may carry variants that are less frequent in Europeans. Children ≤ 18years old with at least 8weeks of a RIS-based regimen were recruited from three autism centers in Riyadh, Saudi Arabia. The primary outcomes measured were plasma concentrations of RIS and 9-hydroxyrisperidone (9-OH-RIS) and their dose-adjusted (C/D) ratios as a function of phenotypes and activity score (AS). For accurate DNA genotyping, targeted pharmacogenomic testing with the Axiom PharmacoFocus Array was performed via examination of a broad collection of probesets targeting CYP2D6 and CYP3A4/5 variants. The frequency of genotypes/phenotypes and the impact of their allele translation and phenoconversion-predicted enzyme activity were examined. The final cohort included 83 individuals. The most common CYP2D6 phenotype in our population was normal metabolizers (NMs, 66.3%). Inconsistent with some previous studies, the three phenotypes of intermediate metabolizers (IMs), NMs, and UMs were significantly different in terms of RIS concentration, the RIS/9-OH-RIS ratio, the RIS C/D ratio and the 9-OH-RIS C/D ratio. According to AS analyses, there were statistically significant differences in the RIS concentration (P = 0.013), RIS/9-OH-RIS ratio (P < 0.001) and RIS C/D ratio (P = 0.030) when patients were categorized into AS ≤ 1 vs. AS > 1. None of the CYP3A4/5 star allele translated phenotypes revealed a significant influence on any of the RIS PK parameters. Notably, neither CYP2D6 nor CYP3A4/5 phenotyping demonstrated a significant impact on the total active moiety, suggesting that other gene variants could modulate RIS PK. The study confirmed the previously reported partial impact of the CYP2D6 gene on RIS PK. However, future studies using contemporary genotyping techniques targeting a wide range of variants in other candidate genes must be conducted to further examine their interactive effects on RIS PK and the clinical response.

Factors influencing concentrations of risperidone and 9-hydroxyrisperidone in psychiatric outpatients taking immediate-release formulations of risperidone.

To analyze the factors affecting the concentrations of the active moiety of risperidone (RIS) and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in psychiatric outpatients taking immediate-release formulations. This is a retrospective study on the therapeutic drug monitoring (TDM) data regarding RIS and 9-OH-RIS in adult psychiatric outpatients. TDM data with simultaneous RIS and 9-OH-RIS monitoring from March 2018 to February 2020 and relevant medical records (including dosage, dosage form, sex, age, diagnosis, combined medication, and comorbid disease) from 399 adult psychiatric outpatients (223 males and 176 females) were included in this study. The daily dose of RIS was 5.56±2.05mg, the concentration of total active moiety was 42.35±25.46ng/mL, and the dose-adjusted plasma concentration (C/D) of active moiety was 7.83±3.87 (ng/ml)/(mg/day). Dose, sex, and age were identified as important factors influencing concentrations of RIS and 9-OH-RIS in adult psychiatric outpatients. Individualized medication adjustments should be made according to the specific conditions of psychiatric outpatients. The findings strongly support the use of TDM to guide dosing decisions in psychiatric outpatients taking RIS.

Physiologically Based Pharmacokinetic Modeling Characterizes the Drug-Drug Interaction Between Saxagliptin and Rifampicin in Patients With Renal Impairment.

The aim of the present study is to develop physiologically based pharmacokinetic (PBPK) models for saxagliptin and its active metabolite, 5-hydroxy saxagliptin, and to predict the effect of coadministration of rifampicin, a strong inducer of cytochrome P450 3A4 enzymes, on the pharmacokinetics of saxagliptin and 5-hydroxy saxagliptin in patients with renal impairment. The PBPK models of saxagliptin and 5-hydroxy saxagliptin were developed and validated in GastroPlus for healthy adults with or without rifampicin and adults with varying renal functions. Then, the effect of renal impairment combined with drug-drug interaction on saxagliptin and 5-hydroxy saxagliptin pharmacokinetics was investigated. The PBPK models successfully predicted the pharmacokinetics. For saxagliptin, the prediction suggests that rifampin greatly weakened the effect of renal impairment on reducing clearance, and the inductive effect of rifampin on parent drug metabolism seems to be increased with an increase in the degree of renal impairment severity. For patients with the same degree of renal impairment, rifampicin would have a slightly synergistic effect on the increase of 5-hydroxy saxagliptin exposure compared with dosed alone. There is an unsignificant decline for the saxagliptin total active moiety exposure values in patients with the same degree of renal impairment. It seems that patients with renal impairment are unlikely to require additional dose adjustments when coadministered with rifampicin, compared with saxagliptin alone. Our study provides a reasonable approach to explore unknown DDI potential in renal impairment.

Population pharmacokinetic modeling of total active moiety exposure following doses of TV-46000, a long-acting subcutaneous antipsychotic injection

Population pharmacokinetic modeling of total active moiety exposure following doses of TV-46000, a long-acting subcutaneous antipsychotic injection

Population Pharmacokinetic Modeling and Simulation of TV-46000: A Long-Acting Injectable Formulation of Risperidone.

TV‐46000 is a long‐acting subcutaneous antipsychotic that uses a novel copolymer drug delivery technology in combination with a well‐characterized molecule, risperidone, that is in clinical development as a treatment for schizophrenia. A population pharmacokinetic (PPK) modeling and simulation approach was implemented to identify TV‐46000 doses and dosing schedules for clinical development that would provide the best balance between clinical efficacy and safety. The PPK model was created by applying pharmacokinetic data from a phase 1 study of 97 patients with a diagnosis of schizophrenia or schizoaffective disorder who received either single or repeated doses of TV‐46000. The PPK model was used to characterize the complex release profile of the total active moiety (TAM; the sum of the risperidone and 9‐OH risperidone concentrations) concentration following subcutaneous injections of TV‐46000. The PK profile was best described by a double Weibull function of the in vivo release rate and by a 2‐compartment disposition and elimination model. Simulations were performed to determine TV‐46000 doses and dosing schedules that maintained a median profile of TAM concentrations similar to published TAM exposure following oral risperidone doses that have been correlated to a 40% to 80% dopamine‐D2 receptor occupancy therapeutic window. The simulations showed that therapeutic dose ranges for TV‐46000 are 50 to 125 mg for once‐monthly and 100 to 250 mg for the once every 2 months regimens. This PPK model provided a basis for prediction of patient‐specific exposure and dopamine‐D2 receptor occupancy estimates to support further clinical development and dose selection for the phase 3 studies.

Association of CYP2B6 genetic polymorphisms with bupropion and hydroxybupropion exposure: A systematic review and meta-analysis.

Bupropion is metabolized to its active metabolite, hydroxybupropion (HB), by the genetically polymorphic cytochrome P450 2B6 (CYP2B6) enzyme. Despite its significant role in bupropion metabolism, the magnitude of the impact of CYP2B6genotype on the exposure of bupropion has not been quantified. A systematic review and meta-analysis was conducted to quantify the association of bupropion and HB exposure with CYP2B6 variant alleles and genotype-defined metabolizer phenotypes. MEDLINE, EMBASE, Web of Science, Scifinder, PsycINFO, and CENTRAL were screened to identify studies that met the following inclusion criteria (search updated on February 2021): (1) area under the plasma drug concentration-time curve (AUC) of bupropion and/or HB in relation to CYP2B6genotypes was studied, and (2) study participants were genotyped for common CYP2B6 variant alleles including at least CYP2B6*6. The Newcastle Ottawa Scale was used to assess risk of bias in each included study. The ratio of means (RoM) between CYP2B6genotype or genotype-defined phenotype groups for bupropion exposure was calculated for each study and combined in a meta-analysis. Eleven studies met the inclusion criteria for this systematic review, and 10 (including N=413 participants) were included in the meta-analysis. All 10studies involved healthy adult volunteers, where other medications were not allowed. The AUCs of HB and the active moiety (bupropion + HB) were significantly reduced in CYP2B6*6 carriers compared with the non-carriers (HB: RoM 0.77, 95% CI 0.71-0.83; active moiety: RoM 0.81, 95% CI 0.75-0.88). Both CYP2B6 poor and intermediate metabolizers had significantly decreased exposures to HB and the active moiety than normal metabolizers. The CYP2B6*6 allele and genotype-determined CYP2B6 poor and intermediate metabolizer phenotypes are associated with significantly lower exposures to HB and the total active moiety. The findings of this study suggest opportunities to further study precision dosing strategies for bupropion therapy based on CYP2B6genotype.

CYP2D6 Genotype-Based Dose Recommendations for Risperidone in Asian People.

The aim of this study was to provide dose recommendations for risperidone in Asian people based on cytochrome P450 enzyme CYP2D6 genotype. First, we investigated the influence of CYP2D6 polymorphism on the pharmacokinetics of risperidone in Chinese patients with schizophrenia. Then, we performed a search for studies covering the relationship between pharmacokinetic parameters of risperidone and CYP2D6 genotype. Pooled pharmacokinetic parameters were meta-analyzed using a random-effects model. Lastly, we calculated the dose adjustment for risperidone based on CYP2D6 genotype for white and Asian people. Significant differences between the extensive metabolizer and intermediate metabolizer groups were observed for dose-adjusted risperidone level, 9-hydroxyrisperidone level, and risperidone/9-hydroxyrisperidone ratio, but not for the total active moiety. Meta-analysis showed that significant differences were observed among the four phenotype groups, including steady state concentration, peak risperidone concentration, and the area under the curve, using the Kruskal-Wallis test. No differences were found in oral clearance. For risperidone, dose recommendations for poor and ultrarapid metabolizers of CYP2D6 for Asians were different compared to that for white people for poor metabolizers (dose adjustment around 45% for white people, while for Asians the risperidone dose should be reduced by 26%). For ultrarapid metabolizers, risperidone dose should be increased by about 33% for white people and 30% for Asians. This was a first attempt to apply pharmacogenetics to suggest dose-regimens for Asian people; further research to replicate and extend these findings is recommended.

Effects of CYP2C19 and CYP3A5 genetic polymorphisms on the pharmacokinetics of cilostazol and its active metabolites.

CYP3A4, CYP2C19, and CYP3A5 are primarily involved in the metabolism of cilostazol. We investigated the effects of CYP2C19 and CYP3A5 genetic polymorphisms on the pharmacokinetics of cilostazol and its two active metabolites. Thirty-three healthy Korean volunteers were administered a single 100-mg oral dose of cilostazol. The concentrations of cilostazol and its active metabolites (OPC-13015 and OPC-13213) in the plasma were determined by HPLC-MS/MS. Although the pharmacokinetic parameters for cilostazol were similar in different CYP2C19 and CYP3A5 genotypes, CYP2C19PM subjects showed significantly higher AUC0-∞ for OPC-13015 and lower for OPC-13213 compared to those in CYP2C19EM subjects (P < 0.01 and P < 0.001, respectively). Pharmacokinetic differences in OPC-13015 between CYP3A5 non-expressors and expressors were significant only within CYP2C19PM subjects. The amount of cilostazol potency-adjusted total active moiety was the greatest in subjects with CYP2C19PM-CYP3A5 non-expressor genotype. These results suggest that CYP2C19 and CYP3A5 genetic polymorphisms affect the plasma exposure of cilostazol total active moiety. CYP2C19 plays a crucial role in the biotransformation of cilostazol.

Pharmacokinetics and Safety of Risperidone Subcutaneous Implants in Stable Patients With Schizophrenia

A subcutaneous risperidone implant (RI) formulation was developed to improve medication adherence in schizophrenia. Two phase 1 studies were conducted to evaluate the pharmacokinetics of RI in adult patients with schizophrenia. In study 1, all subjects were stable on 4 mg oral risperidone; subsequently, the first subject received 375mg RI for 1 month, and the remaining subjects received 375mg RI for 3 months. In study 2, all subjects were stable on oral risperidone 4mg, 6mg, or 8mg and subsequently received RI 480mg, 720mg, or 960mg, respectively, for 6 months. Blood samples were collected at prespecified time points. Various pharmacokinetic parameters were determined in both studies. In both studies risperidone total active moiety plasma concentrations following RI increased slowly, reached therapeutic levels within approximately 2 days, and remained relatively stable. In study 1, the average concentration for RI was 81.3% of the oral trough concentration and 27.5% of the oral peak concentration. In study 2, the steady-state concentration for RI was comparable to the oral trough concentration of the corresponding dose. Patient disease status remained stable with no major safety issues. RI may represent an alternative formulation for schizophrenia treatment with a lower peak-to-trough plasma drug ratio than oral risperidone.

Pharmacokinetics of risperidone in different application forms – Comparing long-acting injectable and oral formulations

We aimed to explore the differences in the pharmacokinetics of risperidone between oral and long-acting injectable (LAI) formulations using a large database of therapeutic drug monitoring (TDM). Plasma concentrations of risperidone (RIS), its active metabolite (9-OH-RIS) and the active moiety (AM) (RIS+9-OH-RIS), their concentration-to-dose (C/D) ratios and ratio of RIS/9-OH-RIS (an index of CYP2D6 metabolic activity) were used to compare patients receiving risperidone orally (n = 851) and those treated with LAI RIS (n = 63). Patients taking CYP inducers or inhibitors or with liver/renal impairment were eliminated. Our study demonstrated that patients on LAI RIS, despite slightly higher RIS doses in the oral group, showed no significant differences in total AM or 9-OH-RIS. Conversely, RIS concentration, RIS C/D ratio and total C/D ratio were slightly higher in the LAI RIS group, reaching significance due to the large sample size. More importantly, the median ratio of RIS/9-OH-RIS was 0.52 in LAI RIS vs. 0.25 in the oral group, providing a significant difference (p < 0.001). After controlling for confounding factors, we replicated the RIS/9-OH–RIS ratio increases in patients with LAI RIS, probably reflecting a decrease in first-pass metabolism. More studies are required to establish the clinical use of TDM for patients on LAI RIS.

Drug metabolizing enzyme and transporter genes associated with plasma risperidone level in Thai autism spectrum disorder

BackgroundThe associations between genetic variants of drug metabolizing enzyme and transporter (DMET) genes and steady-state plasma concentrations of risperidone, 9-hydroxyrisperidone, total active-moiety, and metabolic ratio remain unclear.ObjectiveThe objective of the present study was to present the results of the association between genetic variants of DMET gene and steady-state plasma concentration risperidone and its metabolite using Affymetrix DMET Plus genotyping microarray.MethodsSubjects eligible for this study included male and female adolescents with ASD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria and being treated with risperidone for at least 4 weeks prior to the blood sample collection. Blood samples were drawn prior to the next dose of risperidone intake to determine the steady-state plasma trough concentrations of risperidone and 9-hydroxyrisperidone. Genotyping profile was obtained using the microarray. Steady-state plasma risperidone and 9-hydroxyrisperidone were measured using liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay.ResultsThe polymorphisms of UGT2B4, CYP2D6 were highly associated with metabolic ratio. Of all the DMET analysis, ABCB11 (3084A &gt; G, 420A &gt; G, 368G &gt; A, and 236G &gt; A) and ADH7 (690G &gt; A and –5360G &gt; A) were found to be associated with plasma concentrations of risperidone (P &lt; 0.01). In addition, 6 genetic variations among the SLC transporter family were associated with the plasma concentration of 9-hydroxyrisperidone.DiscussionsThis study provides a pharmacogenomic approach to investigate further among the DMET genetic variants which influence plasma concentration of risperidone. The treatment of ASD should be based on genetic factors making the challenge of psychopharmacological treatment more efficacious with lesser adverse events.Disclosure of interestThe author has not supplied his/her declaration of competing interest.

Lack of a Pharmacokinetic Interaction Between Saxagliptin and Dapagliflozin in Healthy Subjects: A Randomized Crossover Study

PurposeThis single-dose, open-label, randomized, 3-period, 3-treatment crossover drug–drug interaction study was conducted to evaluate differences in the pharmacokinetic properties of saxagliptin and dapagliflozin when coadministered. MethodsHealthy subjects (N = 42) were randomized to receive saxagliptin 5 mg alone, dapagliflozin 10 mg alone, or saxagliptin 5 mg plus dapagliflozin 10 mg coadministered; there was a washout period of ≥6 days between treatments. Serial blood samples for determining saxagliptin, 5-hydroxy saxagliptin (5-OH saxagliptin; major active metabolite) and dapagliflozin plasma concentrations and pharmacokinetic parameters were collected before and up to 60 hours after the dose. No interaction was to be concluded if the 90% CIs for the geometric mean ratios of the combination compared with each drug given alone for Cmax and AUCinf were within 0.80 to 1.25. FindingsThe results indicated that dapagliflozin had no effect on the pharmacokinetic properties of saxagliptin, 5-OH saxagliptin, or saxagliptin total active moiety and vice versa. The 90% CIs for Cmax and AUCinf for all comparisons were contained entirely within the 0.80 to 1.25 equivalence intervals. Other pharmacokinetic parameters (apparent oral clearance or half-life) of saxagliptin or dapagliflozin were similar when each medicine was administered alone or when coadministered. No safety profile or tolerability findings of concern were observed during the study. All adverse events were mild, and no serious adverse events were reported. ImplicationsThese data indicate that coadministration of saxagliptin and dapagliflozin exhibits no pharmacokinetic interaction and is well tolerated. ClinicalTrials.gov identifier: NCT01662999.

Impact of Ageing on Serum Concentrations of Risperidone and Its Active Metabolite in Patients with Known CYP2D6 Genotype

The aim of this study was to investigate the impact of ageing on serum concentrations of risperidone and 9-hydroxyrisperidone in patients with known CYP2D6 genotype. We included retrospective therapeutic drug monitoring data from 464 genotyped patients with measured serum concentrations of risperidone and 9-hydroxyrisperidone after oral administration. Patients were divided into two age subgroups, that is ≤65 (n = 396) and >65 years (n = 68), and dose-adjusted concentrations (C:D ratios) were compared using multiple linear regression analyses with CYP2D6 genotype and gender as covariates. Moreover, absolute concentrations and prescribed daily doses were compared between age subgroups by simple, univariate Mann-Whitney tests. Age had no effect on C:D ratio of risperidone (p > 0.4), but C:D ratios of 9-hydroxyrisperidone and risperidone + 9-hydroxyrisperidone (total active moiety) were estimated to be 2.6 and 2.0 times higher in patients >65 versus ≤65 years (p < 0.001). Female gender and a CYP2D6 poor metabolizer (PM) genotype were also associated with significantly higher C:D ratio of the total active moiety (p < 0.01). Despite lower dosing in patients >65 versus ≤65 years (median 1.5 versus 3.0 mg/day, p < 0.0001), absolute concentration of the total active moiety did not differ between the age subgroups (median 52.5 versus 47.0 nmol/L, p > 0.6). In conclusion, ageing implies significantly increased dose-adjusted serum concentration of risperidone active moiety, and treatment intensity is not generally reduced by halving the oral dose in the elderly. Tolerability of risperidone therapy should therefore be closely monitored in older patients, and female CYP2D6 PMs >65 years might be a particularly vulnerable subgroup of adverse effects.

Impact of CYP2D6 Polymorphism on Steady-State Plasma Levels of Risperidone and 9-Hydroxyrisperidone in Thai Children and Adolescents with Autism Spectrum Disorder.

The purpose of this study was to investigate the influence of CYP2D6 gene polymorphisms on plasma concentrations of risperidone and its metabolite in Thai children and adolescents with autism spectrum disorder (ASD). All 97 autism spectrum disorder patients included in this study had been receiving risperidone at least for 1 month. The CYP2D6 genotypes were determined by real-time polymerase chain reaction (PCR)-based allelic discrimination for CYP2D6*4, *10, and *41 alleles. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Among the 97 patients, the most important nonfunctional alleles (CYP2D6*4 and *5) were detected, whereas the most common allele was CYP2D6*10 (55.9%). CYP2D6 genotyping revealed 90 (92.78%) patients to be extensive metabolizers (EM) and 7 (7.22%) to be intermediate metabolizers (IM). Plasma levels of risperidone were significantly higher in individuals with CYP2D6*5/*10 (p = 0.02), CYP2D6*10/*10 (p = 0.04), and CYP2D6*10/*41 (p = 0.04). Additionally, the plasma concentration of risperidone/9-OH risperidone ratio in patients with a CYP2D6 activity score of 0.5 were significantly higher than those with a CYP2D6 activity score of 2 (p = 0.04). Conversely, no significant influence was found among CYP2D6 polymorphisms, plasma concentrations of 9-hydroxyrisperidone, and the total active moiety. This is the first study to investigate the effects of CYP2D6 genetic polymorphisms on the plasma concentrations of risperidone in Thai children with ASD. The findings indicate that CYP2D6 polymorphisms affect the plasma concentrations of risperidone and the risperidone/9-hydroxyrisperidone ratio. Genetic screening for CYP2D6 polymorphisms could help to predict unexpected adverse events caused by the higher plasma concentration of risperidone.

Impact of the ABCB1 Gene Polymorphism on Plasma 9-Hydroxyrisperidone and Active Moiety Levels in Japanese Patients With Schizophrenia

9-Hydroxyrisperidone (9-OH-RIS) is an active metabolite of the antipsychotic drug risperidone (RIS). The total active moiety level, in other words the sum of the RIS and 9-OH-RIS serum levels, may be important for estimating the clinical effects of RIS treatment. However, there have been no consistent results reported regarding the relationship between cytochrome P450 (CYP) 2D6 or adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) variant alleles and 9-OH-RIS or total active moiety plasma levels. Seventy-four Japanese patients treated with RIS were examined in the present study. Steady-state plasma RIS and 9-OH-RIS were measured. The CYP2D6*5, CYP2D6*10, ABCB1 3435C>T, and ABCB1 2677G>T/A genotypes were detected. Multiple regression analysis showed that the dose-corrected plasma RIS levels were significantly correlated with the number of CYP2D6 variant alleles and ABCB1 3435C>T genotypes, whereas the 9-OH-RIS and total active moiety levels were significantly correlated with the ABCB1 3435C>T genotypes and with age. On the other hand, the ABCB1 2677G>T/A genotypes did not affect plasma RIS, 9-OH-RIS, or total active moiety levels. The ABCB1 3435C>T genetic polymorphism may predict plasma 9-OH-RIS and total active moiety levels.

Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase IV inhibitor LC15-0444 and pioglitazone in healthy volunteers

LC15-0444, a newly developed selective dipeptidyl peptidase IV inhibitor, has the potential to be administered with other antihyperglycemic agents. The aim of this study was to investigate the interaction between LC15-0444 and pioglitazone by comparing the pharmacokinetics of both compounds and their metabolites. A randomized, open-label, multiple dosing, three-sequence, three-period, three-treatment crossover study was performed in healthy volunteers. The three treatment groups were comprised of LC15-0444 200 mg, pioglitazone 30 mg, or coadministration of both drugs once daily for 12 days. Blood samples were collected up to 48 hours after the last dosing. Safety and tolerability were assessed throughout the study. The geometric mean ratios (GMRs; (LC15-0444+Pioglitazone coadministered)/(LC15-0444 or Pioglitazone alone)) (90% confidence intervals (CIs)) for Cmax,ss and AUCt,ss of LC15-0444 were 1.06 (0.96-1.16) and 0.98 (0.93-1.03), respectively. In the case of pioglitazone, the GMRs (90% CIs) for Cmax,ss and AUCt,ss were 0.84 (0.73-0.96) and 0.85 (0.76-0.96), respectively. All reported adverse events were mild in intensity. The pharmacokinetics of LC15-0444 and its metabolites were not altered by pioglitazone. The systemic exposure of pioglitazone was decreased by 15% after coadministration of LC15-0444 with pioglitazone, but this was not judged to be clinically relevant, considering the total active moiety of pioglitazone.

Effects of CYP2D6 Genotype on the Pharmacokinetics, Pharmacodynamics, and Safety of Risperidone in Healthy Volunteers

The objective of this study was to analyze the relationship between CYP2D6 genotype and pharmacokinetics and pharmacodynamics of risperidone. Seventy-one healthy volunteers (36 women and 35 men) received a 1-mg single oral dose of risperidone. Six major CYP2D6 polymorphisms (CYP2D6*3, *4, *5, *6, *7, and *9) and the duplication were detected. Subjects were classified into 4 phenotypic groups: 6 ultrarapid (UMs), 34 extensive (EMs), 25 intermediate (IMs), and 6 poor metabolizers (PMs). There was a clear relationship between the number of active alleles and the pharmacokinetic parameters for risperidone and 9-hydroxyrisperidone, but there were no differences for total active moiety. Area under the curve and half-life of risperidone were significantly higher in PMs and IMs compared with EMs and UMs, which showed higher area under the curve of 9-hydroxyrisperidone. Risperidone produced a small decrease in blood pressure, a mild increase in QTc and a quick increase in prolactin, without significant differences between groups. Surprisingly, the incidence of adverse reactions was lower in PMs (50%) than in other subjects (78%). In conclusion, metabolism of risperidone depends on the number of active CYP2D6 alleles. So, PM subjects show higher concentrations of risperidone and very low concentrations of 9-hydroxyrisperidone. On the contrary, EM and UM subjects show low concentrations of risperidone and high concentrations of 9-hydroxyrisperidone. However, no major pharmacodynamic differences are observed between CYP2D6 genotypes, presumably because of the similar pharmacological activity of parent drug and metabolite.

Intra- and interindividual variations in steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients treated chronically with various doses of risperidone.

The intra- and interindividual variability in apparent steady-state plasma levels of risperidone (RSP) and its metabolite 9-hydroxyrisperidone (9-OHRSP) in schizophrenic patients was investigated. Patients (n = 46, age 26.4 +/- 5.3 years) with diagnosed schizophrenia were treated with a fixed daily oral dose of RSP (1-12 mg/d). The steady-state plasma samples from these patients were collected over a period of 5 years and a total of 549 visits. Plasma concentrations of RSP and 9-OHRSP were determined using a highly sensitive and specific LC-MS-MS method with a detection limit of 0.1 ng/mL. All plasma samples had measurable amounts of 9-OHRSP; however, RSP was nondetectable (<0.1 ng/mL) in 18% of the plasma samples. 9-OHRSP levels were, on average, approximately 22 times higher than those of RSP. The plasma levels of RSP and 9-OHRSP varied widely among patients receiving similar doses of RSP, and the intra- and interindividual variations of RSP and 9-OHRSP plasma levels were found to be large. The data indicated that there was no significant change in the steady-state levels of either RSP or 9-OHRSP during the treatment period. Similarly, the dose-normalized concentration did not vary significantly during the treatment period or with the administered dose. The absence of RSP in many plasma samples (<0.1 ng/mL) and presence of 9-OHRSP at severalfold higher concentrations than RSP indicate that measuring plasma levels of RSP alone may lead to erroneous interpretation in plasma level monitoring studies. The current data support the fact that it is important to measure steady-state levels of total active moiety by analyzing both RSP and 9-OHRSP for plasma drug monitoring.

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.