pharmacokinetics of clozapine

Large interpatient variations in pharmacokinetic parameters of clozapine and its two metabolites were observed. Only six studies [15, 17, 18, 20, 22, 24] investigated the possibility of having a two-compartment model of clozapine. Prevention and treatment information (HHS). This review aimed to introduce a systematic comparison of the published clozapine population pharmacokinetic models as well as to explore identified covariates influencing the clozapine pharmacokinetics models which are yet to be explored. Abstracts and other nonjournal publications were only included if sufficient details were provided. 2019 Mar 6;2019:3163502. doi: 10.1155/2019/3163502. This article reviews the pharmacokinetic and pharmacological properties of clozapine and the clinical implications for monitoring plasma concentrations. In conclusion, although several covariates were incorporated in the population models, the pharmacokinetic variability remained relatively large. The information on this website is not intended for direct diagnostic use or medical decision-making without review by a health care professional. Reviews, methodology articles, in vitro and animal studies, and noncompartmental analysis were excluded. The metabolism of clozapine is affected by multiple pharmacokinetic interactions, so the co-administration of adjunct medications can have a significant clinical effect. 1999 Jul;39(7):721-8. doi: 10.1177/00912709922008245. Plasma clozapine concentration peaked, on average, at 2.3 hours. The reported median IIV median (range) for clozapine Cl and Vd were 43.3% (27.1–60.8%) (n = 7) and 65.7% (10–131.5%) (n = 5), respectively, while for norclozapine Cl and Vd are 47.2% (42.1–60.25%) (n = 4) and 75.6% [23], respectively. Clozapine and metabolite concentrations during treatment of patients with chronic schizophrenia. Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors. eCollection 2019. The number of study participants varied from 13 to 391 (median: 130), totaling 1593 in all twelve publications with reported age ranging from 11 to 86 years. Results. An intraperitoneal injection of 10 mg/kg clozapine was administered to four male CYP1A2 –/– mice and four male wild-type mice. Therefore, these studies may have less information needed to detect a two-compartment model of clozapine pharmacokinetics. Please enable it to take advantage of the complete set of features! A. E. Doude van Troostwijk, R. P. Koopmans, H. D. B. Vermeulen, and H.-J. In study 1, 100 mg of clozapine immediate release tablet was orally administered twice daily for young healthy volunteers (HV) for 3 days. Clozapine is the only licensed medication for treatment-resistant schizophrenia. Because ethnicity has been reported to affect clozapine metabolism, we compared its steady state pharmacokinetics in New Zealand Maori and European patients. Additional publications were identified by reviewing study reference lists and consulting expert review articles identified through the search. Guitton C, Abbar M, Kinowski JM, Chabrand P, Bressolle F. J Clin Psychopharmacol. Pharmacokinetics of clozapine - Volume 175 Issue 4 - M. Kurz. However, external validation using a validation group was only performed in one study [21]; therefore, external validation of the previously published pharmacokinetics models should be conducted in the future to compare their predictive performances. Recent studies have shown that ABCC1 [69] and ABCG2 [72] were found to affect clozapine concentration. Hitherto, the effects of caffeine on Clozapine levels have always been modest, as have the clinical manifestations of toxicity resulting from their interaction. J Pharmacol Exp Ther. Studies’ population characteristics, samples, and concentrations. However, most of the studies have used only trough levels or a random level, which can lead to an inaccurate evaluation of the individual PK estimates especially the absorption rate constant. Norclozapine Cl was found to be higher in smokers [22]. Clozapine plasma levels were monitored in 16 patients during a series of three consecutive treatments (single dose–multiple dose–single dose). Clozapine is approximately 97% bound to serum proteins. The residual error was defined as proportional [18, 26], additive [25], or a combination of the two [20–24]. 2020, Article ID 9872936, 10 pages, 2020. https://doi.org/10.1155/2020/9872936, 1School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, George Town, Penang, Malaysia. These well-designed studies that involved a large sample size (more than 15000 samples [50]) and included elderly patients have achieved sufficient statistical power to present reliable results as compared to other less empowered studies that concluded a negative correlation [9, 29, 35]. Large pharmacokinetic variability remains despite the inclusion of several covariates. External validation should also be performed to the previously published models to compare their predictive performances. Association could not be found in some studies [60, 61]. Inadequate sample size was observed in many of the included studies limiting their power to detect covariate effects on PK parameters. Am J Psychiatry. Population pharmacokinetic modeling requires careful selection and initial screening and evaluation of potential covariates based on scientific knowledge (pharmacology, biology, and pathophysiology) of the drug and the covariate of interest before proceeding to covariate model building [76, 77]. In eleven of the included studies, the clozapine absorption was best described as first order [15, 16, 18–26]. Van Esdonk et al., “Integration of pharmacometabolomics with pharmacokinetics and pharmacodynamics: towards personalized drug therapy,”, L. Yan, J. Zhou, D. Wang et al., “Unbiased lipidomic profiling reveals metabolomic changes during the onset and antipsychotics treatment of schizophrenia disease,”, B. Cao, M. Jin, E. Brietzke et al., “Serum metabolic profiling using small molecular water-soluble metabolites in individuals with schizophrenia: a longitudinal study using a pre-post-treatment design,”, D. R. Mould and R. N. Upton, “Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods,”, W. Byon, M. K. Smith, P. Chan et al., “Establishing best practices and guidance in population modeling: an experience with an internal population pharmacokinetic analysis guidance,”. The race effect has not been studied as a covariate on pharmacokinetic parameters of clozapine and should be considered in future studies. COVID-19 is an emerging, rapidly evolving situation. False-negative results of smoking status might lead to biased associations between the pharmacokinetic parameters and other less important factors. The initial search strategy identified 113 potentially relevant citations, of which 93 remained after duplicates, and review-type articles were removed. The inclusion of studies was based on original studies describing population pharmacokinetic models for clozapine in healthy volunteers or in patients. Clozapine. These studies have revealed a wide interpatient variability in pharmacokinetic parameters that include: time to reach peak plasma concentrations 1.1 to 3.6h; elimination half-life 9.1 to 17.4h; clearance 8.7 to 53.3 L/h; and a volume of distribution of 1.6 to 7.3 L/kg. The possible reasons for the contradictory results may be related to insufficient or inequality in sample sizes, making the differences undetected. As these enzymes are responsible for clozapine metabolism, the race could be a potential covariate explaining part of clozapine PK variability. Clozapine transiently increases serum prolactin levels with minimal changes in homovanillic acid plasma levels. Clozapine pharmacokinetics was described as one-compartment with first-order absorption and elimination in most of the studies. On the other hand, the studies that conclude a one-compartment model involved either a trough or random blood sampling schedule. Population Pharmacokinetics of Clozapine and Norclozapine and Switchability Assessment between Brands in Uruguayan Patients with Schizophrenia. The mean volume of distribution and the total plasma clearance, uncorrected for bioavailability, were 6 L/kg and 38 L/hr, respectively. Population pharmacokinetic modeling is extensively used to identify the pharmacokinetic parameters of a population and investigate the covariates that contribute to pharmacokinetic variability [11]. Clozapine is the most effective drug for treatment-resistant schizophrenia, but its use is limited by toxicity. This was inconsistent with other studies that reported a higher clozapine concentration with increased weight [10] or body mass index (BMI) [46], as well as the tendency of deposition of clozapine in fat tissues that might eventually lead to a decrease in its Cl [51]. Thus, there is an unmet need to predict clinical response to clozapine. FOIA Many studies have investigated the association between metabolic profile and various drug pharmacokinetics. A few drug concentration measurements can guide dosage adjustments using the integration of the population pharmacokinetic model with the Bayesian forecasting method [12]. The protocol was approved by the Ethics Committee of the Second Xiangya Hospital, Central South University and all volunteers signed informed consent before the study. The mechanism of action of Clozapine is unknown. The selection process is described in Figure 1 using the PRISMA 2009 flow diagram, which was previously described [13]. -. This can be improved by including other potential factors such as genetic polymorphisms, metabolic factors, and significant drug-drug interactions in a well-designed population pharmacokinetic model in the future, taking into account the incorporation of larger sample size and more stringent sampling strategy. Li, X.-P. Wang et al., “Population pharmacokinetic/pharmacodynamic model of clozapine for characterizing the relationship between accumulated exposure and PANSS scores in patients with schizophrenia,”, A.-N. Li, F. Dong, J.-L. Several factors were tested in the modeling process, such as age, sex, CYP1A2 activity, weight, height, dose, smoking status, clozapine formulation, and coadministration of other drugs. Careers. According to Perry’s dosing nomogram, 47% of clozapine concentration variability were explained by dose, sex, and smoking status [9], while dose, sex, cigarette smoking, body weight, clozapine level, and clozapine : norclozapine ratio accounted for only 48% of the clozapine concentration variability in Rostami-Hodjegan nomogram [10]. Consistently, plasma levels of norclozapine have been reported to be lower in smokers as well [10, 35, 43]. In the remaining three studies, either clozapine/norclozapine ratio [18], caffeine test [19], or CYP1A2 distribution in other populations [16] were used to assess CYP1A2 activity. Clipboard, Search History, and several other advanced features are temporarily unavailable. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active … However, in only three studies, a two-compartment model was found to be the best fit for the data of clozapine [15, 17, 24]. Furthermore, in all the studies, patients were classified into smokers and nonsmokers, not taking into account the magnitude of smoking or assessing an objective biological reading like serum nicotine or cotinine level.

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