PharmGKB summary

Thorn, Caroline F.; Müller, Daniel J.; Altman, Russ B.; Klein, Teri E.

doi:10.1097/fpc.0000000000000347

Cited by 65 publications

(47 citation statements)

References 82 publications

(119 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cariprazine primarily undergoes dealkylation, dydroxylation, N-oxidation, and cleavage by CYP3A4 and, to a small degree, by CYP2D6 in hepatic microsomes [ 29 ]. Clozapine is mostly metabolized in the liver by the CYP1A2 and CYP1A2 activity is an essential determinant of clozapine dose [ 30 ]. Other liver enzymes involved in clozapine metabolism include CYP2D6 and CYP3A4 [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Cariprazine Add-on in Inadequate Clozapine Response: A Report on Two Cases

Berardis

Rapini²,

Olivieri³

et al. 2021

Clin Psychopharmacol Neurosci

View full text Add to dashboard Cite

Cariprazine is a novel antipsychotic drug that exerts partial agonism of dopamine D 2 /D 3 receptors with preferential binding to the D 3 receptor, antagonism of 5HT 2B receptors, and partial agonism of 5HT 1A . Currently, cariprazine has shown clinical efficacy in patients with schizophrenia and with bipolar disorder, as well as adjunctive treatment in patients with Major Depressive Disorder (MDD) and drug-resistant MDD. In the present case series, we report on two patients with treatment-resistant schizophrenia and partial response to clozapine who benefit from combination with cariprazine. The effects of cariprazine combination were remarkable also concerning the adverse metabolic effects of clozapine.

show abstract

Section: Discussionmentioning

confidence: 99%

Cariprazine Add-on in Inadequate Clozapine Response: A Report on Two Cases

Berardis

Rapini²,

Olivieri³

et al. 2021

Clin Psychopharmacol Neurosci

View full text Add to dashboard Cite

show abstract

“…The total daily dose can be increased by 25–50 mg per day, if well-tolerated, to achieve a target dose of 300–450 mg per day by the end of two weeks [ 6 7 ]. Clozapine presents a narrow therapeutic window and Therapeutic drug monitoring (TDM) is recommended [ 1 3 8 ]. Serum concentrations of clozapine < 250 and > 750 ng/mL are associated with relapse and increased risk of intoxication, respectively [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Clozapine presents a narrow therapeutic window and Therapeutic drug monitoring (TDM) is recommended [ 1 3 8 ]. Serum concentrations of clozapine < 250 and > 750 ng/mL are associated with relapse and increased risk of intoxication, respectively [ 8 ]. Most articles suggested that concentrations > 600–1,000 ng/mL were more likely to evoke adverse effects, especially seizure activity [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, approximately 95% of the drug is bound to plasma proteins [ 1 10 ]. Clozapine is principally eliminated by extensive hepatic metabolism that generates two main metabolites of N -desmethylclozapine (norclozapine) and clozapine N -oxide [ 1 8 ]. The metabolism includes several cytochrome P450 (CYP) isoenzymes, CYP1A2 in particular, and enzymes 3A4, 2C19, and 2D6 [ 1 3 8 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Physiologically-based pharmacokinetic model for clozapine in Korean patients with schizophrenia

Lee

Kim

Jeong

et al. 2021

Transl Clin Pharmacol

View full text Add to dashboard Cite

Clozapine has been used as a treatment of schizophrenia. Despite its large interindividual variability, few reports addressed the physiologically-based pharmacokinetic modeling and simulation (PBPK M&S) of clozapine in patients. This study aimed to develop a PBPK M&S of clozapine in Korean patients with schizophrenia. PBPK modeling for clozapine was constructed using a population-based PBPK platform, the SimCYP ® Simulator (V19; Certara, Sheffield, UK). The PBPK model was developed by optimizing the physiological parameters of the built-in population and compound libraries in the SimCYP ® Simulator. The model verification was performed with the predicted/observed ratio for pharmacokinetic parameters and visual predictive checks (VPCs) plot. Simulations were performed to predict toxicities according to dosing regimens. From published data, 230 virtual trials were simulated for each dosing regimen. The predicted/observed ratio for the area under the curve and peak plasma concentration was calculated to be from 0.78 to 1.34. The observation profiles were within the 5th and 95th percentile range with no serious model misspecification through the VPC plot. A significant impact on age and gender was found for clozapine clearance. The simulation results suggested that 150 mg twice a day and 150 mg three times a day of clozapine have toxicity concerns. In conclusion, a PBPK model was developed and reasonable parameters were made from the data of Korean patients with schizophrenia. The provided model might be used to predict the pharmacokinetics of clozapine and assist dose adjustment in clinical settings.

show abstract

“…Gratifyingly, and while structural similarity is, in part, in the eye of the beholder, a variety of structurally and functionally related antipsychotic drugs such as loxapine, mirtazapine and quetiapine were indeed among the most similar to clozapine, while others not previous considered (such as the antihistamines ketotifen and alcaftadine, and the anti-inflammatory COX inhibitor ketorolac) were also suggested as being similar, providing support for the orthogonal utility of the new VAE-Sim metric. However, the rather promiscuous nature of clozapine binding (e.g., [ 108 , 109 ]), along with that of many of the other drugs (e.g., [ 110 , 111 , 112 , 113 , 114 , 115 , 116 ]), means that this is not the place to delve deeper.…”

Section: Resultsmentioning

confidence: 99%

VAE-Sim: A Novel Molecular Similarity Measure Based on a Variational Autoencoder

et al. 2020

View full text Add to dashboard Cite

Molecular similarity is an elusive but core “unsupervised” cheminformatics concept, yet different “fingerprint” encodings of molecular structures return very different similarity values, even when using the same similarity metric. Each encoding may be of value when applied to other problems with objective or target functions, implying that a priori none are “better” than the others, nor than encoding-free metrics such as maximum common substructure (MCSS). We here introduce a novel approach to molecular similarity, in the form of a variational autoencoder (VAE). This learns the joint distribution p(z|x) where z is a latent vector and x are the (same) input/output data. It takes the form of a “bowtie”-shaped artificial neural network. In the middle is a “bottleneck layer” or latent vector in which inputs are transformed into, and represented as, a vector of numbers (encoding), with a reverse process (decoding) seeking to return the SMILES string that was the input. We train a VAE on over six million druglike molecules and natural products (including over one million in the final holdout set). The VAE vector distances provide a rapid and novel metric for molecular similarity that is both easily and rapidly calculated. We describe the method and its application to a typical similarity problem in cheminformatics.

show abstract

PharmGKB summary

Cited by 65 publications

References 82 publications

Cariprazine Add-on in Inadequate Clozapine Response: A Report on Two Cases

Cariprazine Add-on in Inadequate Clozapine Response: A Report on Two Cases

Physiologically-based pharmacokinetic model for clozapine in Korean patients with schizophrenia

VAE-Sim: A Novel Molecular Similarity Measure Based on a Variational Autoencoder

Contact Info

Product

Resources

About