Effect of <i>CYP1A2</i>
 polymorphism on the pharmacokinetics of agomelatine in Chinese healthy male volunteers

Song, Ling; Du, Qikui; Jiang, Xuehua

doi:10.1111/jcpt.12118

Cited by 26 publications

(31 citation statements)

References 21 publications

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“…The agomelatine pharmacokinetic parameters that we obtained were different from those found in other bioequivalence trial conducted in healthy Chinese subjects (8). It has been previously stated that agomelatine pharmacokinetic profile could be different among races (10), which was also shown in our study as Caucasians showed an approximately 50% less AUC compared to Latin, however, no association was found after correction for the studied genotypes. Thus, these apparently marked differences were due to the different CYP1A2 genotype distribution among the two groups.…”

Section: Agomelatine Pharmacokineticscontrasting

confidence: 95%

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Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics

et al. 2019

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BACKGROUND: Agomelatine is an agonist of the melatoninergic receptors used for the clinical management of depression. Our aim was to evaluate the effect of genetic polymorphisms in its metabolizing enzymes and the P-glycoprotein transporter on the pharmacokinetics and pharmacodynamics of agomelatine in healthy volunteers.METHODS: Twenty-eight healthy volunteers (16 men and 12 women, 22 Caucasians, 5Latin and 1 Black) receiving a single 25 mg oral dose of agomelatine, were genotyped for 9 polymorphisms in cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C9 and CYP2C19) and ATP binding cassette subfamily B member 1 (ABCB1), by real-time PCR.Agomelatine plasma levels were measured by high-performance liquid chromatography combined with tandem mass spectrometry (HPLC-MS/MS).RESULTS: CYP1A2 activity score is directly correlated with agomelatine pharmacokinetic parameters. Individuals with a slower metabolism had a lower Cl/F and, consequently, accumulate higher concentrations of agomelatine. On the other hand, individuals with a high CYP1A2 inducibility showed an extensive Cl/F and lower concentrations of agomelatine. The apparently marked differences showed between races were due to the different CYP1A2 genotype distribution among them. In addition, CYP2C9 intermediate/poor metabolizers individuals showed a significantly higher area under the concentration-time curve and maximum concentration; however, no association was found between CYP2C19 phenotype and agomelatine pharmacokinetics. ABCB1 G2677T/A polymorphism affected the time to reach maximum concentration, as subjects carrying A/A or A/T genotype showed higher values. Agomelatine did not produce a significant change in blood pressure, heart rate or corrected QT interval. CONCLUSION: CYP1A2 phenotype inferred from the genotyping of CYP1A2*1C, *1F and *1B alleles might be a potential predictor of agomelatine exposure. The influence of ABCB1 G2677T/A could mean that this polymorphism enhances P-glycoprotein activity, as subjects with genotypes A/A+A/T had lower agomelatine concentration and thus it takes more time to reach the maximum concentration.

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Section: Agomelatine Pharmacokineticscontrasting

confidence: 95%

“…Not only polymorphisms in CYP1A2 and ABCB1 have been previously associated with the noticeable interindividual variability of agomelatine, but also its pharmacokinetic profile could be different among races (10).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics

et al. 2019

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“…However, the CYP1A2 gene is highly inducible by many environmental factors, and functional polymorphisms have mostly been described in Asian populations (15). The two CYP1A2 variants that fulfilled our criterion of an MAF of greater than 0.05 in Caucasians (CYP1A2*1C and CYP1A2*1F) were not included in the study because of the limited evidence that they have a significant influence on RPV pharmacokinetics (15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Pharmacogenetics Analysis of Rilpivirine in HIV-1-Infected Individuals

Aouri

Barceló

Guidi

et al. 2017

Antimicrob Agents Chemother

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Rilpivirine (RPV), the latest nonnucleoside reverse transcriptase inhibitor active against HIV-1, is prescribed in a standard dosage of 25 mg once a day in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The aim of this observational study was to characterize the RPV pharmacokinetic profile, to quantify interpatient variability, and to identify potential factors that could influence drug exposure. RPV concentration data were collected from HIV-infected patients as part of routine therapeutic drug monitoring performed in our center (Laboratory of Clinical Pharmacology). A population pharmacokinetic analysis was performed with NONMEM by comparing various structural models. The influence of demographic and clinical covariates, as well as frequent genetic polymorphisms in 5 genes (CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*17, UGT1A1*28, and UGT1A4*2), on RPV elimination was explored. A total of 325 plasma concentration measurements were obtained from 249 HIV-positive patients. Plasma concentrations ranged from 12 to 255 ng/ml. A one-compartment model with zero-order absorption best characterized RPV pharmacokinetics. The average RPV clearance (CL) was 11.7 liters/h, the average volume of distribution was 401 liters, and the mean absorption time was 4 h. The interinterindividual variability (IIV) for CL was estimated to be 33%. None of the available demographic or genetic covariates showed any influence on RPV pharmacokinetics, but 29% of the patients were predicted to present minimal concentrations below the recently identified target cutoff value of 50 ng/ml. The variability in RPV pharmacokinetics appears to be lower than that for most other antiretroviral drugs. However, under the standard regimen of 25 mg daily, a significant number of patients might be underdosed. It remains to be investigated whether the underexposure has an impact on the development of resistance while patients are on maintenance therapy.

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“…Several CYP1A2 single nucleotide polymorphism (SNPs, such as srs762551, rs2470890, and rs2472304) have been reported to be involved in the marked variability in metabolism and drug concentrations. 13) This may also provide an explanation to the different pharmacokinetic profiles in different races. Agomelatine is extensively distributed throughout the body, which might also result in high inter-individual variability.…”

Section: )mentioning

confidence: 99%

“…11) Song et al have demonstrated that a genetic polymorphism of CYP1A2 is associated with the marked inter-individual variation in agomelatine metabolism. 13) Besides, the ingestion of high-fat food does not alter the absorption or the bioavailability of agomelatine. 11) To apply for marketing of a generic agomelatine formulation produced by Jinan Limin Pharmaceutical Co., Ltd., a bioequivalence study is required after approval for the clinical trial by the Chinese Food and Drug Administration (CFDA).…”

mentioning

confidence: 99%

Bioequivalence and Pharmacokinetic Profiles of Agomelatine 25-mg Tablets in Healthy Chinese Subjects: A Four-Way Replicate Crossover Study Demonstrating High Intra- and Inter-Individual Variations

Zheng

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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The present study was designed to assess the bioequivalence of two agomelatine formulations (25-mg tablets) in healthy Chinese male subjects. This single-dose, open-label, randomized, four-way replicate study with a 1-week washout period was conducted in 60 healthy Chinese male volunteers under fasting conditions. Blood samples were collected over a 12-h period after a single dose of the 25-mg agomelatine test (T) formulation or a reference (R) formulation, and the drug concentrations were assayed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated using a noncompartmental model. Bioequivalence between the formulations was assessed. Tolerability and safety were monitored by physical examination, electrocardiogram (

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Effect of CYP1A2 polymorphism on the pharmacokinetics of agomelatine in Chinese healthy male volunteers

Cited by 26 publications

References 21 publications

Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics

Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics

Population Pharmacokinetics and Pharmacogenetics Analysis of Rilpivirine in HIV-1-Infected Individuals

Bioequivalence and Pharmacokinetic Profiles of Agomelatine 25-mg Tablets in Healthy Chinese Subjects: A Four-Way Replicate Crossover Study Demonstrating High Intra- and Inter-Individual Variations

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