Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 204–209
doi: 10.1111/jcpt.12118
Pharmacogenetics
Effect of CYP1A2 polymorphism on the pharmacokinetics of agomelatine in Chinese healthy male volunteers L. Song PhD, Q. Du PhD, X. Jiang PhD and L. Wang PhD Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China
Received 30 August 2013, Accepted 20 November 2013
Keywords: agomelatine, CYP1A2, genetic polymorphisms, pharmacokinetics, polymerase chain reaction–restriction fragment length polymorphism, single nucleotide polymorphism
as melatonin. Moreover, it antagonizes serotonin 5-HT(2C) receptors, whereas the neuronal uptake of monoamines is not affected.1 In February 2009, the European Medicines Agency (EMA) approved agomelatine for the treatment of major depressive disorder (MDD) in adults, and it is awaiting approval from the Federal Drug Administration in the USA. Following oral administration, agomelatine is primarily metabolized by the hepatic cytochrome P450 (CYP) isoenzyme CYP1A2 (90%). CYP2C9 and CYP2C19 are of minor importance (10%). The exposure levels of unchanged agomelatine in plasma are characterized by a high inter- and intra-individual variability in pharmacokinetic studies.2 Due to the relatively high expression in liver, CYP1A2 plays a significant role in the metabolism of several clinically important drugs, and it exhibits interindividual variability in metabolic activity due to single nucleotide polymorphisms (SNPs).3 Study on the effect of CYP1A2 genetic polymorphism on the pharmacokinetics of agomelatine has not been reported before. There are 4 CYP1A2 SNPs with MAF (minor allele frequency) greater than 0.15 in Chinese Han people retrieved from HapMap, rs762551, rs2069514, rs2470890 and rs2472304. CYP1A2 -163C>A (rs762551) SNP characterizes the CYP1A2*1F allele that has been associated with a higher enzyme inducibility,4 and 3860G>A (rs2069514) SNP characterizes the CYP1A2*1C allele that has been associated with a decreased enzyme activity.5 Impact of rs2470890 and rs2472304 to the activity of CYP1A2 remains to be studied. To explain the high interindividual variability of the pharmacokinetic profile of agomelatine, in our study, we genotyped the four SNPs of the CYP1A2 in 72 Chinese healthy male volunteers to assess the effect of CYP1A2 genetic polymorphism on the pharmacokinetics of agomelatine.
SUMMARY What is known and objective: Agomelatine is a melatonin (MT) analogue with agonistic properties and has been proven to be effective for various types of depressive symptoms. Following oral administration, agomelatine is primarily metabolized by the hepatic cytochrome P450 isoenzyme CYP1A2. The purpose of this study was to assess the influence of CYP1A2 single nucleotide polymorphisms (SNPs, rs762551, rs2069514, rs2472304, rs2470890) on agomelatine pharmacokinetics in the Chinese population. Methods: Seventy-two healthy Chinese male volunteers enrolled in the study received an oral dose of 25 mg of agomelatine after providing written informed consent. CYP1A2 SNPs were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Agomelatine plasma concentrations were determined by high performance liquid chromatography– tandem mass spectrometry, and the pharmacokinetics analyses were evaluated by nonparametric methods. Results and discussion: After a single oral dose of 25 mg agomelatine, no significant differences existed in agomelatine pharmacokinetics between the rs2069514 GG homozygotes (n = 35) and the rs2069514 AG allele (n = 35) in all subjects. The mean agomelatine AUC0–7, AUC0–∞ and Cmax for the rs762551 CC homozygotes (n = 9), rs2470890 CC homozygotes (n = 54) and rs2472304 GG homozygotes (n = 51) were much higher than the rs762551 AA allele (n = 31), rs2470890 CT allele (n = 17) and rs2472304 AG allele (n = 20) respectively (P < 0.05). What is new and conclusion: The rs762551 A, rs2470890 T and rs2472304 A genotype presented a significantly lower level of agomelatine exposure (AUC, Cmax) compared with the rs762551 C, rs2470890 C and rs2472304 G genotype in Chinese healthy subjects. It suggested that the rs762551, rs2470890 and rs2472304 genetic polymorphism might be associated with the marked interindividual variability of agomelatine, and the pharmacokinetic profile of agomelatine may be different in different races.
MATERIALS AND METHODS Subjects A total of 72 healthy Chinese male volunteers participated in this study after providing written informed consent. None of the subjects had taken any drugs for at least 2 weeks before or during the study. Each subject had physically normal conditions and no history of significant medical illness. The study protocol was approved in advance by the Ethics Committee of the Xijing Hospital affiliated to the Fourth Military Medical University of Chinese People’s Liberation Army. The subjects’ ages, weights, heights and BMIs were 26.1 (SD, 3.1), 63.0 (SD, 1.5), 170.0 (SD, 1.9) and 21.8 (SD, 0.3), respectively.
INTRODUCTION Agomelatine is a melatonin (MT) analogue with agonistic properties. It binds to MT(1) and MT(2) receptors with similar affinity Correspondence: Dr L. Wang, No.17, Section 3, South Renmin Road, Chengdu 610041, P.R. China. Tel.: +86 28 85503968; fax: 86-2885503024; e-mail: [email protected]
© 2013 John Wiley & Sons Ltd
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Table 2. Fragments of the PCR products digested by different restriction enzymes
Study protocol All subjects were admitted to the clinical trial centre on the evening before the day of drug administration. The next morning, they were orally given 25 mg of agomelatine (Valdoxanâ, Servier Lab, Suresnes, France) with 200 mL of water after fasting overnight, and the dosage of administration was determined according to the label. Blood samples were collected immediately before drug administration and 0.0833, 0.176, 0.333, 0.667, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5 and 7 h after drug administration. Blood samples for determination of agomelatine were centrifuged at 1075 g for 5 min, and plasma was subsequently quoted and stored at 20 °C until analysis, and the whole-blood samples for genotyping were collected in tubes containing EDTA-Na2 and stored at 70 °C until analysis. Adverse events were monitored throughout the study based on direct questioning, spontaneous reports, and clinical parameters (e.g. blood pressure, heart rate, respiratory frequency, axillary temperature). The observations were recorded in the CRF tables in detail. In case of serious adverse reactions, timely and appropriate emergency treatment will be taken, and the manufacturers and drug regulatory agencies will be informed within 24 h.
Polymorphism tested
Allele
Fragment (bp)
rs762551
A C G A C T A G
920 709/211 596 464/132 555 425/130 516 274/242
rs2069514 rs2470890 rs2472304
Liquid–liquid extraction was then performed by addition of 4 mL acetic ether, followed by vortex extraction for 3 min (IKA Votex Genius 3 Votex, Germany). After centrifugation at 9677 g for 5 min, the upper organic layer was transferred into another neat tube and evaporated to dryness completely at 37 °C under a stream of nitrogen (Turbovap Zymark, Hopkinton, MA, USA). The dry residue was reconstituted with 100 lL of mobile phase, and a 10 ll of aliquot was injected to HPLC-MS/MS system for analysis. The standard curves were delineated with agomelatine concentrations that ranged from 0.05130 to 10.38 ng/mL (r2 = 0.9994). Intraday and interday coefficients of variation were less than 7.81% and 9.04%, respectively. The lower limit of quantification was 0.05130 ng/mL.
Genotyping of the CYP1A2 polymorphisms Genomic DNA was extracted from peripheral blood using a TIANamp Blood Genomic DNA Purification Kit (Tiangen Biotech CO., LTD. Beijing, China). CYP1A2 genotyping was conducted by a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. In brief, the genomic DNA was amplified by use of two primers for genotyping of each SNP, and the polymorphism chain reaction (PCR) products were digested by different restriction enzymes. The primers and restriction enzymes used in the trial were shown in Table 1,6–9 and fragments of the PCR products digested by different restriction enzymes were shown in Table 2. The results were confirmed for randomly selected individuals for each genotype by direct sequence analysis.
Pharmacokinetic analysis Agomelatine pharmacokinetic parameters were determined by non-compartmental methods using DAS version 2.0. The plasma agomelatine concentration–time curves were generated, and the maximum concentration (Cmax) was read from the curves. The area under concentration–time curve from 0 to 7 h (AUC0–7) was calculated by the log-trapezoidal rule. The AUC from time 0 to infinity (AUC0–∞) was calculated as AUC0–∞ = AUC0–7 + C7/ke, where C7 was the last plasma concentration measured, and the elimination rate constant (ke) was calculated by semi-log linear regression of the terminal phase of plasma concentration–time curve.
Determination of plasma agomelatine concentrations The plasma concentrations of agomelatine were analysed by high performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS). Sample clean-up was achieved by liquid–liquid extraction with acetic ether. For analysis of plasma samples, 50 lL of acetonitrile and 50 lL of IS (mifepristone) working solutions were added to 1 mL plasma and mixed well by vortexing briefly.
Statistical analysis The values were shown as the mean SD. Distribution of continuous data was evaluated according to Shapiro–Wilks, and
Table 1. CYP1A2 primer sequences and restriction enzymes for different PCR products Polymorphism tested
163C>A (rs762551) 3860G>A (rs2069514) 5347T>C (rs2470890) 2159G>A (rs2472304)
Primer name
Sequence (5′–3′)
Restriction enzyme
F R F R F R F R
5′-CAACCCTGCCAATCTCAAGCAC-3′ 5′-AGAAGCTCTGTGGCCGAGAAGG-3′ 5′-GCTACACATGATCGAGCTATAC-3′ 5′-CAGGTCTCTTCACTGTAAAGTTA-3′ 5′-TTCCTTCCCACCTACCCTTCA-3′ 5′-GATTACAGGCCCTGCACTTGGCTAAAGCTG-3′ 5′-GTGTTCTCTGGCCTGTAAGT-3′ 5′-TGCCAATCACAGTGTCTGTA-3′
ApaI
© 2013 John Wiley & Sons Ltd
HpyF3I (DdeI) TasI Alw26I (BsmAI)
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Effect of CYP1A2 polymorphism on agomelatine pharmacokinetics
parametric and nonparametric tests were applied consequently when appropriate. Differences of pharmacokinetic parameters between groups were calculated with one-way ANOVA test or independent-sample t-test. Allelic frequencies were compared using Pearson’s v2, as well as tested for Hardy–Weinberg equilibrium. P values of less than 0.05 were considered to be statistically significant. The linkage disequilibrium (LD) was calculated with the SHEsis program, and haplotypes were reconstructed using PHASE 2.1.
L. Song et al.
plasma concentration–time profiles of agomelatine according to the CYP1A2 genotype. In this study, we observed no significant differences in the pharmacokinetics between the rs2069514 GG genotype and rs2069514 AG genotype. The mean agomelatine Cmax, AUC0–7 and AUC0–∞ were statistically different between rs762551 CC homozygotes and rs762551 AA homozygotes, with the rs762551 A genotype presented a lower Cmax and AUC level of agomelatine compared with the rs762551 C genotype, and the mean agomelatine Cmax, AUC0–7 and AUC0–∞ were not statistically different between rs762551 CC homozygotes and rs762551 AC heterozygotes, rs762551 AC heterozygotes and rs762551 AA homozygotes. The mean agomelatine AUC0–7, AUC0–∞ and Cmax were statistically different between the rs2470890 CC genotype and rs2470890 CT genotype, rs2472304 GG genotype and rs2470304 AG genotype, with the homozygotes presented a higher level of agomelatine exposure.
RESULTS Tolerability and safety All volunteers who started the study continued to the end and were discharged in good health; no subject dropouts for adverse events or other treatment-related issues occurred, and no other clinically significant laboratory abnormalities were detected.
Linkage disequilibrium and haplotypes Genotype
The rs2470890 polymorphism was in complete linkage disequilibrium with the rs2472304 polymorphism with D’ = 1 and r2 = 1. Haplotypes were reconstructed using PHASE 2.1; the results were shown in Table 4, and pharmacokinetic properties of agomelatine after administration of a single 25 mg oral dose of agomelatine for the different haplotypes were shown in Table 5. The h4 and h5 haplotype carriers presented a higher level of agomelatine exposure (AUC, Cmax) compared with h1, h2 and h3 haplotype carriers.
Of the total 72 healthy Chinese male volunteers who enrolled in and completed the study, the frequencies of the different genotypes were shown in Table 3. All the CYP1A2 alleles were consistent with the Hardy–Weinberg equilibrium (P > 0.05, respectively). Effect of CYP1A2 genetic polymorphism on the pharmacokinetics of agomelatine Pharmacokinetic properties of agomelatine after oral administration of a single 25 mg dose of agomelatine for the different CYP1A2 genotypes in 72 healthy Chinese men were shown in Table 3. There were no marked differences in age, weight, height and BMI between the different groups. Fig. 1 showed mean (SD)
DISCUSSION As agomelatine is mainly metabolized by CYP1A2, any factors that may affect CYP1A2 activity may result in its changed pharmacokinetic process.10 Considering the 4 SNPs studied in our research,
Table 3. Pharmacokinetic parameters of agomelatine with regard to the single nucleotide polymorphisms of CYP1A2 (mean valueS.D.) SNPs
Genotype
N
Frequency (%)
Cmax (ng/mL)
AUC0–7 (ng/mLh)
AUC0–∞ (ng/mLh)
rs762551
CC (w/w) AC (w/m) AA (m/m) GG(w/w) AG (w/m) AA (m/m) CC (m/m) CT (w/m) TT(w/w) GG(w/w) AG (w/m) AA (m/m)
9 32 31 35 35 2 54 17 1 51 20 1
12.1 45.3 42.6 53.2 39.5 7.3 75.4 22.9 1.7 71.8 25.9 2.3
23.63 13.80 7.97 9.45 15.32 17.13 14.85 5.51 5.71g 15.45 5.39 5.71g
24.61 14.56 7.83 9.54 16.11 16.14 15.33 5.58 7.00g 16.02 5.30 7.00g
24.84 14.68 7.98 9.67 16.28 16.30 15.50 5.69 7.10g 16.19 5.40 7.10g
rs2069514
rs2470890
rs2472304
19.74 13.89a 6.09 bc 12.96 12.73d 11.86g 14.13 3.90e 14.33 3.61f
22.12 15.05a 6.29bc 14.13 13.93d 8.98g 15.51 3.77e 15.70 3.53f
22.28 15.11a 6.35bc 14.23 13.96d 9.15g 15.59 3.80e 15.78 3.56f
w/w, wild-type subjects; w/m, heterozygous variant subjects; m/m, homozygous variant subjects. a Not significantly different from the w/w by ANOVA followed by Bonferroni correction (P > 0.05). b Not significantly different from the w/m by ANOVA followed by Bonferroni correction (P > 0.05). c Significantly different from the w/w by ANOVA followed by Bonferroni correction (P < 0.05). d Not significantly different from the w/w by independent-sample t-test (P > 0.05). e Significantly different from the m/m by independent-sample t-test (P < 0.05). f Significantly different from the w/w by independent-sample t-test (P < 0.05). g Not statistically analysed due to the limited sample size.
© 2013 John Wiley & Sons Ltd
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Fig. 1. Mean (SD) plasma concentration–time profiles of agomelatine after oral administration of a single 25 mg dose of agomelatine for the different CYP1A2 genotypes. study that parts of the range of Cmax and AUC in different SNPs genotypes were overlapping, metabolic gene polymorphisms may not be the only factor associated with the interindividual variability, further experimental studies are needed to explain the large
mutation frequencies of rs2470890 and rs2472304 are 81.8% and 18.2% (not significantly different from the data retrieved from HapMap) from T allele to C and G allele to A, respectively, in Chinese Han people, but in YRI (Yoruban in Ibadan, Nigeria), the frequencies are 0% and 0.8% (retrieved from HapMap), and in CEU (Utah residents with Northern and Western European ancestry from the CEPH collection), the frequencies are 35.8% and 64.4% (retrieved from HapMap), respectively. In our study, the rs2470890 T and rs2472304 A genotype presented a significantly lower level of agomelatine exposure (AUC, Cmax) compared with the rs2470890 C and rs2472304 G genotype; therefore, the pharmacokinetic profile of agomelatine may be different in different races. In our study, we observed no significant differences in the pharmacokinetic parameters between the rs2069514 GG genotype and rs2069514 AG genotype. As there were only two AA genotype carriers, we need further study with a larger sample size to confirm the influence of rs2069514 on the pharmacokinetic profile of agomelatine. A pharmacokinetic study of agomelatine in Chinese has been reported,11 and the results of our study were in accordance with it. In our study, we also observed large interindividual variability of the pharmacokinetic parameters of agomelatine (Cmax from 0.43 to 71.2 ng/mL, AUC from 0.60 to 57.9 ng/mLh). Considering the large interindividual variability, and the fact we observed in the
Table 5. Pharmacokinetic parameters of agomelatine with regard to the different haplotypes (mean value SD)
Haplotype
h1 h2 h3 h4 h5
rs762551
A A A A C
rs2069514
G G G A G
rs2470890
C C T C C
rs2472304
A G A G G
Frequency
0.0186 0.232 0.132 0.269 0.346
Cmax (ng/mL)
AUC0–7 (ng/mLh)
h1(rs762551/rs2069514/rs2470890/rs2472304:A/G/C/A) 3.74 0.89a h1/ 3 4.75 1.15a / 69 12.86 13.18 13.32 14.34 h2 (rs762551/rs2069514/rs2470890/rs2472304:A/G/C/G) h2/h2 + h2/ 29 6.41 5.29 6.17 5.80 / 43 16.64 14.97b 17.47 16.25b h3(rs762551/rs2069514/rs2470890/rs2472304:A/G/T/A) h3/h3 + h3/ 18 5.52 3.79 5.66 3.67 / 54 14.85 14.13c 15.34 15.51c h4(rs762551/rs2069514/rs2470890/rs2472304:A/A/C/G) h4/h4 + h4/ 37 15.42 12.54 16.11 13.62 9.54 14.13d / 35 9.45 12.96d h5(rs762551/rs2069514/rs2470890/rs2472304:C/G/C/G) h5/h5 + h5/ 41 15.95 15.63 16.77 17.07 / 31 7.97 6.09e 7.83 6.29e
Table 4. CYP1A2 haplotypes and frequencies Haplotype
N
AUC0–∞ (ng/mLh)
3.82 0.89a 13.47 14.41 6.31 5.86 17.62 16.34b 5.76 3.70 15.50 15.59c 16.28 13.67 9.67 14.23d 16.91 17.16 7.98 6.35e
a
Not statistically analysed due to the limited sample size. Significantly different from the h2 haplotype carriers by sample t-test (P < 0.05). c Significantly different from the h3 haplotype carriers by sample t-test (P < 0.05). d Not significantly different from the h4 haplotype carriers by sample t-test (P > 0.05). e Significantly different from the h5 haplotype carriers by sample t-test (P < 0.05).
SE
b
0.005 0.005 0.0001 0.004 0.002
© 2013 John Wiley & Sons Ltd
independentindependentindependentindependent-
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liver metabolism, indicating that it may be a drug with a high hepatic extraction ratio, and effect of hepatic blood flow on the clearance of agomelatine need to be studied.
interindividual variability of agomelatine, also the large intraindividual variability of agomelatine.12–14 In our pharmacokinetic study, of the total 72 healthy Chinese male volunteers, CL/F was (6769 8222) L/h, V/F was (5930 6212) L, and t1/2 was (0.88 0.58) h; volume of distribution and clearance rate may much higher than the previous reports (about 35 L and 1000 mL/min),15–17 even the absolute bioavailability of agomelatine in the volunteers was not available. Statistical analysis showed that t1/2 was not affected by SNPs of CYP1A2 and CL/F and V/F were not statistically different between different genotypes of rs762551 and rs2069514, but different between rs2470890 CC and CT, rs2472304 GG and AG. Considering the large interindividual variability of the parameters and the limited sample size in our study, and the statistical analysis method that may be different in different experiment scheme, study of the effect of SNPs on the volume of distribution and clearance rate of agomelatine in human need to be more detailed. The liver is the major clearance organ for many drugs, and human liver microsomes enable the prediction of the metabolic clearance of drugs in the liver of humans,18–20 but there are also many drugs that have been considered as outliers in the prediction of elimination using human liver microsomes, such as propranolol, lidocaine, midazolam and nifedipine,21,22 and these drugs are eliminated almost exclusively by the liver, with a high hepatic extraction ratio. Under these conditions, body clearance is equal to hepatic clearance and corresponds to hepatic blood flow.23,24 The absolute bioavailability of agomelatine is relatively low ( A polymorphism. Eur J Clin Pharmacol, 2010;66:697–703. 5. Aklillu E, Carrillo JA, Makonnen E, Hellman K, Pitarque M, Bertilsson L, Ingelman SM. Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1. Mol Pharmacol, 2003;64:659–669. 6. Pavanello S, Pulliero A, Lupi S, Gregorio P, Clonfero E. Influence of the genetic polymorphism in the 5′-noncoding region of the CYP1A2 gene on CYP1A2 phenotype and
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urinary mutagenicity in smokers. Mutat ResGen Tox En, 2005;587:59–66. Sachse C, Bhambra U, Smith G et al. Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Brit J Clin Pharmacol, 2003;55:68–76. Tiwari AK, Deshpande SN, Lerer B, Nimgaonkar VL, Thelma BK. Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C> T polymorphism. Pharmacogenomics J, 2006;7:305–311. Womack CJ, Saunders MJ, Bechtel MK et al. The influence of a CYP1A2 polymorphism on the ergogenic effects of caffeine. J Int Soc Sports Nutr, 2012;9:1–6. Gunes A, Dahl ML. Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms. Pharmacogenomics, 2008;9: 625–637. Wang X, Zhang D, Liu M et al. LC-MS/MS method for the determination of agomelatine in human plasma and its application to a pharmacokinetic study. Biomed Chromatogr, 2013. doi: 10.1002/bmc.3008 Howland RH. Critical appraisal and update on the clinical utility of agomelatine, a
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melatonergic agonist, for the treatment of major depressive disease in adults. Neuropsychiatr Dis Treat, 2009;5:563. Hiemke C, Baumann P, Bergemann N et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry, 2011;44:195–235. Ostad Haji E, Hiemke C, Pfuhlmann B Therapeutic drug monitoring for antidepressant drug treatment. Curr Pharm Des, 2012;18:5818–5827. De Berardis D, Marini S, Fornaro M et al. The melatonergic system in mood and anxiety disorders and the role of agomelatine: implications for clinical practice. Int J Mol Sci, 2013;14:12458–12483. Patil SR, Nerurkar KK, Kalamkar AM et al. Validated LC–MS/MS method for quantification of agomelatine in human plasma and its application in a pharmacokinetic study. J Mass Spectrom, 2012;47:23–28. Jackson JM Drug review–Valdoxan© (agomelatine). Drugs in Context, 2010;5: 17–32. Naritomi Y, Terashita S, Kimura S et al. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metab Dispos, 2001;29:1316–1324.
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19. Stringer R, Nicklin PL, Houston JB. Reliability of human cryopreserved hepatocytes and liver microsomes as in vitro systems to predict metabolic clearance. Xenobiotica, 2008;38:1313–1329. 20. Kilford PJ, Stringer R, Sohal B et al. Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab Dispos, 2009;37:82–89.
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21. Wilby KJ, Gilchrist SE, Ensom MHH. A review of the pharmacokinetic implications of schistosomiasis. Clin Pharmacokinet, 2013;00:1–10. 22. Aoki M, Okudaira K, Haga M et al. Contribution of rat pulmonary metabolism to the elimination of lidocaine, midazolam, and nifedipine. Drug Metab Dispos, 2010;38: 1183–1188. 23. Henrion J, Descamps O, Luwaert R et al. Hypoxic hepatitis in patients with
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cardiac failure: incidence in a coronary care unit and measurement of hepatic blood flow. J Hepatol, 1994;21: 696–703. 24. Watanabe T, Kusuhara H, Sugiyama Y. Application of physiologically based pharmacokinetic modeling and clearance concept to drugs showing transportermediated distribution and clearance in humans[J]. J Pharmacokinet Phar, 2010;37: 575–590.
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doi: 10.1111/jcpt.12118
Pharmacogenetics
Effect of CYP1A2 polymorphism on the pharmacokinetics of agomelatine in Chinese healthy male volunteers L. Song PhD, Q. Du PhD, X. Jiang PhD and L. Wang PhD Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China
Received 30 August 2013, Accepted 20 November 2013
Keywords: agomelatine, CYP1A2, genetic polymorphisms, pharmacokinetics, polymerase chain reaction–restriction fragment length polymorphism, single nucleotide polymorphism
as melatonin. Moreover, it antagonizes serotonin 5-HT(2C) receptors, whereas the neuronal uptake of monoamines is not affected.1 In February 2009, the European Medicines Agency (EMA) approved agomelatine for the treatment of major depressive disorder (MDD) in adults, and it is awaiting approval from the Federal Drug Administration in the USA. Following oral administration, agomelatine is primarily metabolized by the hepatic cytochrome P450 (CYP) isoenzyme CYP1A2 (90%). CYP2C9 and CYP2C19 are of minor importance (10%). The exposure levels of unchanged agomelatine in plasma are characterized by a high inter- and intra-individual variability in pharmacokinetic studies.2 Due to the relatively high expression in liver, CYP1A2 plays a significant role in the metabolism of several clinically important drugs, and it exhibits interindividual variability in metabolic activity due to single nucleotide polymorphisms (SNPs).3 Study on the effect of CYP1A2 genetic polymorphism on the pharmacokinetics of agomelatine has not been reported before. There are 4 CYP1A2 SNPs with MAF (minor allele frequency) greater than 0.15 in Chinese Han people retrieved from HapMap, rs762551, rs2069514, rs2470890 and rs2472304. CYP1A2 -163C>A (rs762551) SNP characterizes the CYP1A2*1F allele that has been associated with a higher enzyme inducibility,4 and 3860G>A (rs2069514) SNP characterizes the CYP1A2*1C allele that has been associated with a decreased enzyme activity.5 Impact of rs2470890 and rs2472304 to the activity of CYP1A2 remains to be studied. To explain the high interindividual variability of the pharmacokinetic profile of agomelatine, in our study, we genotyped the four SNPs of the CYP1A2 in 72 Chinese healthy male volunteers to assess the effect of CYP1A2 genetic polymorphism on the pharmacokinetics of agomelatine.
SUMMARY What is known and objective: Agomelatine is a melatonin (MT) analogue with agonistic properties and has been proven to be effective for various types of depressive symptoms. Following oral administration, agomelatine is primarily metabolized by the hepatic cytochrome P450 isoenzyme CYP1A2. The purpose of this study was to assess the influence of CYP1A2 single nucleotide polymorphisms (SNPs, rs762551, rs2069514, rs2472304, rs2470890) on agomelatine pharmacokinetics in the Chinese population. Methods: Seventy-two healthy Chinese male volunteers enrolled in the study received an oral dose of 25 mg of agomelatine after providing written informed consent. CYP1A2 SNPs were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Agomelatine plasma concentrations were determined by high performance liquid chromatography– tandem mass spectrometry, and the pharmacokinetics analyses were evaluated by nonparametric methods. Results and discussion: After a single oral dose of 25 mg agomelatine, no significant differences existed in agomelatine pharmacokinetics between the rs2069514 GG homozygotes (n = 35) and the rs2069514 AG allele (n = 35) in all subjects. The mean agomelatine AUC0–7, AUC0–∞ and Cmax for the rs762551 CC homozygotes (n = 9), rs2470890 CC homozygotes (n = 54) and rs2472304 GG homozygotes (n = 51) were much higher than the rs762551 AA allele (n = 31), rs2470890 CT allele (n = 17) and rs2472304 AG allele (n = 20) respectively (P < 0.05). What is new and conclusion: The rs762551 A, rs2470890 T and rs2472304 A genotype presented a significantly lower level of agomelatine exposure (AUC, Cmax) compared with the rs762551 C, rs2470890 C and rs2472304 G genotype in Chinese healthy subjects. It suggested that the rs762551, rs2470890 and rs2472304 genetic polymorphism might be associated with the marked interindividual variability of agomelatine, and the pharmacokinetic profile of agomelatine may be different in different races.
MATERIALS AND METHODS Subjects A total of 72 healthy Chinese male volunteers participated in this study after providing written informed consent. None of the subjects had taken any drugs for at least 2 weeks before or during the study. Each subject had physically normal conditions and no history of significant medical illness. The study protocol was approved in advance by the Ethics Committee of the Xijing Hospital affiliated to the Fourth Military Medical University of Chinese People’s Liberation Army. The subjects’ ages, weights, heights and BMIs were 26.1 (SD, 3.1), 63.0 (SD, 1.5), 170.0 (SD, 1.9) and 21.8 (SD, 0.3), respectively.
INTRODUCTION Agomelatine is a melatonin (MT) analogue with agonistic properties. It binds to MT(1) and MT(2) receptors with similar affinity Correspondence: Dr L. Wang, No.17, Section 3, South Renmin Road, Chengdu 610041, P.R. China. Tel.: +86 28 85503968; fax: 86-2885503024; e-mail: [email protected]
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Table 2. Fragments of the PCR products digested by different restriction enzymes
Study protocol All subjects were admitted to the clinical trial centre on the evening before the day of drug administration. The next morning, they were orally given 25 mg of agomelatine (Valdoxanâ, Servier Lab, Suresnes, France) with 200 mL of water after fasting overnight, and the dosage of administration was determined according to the label. Blood samples were collected immediately before drug administration and 0.0833, 0.176, 0.333, 0.667, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5 and 7 h after drug administration. Blood samples for determination of agomelatine were centrifuged at 1075 g for 5 min, and plasma was subsequently quoted and stored at 20 °C until analysis, and the whole-blood samples for genotyping were collected in tubes containing EDTA-Na2 and stored at 70 °C until analysis. Adverse events were monitored throughout the study based on direct questioning, spontaneous reports, and clinical parameters (e.g. blood pressure, heart rate, respiratory frequency, axillary temperature). The observations were recorded in the CRF tables in detail. In case of serious adverse reactions, timely and appropriate emergency treatment will be taken, and the manufacturers and drug regulatory agencies will be informed within 24 h.
Polymorphism tested
Allele
Fragment (bp)
rs762551
A C G A C T A G
920 709/211 596 464/132 555 425/130 516 274/242
rs2069514 rs2470890 rs2472304
Liquid–liquid extraction was then performed by addition of 4 mL acetic ether, followed by vortex extraction for 3 min (IKA Votex Genius 3 Votex, Germany). After centrifugation at 9677 g for 5 min, the upper organic layer was transferred into another neat tube and evaporated to dryness completely at 37 °C under a stream of nitrogen (Turbovap Zymark, Hopkinton, MA, USA). The dry residue was reconstituted with 100 lL of mobile phase, and a 10 ll of aliquot was injected to HPLC-MS/MS system for analysis. The standard curves were delineated with agomelatine concentrations that ranged from 0.05130 to 10.38 ng/mL (r2 = 0.9994). Intraday and interday coefficients of variation were less than 7.81% and 9.04%, respectively. The lower limit of quantification was 0.05130 ng/mL.
Genotyping of the CYP1A2 polymorphisms Genomic DNA was extracted from peripheral blood using a TIANamp Blood Genomic DNA Purification Kit (Tiangen Biotech CO., LTD. Beijing, China). CYP1A2 genotyping was conducted by a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. In brief, the genomic DNA was amplified by use of two primers for genotyping of each SNP, and the polymorphism chain reaction (PCR) products were digested by different restriction enzymes. The primers and restriction enzymes used in the trial were shown in Table 1,6–9 and fragments of the PCR products digested by different restriction enzymes were shown in Table 2. The results were confirmed for randomly selected individuals for each genotype by direct sequence analysis.
Pharmacokinetic analysis Agomelatine pharmacokinetic parameters were determined by non-compartmental methods using DAS version 2.0. The plasma agomelatine concentration–time curves were generated, and the maximum concentration (Cmax) was read from the curves. The area under concentration–time curve from 0 to 7 h (AUC0–7) was calculated by the log-trapezoidal rule. The AUC from time 0 to infinity (AUC0–∞) was calculated as AUC0–∞ = AUC0–7 + C7/ke, where C7 was the last plasma concentration measured, and the elimination rate constant (ke) was calculated by semi-log linear regression of the terminal phase of plasma concentration–time curve.
Determination of plasma agomelatine concentrations The plasma concentrations of agomelatine were analysed by high performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS). Sample clean-up was achieved by liquid–liquid extraction with acetic ether. For analysis of plasma samples, 50 lL of acetonitrile and 50 lL of IS (mifepristone) working solutions were added to 1 mL plasma and mixed well by vortexing briefly.
Statistical analysis The values were shown as the mean SD. Distribution of continuous data was evaluated according to Shapiro–Wilks, and
Table 1. CYP1A2 primer sequences and restriction enzymes for different PCR products Polymorphism tested
163C>A (rs762551) 3860G>A (rs2069514) 5347T>C (rs2470890) 2159G>A (rs2472304)
Primer name
Sequence (5′–3′)
Restriction enzyme
F R F R F R F R
5′-CAACCCTGCCAATCTCAAGCAC-3′ 5′-AGAAGCTCTGTGGCCGAGAAGG-3′ 5′-GCTACACATGATCGAGCTATAC-3′ 5′-CAGGTCTCTTCACTGTAAAGTTA-3′ 5′-TTCCTTCCCACCTACCCTTCA-3′ 5′-GATTACAGGCCCTGCACTTGGCTAAAGCTG-3′ 5′-GTGTTCTCTGGCCTGTAAGT-3′ 5′-TGCCAATCACAGTGTCTGTA-3′
ApaI
© 2013 John Wiley & Sons Ltd
HpyF3I (DdeI) TasI Alw26I (BsmAI)
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parametric and nonparametric tests were applied consequently when appropriate. Differences of pharmacokinetic parameters between groups were calculated with one-way ANOVA test or independent-sample t-test. Allelic frequencies were compared using Pearson’s v2, as well as tested for Hardy–Weinberg equilibrium. P values of less than 0.05 were considered to be statistically significant. The linkage disequilibrium (LD) was calculated with the SHEsis program, and haplotypes were reconstructed using PHASE 2.1.
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plasma concentration–time profiles of agomelatine according to the CYP1A2 genotype. In this study, we observed no significant differences in the pharmacokinetics between the rs2069514 GG genotype and rs2069514 AG genotype. The mean agomelatine Cmax, AUC0–7 and AUC0–∞ were statistically different between rs762551 CC homozygotes and rs762551 AA homozygotes, with the rs762551 A genotype presented a lower Cmax and AUC level of agomelatine compared with the rs762551 C genotype, and the mean agomelatine Cmax, AUC0–7 and AUC0–∞ were not statistically different between rs762551 CC homozygotes and rs762551 AC heterozygotes, rs762551 AC heterozygotes and rs762551 AA homozygotes. The mean agomelatine AUC0–7, AUC0–∞ and Cmax were statistically different between the rs2470890 CC genotype and rs2470890 CT genotype, rs2472304 GG genotype and rs2470304 AG genotype, with the homozygotes presented a higher level of agomelatine exposure.
RESULTS Tolerability and safety All volunteers who started the study continued to the end and were discharged in good health; no subject dropouts for adverse events or other treatment-related issues occurred, and no other clinically significant laboratory abnormalities were detected.
Linkage disequilibrium and haplotypes Genotype
The rs2470890 polymorphism was in complete linkage disequilibrium with the rs2472304 polymorphism with D’ = 1 and r2 = 1. Haplotypes were reconstructed using PHASE 2.1; the results were shown in Table 4, and pharmacokinetic properties of agomelatine after administration of a single 25 mg oral dose of agomelatine for the different haplotypes were shown in Table 5. The h4 and h5 haplotype carriers presented a higher level of agomelatine exposure (AUC, Cmax) compared with h1, h2 and h3 haplotype carriers.
Of the total 72 healthy Chinese male volunteers who enrolled in and completed the study, the frequencies of the different genotypes were shown in Table 3. All the CYP1A2 alleles were consistent with the Hardy–Weinberg equilibrium (P > 0.05, respectively). Effect of CYP1A2 genetic polymorphism on the pharmacokinetics of agomelatine Pharmacokinetic properties of agomelatine after oral administration of a single 25 mg dose of agomelatine for the different CYP1A2 genotypes in 72 healthy Chinese men were shown in Table 3. There were no marked differences in age, weight, height and BMI between the different groups. Fig. 1 showed mean (SD)
DISCUSSION As agomelatine is mainly metabolized by CYP1A2, any factors that may affect CYP1A2 activity may result in its changed pharmacokinetic process.10 Considering the 4 SNPs studied in our research,
Table 3. Pharmacokinetic parameters of agomelatine with regard to the single nucleotide polymorphisms of CYP1A2 (mean valueS.D.) SNPs
Genotype
N
Frequency (%)
Cmax (ng/mL)
AUC0–7 (ng/mLh)
AUC0–∞ (ng/mLh)
rs762551
CC (w/w) AC (w/m) AA (m/m) GG(w/w) AG (w/m) AA (m/m) CC (m/m) CT (w/m) TT(w/w) GG(w/w) AG (w/m) AA (m/m)
9 32 31 35 35 2 54 17 1 51 20 1
12.1 45.3 42.6 53.2 39.5 7.3 75.4 22.9 1.7 71.8 25.9 2.3
23.63 13.80 7.97 9.45 15.32 17.13 14.85 5.51 5.71g 15.45 5.39 5.71g
24.61 14.56 7.83 9.54 16.11 16.14 15.33 5.58 7.00g 16.02 5.30 7.00g
24.84 14.68 7.98 9.67 16.28 16.30 15.50 5.69 7.10g 16.19 5.40 7.10g
rs2069514
rs2470890
rs2472304
19.74 13.89a 6.09 bc 12.96 12.73d 11.86g 14.13 3.90e 14.33 3.61f
22.12 15.05a 6.29bc 14.13 13.93d 8.98g 15.51 3.77e 15.70 3.53f
22.28 15.11a 6.35bc 14.23 13.96d 9.15g 15.59 3.80e 15.78 3.56f
w/w, wild-type subjects; w/m, heterozygous variant subjects; m/m, homozygous variant subjects. a Not significantly different from the w/w by ANOVA followed by Bonferroni correction (P > 0.05). b Not significantly different from the w/m by ANOVA followed by Bonferroni correction (P > 0.05). c Significantly different from the w/w by ANOVA followed by Bonferroni correction (P < 0.05). d Not significantly different from the w/w by independent-sample t-test (P > 0.05). e Significantly different from the m/m by independent-sample t-test (P < 0.05). f Significantly different from the w/w by independent-sample t-test (P < 0.05). g Not statistically analysed due to the limited sample size.
© 2013 John Wiley & Sons Ltd
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Fig. 1. Mean (SD) plasma concentration–time profiles of agomelatine after oral administration of a single 25 mg dose of agomelatine for the different CYP1A2 genotypes. study that parts of the range of Cmax and AUC in different SNPs genotypes were overlapping, metabolic gene polymorphisms may not be the only factor associated with the interindividual variability, further experimental studies are needed to explain the large
mutation frequencies of rs2470890 and rs2472304 are 81.8% and 18.2% (not significantly different from the data retrieved from HapMap) from T allele to C and G allele to A, respectively, in Chinese Han people, but in YRI (Yoruban in Ibadan, Nigeria), the frequencies are 0% and 0.8% (retrieved from HapMap), and in CEU (Utah residents with Northern and Western European ancestry from the CEPH collection), the frequencies are 35.8% and 64.4% (retrieved from HapMap), respectively. In our study, the rs2470890 T and rs2472304 A genotype presented a significantly lower level of agomelatine exposure (AUC, Cmax) compared with the rs2470890 C and rs2472304 G genotype; therefore, the pharmacokinetic profile of agomelatine may be different in different races. In our study, we observed no significant differences in the pharmacokinetic parameters between the rs2069514 GG genotype and rs2069514 AG genotype. As there were only two AA genotype carriers, we need further study with a larger sample size to confirm the influence of rs2069514 on the pharmacokinetic profile of agomelatine. A pharmacokinetic study of agomelatine in Chinese has been reported,11 and the results of our study were in accordance with it. In our study, we also observed large interindividual variability of the pharmacokinetic parameters of agomelatine (Cmax from 0.43 to 71.2 ng/mL, AUC from 0.60 to 57.9 ng/mLh). Considering the large interindividual variability, and the fact we observed in the
Table 5. Pharmacokinetic parameters of agomelatine with regard to the different haplotypes (mean value SD)
Haplotype
h1 h2 h3 h4 h5
rs762551
A A A A C
rs2069514
G G G A G
rs2470890
C C T C C
rs2472304
A G A G G
Frequency
0.0186 0.232 0.132 0.269 0.346
Cmax (ng/mL)
AUC0–7 (ng/mLh)
h1(rs762551/rs2069514/rs2470890/rs2472304:A/G/C/A) 3.74 0.89a h1/ 3 4.75 1.15a / 69 12.86 13.18 13.32 14.34 h2 (rs762551/rs2069514/rs2470890/rs2472304:A/G/C/G) h2/h2 + h2/ 29 6.41 5.29 6.17 5.80 / 43 16.64 14.97b 17.47 16.25b h3(rs762551/rs2069514/rs2470890/rs2472304:A/G/T/A) h3/h3 + h3/ 18 5.52 3.79 5.66 3.67 / 54 14.85 14.13c 15.34 15.51c h4(rs762551/rs2069514/rs2470890/rs2472304:A/A/C/G) h4/h4 + h4/ 37 15.42 12.54 16.11 13.62 9.54 14.13d / 35 9.45 12.96d h5(rs762551/rs2069514/rs2470890/rs2472304:C/G/C/G) h5/h5 + h5/ 41 15.95 15.63 16.77 17.07 / 31 7.97 6.09e 7.83 6.29e
Table 4. CYP1A2 haplotypes and frequencies Haplotype
N
AUC0–∞ (ng/mLh)
3.82 0.89a 13.47 14.41 6.31 5.86 17.62 16.34b 5.76 3.70 15.50 15.59c 16.28 13.67 9.67 14.23d 16.91 17.16 7.98 6.35e
a
Not statistically analysed due to the limited sample size. Significantly different from the h2 haplotype carriers by sample t-test (P < 0.05). c Significantly different from the h3 haplotype carriers by sample t-test (P < 0.05). d Not significantly different from the h4 haplotype carriers by sample t-test (P > 0.05). e Significantly different from the h5 haplotype carriers by sample t-test (P < 0.05).
SE
b
0.005 0.005 0.0001 0.004 0.002
© 2013 John Wiley & Sons Ltd
independentindependentindependentindependent-
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liver metabolism, indicating that it may be a drug with a high hepatic extraction ratio, and effect of hepatic blood flow on the clearance of agomelatine need to be studied.
interindividual variability of agomelatine, also the large intraindividual variability of agomelatine.12–14 In our pharmacokinetic study, of the total 72 healthy Chinese male volunteers, CL/F was (6769 8222) L/h, V/F was (5930 6212) L, and t1/2 was (0.88 0.58) h; volume of distribution and clearance rate may much higher than the previous reports (about 35 L and 1000 mL/min),15–17 even the absolute bioavailability of agomelatine in the volunteers was not available. Statistical analysis showed that t1/2 was not affected by SNPs of CYP1A2 and CL/F and V/F were not statistically different between different genotypes of rs762551 and rs2069514, but different between rs2470890 CC and CT, rs2472304 GG and AG. Considering the large interindividual variability of the parameters and the limited sample size in our study, and the statistical analysis method that may be different in different experiment scheme, study of the effect of SNPs on the volume of distribution and clearance rate of agomelatine in human need to be more detailed. The liver is the major clearance organ for many drugs, and human liver microsomes enable the prediction of the metabolic clearance of drugs in the liver of humans,18–20 but there are also many drugs that have been considered as outliers in the prediction of elimination using human liver microsomes, such as propranolol, lidocaine, midazolam and nifedipine,21,22 and these drugs are eliminated almost exclusively by the liver, with a high hepatic extraction ratio. Under these conditions, body clearance is equal to hepatic clearance and corresponds to hepatic blood flow.23,24 The absolute bioavailability of agomelatine is relatively low ( A polymorphism. Eur J Clin Pharmacol, 2010;66:697–703. 5. Aklillu E, Carrillo JA, Makonnen E, Hellman K, Pitarque M, Bertilsson L, Ingelman SM. Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1. Mol Pharmacol, 2003;64:659–669. 6. Pavanello S, Pulliero A, Lupi S, Gregorio P, Clonfero E. Influence of the genetic polymorphism in the 5′-noncoding region of the CYP1A2 gene on CYP1A2 phenotype and
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