RP-HPLC-UV Method for Simultaneous Quantification of Second Generation Non-Steroidal Antiandrogens Along with their Active Metabolites in Mice Plasma: Application to a Pharmacokinetic Study

Ashok Zakkula; Vinay Kiran; Umesh Todmal; Suresh P Sulochana; Ramesh Mullangi

doi:10.1055/a-0790-8309

Drug Research, Inhaltsverzeichnis

Drug Res (Stuttg) 2019; 69(10): 537-544
DOI: 10.1055/a-0790-8309

Original Article

RP-HPLC-UV Method for Simultaneous Quantification of Second Generation Non-Steroidal Antiandrogens Along with their Active Metabolites in Mice Plasma: Application to a Pharmacokinetic Study

Ashok Zakkula

¹Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore, India

,

Vinay Kiran

¹Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore, India

,

Umesh Todmal

¹Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore, India

,

Suresh P Sulochana

¹Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore, India

,

Ramesh Mullangi

¹Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore, India

› Institutsangaben

Abstract

A simple, specific and reproducible high-performance liquid chromatography (HPLC) assay method has been developed and validated for the quantitation of second generation antiandrogens and their active metabolites namely apalutamide, enzalutamide, N-desmethylenzalutamide (active metabolite of enzalutamide), darolutamide and ORM-15341 (active metabolite of darolutamide) in mice plasma. The method involves extraction of apalutamide, enzalutamide, N-desmethylenzalutamide, darolutamide and ORM-15341 along with internal standard (IS) from 100 µL mice plasma through a simple protein precipitation process. The chromatographic analysis was performed on a Waters Alliance HPLC system using a gradient mobile phase (comprising 10 mM ammonium acetate and acetonitrile in a flow-gradient) and X-Terra Phenyl column. The UV detection wave length was set at λ_max 250 nm. Apalutamide, enzalutamide, N-desmethylenzalutamide, darolutamide and ORM-15341 and the IS eluted at 13.6, 11.4, 9.68, 6.11, 6.93 and 4.69 min, respectively with a total run time of 15 min. Method validation was performed as per regulatory guidelines and the results met the acceptance criteria. The calibration curve was linear over a concentration range of 209 – 5215 ng/mL (r ²=0.998). The intra- and inter-day precisions were in the range of 0.56–13.5 and 1.04–13.9%, respectively. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.

Key words

apalutamide - darolutamide - ORM-15341 - enzalutamide - N-desmethylenzalutamide - HPLC - method validation - mice plasma - pharmacokinetics

Volltext

Referenzen

References
1 Siegel RL, Miller KD, Jemal A. Cancer statistics 2017. CA Cancer J Clin 2017; 67: 7-30
2 Ryan CJ, Cheng ML. Abiraterone acetate for the treatment of prostate cancer. Expert Opin Pharmacother 2013; 14: 91-96
3 Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: Directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 2005; 23: 8253-8261
4 Scott LJ. Abiraterone acetate: A review in metastatic castration-resistant prostrate cancer. Drugs 2017; 77: 1565-1576
5 Mullard A. 2012 FDA drug approvals. Nat Rev Drug Discov 2013; 12: 87-90
6 Al-Salama ZT. Apalutamide: First global approval. Drugs 2018; 78: 699-705
7 Moilanen AM, Riikonen R, Oksala R. et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep 2017; 5: 12007
8 Tran C, Ouk S, Clegg NJ. et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324: 787-790
9 Clegg NJ, Wongvipat J, Joseph JD. et al. ARN-509: A novel antiandrogen for prostate cancer treatment. Cancer Res 2012; 72: 1494-1503
10 Erleada™. https://www.jnj.com/media-center/press-releases/erleada-apalutamide-a-next-generation-androgen-receptor-inhibitorgranted-us-fda-approval-for-the-treatment-of-patients-with-non-metastatic-castration-resistant-prostate-cancer Accessed on 10 June 2018
11 Semenas J, Dizeyi N, Persson JL. Enzalutamide as a second generation antiandrogen for treatment of advanced prostate cancer. Drug Des Devel Ther 2013; 7: 875-881
12 Gibbons JA, Ouatas T, Krauwinkel W. et al. Clinical pharmacokinetic studies of enzalutamide. Clin Pharmacokinet 2015; 54: 1043-1055
13 Weiss J, Kocher J, Mueller C. et al. Impact of enzalutamide and its main metabolite N-desmethylenzalutamide on pharmacokinetically important drug metabolizing enzymes and drug transporters. Biopharm Drug Dispos 2017; 38: 517-525
14 Fizazi K, Massard C, James ND. ODM-201, a new generation androgen receptor inhibitor for castration-resistant prostate cancer: Preclinical and phase I data. Am Soc Clin Oncol J 2013; 31 (Suppl 6): Abstract 65
15 Moilanen A, Riikonen R, Oksala R. ODM-201 - new generation antiandrogen with excellent antiandrogenic and antitumor activity in nonclinical models of CRPC. Eur J Cancer 2013; 49 (Suppl. 02) Abstract 685
16 Orion Pharma Clinical Study Code: 3104001/EN3386-201 (accessed on 10 July 2018)
17 Dittakavi S, Nagasuri PKVSP, Sulochana SP. et al. LC-MS/MS-ESI method for simultaneous quantification of darolutamide and its active metabolite, ORM-15341 in mice plasma and its application to a pharmacokinetic study. J Pharm Biomed Anal 2017; 145: 454-461
18 Sulochana SP, Saini NK, Daram P. et al. Validation of an LC-MS/MS method for simultaneous quantitation of enzalutamide, N-desmethyl-enzalutamide, apalutamide, darolutamide and ORM-15341 in mice plasma and its application to a mice pharmacokinetic study. J Pharm Biomed Anal 2018; 156: 170-178
19 Hallur G, Purra BR, Sulochana SP. et al. Validation of an LC-ESI-MS/MS method for the determination of apalutamide, a novel non-steroidal anti-androgen in mice plasma and its application to a pharmacokinetic study in mice. J Pharm Biomed Anal 2018; 153: 260-266
20 Song JH, Kim TH, Jung JW. et al. Quantitative determination of enzalutamide, an anti-prostate cancer drug, in rat plasma using liquid chromatography-tandem mass spectrometry, and its application to a pharmacokinetic study. Biomed Chromatogr 2014; 28: 1112-1117
21 Bennett S, Gibbons JA, Mol R. et al. Validation of a method for quantifying enzalutamide and its major metabolites in human plasma by LC-MS/MS. Bioanalysis 2014; 6: 737-744
22 Ohtsu Y, Thakker DR, Gibbons JA. et al. Determination of the androgen receptor inhibitor enzalutamide and its metabolites in animal plasma and brain homogenates using LC-MS/MS and its application to pharmacokinetic studies. Chromatogr 2015; 36: 115-122
23 Kim KP, Parise RA, Holleran JL. et al. Simultaneous quantitation of abiraterone, enzalutamide, N-desmethylenzalutamide, and bicalutamide in human plasma by LC-MS/MS. J Pharm Biomed Anal 2017; 138: 197-205
24 van Nuland M, Hillebrand MJX, Rosing H. et al. Development and validation of an LC-MS/MS method for the simultaneous quantification of abiraterone, enzalutamide, and their major metabolites in human plasma. Ther Drug Monit 2017; 39: 243-251
25 Herbrink M, de Vries N, Rosing H. et al. Development and validation of a liquid chromatography-tandem mass spectrometry analytical method for the therapeutic drug monitoring of eight novel anticancer drugs. Biomed Chromatogr 2017; 32: e4147
26 Balaji N, Sulochana SP, Saini NK. et al. Validation of a chiral LC-MS/MS-ESI method for the simultaneous quantification of darolutamide diastereomers in mouse plasma and its application to a stereoselective pharmacokinetic study in mice. Biomed Chromatogr 2018; 32: e4173
27 Balaji N, Sulochana SP, Saini NK. et al. Validated chiral LC-ESI-MS/MS method for the simultaneous quantification of darolutamide diastereomers and its active metabolite in mice plasma: Application to a pharmacokinetic study. Drug Res 2018; 68: 615-624
28 Saini NK, Sulochana SP, Zainuddin M. et al. Development and validation of a novel method for simultaneous quantification of enzalutamide, darolutamide and their active metabolites in mice dried blood spots using LC-MS/MS: Application to pharmacokinetic study in mice. ADMET & DMPK 2018; 6: 242-257
29 Saini NK, Sulochana SP, Kiran V. et al. A novel dried blood spot LC-MS/MS method for the quantification of apalutamide in mice whole blood: Application to pharmacokinetic study in mice. Biomed Chromatogr 2018; 32: e4344
30 Puszkiel A, Plé A, Huillard O. et al. A simple HPLC-UV method for quantification of enzalutamide and its active metabolite N-desmethyl enzalutamide in patients with metastatic castration-resistant prostate cancer. J Chromatogr B 2017; 1058: 102-107
31 Rej RK, Acharyya RK, Nanda S. Asymmetric synthesis of dihydroartemisinic acid through intramolecular Stetter reaction. Tetrahedron 2016; 72: 4931-4937
32 Pang X, Wang Y, Chen Y. Design, synthesis, and biological evaluation of deuterated apalutamide with improved pharmacokinetic profiles. Bioorganic & Med Chem Lett 2017; 27: 2803-2806
33 US DHHS, FDA, CDER, CVM, Guidance for Industry: Bioanalytical method validation, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CV), (2018), Rockville, MD, USA