Adv Ther (2017) 34:2466–2480 DOI 10.1007/s12325-017-0634-4 ORIGINAL RESEARCH Pharmacokinetic Evaluation of the Interactions of Amenamevir (ASP2151) with Ketoconazole, Rifampicin, Midazolam, and Warfarin in Healthy Adults Tomohiro Kusawake . Martin den Adel . Dorien Groenendaal-van de Meent . Alberto Garcia-Hernandez . Akitsugu Takada . Kota Kato . Yoshiaki Ohtsu . Masataka Katashima Received: September 1, 2017 / Published online: October 26, 2017 Ó The Author(s) 2017. This article is an open access publication ABSTRACT single dose of midazolam (7.5 mg) and warfarin (25 mg). A drug interaction was considered to Introduction: Amenamevir is a nonnucleoside occur if the 90% confidence interval (CI) of the antiherpes virus compound available for treat- least squares geometric mean ratio (GMR) of ing herpes zoster infections. Four studies aimed amenamevir to the comparator was outside the to determine any potential interactions prespecified interval of 0.80–1.25. between amenamevir and ketoconazole, rifam- Results: Interactions were observed between picin, midazolam, or warfarin in healthy male amenamevir and ketoconazole, rifampicin, and participants. midazolam, but not between amenamevir and Methods: Two studies were open-label studies warfarin. After a single 400-mg dose of ame- that evaluated the effects of multiple doses of namevir, the GMRs of amenamevir plus keto- ketoconazole (400 mg) and rifampicin (600 mg) conazole or rifampicin versus amenamevir on the pharmacokinetics of a single oral dose of alone for Cmax and the area under the plasma amenamevir. The other two studies were ran- concentration–time curve from time zero to domized, double-blind, parallel-group studies infinity (AUCinf) were 1.30 (90% CI 1.17–1.45) that evaluated the effects of multiple doses of and 2.58 (90% CI 2.32–2.87), respectively, for amenamevir on the pharmacokinetics of a ketoconazole and 0.42 (90% CI 0.37–0.49) and 0.17 (90% CI 0.15–0.19), respectively, for Enhanced content To view enhanced content for this rifampicin. Following multiple doses of ame- article go to http://www.medengine.com/Redeem/ namevir (400 mg), the GMRs of midazolam plus C8CCF060639C490D. amenamevir versus midazolam alone for AUCinf and C were 0.53 (90% CI 0.47–0.61) and 0.63 T. Kusawake (&) max Astellas Pharma Global Development Inc., (90% CI 0.50–0.80), respectively. After a single Northbrook, IL, USA dose of warfarin, the (S)-warfarin and (R)-war- e-mail: [email protected] farin mean Cmax increased and mean AUCinf decreased in the presence of amenamevir; M. den Adel Á D. Groenendaal-van de Meent Á A. Garcia-Hernandez however, the 90% CIs of the GMRs for these Astellas Pharma Europe B.V., Leiden, The parameters remained within the predefined Netherlands limits. A. Takada Á M. Katashima Conclusion: These findings confirm that ame- Astellas Pharma Inc., Tokyo, Japan namevir (as a cytochrome P450 3A4 substrate) can interact with ketoconazole or rifampicin, K. Kato Á Y. Ohtsu Astellas Pharma Inc., Tsukuba, Japan and (as a cytochrome P450 3A4 inducer) can Adv Ther (2017) 34:2466–2480 2467 interact with midazolam; however, no interac- elimination pathway of amenamevir was hep- tion between amenamevir and (S)-warfarin was atic metabolism in animal studies (unpublished observed, indicating that amenamevir is not an data). In a study in healthy volunteers, urinary inducer of cytochrome P450 2C9. excretion as unchanged drug was approxi- Funding: Astellas Pharma. mately 10% [9]. In vitro data further clarified Trial registration: EudraCT2007-002227-33 the main elimination pathway; the metabolism (study 15L-CL-008), EudraCT2007-002228-14 of amenamevir is significantly correlated with (study 15L-CL-009), EudraCT2007-002761-13 marker-enzyme activities specific for the (study 15L-CL-010), and EudraCT2007-002779- cytochrome P450 (CYP) isozymes CYP2B6, 14 (study 15L-CL-018). CYP2C19, and CYP3A4/5 [10]. The strongest correlation was observed for CYP3A4/5 2 Keywords: Amenamevir; Drug–drug (r = 0.9236, p\0.0001), suggesting CYP3A4/ interactions; Ketoconazole; Midazolam; 5-mediated metabolism is the main pathway for Pharmacokinetics; Rifampicin; Safety; elimination of amenamevir. In addition, Varicella–zoster virus; Warfarin in vitro enzyme induction data indicated that amenamevir potentially induces CYP3A4 and CYP2C9 activities, with a weak potential for INTRODUCTION inducing CYP2C19 (unpublished data). Herpes zoster is a major disease of the elderly Varicella–zoster virus (VZV) is a human her- population, and patients often require con- pesvirus (HHV) that leads to the development of comitant medications for the treatment of two distinct diseases: varicella (chicken pox) as other comorbidities [11]. Therefore, it is the first episode and herpes zoster (shingles) as important to determine any potential interac- the recurrent episode [1]. VZV is neurotrophic tions between medications whose metabolism is and remains latent in dorsal sensory ganglia mediated by CYP3A4 and CYP2C9. after the initial infection [2]. Herpes zoster is a This article summarizes the results of four manifestation of the reactivation of latent VZV. drug–drug interaction phase 1 studies that It is relatively uncommon in immunocompe- investigated potential interactions between tent individuals younger than 40 years, but the amenamevir and ketoconazole (a strong CYP3A4 incidence of herpes zoster markedly increases in inhibitor), rifampicin (a strong CYP3A4 inducer), those older than 50 years [3]. While the inci- midazolam (a CYP3A4 substrate), and (S)-war- dence rate of developing herpes zoster is 6–8 per farin (a CYP2C9 substrate) in healthy adults. 1000 person-years at 60 years of age, the inci- dence rate in patients aged 80 years or older increases to 8–12 per 1000 person-years [3]. METHODS Nucleoside analogs such as acyclovir [4], valacyclovir [5], and famciclovir [6] have been Study Design approved for the treatment of herpes simplex virus 1, herpes simplex virus 2, and VZV infec- Each of the four drug–drug interaction studies tions. Although these drugs are used for the was conducted at a single study site in France by treatment of HHV infections, there is a medical the contract research organization SGS-Aster. need for therapies with improved antiviral Study 15L-CL-008 (EudraCT2007-002227-33) activity to provide more rapid and complete was conducted between October 17, 2007, and resolution of signs and symptoms. November 28, 2007, study 15L-CL-009 (Eu- Amenamevir (ASP2151) is a nonnucleoside draCT2007-002228-14) was conducted between antiherpes compound developed for the treat- October 19, 2007, and November 28, 2007, ment of VZV infections. Preclinical studies have study 15L-CL-010 (EudraCT2007-002761-13) indicated that amenamevir targets the viral was conducted between September 13, 2007, helicase–primase complex, which is essential for and November 17, 2007, and study 15L-CL-018 viral DNA replication [7, 8]. The main (EudraCT2007-002779-14) was conducted 2468 Adv Ther (2017) 34:2466–2480 between September 13, 2007, and December 3, respiratory, renal, hepatic, neurological, der- 2007. Two of the studies were open-label studies matological, psychiatric, or metabolic disorders, that evaluated the effects of multiple doses of as judged by the study investigator. Study ketoconazole (study 15L-CL-008) and rifampi- 15L-CL-018 excluded participants with a history cin (study 15L-CL-009) on the pharmacokinet- of and/or signs and symptoms of current ics of a single oral dose of amenamevir. The abnormal hemostasis or blood dyscrasia or other two studies were randomized, dou- abnormal prothrombin time (PT) or activated ble-blind, parallel-group studies that evaluated partial thromboplastin time at screening. the effects of multiple doses of amenamevir (200 and 400 mg) on the pharmacokinetics of a Dosing and Sampling Schedules single dose of midazolam (study 15L-CL-010) and a single dose of warfarin (study In study 15L-CL-008, participants received a 15L-CL-018). single oral dose of amenamevir (400 mg as two The study protocols were approved by the 200-mg tablets) on day 1, after which they institutional review boards at the study site underwent a 48-h washout period. They then ˆ ´ ´ [Hopital Ambroise-Pare, Secretariat du CPP Ile received ketoconazole orally (400 mg as two de France VIII, Laboratoire d’Anatomopatholo- 200-mg tablets) once daily on days 3–13, with a gie (studies 15L-CL-008 and 15L-CL-009) and second single dose of amenamevir (400 mg) ´ CPP Ile de France I, Secretariat du CPP Ile de administered in combination with ketocona- ˆ France I, Hopital Hotel-Dieu (studies zole on day 10. Blood samples for amenamevir 15L-CL-010 and 15L-CL-018)]. All procedures analysis were collected before dosing and followed were in accordance with the ethical 30 min and 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, and standards of the responsible committee on 36 h after dosing on day 1, before dosing on day human experimentation (institutional and 3, and before dosing and 30 min and 1, 1.5, 2, 3, national) and with the Helsinki Declaration of 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84, and 96 h 1964, as revised in 2000. Informed consent was after dosing on day 10. obtained from all participants for their being In study 15L-CL-009, participants received a included in the study. single oral dose of amenamevir (400 mg) on day 1 and underwent a 48-h washout period, Study Participants after which they received rifampicin orally (600 mg as two 300-mg tablets) once daily on All four studies enrolled healthy male adults (aged days 3–11, with a second single dose of ame- 18–55 years). Studies 15L-CL-008 and 15L-CL-009 namevir (400 mg) administered with rifampi- required participants to have a body weight of at cin on day 10. Blood samples for amenamevir least 60 kg but less than 100 kg and a body mass analysis were collected before dosing and index of at least 18 kg/m2 but less than 30 kg/m2.