Pharmacokinetics, Pharmacodynamics and Population
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Clin Drug Investig DOI 10.1007/s40261-016-0447-2 ORIGINAL RESEARCH ARTICLE Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects 1 2 3 4 Michinori Togawa • Hidetoshi Yamaya • Mo´nica Rodrı´guez • Hirotaka Nagashima Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract administration, no remarkable differences were observed Background and objectives Bilastine is a novel second- between Day 1 and Day 14 for Cmax or AUC. For inhibitory generation antihistamine for the symptomatic treatment of effects on wheal and flare response, bilastine 20 and 50 mg allergic rhinitis and urticaria. The objective of this study showed significant inhibition from 1.5 h after administra- was to evaluate the pharmacokinetics, pharmacodynamics, tion as compared with placebo, and the significant effect and tolerability of bilastine following single and multiple persisted for 24 h after administration. The rates of adverse oral doses in healthy Japanese subjects. The pharmacoki- events (AEs) were comparable between bilastine and pla- netic and pharmacodynamic profiles were compared with cebo in both Part I and Part II. In addition, no dose- or those reported in Caucasian subjects. administration period-dependent tendency of increase in Methods In a single-blind, randomized, placebo-con- rate of AEs or worsening of severity was observed. trolled, parallel-group, single- and multiple-ascending dose Conclusion Bilastine exhibits similar single- and multiple- study, bilastine tablets were administered at single doses of dose pharmacokinetic and pharmacodynamic characteris- 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 tics in healthy Japanese subjects compared with those and 50 mg (Part II). observed in Caucasian subjects in previous studies. Results After single oral doses, maximum plasma con- centrations (Cmax) were reached at 1.0–1.5 h postdose. Plasma exposure [C and area under the plasma con- max Key Points centration-time curve (AUC)] increased dose-proportion- ally at single doses of 10–50 mg. In repeated-dose Bilastine exhibited dose-proportional pharmacokinetics in Japanese subjects, and was well tolerated. Electronic supplementary material The online version of this article (doi:10.1007/s40261-016-0447-2) contains supplementary The pharmacokinetic and pharmacodynamic profiles material, which is available to authorized users. in these Japanese subjects were similar to those of & Michinori Togawa Caucasian subjects. [email protected] 1 Project Management Department, TAIHO Pharmaceutical Co., Ltd., 1-2-4, Uchikanda, Chiyoda-ku, Tokyo 101-0047, Japan 2 Tsukuba Research Center, TAIHO Pharmaceutical Co., Ltd., 1 Introduction 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan 3 Drug Modeling and Consulting, DynaKin, S.L. Bizkaia Bilastine, a novel second-generation H1 antihistamine, has Technology Park, 48160 Derio, Vizcaya, Spain been granted marketing authorization for adults and ado- 4 Shinjuku Research Park Clinic, 1-22-17, Hyakunin-cho, lescents (12 years and over) in most European countries Shinjuku-ku, Tokyo 169-0073, Japan M. Togawa et al. since 2010. The approved dose is 20 mg once a day for board. All subjects gave written informed consent before symptomatic treatment of allergic rhinoconjunctivitis and the initiation of any study-specific procedure. urticaria [1]. The pharmacokinetic (PK) profile of bilastine after 2.1 Study Design single and multiple oral doses ranging from 5 to 220 mg has been reported in healthy Caucasian adult subjects. This was a single-center, randomized, single-blind (for Absorption of bilastine is rapid and proportional to dose, subjects), placebo-controlled, ascending dose, single and with its oral bioavailability being reduced by foods and multiple dose study in 60 healthy male subjects to assess grapefruit juice [1]. Absolute oral bioavailability of bilas- the PK, PD, safety, and tolerability of bilastine. The study tine is 60.67 % [2]. No accumulation pattern was shown for consisted of two parts. In Part I, each subject received a bilastine after repeated dosing in a 14-day PK study of single oral dose of bilastine [10, 20, or 50 mg (as escalating daily doses from 10 to 100 mg [3]. In the mass- 10 mg ? 20 mg 9 2 tablets)], or matching placebo (n = 9 balance study, bilastine was not significantly metabolized active, n = 3/step placebo). Subjects (n = 12/step) were in humans and is largely eliminated unchanged both in fasted overnight prior to dosing and remained fasted until urine (33.1 %) and feces (67 %) [4]. Population PK mod- 4 h postdose. In Part II, each subject received an oral dose eling with an indirect response model based on data from of bilastine (20 or 50 mg) or matching placebo (n = 9 310 healthy volunteers suggested that bilastine PK follows active, n = 3/step placebo) once a day for 14 days (Day a two-compartmental model with first-order absorption and 1–14). Subjects (n = 12/step) were fasted overnight prior elimination [5]. to dosing and remained fasted until 4 h postdose on Day 1 Exposure and accumulation of bilastine are modified and Day 14. Subjects were admitted to the clinical site on when the drug is simultaneously administered with some the day before dosing (Day -1) and were confined until membrane transport protein inhibitors. In particular, discharge on Day 4 (Part I) or Day 17 (Part II). bioavailability of bilastine is significantly increased when co-administered with P-glycoprotein (P-gp) inhibitors [1]. 2.2 Subjects Bilastine is a substrate of P-gp and organic anion trans- porting polypeptide, but not of human breast cancer Subjects were eligible for inclusion in the study if they met resistance protein, organic anion transporter 1 or 3, or the following criteria: males aged 20–39 years at the time organic cation transporter 2 [6]. Further, bilastine is not of signing the informed consent, with a body mass index metabolized and does not interact significantly, either as an (BMI) of 18.5 to\25 kg/m2 and weight of C50 kg, and no inhibitor or inducer, with the cytochrome P450 enzyme use of tobacco/nicotine for 90 days prior to the study drug system, suggesting a low propensity for drug–drug inter- administration. Subjects were excluded from the study if actions involving this metabolic pathway [7]. there was evidence of any of the following criteria at As part of the clinical development program in Japan to screening or at any time during the study: (1) any acute or confirm extrapolation of foreign clinical data as support for chronic disease state, including but not limited to hepatic, new drug application in Japan, we conducted a phase I renal, gastrointestinal, pulmonary, endocrine, cardiovas- study to evaluate the PK, pharmacodynamics (PD), safety, cular, hematologic, neurologic, psychiatric, immunologic, and tolerability of bilastine in healthy Japanese subjects. oncologic, infectious disease, or any other condition The PK and PD results obtained in this study were subse- determined to be clinically significant by the investigator, quently compared with those previously reported for (2) subjects with a history of drug allergy, (3) subjects with healthy Caucasian subjects. a history of adverse effect for which they had received medical treatment including antihistamines, (4) subjects who participated in a previous clinical trial within 90 days 2 Methods prior to dosing, (5) subjects who had taken ketoconazole, erythromycin, cyclosporine, diltiazem, or other drug that This study was conducted in accordance with the ethical has an inhibitory effect of P-gp, within 30 days prior to principles based on the Declaration of Helsinki, and Good dosing, (6) subjects who had taken any medication (in- Clinical Practice as defined by the Ministerial Ordinance cluding prescription and over-the-counter, except for concerning the standards for the implementation of clinical external preparation) within 14 days prior to dosing, (7) studies on pharmaceutical products, and the regulations subjects who have had food or beverage containing alco- stipulated in the Japanese Pharmaceutical Affairs Law. hol, caffeine/xanthine, grapefruit, citrus fruit, fruit juice, This study was conducted at Yanagibashi Hospital (Tokyo, cranberries, or St. John’s Wort 24 h prior to dosing, (8) Japan) in 2013. The protocol and the informed consent subjects with clinically significant abnormal findings documents were approved by the institutional review determined by the investigator on the physical PK and PD of Bilastine in Japanese Subjects examination, vital signs, electrocardiogram (ECG), or variation ranged between 2.74 and 10.31 % for plasma, clinical laboratory determinations, (9) subjects who had a and between 1.58 and 9.91 % for urine. The within-run [2 mm wheal reaction to saline and/or \3 mm wheal percentages of nominal concentrations ranged between reaction to histamine skin prick test (1 mg/ml) at screen- 96.91 and 113.33 % for plasma, and between 91.96 and ing, (10) positive serum test for human immunodeficiency 105.02 % for urine. virus, hepatitis B virus, hepatitis C virus, or Wassermann Concentration data of bilastine in plasma and urine were reaction at screening, (11) subjects who had a positive analyzed by non-compartmental methods using PhoenixTM urine screen for alcohol or drug of abuse at screening, (12) WinNonlinÒ Professional version 6.1 (CERTARA, St. subjects who were not willing to use appropriate contra- Louis, MO, USA). The following pharmacokinetic