Journal name: Drug Design, Development and Therapy Article Designation: Original Research Year: 2016 Volume: 10 Drug Design, Development and Therapy Dovepress Running head verso: Zhang et al Running head recto: Effects of probenecid and cimetidine on the pharmacokinetics of nemonoxacin open access to scientific and medical research doi: http://dx.doi.org/10.2147/DDDT.S95934 Open Access Full Text Article ORIGINAL RESEARCH Effects of probenecid and cimetidine on the pharmacokinetics of nemonoxacin in healthy Chinese volunteers Yi-fan Zhang1 Purpose: To investigate the effects of probenecid and cimetidine on the pharmacokinetics of Xiao-jian Dai1 nemonoxacin in humans. Yong Yang1 Methods: Two independent, open-label, randomized, crossover studies were conducted in Xiao-yan Chen1 24 (12 per study) healthy Chinese volunteers. In Study 1, each volunteer received a single oral Ting Wang2 dose of 500 mg of nemonoxacin alone or with 1.5 g of probenecid divided into three doses within Yun-biao Tang3 25 hours. In Study 2, each volunteer received a single oral dose of 500 mg of nemonoxacin alone or with multiple doses of cimetidine (400 mg thrice daily for 7 days). The plasma and urine Cheng-yuan Tsai4 nemonoxacin concentrations were determined using validated liquid chromatography–tandem Li-wen Chang4 mass spectrometry methods. Yu-ting Chang4 Results: Coadministration of nemonoxacin with probenecid reduced the renal clearance (CL ) 1 r Da-fang Zhong of nemonoxacin by 22.6%, and increased the area under the plasma concentration–time curve 1State Key Laboratory of Drug from time 0 to infinity (AUC0–∞) by 26.2%. Coadministration of nemonoxacin with cimetidine Research, Shanghai Institute of reduced the CL of nemonoxacin by 13.3% and increased AUC by 9.4%. Coadministration of Materia Medica, Chinese Academy of r 0–∞ Sciences, Shanghai, 2Department of nemonoxacin with probenecid or cimetidine did not significantly affect the maximum concentra- Pharmacy, The First Hospital Affiliated tion of nemonoxacin or the percentage of the administered dose recovered in the urine. to Lanzhou University, Lanzhou, Although probenecid reduced the CL and increased the plasma exposure of nem- 3Department of Pharmacy, The Conclusion: r General Hospital of Shenyang Military onoxacin, these effects are unlikely to be clinically meaningful at therapeutic doses. Cimetidine Region, Shenyang, People’s Republic had weaker, clinically meaningless effects on the pharmacokinetics of nemonoxacin. of China; 4TaiGen Biotechnology Co., Ltd., Taipei, Taiwan Keywords: nemonoxacin, probenecid, cimetidine, clinical pharmacokinetics, drug–drug interaction Introduction Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone developed by TaiGen Biotechnology Co., Ltd (Taipei, Taiwan). It shows a broad spectrum of activity against Gram-positive, Gram-negative, and atypical pathogens,1,2 and it appears to be more potent than other fluorinated quinolones (FQs), including ciprofloxacin, levofloxacin, and moxifloxacin.3 Clinical studies have shown that nemonoxacin has good safety/ tolerability and efficacy profiles in the treatment of community-acquired pneumonia (CAP), superior to those of levofloxacin.4,5 The premarketing clinical studies for the oral formulation have been completed, and the Taiwan Food and Drug Administration Correspondence: Da-fang Zhong approved oral nemonoxacin for the treatment of CAP in March 2014 (Manufacturing State Key Laboratory of Drug licence No. 058540). Research, Shanghai Institute of Materia To further understand the safety and effectiveness of new drugs, drug–drug inter- Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, action (DDI) studies must be considered. Nemonoxacin is quickly and completely People’s Republic of China absorbed after its oral administration and has a half-life of 10–13 hours, which sup- Tel/fax +86 21 5080 0738 Email [email protected] ports its once-daily administration.6–8 Like other FQs, the absorption of nemonoxacin submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2016:10 357–370 357 Dovepress © 2016 Zhang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/DDDT.S95934 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Zhang et al Dovepress is reduced in the presence of polyvalent metal ions, such as mean body mass index (BMI) was 21.8±2.8 kg/m2 (range Al3+, Mg2+, and Fe2+, because of its ability to chelate with 19.6–23.9 kg/m2). In Study 2, one male volunteer withdrew metals.9 Because no major or minor metabolites of nemon- for personal reasons after the administration of cimetidine oxacin have been found in in vitro or in vivo studies,6–8 the on day 4 in Period 1. The other eleven volunteers completed risk of metabolism-related DDIs is very low. Mass balance the study and were included in the pharmacokinetic analysis. studies in healthy volunteers have shown that nemonoxacin is Their mean age was 21.8±1.6 years (range 18–24 years), predominantly eliminated by the kidney, and 50%–70% of the mean body weight was 58.4±3.9 kg (range 51–65 kg), and dose is excreted unchanged in the urine more than 72 hours mean BMI was 21.0±1.2 kg/m2 (range 19.7–23.2 kg/m2). after its administration.6–9 After its binding by plasma proteins The volunteers were in good health in terms of their medical is considered (16%), the renal clearance (CLr) of the free history, physical examination, electrocardiography (ECG), (unbound) fraction of nemonoxacin is 132–164 mL/min, and routine laboratory tests. None of the subjects had used which is greater than the normal glomerular filtration rate any drugs for $2 weeks before the study and alcohol was (GFR) (ie, 125 mL/min), suggesting active renal secretion of forbidden from 72 hours before the administration of the the unchanged drug. Because nemonoxacin primarily exists study drugs. All volunteers provided written informed con- as a zwitterion at physiological pH, it is likely to interact sent before enrollment. with organic anion transporters (OATs) and organic cation transporters (OCTs) in renal tubule cells. It is well docu- Study design mented that probenecid, which is actively secreted via the Two independent, open-label, randomized, two-treatment, renal tubules and has a high affinity for OATs and OCTs, two-sequence, two-period crossover studies were designed decreases the CLr of many FQs, including ciprofloxacin, to assess the effects of probenecid and cimetidine on the gemifloxacin, gatifloxacin, and levofloxacin.10–13 It was also pharmacokinetics of nemonoxacin in healthy volunteers. Both reported that coadministration of cimetidine, a competitive studies included a washout period of 7 days between each OCT2 inhibitor, significantly reduces the CLr of enoxacin, study period. In Study 1, each volunteer received a single oral fleroxacin, gemifloxacin, or levofloxacin (by 13%–28%).13–15 dose of 500 mg of nemonoxacin alone (Treatment A) or with Here, we performed two studies to determine the effects 500-mg oral doses of probenecid 1 hour prior to and 12 and 24 of probenecid and cimetidine on the pharmacokinetics of hours after the administration of nemonoxacin (Treatment B). nemonoxacin in healthy volunteers. In Study 2, each volunteer received a single oral dose of 500 mg of nemonoxacin alone (Treatment C) or with multiple Materials and methods doses of cimetidine (Treatment D). In Treatment D, 400 mg Study drugs of cimetidine was orally administered thrice daily for 7 days, Nemonoxacin malate capsules (250 mg of nemonoxacin and nemonoxacin was administered on day 5. In both studies, per capsule, Batch number: 12031007, Expiry date: March, nemonoxacin was orally administered to the subjects after an 2014) were provided by TaiGen Biotechnology Co., Ltd. overnight fast of $10 hours. No food was allowed for $4 hours Probenecid tablets (250 mg of probenecid per tablet, Batch after administration of the drug. Water was allowed as desired, number: 110502, Expiry date: May, 2014) were manufactured except 2 hours before and 2 hours after drug administration. by Shanghai Sine Pharmaceutical Co., Ltd (Shanghai, Peo- Study 1 was conducted at the General Hospital of Shenyang ple’s Republic of China) and Tagment® tablets (400 mg of Military Region and Study 2 was conducted at the First Hos- cimetidine per tablet, Batch number: 12100066, Expiry date: pital Affiliated to Lanzhou University. The protocols of Study July, 2014) were manufactured by GlaxoSmithKline (China) 1 and Study 2 were approved by the Independent Ethics Com- Investment Co., Ltd (London, UK). mittee of the General Hospital of Shenyang Military Region and the Independent Ethics Committee of the First Hospital Volunteers Affiliated to Lanzhou University, respectively. Twenty-four healthy Chinese volunteers were initially enrolled in the studies, with 12 volunteers (six males and six Safety evaluation females) per study. In Study 1, all 12 volunteers completed All the volunteers who participated in the studies were included the study and were included in the pharmacokinetic analyses. in the safety analysis. Safety was evaluated in terms of physi- Their mean age was 23.3±2.7 years (range 19–27 years), cal examinations, vital signs (blood pressure, pulse, respiratory mean body weight was 62.0±9.6 kg (range 58–80 kg), and rate, and body temperature), 12-lead ECG, laboratory tests 358 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2016:10 Dovepress Dovepress Effects of probenecid and cimetidine on the pharmacokinetics of nemonoxacin (clinical chemistry, hematology, urinalysis, and serology), precision was ,5.5% and 7.1%, respectively.