Original Article 263 Pharmacokinetics, Safety and Tolerability of Trifl usal and its Main Active Metabolite HTB in Healthy Chinese Subjects Authors M. Wang , Q. Zhang , M. Huang , S. Zong , W. Hua , W. Zhou Affi liation Clinical Pharmacology Laboratory, The Second Affi liated Hospital of Soochow University, Suzhou, China Key words Abstract rapidly absorbed with a mean Tmax of 0.55–0.92 h ● ▶ trifl usal ▼ and a mean t1/2 kel of 0.35–0.65 h, HTB was ● ▶ pharmacokinetics Objective: T r i fl usal presents comparable absorbed with a mean Tmax of 2.35–3.03 h and a ● ▶ antiplatelet activity antiplatelet activity to aspirin while presenting a mean t of 52.5–65.57 h. C and AUC for tri- ● ▶ safety 1/2 kel max more favourable safety profi le, and is used in the fl usal and HTB were approximately dose propor- treatment of thrombosis. The study aimed to tional over the 300–900 mg dose range. In the evaluate the pharmacokinetics and safety of trif- steady state, the accumulation index (R) indi- lusal and its major metabolite 2-(hydroxyl)-4- cated that the exposure of trifl usal increased (trifl uoromethyl)- benzoic acid (HTB) in healthy slightly with repeated dosing, and the exposure Chinese subjects. of HTB increased obviously. 3 adverse events cer- Methods: 30 healthy subjects were recruited in tainly related to the investigational drugs this randomized, single-center, and open-label, occurred in the multiple-dose phase. parallel, single ascending doses (300, 600, Conclusion: Following oral dosing under fast- 900 mg) and multiple doses (600 mg, once daily ing condition, trifl usal is promptly absorbed and for 7 days) study. Plasma samples were analyzed rapidly depleted from the systemic circulation. with a validated liquid chromatography tandem HTB is quickly generated from trifl usal and mass spectrometry (LC/MS/MS) method. Safety slowly eliminated. Trifl usal accumulates slightly was assessed by adverse events, ECG, laboratory in the body. HTB plasma concentration builds up testing, and vital signs. progressively toward steady-state. received 06 . 08 . 2013 Results: T r i fl usal was safe and well tolerated. accepted 13 . 09 . 2013 After single-dose administration, trifl usal was Bibliography DOI http://dx.doi.org/ Introduction trifl usal is deacetylated in the liver to HTB as the 10.1055/s-0033-1357180 Published online: ▼ main active metabolite. And unchanged trifl usal October 8, 2013 T r i fl usal (2-acetoxy-4-trifl uoromethyl benzoic and HTB are eliminated primarily through the Drug Res 2014; acid; CAS 322-79-2) is a new molecule related to kidneys [ 5 ] . Unchanged trifl usal, HTB and HTB This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 64: 263–268 salicylic acid which is used in the prevention and glycine conjugate have been identifi ed in the © Georg Thieme Verlag KG treatment of thromboembolic disease [ 1 , 2 ] . Trif- urine. Trifl usal has 2 major pharmacological Stuttgart · New York lusal inhibits cycloxygenase-1 in platelets, but eff ects: in platelets it inhibits activation of ISSN 2194-9379 seems to leave intact the arachidonic acid meta- thrombogenic mechanisms, while in the nervous bolic pathway in endothelial cells. Trifusal and system it blocks the main biochemical pathways Correspondence Q. Zhang HTB stimulate the constitutive activity of NO that lead to cell damage during ischemia [ 3 ] . Chief Pharmacist synthase (cNOS) and consequently increase NO Following oral dosing, trifl usal is promptly Clinical Pharmacology Laboratory production by endothelial cells and leucocytes. absorbed and rapidly depleted from the systemic The Second Affi liated Hospital Trifl usal presents comparable antiplatelet activ- circulation. Its concentration was measurable of Soochow University ity to aspirin while presenting a more favourable only up to 4 h after administration [ 2 ] . Main NO.1055 Sanxiang Road safety profi le [ 3 ] . pharmacokinetic parameters of trifl usal and HTB 215004 Suzhou T r i fl usal is absorbed in the small intestine and its in healthy subjects of literature data [ 1 , 6 , 7 ] are China ▶ Tel.: + 86/512/67783 687 bioavailability ranges from 83 to 100 % [ 1 , 4 ] . It summarized in ● Table 1 . The pharmacokinetic Fax: + 86/512/67783 686 binds to plasma proteins almost entirely (99 %) profi les of trifl usal or HTB do not appear to have [email protected] and crosses organic barriers readily. In humans, clinically signifi cant diff erences in elderly or Wang M et al. Trifl usal and HTB PK in Chinese Subjects … Drug Res 2014; 64: 263–268 264 Original Article Study population Table 1 Pharmacokinetics of trifl usal and HTB in healthy subjects from literature data. Chinese healthy volunteers, aged 18–40 years, male and female (nonpregnant and nonlactating), weighing not less than 50 kg, PK parameters a 300 mg [6] 600 mg [7] 900 mg [1] body mass index (BMI) between 19 and 24 kg/m2 , were enrolled. (n = 9) (n = 24) (n = 8) Subjects were all in good health as determined by their past Trifl usal medical history, physical examination, vital signs, standard lab- C max (μg/mL) – 14.48 ± 7.22 11.61 ± 1.68 oratory parameters (e. g. haematology, blood chemistry and uri- b T max (h) – 0.875 (0.25–1.5) 0.88 ± 0.26 nalysis), and 12-lead ECG within 2 weeks before the fi rst dosing tl/2 kel (h) 0.64 ± 0.08 0.76 ± 0.64 0.53 ± 0.12 of the study medication. Female subjects were required to have AUC0–t (μg/mL · h) 3.0 ± 0.5 16.22 ± 7.58 – a negative pregnancy test at screening and to agree on using an HTB eff ective contraception method during the study period. C (μg/mL) – 65.51 ± 19.44 92.71 ± 17.14 max The persons are excluded out of the study who are: infected of T (h) – 2 (0.75–12) b 4.96 ± 1.37 max hepatitis B or C virus or HIV or Syphilis; pregnant or breastfeed- tl/2 kel (h) 59.7 ± 11.3 43.13 ± 6.56 34.29 ± 5.32 ing; having a history of or having pulmonary, cardiovascular, AUC0–t (μg/mL · h) 1321 ± 304 2877.97 ± 881.24 - a Data were presented as mean ± SD neurological, psychiatric, endocrine or coagulation disorders, b Median (range) having renal or hepatic disease or any physical attributes that may infl uence the trial results; medicated or using drugs of any younger volunteers [ 3 , 8 ] . No plasma accumulation of the parent kind in ≤ 2 weeks before the study commencement; having a his- compound was noticed in volunteers > 80 years old who received tory of or currently abusing of drugs or alcohol; smoking of trifl usal 300 mg × 2/day for 13 days [ 9 ] . Additionally, the steady- more than 5 cigarettes per day or equivalent; participating in state level of HTB is reached within 8–10 days of treatment another drug study or donation of blood in ≤ 90 days prior to the [ 10 , 11 ] . study. At present, no available data on pharmacokinetics of trifl usal and HTB in Chinese subjects are reported. The objective of this Study design study was to evaluate the pharmacokinetic profi les of trifl usal This was a randomized, single-center, open-label study in which and HTB after oral single doses (300, 600, 900 mg) and multiple 30 healthy subjects of either sex were randomly assigned to doses (600 mg, once daily for 7 days) of trifl usal capsules in group 1, group 2, and group 3 (5 females and 5 males in each healthy Chinese subjects. Moreover, the safety and tolerability of group). The subjects were hospitalized at 7:00 pm the night trifl usal in Chinese subjects were also assessed. before dosing and required to fast overnight (10 h). Throughout the sequential single-dose and multiple-dose trials, trifl usal was administrated in fasting state. After the trial, the subjects were Subjects and Methods released and visited the clinic for post-test of vital signs, 12-lead ▼ ECG, physical examination, and routine laboratory test. If the Study approval principal investigator determined that a subject required addi- The clinical trial was licensed in State Food and Drug Adminis- tional tests, the subject obeyed these orders. tration in China with the registration number of 2010L01996. The study was performed at the Second Affi liated Hospital of Single dose administration Soochow University in Suzhou, China. The study was conducted The therapeutic dose of trifl usal capsule was 300 mg, 600 mg or in accordance with the principles of the Declaration of Helsinki 900 mg once daily. On day 1, subjects of group 1, group 2, and [ 12 ] and Good Clinical Practice (GCP) in China [ 13 ] , and the pro- group 3 received a single oral administration of 300 mg, 600 mg, tocol was approved by the Independent Ethics Committee of the and 900 mg of trifl usal capsules, respectively. Study medication hospital with the approval number of 2013 (12). All study par- was administered at 7:00 am with 250 mL of water. Water intake ticipants gave written informed consent before the conduct of was prohibited within the following 2 h after drug administration the study-related procedures. and a standard lunch was served 4 h after dosing. Blood samples (4 mL each) were collected from vein vessels in the antebrachium predose (0 h) and 10, 20, 30 and 45 min, and 1, 1.25, 1.5, 2, 2.5, 3, Materials and reagents This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. T r i fl usal reference standard (purity of 99.7 %) and HTB reference 3.5, 4, 6, 8, 12, 24, 48, 72, 120 and 168 h after dosing.