Study On Pharmacokinetic Of Pitavastatin In Healthy Chinese Volunteers

Objective：According to the regulations of drug registration issued from chemicalmedicine from State Food and Drug Administration （SFDA）, pitavastatin belongsto the3.1new drug, namely, it has been on market on aboard but not yet in China.Our aim is to assess pharmacokinetic characteristics of pitavastatin in healthyChinese volunteers and to investigate the rate and extent of absorption,distribution, metabolism and elimination of pitavastatin in human body. Based onour study, it can provide references for phase â…¡ clinical trial protocol designand clinical dosage regimen for Chinese patients with hypercholesterolemia.Methods：Single-dose study: Twenty healthy subjects were enrolled in this studyand all subjects were randomly divided into two groups, such as group I andgroup â…¡ （five males and five females in each group）. Groups I and â…¡ wereadministered a single dose of pitavastatin tablet1.0mg and2.0mg with250mLof warm water, respectively and after one week washout period, group I also received a single dose of4.0mg pitavastatin with250mL warm water. Waterintake was allowed2h post-dose and standard meals were provided at4h and10h post-dose. Blood samples （4ml） were collected at0h （pre-dose） and15,30and45min, and1,1.5,2,3,4,6,8,12,24,36, and48h post-dose (whole samplingperiod should at least last for3-5half-life or drug concentration in blood being1/10¹/20of C_max). The samples were transferred to heparinized tube andcentrifuged at3000g for10min. Plasma was separated and stored at-80C untilanalysis.Multiple-dose study: In the design of multiple doses, group â…¡ received2mgpitavastatin tablets at8:00a.m. for consecutive6days. In days3,4and5,4ml ofvenous blood was drawn to observe minimum value of steady plasma-drugconcentration before every dosing at8:00a.m. In day7, the procedure was thesame as that of single dose mentioned above. The concentrations of pitavastatinin plasma were determined by LC-MS/MS method developed in this study.Results： Single-dose study: The main pharmacokinetic parameters ofpitavastatin after single oral doses （1,2and4mg） were as follows: T_1/2were11.29±4.28h,13.52±5.65h and11.87±2.87h, respectively; T_maxwere0.78±0.32h,0.75±0.17h and0.93±0.31h, respectively; Cmaxwere15.80±7.34ng/mL,36.54±6.29ng/mL and61.32±15.09ng/mL, respectively; AUC0-48were36.4621.86ng h/mL,107.9028.55ng h/mL and187.7662.62ng h/mL,respectively; AUC_0-were40.9123.20ng h/mL,112.9729.08ng h/mL and197.5568.51ng h/mL, respectively. The single-dose pharmacokinetic study wasshown that the metabolism of pitavastatin was linear in the range of1.0to4.0mg.Multiple-dose study: The main pharmacokinetic parameters of pitavastatintablet after mutiple-dose （2mg） were as follows: T_1/2were13.07±2.16h, Tmax were0.68±0.12h, C_maxwere33.88±6.91ng/mL, AUC_sswere68.21±20.82ng h/mL, AUC_0-48were77.7826.50ng h/mL, AUC（0-）were82.59±26.58ng h/mL. Accumulation ratio of AUC_0-48and C_maxwere0.72±0.93and0.93±1.10, respectively. Compared with single-dose pharmacokinetics, there wasno significantly difference of AUC（0-48）and Cmaxfor multiple-dose pitavastatinpharmacokinetic study. It was indicated that no accumulation phenomenon wasobserved after mutiple doses of2.0mg pitavastatin.Safety study: During the whole study, no serious adverse events occurred and allhealthy volunteers were safe and tolerated.Conclusion：Linear PK properties were found with increasing single doses ofpitavastatin1.0to4.0mg. Compared with single-dose pharmacokinetics, therewas no significantly difference of AUC_0-48and C_maxfor multiple-dosepitavastatin pharmacokinetic study. It was indicated that no accumulationphenomenon was observed after multiple doses of2.0mg pitavastatin.