Pharmacokinetics And Bioequivalence Of Roflumilast And Its Active Metabolite Roflumilast N-oxide In Healthy Chinese Volunteers

Objective To develop and establish a HPLC-MS/MS method for determining roflumilast and its active metabolite roflumilast N-oxide in human plasma,and to validate completely this methodological validation.To evaluate the pharmacokinetic profile and bioequivalence of Chinese healthy volunteers after oral roflumilast tablets.Method 24 healthy subjects were randomly divided into two groups according to their weight,and the two groups were randomly assigned to the two-period crossover drug design.A single oral dose(0.5mg)of test and reference roflumilast were given to 24 healthy male volunteers in study.Blood samples were collected after each oral drug.Concentrations of roflumilast and its active metabolite roflumilast N-oxide in plasma were determined by HPLC-MS/MS method.The measured RFM and RFN plasma concentration-time data were analyzed by DAS2.1 software(Cmax and Tmax were measured,and AUC was calculated by trapezoid method.Cmax,AUC0-t,AUC0-? carries on the double cross experiment design analysis of variance after the logarithmic transformation,the bidirectional one-side t test was used to calculate the 90% confidence interval,Tmax using nonparametric test)to evaluate the bioequivalence of two formulations.Result The concentration-time curves of roflumilast and its active metabolite roflumilast N-oxide were described by a one-compartment open model.The main pharmacokinetic parameters of roflumilast test and reference preparations were as follows after a single dose: Cmax(8.19±2.62)?g?L-1 and(8.12±2.25)?g?L-1,Tmax(0.98±0.48h)and(0.92±0.50)h,T1/2(15.93±7.00)h and(15.66±6.16)h,AUC0-48h(44.91±14.47)?g?h-1?L-1 and(46.31±12.59)?g?h-1?L-1,respectively.The main pharmacokinetic parameters of roflumilast N-oxide were as follows after a single dose: Cmax(10.84±2.67)?g?L-1 and(10.84±2.73)?g?L-1,Tmax(9.13±5.62)h and (10.96±7.88)h,T1/2(26.63±6.23)h and(28.45±8.69)h,AUC0-120h(558.5±144.3)?g?h-1?L-1 and(580.9±166.1)?g?h-1?L-1,respectively.The relative bioavailability of roflumilast and its active metabolite roflumilast N-oxide were(96.84±13.10)% and(97.70±14.30)%.Conclusion The established HPLC-MS/MS method was accurate and sensitive,and it was successfully applied to the pharmacokinetics and bioequivalence of Chinese healthy volunteers.The result of the statistical analysis showed that the two formulations were bioequivalent.