Studies On Bioequivalence And In Vitro/in Vivo Correlations Of Potassium Chloride Sustained-release Tablets In Healthy Volunteers

Objective: To study the relative bioavailability of potassium chloride sustained-release tablets in healthy volunteers and to evaluate the bioequivalence and To investigate the in vitro/in vivo correlations.Methods: A randomized two-crossover study was performed in 12 healthy male volunteers. Because the potassium ion (K+) is endogenous substance, each of the 8 days periods are divided into three phases: diet equilibration days (1-3), baseline days (4-6), drug dosing days (7-8). At 8:00 AM of day 4, a single 26.85mEq (2000mg, 500mg/tablet) dose of the two kinds of potassium chloride sustained-release tablets was administered, in each period the urine samples were collected at the following intervals:0-2,2-4,4-6,6-8,8-12,12-24,24-48h after dose and measure the amount of K+ in urine by flame emission spectroscopy. The relative bioavailability was represented by the net cumulative amount of K+ excreted in urine 24h after drug administration, the bioequivalence of the two formulations was evaluated by ANONA and two one - side t test. All pharmacokinetic data were treated by 3P97 software, then parameters were calculated and curve-equations were fitted. The in vivo input rate (e.g. the in vivo dissolution of the drug from the dosage form) was calculated by Wagner-Nelson equation; the in vitro dissolution rate was calculated by in vitro dissolution testing, then the correlation is generally studied by liner and a point-to-point relationship between them.Results: The results of the TT(test tablet)and RT(reference tablet)were as follow:Ae0-24h (cumulative urinary excretion from 0-24h, mEq) were 17.00 + 5.53 and 16.49 + 5.04; VmaX(maximal rate of urinary excretion, mEq h-1) were 1.46 + 0.53 and 1.61+0.85; Tmax(time of maximal urinary excretion, h) were 5.33+4.72and 5.50+4.66, respectively. Ae0-24h and Vmax which were In-transformed and Tmax as the index to evaluate the bioequivalence with ANONA and two one - side / test. The relative bioequivalence of the TT was 107.04 + 28.90% compared to RT. After calculated by 3p97 package, the pharmacokinetic process of potassium chloride sustained-release tablets in healthy volunteers accords with one-compartment model. The main pharmacokinetic parameters of TT and RT were as follow: Ke(h-1): 0.0412 and 0.0416; Ku(h-1): 0.0426 and 0.0419; Ka(h-1): 1.906 and 1.798; Xu0 (mEq): 27.78 and 27.06. The correlations between in vivo input rate and in vitro dissolution rate of TT and RT were: rrr=0.9471 (p=0.217) and rRT=0.9617 (p=0.177). The correlations between excretion rate and in vitro dissolution rate of TT and RT were: rTT=0.9998 (p=0.017) and rRT=0.9994 (p=0.022).Conclusion: the bioequivalence of the two formulations was evaluated by ANONA and two one - sided t test. The result indicated there was no significant difference between the two formulations and they were bioequiovalent. The results of in vitro/in vivo correlation of TT and RT indicated the two kinds methods had somedifference, and need further studies.