Category: Preclinical Development
Purpose: In the human bioequivalence (BE) study for oral drug products, inter-individual variability in oral absorption and PK profiles are negligible because of the cross-over way of clinical study. However, high variability in drug absorption sometimes makes it difficult to prove the BE between test and reference products, due to the large intra-individual variability. In such a case, large number of subjects are required for BE study, but still the high risk of failure. In this study, as one of the possible factors for intra-individual variability in oral drug absorption, effects of the pH profile in the GI tract were investigated because the pH value in the GI tract fluctuates intra-individually. Dissolution of basic drugs in various conditions are analyzed in vitro, using a newly developed pH-varying system.
Methods: As basic drugs which showed large intra-individual variability in maximum plasma concentration (Cmax) in the human BE study, terbinafine hydrochloride (TER-HCl) and telmisartan (TEL) were selected from the list in the report of Sugihara et al. (Mol Pharm. 12: 4405, 2015). Pioglitazone hydrochloride (PIO-HCl) was used as a reference drug with a relatively small variability. In the in vitro experiment, these drugs were first added to the gastric simulated fluid (10 mL of FaSSGF, pH 1.6 for normal and pH 4.0 for high-gastric pH case) as an original powder or a ground product of their marketed formulation. Then, concentrated solution of 5 mL of FaSSIF having a higher pH than 6.5 was dropped into FaSSGF to raise the fluid pH gradually and finally make a normal FaSSIF with pH 6.5 in 10 minutes (in vitro pH-varying system). Dissolved concentration of drugs were monitored every 1 minute for first 10 minutes, then every 10 minute till the end of the experiment (for 60 minutes). The change in pH of the fluid was also monitored during the experiment.
Results: All three drugs showed higher initial dissolution rate in FaSSGF with pH 1.6 than in that with pH 4.0. This was remarkable for the original powder of TEL because other two drugs were used as a form of HCl salt In the case of PIO-HCl, a dissolved concentration rapidly decreased and when the solution has turned out to FaSSIF with pH 6.5, fractions of dissolved drugs were less than 1% in all cases regardless of the initial pH of FaSSGF. On the other hand, initial pH of FaSSGF profoundly affected the dissolved concentration of TER-HCl. When FaSSGF with pH 1.6 was used as an initial fluid, more than 80% of drugs was kept dissolved even in FaSSIF for 60 minutes, whereas the fraction of dissolved drug was dropped to less than 40% when started with pH 4.0 FaSSGF. This difference in the dissolved fraction in FaSSIF could be one of the reasons of intra-individual variability in Cmax in human BE study of TER-HCl products.
Since the marketed formulation of TEL includes meglumine as a pH modifier, the ground product of the formulation gave a higher dissolved concentration of TEL in FaSSGF and minimized the pH-dependent variability in dissolved concentration. When the fluid became FaSSIF with pH 6.5, the dissolved fraction of TEL from marketed formulation was almost 100%, then gradually deceased due to a progression of precipitation. Final dissolved concentration of TEL in FaSSIF (after 60 minutes) was clearly influenced by the initial pH of FaSSGF and significantly higher when started with pH 4.0 FaSSGF than pH 1.6. Although the reason of this phenomena has not been clarified yet, the slower dissolution rate of TEL in pH 4.0 FaSSGF than that in pH 1.6 might result in the slower precipitation rate in pH 6.5 FaSSIF.
Conclusion: From the time-profile of dissolved concentration of drugs in the course of pH-shift which mimicked the transition from stomach to small intestine, It was revealed that the fluctuation in the gastric pH is one of the reasons of large intra-individual variability in the oral absorption of TER-HCl and TEL, but not of PIO-HCl. Also, the effect of pH–modifier in the marketed product of TEL was clearly detected. Although the in vitro pH-varying system developed in this study is quite simple, it can give useful information on the variability of oral drug absorption caused by the fluctuation of pH in the GI tract.
Keiko Minami– Researcher, Japan, Hirakata, Osaka, Japan
Haruki Higashino– Assistant Professor, Setsunan University, Hirakata, Osaka, Japan
Makoto Kataoka– Hirakata, Osaka, Japan
Shinji Yamashita– Hirakata, Osaka, Japan