Ultrasound holds promise for enhancing the vancomycin release from cement though the length of time when local drug level exceeded the minimum inhibitory concentration (T(>MIC)) was not prolonged by the previous protocol of milliwatt-level ultrasonication. Here vancomycin-loaded cements were subjected to continuous watt-level ultrasonication (CUG), intermittent watt-level ultrasonication (IUG) or no ultrasonication (NUG) for 14 d during immersion in 40-ml phosphate buffered saline (PBS) for 28 d. The T(>MIC) for IUG was more than three times that for NUG. In contrast, T(>MIC) for CUG was slightly shortened. The subtherapeutic release of vancomycin between 15 d and 28 d for IUG was one-ninth that for NUG. The fitting equations indicated a significant enhancement on the burst release and the slow release for IUG; however, the continuous ultrasonication hampered the slow release. SEM images exhibited denser craters and pores with larger diameters and less residual drug in specimens from IUG relative to those from both CUG and NUG. Intermittent watt-level ultrasonication improved the ultrasound-enhanced vancomycin release from cement in view of the prolonged T(>MIC) and the inhibited subtherapeutic release compared with continuous ultrasonication. The mechanisms may be associated with the distinctive effects of detaching forces and pushing forces by acoustic microstreams.

In vitro‐in vivo correlation (IVIVC) allows prediction of the in vivo performance of a pharmaceutical product based on its in vitro drug release profiles and can be used to reduce the number of bioequivalence (BE) studies during product development, and facilitate certain regulatory decisions. Here, we developed an IVIVC model for pitavastatin calcium, a basic Biopharmaceutics Classification System (BCS) II lipid‐lowering drug, which was then used to predict the BE outcome of formulations manufactured at two manufacturers. In addition, virtual trials using the IVIVC model using pH 4.0 acetate buffer dissolution showed similarity in areas under the curves and maximum plasma concentration (Cmax) for test and reference tablets under fasting condition. These predicted results were verified in definitive BE study. In conclusion, we demonstrated that for certain BCS II molecules, IVIVC modeling could be used as a priori to predict the BE outcome.

Salvianolic acid A (SAA) is a water-soluble phenolic acid component from Salvia miltiorrhiza Bunge currently under development for myocardial protection treatment for coronary heart disease (CHD). We investigated the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of SAA. Additionally, a physiologically based pharmacokinetic (PBPK) model was developed to simulate the pharmacokinetics of SAA. This was a first-in-human (FIH), randomized, double-blind, placebo-controlled, single, and multiple-dose study in 116 healthy Chinese subjects with the range of 10–300 mg and 60–200 mg SAA, respectively. SAA was well tolerated at all dose levels, following both single and multiple doses, with a low overall incidence of treatment-emergent adverse events (TEAEs) which appeared to be no dose-related. The main pharmacokinetic parameter of SAA, assessed by the power model, was the lack of proportionality with the dose range after single dosing. The 90% CIs of the slope β of Cmax (1.214 [1.150–1.278]) and AUC0-t (1.222 [1.156–1.288]) were not within the predefined acceptance range, and the direction of the deviation was higher than expected. PBPK modeling suggested the transfer ability saturation of hepatic organic anion-transporting polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp) might result in a relatively low distribution rate at higher doses. Clinical plasma concentrations observed were in good agreement with PBPK prediction. SAA showed well-characterized pharmacokinetics and was generally well tolerated in the dose range investigated. The PBPK model provides valuable pharmacokinetic knowledge for further clinical development.

Febuxostat is recommended by the American College of Rheumatology GoutManagement Guidelines as a first-line therapy for lowering the level of urate in patients with gout. At present, this drug is being prescribed mainly based on the clinical experience of doctors. The potential effects of clinical and demographic variables on the bioavailability and therapeutic effectiveness of febuxostat are not being considered. In this study a physiologically based pharmacokinetic (PBPK) model of febuxostat was developed, thereby providing a theoretical basis for the individualized dosing of this drug in gout patients. The plasma concentration-time profiles corresponding to healthy subjects and gout patients with normal kidney function were simulated and validated; then, the model was used to predict the pharmacokinetic (PK) data of the drug in gout patients suffering from varying degrees of impaired kidney function. The error values (the predicted value/observed value) were used to validate the simulated PK parameters predicted by the PBPK model, including the area under the plasma concentration-time curve, the maximum plasma concentration, and time to maximum plasma concentration. Considering that to all error fold changes were smaller than 2, the PBPK model was. In subjects suffering from mild kidney impairment, moderate kidney impairment, severe kidney impairment, and endstage kidney disease (ESRD), the predicted AUC 0-24h values increased by 1.62, 1.74, 2.27, and 2.65-fold, respectively, compared to gout patients with normal kidney function. Overall, the results showed that the PBPK model constructed in this study predict the pharmacokinetic changes in gout patients suffering from varying degrees of impaired kidney function.

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