AYŞE NUR OKTAY, JAMES E POLLI
Turkish Journal of Pharmaceutical Sciences - 2025;22(4):270-278
Objectives Norvir® oral powder [ritonavir (RTV)] employs polyvinylpyrrolidone/vinyl acetate as the polymer to formulate an amorphous solid dispersion. Its oral absolute bioavailability is 70% in the fasted state, and it has negative food effects. The aim of this study was to perform in vitro dissolution of Norvir® powder and Wagner-Nelson deconvolution of in vivo data under fasted, moderate fat, and high fat conditions in order to elucidate the relevance of in vitro dissolution testing. Materials and Methods In vitro dissolution of Norvir® oral powder was conducted, and the human pharmacokinetic data of Norvir® powder were obtained from literature, under fasted, moderate fat, and high fat conditions. Wagner-Nelson deconvolutions were performed. The absolute fraction absorbed (Fa) profiles were compared to the in vitro dissolution (Fd) profiles. Levy-Polli plot analysis was also conducted. For each pharmacokinetic condition, a scale factor was estimated to approximate the extent to which in vitro dissolution needed to be slowed down to mimic in vivo dissolution. RESULTS Qualitatively, there was a large difference between in vitro and in vivo dissolution. In vitro dissolution showed 98% release in 5 minutes. Meanwhile, from Wagner-Nelson analysis, only 5.5% of the drug dissolved (and absorbed) in vivo in 5 min under fasted conditions. It was not until 2 hr that 49% of the RTV dose dissolved (and was absorbed) in vivo. In vivo, moderate fat and high fat conditions were even slower in producing a certain effect. The Levy-Polli plot exhibited a “reverse-L” profile. It was concluded that such rapid in vitro dissolution did not mimic the in vivo dissolution of RTV. In vitro dissolution needed to be slowed by 100-fold for fasting. CONCLUSION Biopharmaceutic consideration of in vitro dissolution, in vivo pharmacokinetics, and deconvolution analysis indicated that in vitro dissolution was “too rapid” to adequately mimic in vivo dissolution. Findings suggest greater inspection of in vitro methods for poorly water-soluble drugs, especially those drugs where in vivo absorption is expected to be rate-limited by dissolution.
