Comparison of In Vitro and Dissolution of Norvir Oral Powder: Relevance of a too Rapid Dissolution Test.

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 data under fasted, moderate fat, and high fat conditions in order to elucidate the relevance of dissolution testing.

MATERIALS AND METHODS

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 (F) profiles were compared to the dissolution (F) profiles. Levy-Polli plot analysis was also conducted. For each pharmacokinetic condition, a scale factor was estimated to approximate the extent to which dissolution needed to be slowed down to mimic dissolution.

RESULTS

Qualitatively, there was a large difference between and dissolution. dissolution showed 98% release in 5 minutes. Meanwhile, from Wagner-Nelson analysis, only 5.5% of the drug dissolved (and absorbed) in 5 min under fasted conditions. It was not until 2 hr that 49% of the RTV dose dissolved (and was absorbed) . , 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 dissolution did not mimic the dissolution of RTV.

CONCLUSION

Biopharmaceutic consideration of dissolution, pharmacokinetics, and deconvolution analysis indicated that dissolution was "too rapid" to adequately mimic dissolution. Findings suggest greater inspection of methods for poorly water-soluble drugs, especially those drugs where absorption is expected to be rate-limited by dissolution.