There is limited information on how to perform in vitro release tests for intravenously 27 administered parenteral formulations and how to relate the in vitro release with an in vivo 28 pharmacokinetic parameter after the administration of the formulation. In this study, the effect 29 of hydrodynamics (using sample and separate and continuous flow conditions) and medium 30 components (synthetic surfactants, albumin and buffers) on the release of Amphotericin B from the liposomal Ambisome® 31 formulation were investigated. Pharmacokinetic modeling of plasma concentration profiles from healthy subjects administered Ambisome® 32 was used to 33 estimate the in vivo release rate constant of drug from the formulation in order to compare it 34 with the in vitro release profiles. With the estimated in vivo and in vitro release rate constants, 35 release profiles were generated. Two approaches were followed: comparison of in vivo and in 36 vitro release rate constants and comparison of the area under the percent release-time curve 37 from observed in vitro release data and simulated in vivo release data. Albumin was found to 38 be most critical factor for the release of the drug by having a negative effect on the amount of 39 Amphotericin B released. The release profiles obtained with the sample and separate method 40 in both Krebs Ringer buffer- and Phosphate Saline buffer - albumin 4.0% w/v were predictive 41 of the in vivo release profiles in healthy subjects. Determining the factors affecting drug release 42 from parenteral formulations and relating the release profiles to a pharmacokinetic parameter 43 in vivo supports the development of in vitro in vivo relations for parenteral products.
|Journal||European Journal of Pharmaceutics and Biopharmaceutics|
|Early online date||25 Jul 2020|
|Publication status||Early online date - 25 Jul 2020|
- Amphotericin B
- in vitro