Population in vitro-in vivo correlation model linking gastrointestinal transit time, pH with the in vivo disposition kinetics of itraconazole


Sporanox and SUBA-itraconazole are oral capsule formulations of itraconazole with characteristically different pH-dissolution profiles. Oral administration of itraconazole is associated with marked inter-subject and intra‑subject pharmacokinetic variability due, in part, to variability in the drug’s absorption from the GI tract [1].


The objectives of this work were to : (1) Establish an in vitro-in vivo correlation (IVIVC) model for Sporanox and SUBA‑itraconazole through linking in vitro drug release kinetics at different pH to the in vivo disposition kinetics and prior literature information of regional GI pH and GI transit times. (2) Describe the influence of GI pH, GI transit times, and food solubilizing capacity on itraconazole pharmacokinetics. (3) Show the applicability of using the developed IVIVC model to make predictions for the impact of GI pH and transit times on itraconazole exposure in plasma for certain population subgroups.


IVIVC was developed based on fed/fasted pharmacokinetic data from randomized cross‑over trials, in vitro dissolution studies for Sporanox and SUBA-itraconazole formulations, and prior information about typical and between subject variability of GI pH and transit times. Data were analysed using the population modelling approach as implemented in NONMEM.


Dissolution kinetics were described using first order models. The in vivo pharmacokinetics of itraconazole was described with a 2-compartment model with 4-transit absorption compartments. Pharmacokinetic profiles for fasted itraconazole periods were described based on the in vitro dissolution model, in vivo disposition model, and the prior information on GI pH and transit times. The IVIVC model indicated that drug dissolution in the fed state required an additional pH-independent dissolution pathway. The IVIVC models were presented in a ‘Shiny’ application.


An IVIVC model was established and internally evaluated for the two itraconazole formulations. The IVIVC model provided more insight into the observed variability of itraconazole pharmacokinetics and indicated that GI pH and transit times influence in vivo dissolution and drug exposure.


[1] Abuhelwa AY, Foster DJ, Mudge S, Hayes D, Upton RN. Population pharmacokinetic modelling of itraconazole and hydroxyl-itraconazole for oral SUBA-itraconazole and Sporanox capsule formulations in healthy subjects in fed and fasted states. Antimicrob Agents Chemother. 2015.