TY - JOUR
T1 - Population In Vitro-In Vivo Correlation Model Linking Gastrointestinal Transit Time, pH, and Pharmacokinetics
T2 - Itraconazole as a Model Drug
AU - Abuhelwa, Ahmad Y.
AU - Mudge, Stuart
AU - Hayes, David
AU - Upton, Richard N.
AU - Foster, David J.R.
PY - 2016/7
Y1 - 2016/7
N2 - Purpose: To establish an in vitro-in vivo correlation (IVIVC) model for Sporanox and SUBA-itraconazole formulations and to understand the impact of gastrointestinal (GI) pH and transit times on itraconazole dissolution and absorption. Methods: IVIVC was developed based on fed/fasted pharmacokinetic data from randomized cross-over trials, in vitro dissolution studies, 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. Results: 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. Conclusion: An IVIVC model was established and internally evaluated for the two itraconazole formulations. The IVIVC model provides more insight into the observed variability of itraconazole pharmacokinetics and indicated that GI pH and transit times influence in vivo dissolution and exposure.
AB - Purpose: To establish an in vitro-in vivo correlation (IVIVC) model for Sporanox and SUBA-itraconazole formulations and to understand the impact of gastrointestinal (GI) pH and transit times on itraconazole dissolution and absorption. Methods: IVIVC was developed based on fed/fasted pharmacokinetic data from randomized cross-over trials, in vitro dissolution studies, 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. Results: 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. Conclusion: An IVIVC model was established and internally evaluated for the two itraconazole formulations. The IVIVC model provides more insight into the observed variability of itraconazole pharmacokinetics and indicated that GI pH and transit times influence in vivo dissolution and exposure.
KW - in vitro- in vivo correlation
KW - itraconazole
KW - NONMEM
KW - population pharmacokinetic
UR - http://www.scopus.com/inward/record.url?scp=84964494525&partnerID=8YFLogxK
U2 - 10.1007/s11095-016-1917-1
DO - 10.1007/s11095-016-1917-1
M3 - Article
C2 - 27119846
AN - SCOPUS:84964494525
VL - 33
SP - 1782
EP - 1794
JO - PHARMACEUTICAL RESEARCH
JF - PHARMACEUTICAL RESEARCH
SN - 0724-8741
IS - 7
ER -