Cilostazol and midazolam absorption and pharmacokinetics were simulated using GastroPlus™ 6.0 (Simulations Plus, Inc.). The program’s Advanced Compartmental and Transit model described the absorption and intestinal metabolism of both drugs; pharmacokinetics was simulated with a physiologically-based pharmacokinetics (PBPK) model. Human organ weights, volumes, and blood perfusion rates were generated by the program’s internal Population Estimates for Age-Related (PEAR) Physiology™. Tissue/plasma partition coefficients were calculated using a modified Rodgers approach. The metabolism of both drugs in gut and liver was estimated from published in vitro enzyme kinetic constants combined with built-in in vitro values for 3A4 distribution in the gut and the average enzyme expressions in liver. The resultant models accurately reproduced in vivo plasma concentration-time profiles in human for solid oral doses in ranges 7.5-30mg and 25-300mg for midazolam and cilostazol, respectively. Both compounds show nonlinear dose-dependent bioavailability. Mechanistic simulations allowed estimating the contributions of limited dissolution (cilostazol) and first pass extraction (FPE) in gut and liver to low bioavailability. While gut FPE was dose-dependent, the liver FPE was nearly constant for both compounds. The main contributor to limited cilostazol bioavailability at higher doses was insufficient solubility.
2nd Pharmaceutical Sciences Fair and Exhibition, June 8-12, 2009, Nice, France
By Viera Lukacova, Michael B. Bolger, and Walter S. Woltosz