mp9b00350_si_001.pdf (1.07 MB)
Justification of Biowaiver and Dissolution Rate Specifications for Piroxicam Immediate Release Products Based on Physiologically Based Pharmacokinetic Modeling: An In-Depth Analysis
journal contribution
posted on 2019-08-22, 16:37 authored by Xiaoting Li, Yuanhang Yang, Yu Zhang, Chunnuan Wu, Qikun Jiang, Weiping Wang, Huixin Li, Jing Li, Cong Luo, Wenying Wu, Yingli Wang, Tianhong ZhangA quantitative
prediction of human pharmacokinetic (PK) profiles
has become an increasing demand for the reduction of the clinical
failure of drug formulations. The existing in vitro and in vivo correlation
(IVIVC) methodology could achieve this goal, but the development of
IVIVC for immediate release (IR) products is challenging. Herein,
we report that for certain weakly acidic biopharmaceutical classification
system (BCS) class II molecules (piroxicam, PIRO), physiologically
based PK (PBPK) modeling could be used as a tool to quantitatively
predict PK in beagle dogs and to conduct an interspecies extrapolation
to humans. First, robust PBPK models were constructed in beagle dogs
under both fasted and fed states. Then, a Z-factor
model was integrated to assess the effect of in vitro dissolution
rates on the in vivo PK performance, and the results illustrated that
PIRO IR products had a much wider dissolution space than was anticipated
by bioequivalence. In addition, the parameter sensitivity analysis
(PSA) assay showed that good oral absorption was achieved only when
the particle size was below 150 μm. Finally, the combined PBPK
models were extrapolated to humans to specify a quality control strategy;
this extrapolation constituted an extension of a biowaiver for PIRO
IR formulations. The results showed that the developed method can
be utilized to quantitatively predict human PK, which would be meaningful
for future scale-up or postapproval changes.