Tissue distribution and elimination of C-14 apixaban in rats

Abbreviations used: AUC, area under the plasma concentration-time curve; BCRP, breast cancer resistance protein; BLQ, below limit of quantitation; LSC, liquid scintillation counting; LC/MS, liquid chromatography/mass spectrometry; MS/MS, tandem mass spectrometry; Mrp, multidrug resistance protein; LLOQ, low limit of quantitation; P-gp, Pglycoprotein; PK, pharmacokinetics; QWBA, Whole-body autoradiography; SD, SpragueDawley rats. ABSTRACT Apixaban, a potent and highly selective factor Xa inhibitor, is currently under development for treatment of arterial and venous thrombotic diseases. The distribution, metabolism, and elimination of C-14 apixaban were investigated in male, female, pregnant and lactating rats following single oral doses. Tissue distribution of radioactivity in rats was measured using quantitative whole-body autoradiography. Following single oral administration, radioactivity distributed quickly in rats with C max at 1 h for most tissues. The elimination t 1/2 of radioactivity in blood was 1.7 to 4.2 h. The blood AUC of radioactivity was similar between male and female rats and was slightly higher in pregnant and lower in lactating rats. The radioactivity concentration in tissues involved in elimination was greater than blood with the highest concentration in gastrointestinal tracts, liver, urinary bladder/contents, and lowest level in brains. In pregnant rats, the whole-body autoradiogram showed that low levels of radioactivity were present in fetal blood, liver, and kidney, and were much lower than the radioactivity in respective maternal organs. Fecal route was the major (74% of dose) and urinary was minor pathway (14%) for apixaban elimination. Following single oral doses of C-14 apixaban to lactating rats, apixaban exhibited extensive lacteal excretion with apixaban as the major component. In summary, tissue distribution of apixaban in rats was extensive, but with limited transfer to fetal and brain tissues and extensive secretion into rat milk with parent drug as the major component. Milk excretion could account for 10% of apixaban dose, which was comparable to urinary elimination in rats. Tissue distribution and drug excretion of apixaban are consistent with a moderately permeable drug that is a substrate for P-gp and BCRP efflux transporters

Assessment of Drug Metabolism Enzyme and Transporter Pharmacogenetics in Drug Discovery and Early Development: Perspectives of the I-PWG

Genetic variants of drug metabolism enzymes and transporters can result in high pharmacokinetic and pharmacodynamics variability, unwanted characteristics of efficacious and safe drugs. Ideally, the contributions of these enzymes and transporters to drug disposition can be predicted from in vitro experiments and in silico modeling in discovery or early development, and then be utilized during clinical development. Recently, regulatory agencies have provided guidance on the preclinical investigation of pharmacogenetics, for application to clinical drug development. This white paper summarizes the results of an industry survey on current practice and challenges with using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition