Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA‐14, a new dopamine D₃ receptor antagonist candidate for treatment of drug addiction

Abstract

YQA-14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA-14, then to simulate the clinical PK of YQA-14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA-14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA-14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA-14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA-14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic.

A selective D3 receptor antagonist YQA14 attenuates methamphetamine-induced behavioral sensitization and conditioned place preference in mice

“…All animals were then returned to their home cages without METH or saline treatment for a 7-d withdrawal period (d [14][15][16][17][18][19][20]. Finally, all of the mice were challenged with METH (0.5 mg/kg, ip) on d 21.…”

“…YQA14 displays more than 150-fold selectivity for D 3 Rs over D 2 Rs and more than 1000-fold selectivity for D 3 Rs over other DA receptors [12] . Moreover, pharmacokinetic assays demonstrate that YQA14 has improved oral bioavailability (~20%) in vivo in dogs and a longer half-life (>1.5 h in human liver microsome enzymes) compared with SB-277011A (~20 min) in vitro [20] . YQA14 appears to have no rewarding or addictive potential because it does not sustain self-administration in rats that previously self-administered cocaine [21] or induce conditioned place preference (CPP) or conditioned place aversion (CPA) [22] .…”

P-Glycoprotein (ABCB1) Limits the Brain Distribution of YQA-14, a Novel Dopamine D₃ Receptor Antagonist

“…25,28) In addition, the extremely high plasma protein binding of YQA-14 (99%) also contributes to its poor brain distribution. 14) Animal models are used to evaluate anti-drug abuse effects in ethology, such as self-administration, drug seeking behavior and behavior sensitization, yet these models are generally complicated and not easy to measure. Therefore, we did not investigate the influence of co-administration with inhibitors on the effective dose in vivo of YQA-14.…”

“…YQA-14 was dissolved in normal saline containing 25% 2-hydroxylpropyl-β-cyclodextrin (HP-β-CD) then injected intraperitoneally into mice at the dose of 25 mg/kg. 2,14) Blood Caco-2 cell monolayers were incubated at 37°C or 4°C in 1.2 mL HBSS (pH 7.4) with 100 μM YQA-14 added to the AP or BL side for 90 min (n=3). **Significant difference (p<0.05) compared to those at 37°C.…”

PBPK modeling and simulation in drug research and development

“…Earlier compounds in its structural class tend to have poor oral bioavailability in humans due to the pronounced metabolism from aldehyde oxidase (AO). The aim of this study was to simulate the clinical pharmacokinetic behavior of YQA-14 using a PBPK model to assess the likelihood of developing YQA-14 as a clinical candidate 12 . YQA-14 is a lipophilic and basic compound with three p K a values (6.91, 9.30, and 10.91) and a log D 7.4 value of 2.15.…”