Prediction of combination effect of quinidine on the pharmacokinetics of tipepidine using a physiologically based pharmacokinetic model
Creators: name: Hayashi, Shun
name: Kawaguchi, Hiroko
name: Watanabe, Takao
name: Miyawaki, Izuru
name: Fukami, Tatsuki
name: Nakajima, Miki
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Physiology
subject: Pharmacology
subject: Biotechnology
subject: Biological Sciences not elsewhere classified
subject: Information Systems not elsewhere classified
subject: Cancer

description: Tipepidine, an antitussive drug, has been reported to have central pharmacological effects and can be expected to be safely repositioned as treatment for psychiatric disorders. Since tipepidine requires three doses per day, development of a once-daily medication would be highly beneficial. Previously, we reported that combination use with quinidine, a CYP2D6 inhibitor, prolongs the half-life of tipepidine in chimeric mice with humanised liver.In this study, to predict this combination effect in humans, a physiologically based pharmacokinetic (PBPK) model was developed, and quantitative simulation was conducted. The simulation results indicated that concomitant administration of tipepidine with quinidine increased the predicted <i>C</i><sub>max</sub>, <i>AUC</i>, and <i>t</i><sub>1/2</sub> of tipepidine in the Japanese population by 3.4-, 6.6-, and 2.4-fold, respectively.Furthermore, to compare with another approach that aims to prolong the half-life, the PK profile of tipepidine administered in hypothetical extended-release form was simulated. Extended-release form was predicted to be more influenced by <i>CYP2D6</i> genotype than combination with quinidine, and the predicted plasma exposure was markedly increased in poor metabolizers, potentially leading to adverse effects.In conclusion, quantitative simulation using the PBPK model suggests the feasibility of the safe repositioning of tipepidine as a once-daily medication in combination with quinidine. Tipepidine, an antitussive drug, has been reported to have central pharmacological effects and can be expected to be safely repositioned as treatment for psychiatric disorders. Since tipepidine requires three doses per day, development of a once-daily medication would be highly beneficial. Previously, we reported that combination use with quinidine, a CYP2D6 inhibitor, prolongs the half-life of tipepidine in chimeric mice with humanised liver. In this study, to predict this combination effect in humans, a physiologically based pharmacokinetic (PBPK) model was developed, and quantitative simulation was conducted. The simulation results indicated that concomitant administration of tipepidine with quinidine increased the predicted <i>C</i><sub>max</sub>, <i>AUC</i>, and <i>t</i><sub>1/2</sub> of tipepidine in the Japanese population by 3.4-, 6.6-, and 2.4-fold, respectively. Furthermore, to compare with another approach that aims to prolong the half-life, the PK profile of tipepidine administered in hypothetical extended-release form was simulated. Extended-release form was predicted to be more influenced by <i>CYP2D6</i> genotype than combination with quinidine, and the predicted plasma exposure was markedly increased in poor metabolizers, potentially leading to adverse effects. In conclusion, quantitative simulation using the PBPK model suggests the feasibility of the safe repositioning of tipepidine as a once-daily medication in combination with quinidine.