Prediction of combination effect of quinidine on the pharmacokinetics of tipepidine using a physiologically based pharmacokinetic model

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 Cmax, AUC, and t1/2 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 CYP2D6 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 Cmax, AUC, and t1/2 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 CYP2D6 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.</p

Plasma ALT, AST or T-Bil levels and histopathological changes of liver in rat models of hepatocellular injury induced by the administration of APAP (n = 6–8) or MP (n = 6) (A); cholestasis induced by the administration of ANIT, or BDL (n = 5) (B); steatosis or steatohepatitis induced by feeding of HFD (n = 5) or MCDD (n = 5) (C); and fibrosis induced by the administration of CCl4 (n = 6) (D).

<p>Data are mean ± SD. Significantly different from control group (*<i>P</i><0.05 and **<i>P</i><0.01). Liver sections were stained with HE for all models (original magnification×200) and Oil red O for the chronic liver injury models (original magnification×400). CV: Central vein; P: Portal region; BD: Bile duct.</p

Number of miRNAs whose expressions were detected and changed with liver injury in rat plasma.

<p>The total number of miRNAs on the array system is 585.</p><p>APAP: acetaminophen; MP: methapyrilene; ANIT: α-naphthyl isothiocyanate; BDL: bile duct ligation; StdD: standard diet; HFD: high fat diet; MCDD: methionine choline-deficient diet.</p

Association of plasma miR-122 level with hepatocellular injury.

<p>The extent of hepatocellular necrosis and inflammation was scored + (closed circle), ++ (closed triangle), and +++ (closed square) by histopathological examination, and was compared with the plasma ALT (A) and miR-122 (B) levels in rats administered 1000 mg/kg (high dose) or 500 mg/kg (low dose) of APAP with fasting, low dose of APAP without fasting, and CMC (as a control).</p

Time-dependent changes of plasma ALT and miR-122 levels in individual rat orally administered 1000 mg/kg of APAP (n = 6) with fasting (A) or 300 mg/kg MP (n = 5) (B).

<p>Graphs with magnified abscissa are also shown. The miR-122 levels represent relative value to control.</p

The miRNAs whose expressions were changed only in the given model of liver injury.

<p>The miRNAs whose expressions were changed only in the given model of liver injury.</p

The miRNAs whose expressions were changed in hepatocellular injury, cholestasis and steatosis.

<p>The miRNAs whose expressions were changed in hepatocellular injury, cholestasis and steatosis.</p

Stability of miR-16, miR-122 or miR-21 in rat (A) or human (B) plasma.

<p>Plasma samples from 2 non-treated male rats or 9 male healthy subjects were pooled and incubated at 4°C, room temperature (RT) or 37°C. Data represent copy numbers per one µL of plasma. Data are mean ± SD of triplicate determination (n = 3).</p

Up- or down-regulated miRNAs in hepatocellular injury models (A), cholestasis models (B), and chronic liver injury models (C).

<p>Venn diagram shows the number of changed miRNAs. The numbers in the parenthesis are the numbers of miRNAs whose expressions were specifically changed only in the given models. Heat map of 67 miRNAs in all models, which were commonly up-regulated with necrosis and inflammation (D).</p

Hierarchical clustering of plasma miRNA expression profiles in rats with liver injury (A) and the fold changes between the injury model and control (B).

<p>The levels were clustered by using Cluster 3.0 software (complete linkage) and visualized by using MapleTree software. Data are presented as 40-Ct (A) and log₂ (B) value.</p