Effect Of Bupropion On The Pharmacokinetics Of Digoxin In Cynomolgus Monkey

Backgroud:Comorbid depression is 2 to 3 times more common in heart failure(HF)patients than that in the general population.Unexpectedly,the prescription of main classes of antidepressant,the tricyclic antidepressants(TCAs)and selective serotonin reuptake inhibitors(SSRIs),is associated with increased risk of cardiovascular events or all-cause mortality in HF patients.Bupropion(BUP),a dopamine-norepinephrine reuptake inhibitor,is chemically unrelated to TCAs,SSRIs or other known antidepressant agents.It is generally prescribed to treat major depressive disorder and to aid smoking cessation or obesity management.DIG is recommended for the management of reduced ejection fraction and/or atrial fibrillation.DIG has a narrow therapeutic window with target serum concentration of 0.5-0.9 ng/m L and daily dose of 0.0625-0.25 mg.Elevated DIG plasma exposures caused by clinical significant DDI have been associated with adverse reactions such as digitalis toxicity.DIG is a substrate of P-glycoprotein(P-gp)in the gut,liver,and kidney.It is also a substrate for organic anion-transporting polypeptide(OATP)4C1 expressed in the kidney.Kirby BJ et al.observed a BUP-digoxin(DIG)drug-drug interaction(DDI),in which staggered dosing of BUP(150 mg,extended release tablet)and DIG(0.5 mg)increased DIG renal clearance(CLr)by 80 % and decreased its plasma AUC by 40 %.Our following study in rats found BUP significantly increased DIG CLr by 51 %,but it had no effect on the systemic disposition of DIG.It is quite unusual that a perpetrator,except for rifampin,could cause a decrease in plasma exposure of DIG.The opposite localization of Oatp4c1 suggests that rat is not an appropriate animal model to elucidate the mechanisms underlying DIG renal elimination.The data extrapolation from rat to human might be misleading.Furthermore,the staggered dosing of BUP and DIG in Kirby’s study made it unable to assess the exact site and the magnitude of the observed BUP-DIG DDI.To our knowledge,no complete study has reported the chronic effect of BUP on DIG disposition in vivo.Therefore,it is necessary to perform a DIG-BUP DDI study and evaluate related clinical risks.Objective:A pharmacokinetic study in cynomolgus monkeys(Macaca fascicularis)was conducted to assess the effect of BUP as a perpetrator of a BUP-DIG DDI before embarking on a clinical trial.The second aim of this study was to comprehensively evaluate the magnitude of this unusual DDI and to get an insight into its mechanism and potential clinical risk.Methods:1.Simultaneous determination of DIG,BUP and its three major metabolites in cynomolgus monkey plasma by UPLC-MS/MS2.Simultaneous determination of DIG,BUP and its three major metabolites in cynomolgus monkey urine by UPLC-MS/MS3.A three-period,randomized,and fixed sequence DIG-BUP DDI study was performed in cynomolgus monkeys.In control period,the monkeys were administered either an i.v.infusion of DIG(0.1 mg/kg)or an oral dose of DIG(0.2 mg/kg).In single-dosing period,the monkeys received an i.v.infusion of BUP at 1.5 mg/kg together with an infusion or oral dosing of DIG,respectively.During multiple-dosing period,BUP was orally administered q.d.at 7.72 mg/kg for 12 consecutive days.Then it was co-administered with an i.v.infusion or oral dosing of DIG,respectively.4.Plasma and urine creatinine concentration were measured by enzymatic method with creatininase coupled sarcosine oxidase in automatic analyzer.The determination of BUP,its metabolites and DIG were using UPLC-MS/MS.Phoenix? Win Nonlin? version 6.4 was used to calculate the pharmacokinetic parameters in cynomolgus monkeys by the non-compartmental method.Results:1.The plasma calibration range of BUP,HBUP,EBUP,TBUP and DIG was 0.2-1000 ng/m L,0.2-1000 ng/m L,0.2-50 ng/m L and 0.25-100 ng/m L,respectively.The calibration curve was linear(r≥0.9950)over the tested concentration range for each analyte in plasma.Precision and accuracy were within 10.69 %,recoveries were between 83.8 %-104.2 % and matrix effects were less than 13.1 %.2.The urine calibration range of BUP/HBUP,EBUP/TBUP and DIG was 0.2-1000 ng/m L,0.2-50 ng/m L and 0.25-100 ng/m L,respectively.The calibration curve was linear(r≥0.9940)over the tested concentration range for each analyte in urine.Precision and accuracy were within 11.58 %,recoveries were between 80.4 %-99.1 % and matrix effects were less than 10.9 %.3.BUP significantly increased i.v.DIG renal clearance(CLr 0-48h)by 1 fold in single-dosing period.But it did not have an effect on the systemic disposition of i.v.or oral DIG.In multiple-dosing period,BUP significantly increased oral DIG CLr 0-48 h,total clearance(CLtot 0-48h),non-renal clearance(CLnr 0-48h),and decreased its plasma exposure.The presence of BUP and its metabolites did not alter creatinine clearance of DIG and unbound fraction of DIG.Conclusions:1.A LC-MS/MS method for simultaneous determination of BUP,HBUP,EBUP,TBUP and DIG in cynomolgus monkey plasma and urine was developed.This established method is simple,sensitive,specific and accurate,and is successfully applied to the drug-drug interaction studies in cynomolgus monkeys.2.The effect of multiple dosing with BUP on the pharmacokinetics of DIG is found to be more pronounced compared with single dose.The lack of systemic exposure after a single dose but a significant decrease in exposure mediated by an increase in the DIG CLnr 0-48 h with repeated dosing is likely to be the more clinically relevant.3.The starting of antidepressant therapies by BUP may cause sub-therapeutic DIG concentration and result in clinical ineffective.And sudden withdrawal of the BUP in these patients may lead to an unexpected overexposure of DIG and increase associated cardiovascular risks.Individualized dosing regimen for DIG and antidepressant,especially BUP,are important strategies to improve clinical outcomes.