Desipramine Pharmacokinetics When Coadministered With Paroxetine or Sertraline in Extensive Metabolizers

Abstract

In vitro studies have shown that fluoxetine and paroxetine are more potent inhibitors of cytochrome CYP2D6 than sertraline. The pharmacokinetics of desipramine when coadministered with the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline were studied in 24 healthy male volunteers (CYP2D6 extensive metabolizers). Desipramine (50 mg/day) was administered for 23 days in each phase of the crossover study with a 7-day drug-free period between phases. In addition, subjects were randomly assigned to receive concomitant paroxetine (20 mg/day on days 8 through 17 followed by 30 mg/day on days 18 through 20) or sertraline (50 mg/day on days 8 through 17 and 100 mg/day on days 18 through 20). SSRI treatments were switched between phases. After 10 days of coadministration at the lower dose, mean desipramine maximum concentration in plasma (Cmax) relative to baseline increased from 37.8 to 173 ng/mL (+358%) with paroxetine versus from 36.1 to 51.9 ng/mL (+44%) with sertraline; the mean desipramine 24-hour area under the concentration-time curve (AUC[24]) increased from 634 to 3,305 ng x h/mL (+421%) with paroxetine versus from 611 to 838 ng x h/mL (+37%) with sertraline; and the mean desipramine trough value (C0) increased from 18.5 to 113 ng/mL (+511%) with paroxetine versus from 18.3 to 21.8 ng/mL (+19%) with sertraline (all increases, p < 0.001). An approximately 10-fold increase in the Cmax and AUC(24) of paroxetine and an approximately 2-fold increase in these parameters for sertraline occurred simultaneously with the desipramine concentration changes. Thus, when coadministered with 50 mg/day desipramine, sertraline had significantly less pharmacokinetic interaction than paroxetine with desipramine at the recommended starting dosages of 50 mg/day and 20 mg/day, respectively.

Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

“…Nonetheless usual doses and plasma levels of paroxetine can produce extensive inhibition of clearance of coadministered drugs that are substrates for CYP2D6 (Brøsen et al, 1993;Alderman et al, 1997;Ö zdemir et al, 1998;Alfaro et al, 1999). Approaches to predicting clinical pharmacokinetic drug interactions based on in vitro data continue to be controversial (Bertz and Granneman, 1997;Ito et al, 1998;von Moltke et al, 1998b;Venkatakrishnan et al, 2001).…”

“…We previously observed that the in vitro K i for paroxetine versus desipramine hydroxylation yielded an underestimate of the degree of desipramine clearance inhibition when desipramine was coadministered with paroxetine in a clinical study (von Moltke et al, 1995;Alderman et al, 1997). We accounted for this discrepancy on the basis of extensive partitioning of paroxetine from plasma into hepatic tissues such that intrahepatic concentrations substantially exceeded total plasma concentrations (von Moltke et al, 1995).…”

In Vitro-in Vivo Extrapolation of Cyp2d6 Inactivation by Paroxetine: Prediction of Nonstationary Pharmacokinetics and Drug Interaction Magnitude

“…2 for the interaction of paroxetine with desipramine (Alderman et al, 1997). For purposes of this exercise, the steady-state pharmacokinetic profile of desipramine (50 mg q.d.)…”

“…Examples of characterized clinical interactions with paroxetine include its effects on the kinetics of desipramine (Brøsen et al, 1993;Alderman et al, 1997), perphenazine (Ö zdemir et al, 1997), metoprolol (Hemeryck et al, 2000), risperidone (Spina et al, 2001), and atomoxetine (Belle et al, 2002), where the clearance of the victim drugs is impaired by 5-to 8-fold. In addition, paroxetine displays nonlinear accumulation kinetics with steady-state exposures exceeding projections from single-dose kinetics by ϳ5-fold in CYP2D6 extensive metabolizers but not in CYP2D6 poor metabolizers (Kaye et al, 1989;Sindrup et al, 1992).…”

Pharmacogenomics of Antidepressants

“…An approximately 10-fold increase in the C max and AUC 24 of paroxetine and an approximately 2-fold increase in these parameters for sertraline occurred simultaneously with the desipramine concentration changes. Thus, when co-administered with 50 mg/day desipramine, sertraline had significantly less pharmacokinetic interaction than paroxetine with desipramine at the recommended starting dosages of 50 mg/day and 20 mg/day, respectively, as initially reported by Alderman et al, [81].…”