NDA 21-515

WELLBUTRIN XL

 

(adverse event drug interactions with bupropion and an inhibitor/substrate such as paroxetine, sertraline, fluvoxamine, norfluoxetine, efavirenz, ritonavir, and nelfinavir.

 

·         Will the in vitro studies predict a clinically significant drug interaction?

 

The Sponsor suggests that clinically significant interactions are unlikely.  Their rationale is that 1) bupropion is metabolized by multiple pathways so that other pathways can compensate, 2) multiple P450 isozymes catalyze the hydroxylation of bupropion to hydroxybupropion, and 3) low unbound plasma concentrations of these highly protein bound substrates/inhibitors relative to the in vitro IC₅₀ make a clinically significant interaction unlikely.

 

Although bupropion is metabolized by multiple pathways to multiple metabolites so that other metabolites may be formed if formation of hydroxybupropion is blocked, the contributions to efficacy and safety of the various other metabolites, at concentrations which cannot be predicted at this point, is unknown.  In addition the actual role of other P450s in catalyzing the hydroxylation of bupropion if CYP2B6 were blocked is unknown.  (Greenblatt et al² evaluated the hydroxylation in human liver microsomes, and reported that hydroxylation is mediated almost exclusively by CYP2B6).   Finally, the literature is unclear as to how to extrapolate data from in vitro binding studies with drugs that are highly protein bound.  For example, paroxetine has a free fraction of 0.05, has an IC50 of approximately 2.54 µM for inhibiting CYP2D6 in human liver microsomes in vitro (determined under similar experimental conditions as reported by Greenblatt et al to evaluate paroxetine’s effect on bupropion hydroxylation in which the IC50 was reported to be approximately 1.6 µM).³  Paroxetine, although it is highly protein bound, resulted in more than a 3-fold increase in Cmax, AUC, and t/12 of atomoxetine, a CYP2S6 substrate when paroxetine was given at a dose of 20 mg daily, achieving paroxetine Cmax concentrations of approximately 39.5 ng/ml.⁴  Thus, the effect of protein binding on P450 inhibition in humans is difficult to predict.

 

Finally the Sponsor cites, as evidence for the importance of other metabolic pathways, an abstract by Brockmoller et al in which known variants of CYP2B6 did not appear to result in outliers in terms of bupropion pharmacokinetics.⁵  The authors concluded that there is no evidence of “bupropion poor metabolizer phenotypes or genotypes”.  In addition, the study apparently evaluate only bupropion pharmacokinetics, and did not include metabolites.  Thus the results of this citation cannot be used to conclude that CYP2B6 interactions are unlikely to be clinically significant.

 

The following table, provided by the Reviewer, uses total, rather than unbound, plasma concentrations (provided by Sponsor) relative to IC₅₀ values for inhibition of bupropion hydroxylation as reported in the literature^1,2.

 

 

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