Drug interaction between St John's wort and nevirapine

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Cases have been reported that suggest that extracts from St John's wort (Hypericum perforatum), mainly used as an antidepressant [1], contain potent inducers of hepatic enzymes, raising the possibility of clinically relevant drug interactions.
Recent pharmacokinetic data show substantially decreased exposure to the antiretroviral drug indinavir by the concomitant use of St John's wort, probably because of the induction of the 3A4 isoform of the cytochrome P450 system. St John's wort reduced the area under the plasma concentration versus time curve of indinavir by 57% (SD 19%), and decreased the extrapolated 8 h trough concentration by 81% (SD 16%) in eight healthy volunteers [2]. This interaction has been recognized as being clinically relevant. An interaction study [3] with digoxin suggested induction of the expression of the drug-transporter P-glycoprotein. Compared with placebo, the co-administration of Hypericum extracts significantly decreased digoxin concentrations, an effect that increased with the number of days on Hypericum extracts [3]. In addition to such studies, several case reports [4] have shown decreased plasma concentrations or decreased activity of cyclosporin, oral contraceptives, theophylline and warfarin with the concomitant use of St John's wort.
As all of the currently marketed protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTI) are substrates for the multidrug transporter P-glycoprotein and/or are extensively metabolized via the cytochrome P450 enzyme system, the concomitant use of St John's wort may result in decreased exposure to these classes of antiretroviral drugs, with clinical consequences.
We present five patients (all men, aged 34–53 years) infected with HIV-1, who had been treated with the NNRTI nevirapine and two nucleoside analogue reverse transcriptase inhibitors for over a year, and who concomitantly used St John's wort for several months. At our clinic, nevirapine plasma concentrations from each patient are routinely measured every 3 months. The five patients had at least one nevirapine plasma concentration with and at least one without St John's wort as co-medication. We noticed that the nevirapine plasma concentrations of these patients were consistently lower on some occasions. To determine whether these lower exposures were caused by the use of St John's wort, a non-linear mixed-effect modelling analysis (NONMEM) was performed [5]. A database consisting of 1330 nevirapine plasma concentrations of 176 patients, collected during 789 visits, was available for this analysis. The pharmacokinetics of nevirapine were described with a one-compartment model with first-order absorption and elimination (Table 1). The median oral clearance was 3.2 l/h, which is in accordance with an earlier reported value [6]. Interindividual and interoccasion (intervisit) variability were 29 and 22%, respectively. With the concomitant use of St John's wort included as a co-variate for oral clearance in the population pharmacokinetic model, the oral clearance of nevirapine was significantly increased with 35% (SE 15%) (P = 0.02) for patients using St John's wort, thus leading to a decreased exposure. None of the five patients in our population used any co-medication that could have resulted in an increased oral clearance. As nevirapine is extensively metabolized via the CYP450 system, the concomitant use of St John's wort can therefore explain the increase in oral clearance.
In conclusion, we have shown that St John's wort decreases the exposure to the NNRTI nevirapine by increasing its oral clearance. Because a low exposure to nevirapine may eventually result in antiretroviral resistance and treatment failure [7], the concomitant use of nevirapine and St John's wort should be avoided.
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