The Effect of Induction of CYP3A4 by St John's Wort on Ambrisentan Plasma Pharmacokinetics in Volunteers of known CYP2C19 Genotype

Abstract

To evaluate the impact of CYP2C19 polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 CYP2C19 extensive, four poor and six ultrarapid metabolizers) received therapeutic doses of ambrisentan (5 mg qd po) for 20 days and concomitantly SJW (300 mg tid po) for the last 10 days. To quantify changes of CYP3A4 activity, midazolam (3 mg po) as a probe drug was used. Ambrisentan pharmacokinetics was assessed on days 1, 10 and 20, and midazolam pharmacokinetics before and on days 1, 10, 17 and 20. At steady state, ambrisentan exposure was similar in extensive and ultrarapid metabolizers but 43% larger in poor metabolizers (p < 0.01). In all volunteers, SJW reduced ambrisentan exposure and the relative change (17-26%) was similar in all genotype groups. The extent of this interaction did not correlate with the changes in CYP3A activity (midazolam clearance) (r s = 0.23, p = 0.34). Ambrisentan had no effect on midazolam pharmacokinetics. In conclusion, SJW significantly reduced exposure with ambrisentan irrespective of the CYP2C19 genotype. The extent of this interaction was small and thus likely without clinical relevance.Ambrisentan is an ET A -selective endothelin-1 receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), which is a devastating disease characterized by elevated pulmonary arterial pressure, right ventricular failure and ultimately death. Ambrisentan improved the quality of life and exercise capacity as determined by the 6-min. walking distance, decreased dyspnoea and delayed the time to clinical worsening in patients with PAH. Also haemodynamic (e.g. pulmonary vascular resistance) and hormonal (e.g. N-terminal-pro-hormone-brain natriuretic peptide) endpoints were improved [1,2].Common side effects of ERA include headache, hepatotoxicity, peripheral oedema and nasal congestion, which dose dependently increase in frequency; for example, doubling the dose doubled ambrisentan-associated nasal congestion [1]. Higher doses of ambrisentan also lead to more pronounced beneficial effects [1], suggesting that effects and side effects of ambrisentan are dose dependent, and substantial changes in exposure are likely of clinical relevance.Clearance of ambrisentan is mainly determined by the uridine diphosphate glucuronosyltransferase (UGT) isozymes UGT1A9, UGT2B7 and UGT1A3. A minor part of the drug (20%) undergoes phase I oxidative metabolism mainly by cytochrome P450 (CYP) 3A4 and to a lesser extent by the polymorphic CYPs 3A5 and 2C19 to form the pharmacologically inactive 4-hydroxymethyl ambrisentan [3]. Organic anion-transporting polypeptides (OATP) partly mediate the hepatic uptake of ambrisentan, while efflux transporters do not appear to be involved in its kinetics [4,5].More than 50% of PAH patients show depressive symptoms [6] with every fifth patient being in need of pharmacological therapy [7]. Self-medication of St John's wort (Hypericum perforatum, SJW) is often unrecognized [8] and may de...

Ambrisentan use in a HIV-1 infected patient with end-stage renal disease and pulmonary hypertension: minimal removal by hemodialysis - a case report

“…Moreover, ambrisentan does not have any significant effect on the activity of UGT or cytochrome P450 isozymes or drug transporters, limiting the possibility of drug-drug interactions. It is noteworthy that ambrisentan concentrations at the end of the dialysis session were in the same range as those described in healthy volunteers receiving regular doses [14,15], suggesting the absence of a need for dose adjustment in patients with ESRD.…”

Understanding drug interactions with St John's wort (Hypericum perforatumL.): impact of hyperforin content

“…Overall, this resulted in a total of 59 pharmacokinetic interaction studies (Table 1) [4, of which 12 were identified since 2010. [5,19,20,22,36,39,41] Each study investigated interactions with Hypericum products reported to have a highhyperforin content. These studies typically investigated St John's wort interactions in 12 (median; range 5-28) participants (usually healthy, but some patient groups) with a median duration of St John's wort administration of 14 days (range 10-56 days).…”

“…Search term ‘Hypericum’ resulted in 2500 references, of which 807 were published after 31 December 2009. Overall, this resulted in a total of 59 pharmacokinetic interaction studies (Table ) of which 12 were identified since 2010 . Each study investigated interactions with Hypericum products reported to have a high‐hyperforin content.…”

Pharmacokinetic Interactions between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance

“…In fact, some data show that a treatment period of 14-days with SJW [33,34] is needed to produce significant effect on CYP3A4 activity while a short-term one doesn't induce any effect [33,35]. Therefore, several controlled clinical studies have been issued proving that SJW significantly modifies the pharmacokinetics of drugs that are substrate of CYP3A, 2C9, 2C19, 2E1 or transported by P-gp or both, including midazolam [33], simvastatin [36], amitriptyline [37], chlorzoxazone [38,39], methadone [40], ethinyl estradiol/norethindrone combination oral contraceptives [41,42], fexofenadine [43], warfarin [44], imatinib [45], omeprazole [46], mephenitoin [47], tacrolimus [48], verapamil [49], voriconazole [50], talinolol [51], gliclazide [52], nifedipine [53], ketamine [54], zolpidem [55], bosentan [56], ambrisentan [57] and docetaxel [58] (Table 1). Intriguingly, SJW interaction was expanded to multidrug resistance ATP-binding cassette (ABC) proteins and solute carrier (SLC) transporters as reported initially in a case report [59].…”