Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1

Markert, Christoph; Hellwig, Regina; Burhenne, Jürgen; Hoffmann, Michael M.; Weiß, Johanna; Mikus, Gerd; Haefeli, Walter E.

doi:10.1007/s00228-013-1529-1

Cited by 25 publications

(15 citation statements)

References 20 publications

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“…Before inclusion into the study, CYP2C19 alleles *2 , *3 , *4 and *17 were determined and participants were then stratified into three groups of homozygous wild‐type, poor and ultrarapid metabolizers: Extensive metabolizer group: CYP2C19*1/*1 (n = 10; wild‐type extensive metabolizer defined as absence of *2 , *3 , *4 and *17 alleles) Poor metabolizer group: CYP2C19*2/*2 (n = 4) Ultrarapid metabolizer group: CYP2C19*17/*17 (n = 6) …”

Section: Methodsmentioning

confidence: 99%

“…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 . Organic anion‐transporting polypeptides (OATP) partly mediate the hepatic uptake of ambrisentan, while efflux transporters do not appear to be involved in its kinetics .…”

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confidence: 99%

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

Markert

Kästner

Hellwig

et al. 2014

Basic Clin Pharma Tox

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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...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Markert

Kästner

Hellwig

et al. 2014

Basic Clin Pharma Tox

Self Cite

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“…This combinatorial approach will include factors such as genetics (including rare variants), underlying disease states, and polypharmacy (drug-drug interactions) (Markert et al, 2013; Ritchie, 2012). Dr. Scott Friedman in his highlight of our recent article suggested that the confluence of multiple factors could explain some of the less common “idiosyncratic” or type B ADRs (Figure 2) (Friedman, 2014).…”

Section: Moving Forward With Precision Medicinementioning

confidence: 99%

Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability

Clarke

Cherrington

2015

Pharmacology & Therapeutics

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There are numerous factors in individual variability that make the development and implementation of precision medicine a challenge in the clinic. One of the main goals of precision medicine is to identify the correct dose for each individual in order to maximize therapeutic effect and minimize the occurrence of adverse drug reactions. Many promising advances have been made in identifying and understanding how factors such as genetic polymorphisms can influence drug pharmacokinetics (PK) and contribute to variable drug response (VDR), but it is clear that there remain many unidentified variables. Underlying liver diseases such as nonalcoholic steatohepatitis (NASH) alter absorption, distribution, metabolism, and excretion (ADME) processes and must be considered in the implementation of precision medicine. There is still a profound need for clinical investigation into how NASH-associated changes in ADME mediators, such as metabolism enzymes and transporters, affect the pharmacokinetics of individual drugs known to rely on these pathways for elimination. This review summarizes the key PK factors in individual variability and VDR and highlights NASH as an essential underlying factor that must be considered as the development of precision medicine advances. A multifactorial approach to precision medicine that considers the combination of two or more risk factors (e.g. genetics and NASH) will be required in our effort to provide a new era of benefit for patients.

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“…The overall increase of only 33% in AUC with individual data within the ''No Effect Boundary'' indicated that no relevant clinical drug interactions were expected from subjects regardless of their CYP2D6 polymorphism, when BCQB is co-administered with paroxetine. Recent studies on drug interactions between paroxetine and aripiprazole and between clarithromycin and ambrisentan showed similar inhibition extent (30%), and found clinically minor and likely irrelevant (Azuma et al, 2012;Markert et al, 2013). Roxithromycin is known as anti-infective but also as immunomodulator, and widely used in the management and treatment of infective and/or inflammatory diseases, particularly in upper respiratory tract infections (Itkin and Menzel, 1970;Kadota et al, 1993;Plewig and Schopf, 1975).…”

Section: Discussionmentioning

confidence: 83%

Study of pharmacokinetic interaction of paroxetine and roxithromycin on bencycloquidium bromide in healthy subjects

Agbokponto

Luo

Liu

et al. 2015

European Journal of Pharmaceutical Sciences

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Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1

Abstract: Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.

Cited by 25 publications

References 20 publications

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

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

Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability

Study of pharmacokinetic interaction of paroxetine and roxithromycin on bencycloquidium bromide in healthy subjects

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