Flucloxacillin Is a Weak Inducer of CYP3A4 in Healthy Adults and 3D Spheroid of Primary Human Hepatocytes

Iversen, Ditte B.; Dunvald, Ann‐Cathrine Dalgård; Jespersen, Daniel M.; Nielsen, Flemming; Brøsen, Kim; Damkier, Per; Hammer, Helen S.; Pötz, Oliver; Järvinen, Erkka; Stage, Tore B.

doi:10.1002/cpt.2959

Cited by 5 publications

(1 citation statement)

References 39 publications

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“…Most knowledge of interactions with other treatments has been obtained from clinical cases, as there are few prospective studies examining potential interactions. The most often described potential interactions are induction of the CYP3A4 enzyme by flucloxacillin (weak inducer) and/or nafcillin (moderate inducer), effect on intestinal flora, effect on renal clearance (i.e., if the co-administered drug has a higher affinity for the renal transporter, a decrease in tubular excretion of the antibiotic will be seen) and possible decreased plasma protein binding of the drug [ 6 , 7 , 19 ].…”

Section: Beta-lactam Antibioticsmentioning

confidence: 99%

Clinically important pharmacokinetic drug-drug interactions with antibacterial agents

Torrent Rodríguez,

Font i Barceló,

Barrantes González

et al. 2024

Rev Esp Quimioter

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Antimicrobial agents are widely used, and drug interactions are challenging due to increased risk of adverse effects or reduced efficacy. Among the interactions, the most important are those affecting metabolism, although those involving drug transporters are becoming increasingly known. To make clinical decisions, it is key to know the intensity of the interaction, as well as its duration and time-dependent recovery after discontinuation of the causative agents. It is not only important to be aware of all patient treatments, but also of supplements and natural medications that may also interact. Although they can have serious consequences, most interactions can be adequately managed with a good understanding of them. Especially in patients with polipharmacy it is compulsory to check them with an electronic clinical decision support database. This article aims to conduct a narrative review focusing on the major clinically significant pharmacokinetic drug-drug interactions that can be seen in patients receiving treatment for bacterial infections.

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Section: Beta-lactam Antibioticsmentioning

confidence: 99%

Clinically important pharmacokinetic drug-drug interactions with antibacterial agents

Torrent Rodríguez,

Font i Barceló,

Barrantes González

et al. 2024

Rev Esp Quimioter

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Whole Body Physiologically Based Pharmacokinetic Model to Explain A Patient With Drug–Drug Interaction Between Voriconazole and Flucloxacillin

Abdullah-Koolmees,

van den Nieuwendijk,

Hoope

et al. 2024

Eur J Drug Metab Pharmacokinet

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Background and Objectives Voriconazole administered concomitantly with flucloxacillin may result in subtherapeutic plasma concentrations as shown in a patient with Staphylococcus aureus sepsis and a probable pulmonary aspergillosis. After switching our patient to posaconazole, therapeutic concentrations were reached. The aim of this study was to first test our hypothesis that flucloxacillin competes with voriconazole not posaconazole for binding to albumin ex vivo, leading to lower total concentrations in plasma. Methods A physiologically based pharmacokinetic (PBPK) model was then applied to predict the mechanism of action of the drug–drug interaction (DDI). The model included non-linear hepatic metabolism and the effect of a severe infectious disease on cytochrome P450 (CYP) enzymes activity. Results The unbound voriconazole concentration remained unchanged in plasma after adding flucloxacillin, thereby rejecting our hypothesis of albumin-binding site competition. The PBPK model was able to adequately predict the plasma concentration of both voriconazole and posaconazole over time in healthy volunteers. Upregulation of CYP3A4, CYP2C9, and CYP2C19 through the pregnane X receptor (PXR) gene by flucloxacillin resulted in decreased voriconazole plasma concentrations, reflecting the DDI observations in our patient. Posaconazole metabolism was not affected, or was only limitedly affected, by the changes through the PXR gene, which agrees with the observed plasma concentrations within the target range in our patient. Conclusions Ex vivo experiments reported that the unbound voriconazole plasma concentration remained unchanged after adding flucloxacillin. The PBPK model describes the potential mechanism driving the drug–drug and drug–disease interaction of voriconazole and flucloxacillin, highlighting the large substantial influence of flucloxacillin on the PXR gene and the influence of infection on voriconazole plasma concentrations, and suggests a more limited effect on other triazoles. Supplementary Information The online version contains supplementary material available at 10.1007/s13318-024-00916-1.

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Clinical pharmacology considerations and drug–drug interactions with long‐acting cabotegravir and rilpivirine relevant to sub‐Saharan Africa

Steulet,

Obura,

Waitt

et al. 2024

Brit J Clinical Pharma

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Long‐acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre‐exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake ‘traditional’ pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug–drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant co‐medications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed (https://www.hiv-druginteractions.org/checker). LAI cabotegravir and rilpivirine have half‐lives of 6–12 and 13–28 weeks, respectively. Cabotegravir is primarily metabolized by UDP‐glucuronyltransferase (UGT)‐1A1 and rilpivirine by cytochrome P450 (CYP)‐3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with co‐medications as they do not induce or inhibit the major drug metabolizing enzymes. However, they are victims of DDIs relating to the induction of their metabolizing enzymes by concomitantly administered medication. Noteworthy contraindicated co‐medications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimize risk.

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Flucloxacillin Is a Weak Inducer of CYP3A4 in Healthy Adults and 3D Spheroid of Primary Human Hepatocytes

Cited by 5 publications

References 39 publications

Clinically important pharmacokinetic drug-drug interactions with antibacterial agents

Clinically important pharmacokinetic drug-drug interactions with antibacterial agents

Whole Body Physiologically Based Pharmacokinetic Model to Explain A Patient With Drug–Drug Interaction Between Voriconazole and Flucloxacillin

Clinical pharmacology considerations and drug–drug interactions with long‐acting cabotegravir and rilpivirine relevant to sub‐Saharan Africa

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