Abstract:Numerous drug‐drug interaction (DDI) trials have to be conducted in healthy volunteers based on current regulatory guidelines. Because the worst‐case scenario of strong cytochrome P450 (CYP) inhibitors has to be tested, the results and their validity have to be balanced with the risk to volunteer safety. The use of ketoconazole in clinical DDI studies has been discouraged by regulatory agencies due to an alleged risk of liver injury. In order to reduce the risk to healthy volunteers, we carried out a study wit… Show more
“…The CL/ F values of the FXaIs during treatment with different azoles (expressed as a percentage of baseline CL/ F ) are shown in Fig. 4 , together with the concurrently observed midazolam clearances as previously reported [ 32 ]. Fig.…”
Section: Resultssupporting
confidence: 60%
“…None of the participants was a CYP2C19 poor metaboliser. All safety data have already been comprehensively reported [ 32 ], with voriconazole causing the highest number of adverse events.…”
Section: Resultsmentioning
confidence: 99%
“…Interestingly, the effect of posaconazole and itraconazole as CYP3A and P-gp/BCRP inhibitors was less pronounced, which, in the case of itraconazole, may be due to the fact that it appears to not inhibit CYP2J2 [ 48 ], and also because the inhibitors were not administered to steady-state. For posaconazole, this could have resulted from the methodological limitations of the study, which were also reflected in the lower CYP3A inhibition [ 32 ].…”
Section: Discussionmentioning
confidence: 99%
“…To determine the effect of the azoles on CYP3A activity, the previously established limited sampling method for midazolam was applied to determine midazolam partial metabolic clearance (CL met ) by using midazolam concentrations at 2, 2.5, 3, and 4 h after dosing [ 29 – 31 ]. These data have been previously published [ 32 ].…”
Background Factor Xa inhibitors (FXaIs) are increasingly used without having sufficient drug-drug interaction data. Using a microdosed cocktail methodology could support filling the knowledge gap quickly. Methods In a randomised crossover trial, we investigated the drug-drug interactions between six oral azole antifungals and a microdosed FXaI cocktail containing 25 µg rivaroxaban, 25 µg apixaban, and 50 µg edoxaban. Additionally, different enzyme activities were also monitored using a microdosed cocktail approach. The six different azole antifungals were administered in therapeutic doses over a 24 h period, while the microdosed cocktails were administered 1 h after administration of the azole antifungals. Results Ketoconazole and posaconazole were the strongest perpetrators, showing similar increases as apixaban (area under the concentration-time curve ratio [AUCR] 1.64 and 1.62, respectively) and edoxaban (AUCR 2.08 and 2.1, respectively), whereas ketoconazole increased rivaroxaban 2.32-fold but only increased posaconazole 1.37-fold. All other azole antifungals showed less perpetrator effects on the FXaIs. Cytochrome P450 (CYP) 3A inhibition was confirmed using microdosed midazolam, with ketoconazole also the most potent perpetrator (8.42-fold). Conclusion Drug-drug interactions for three victim drugs of the same drug class (FXaIs) with different clearance mechanisms can be studied using a microdosed cocktail approach. Using members of the azole antifungal drug class as perpetrators, multiple interactions can be studied in one trial, and a more detailed insight into the underlying interaction mechanisms is possible. Clinical Trial Registration EudraCT number: 2017-004453-16.
“…The CL/ F values of the FXaIs during treatment with different azoles (expressed as a percentage of baseline CL/ F ) are shown in Fig. 4 , together with the concurrently observed midazolam clearances as previously reported [ 32 ]. Fig.…”
Section: Resultssupporting
confidence: 60%
“…None of the participants was a CYP2C19 poor metaboliser. All safety data have already been comprehensively reported [ 32 ], with voriconazole causing the highest number of adverse events.…”
Section: Resultsmentioning
confidence: 99%
“…Interestingly, the effect of posaconazole and itraconazole as CYP3A and P-gp/BCRP inhibitors was less pronounced, which, in the case of itraconazole, may be due to the fact that it appears to not inhibit CYP2J2 [ 48 ], and also because the inhibitors were not administered to steady-state. For posaconazole, this could have resulted from the methodological limitations of the study, which were also reflected in the lower CYP3A inhibition [ 32 ].…”
Section: Discussionmentioning
confidence: 99%
“…To determine the effect of the azoles on CYP3A activity, the previously established limited sampling method for midazolam was applied to determine midazolam partial metabolic clearance (CL met ) by using midazolam concentrations at 2, 2.5, 3, and 4 h after dosing [ 29 – 31 ]. These data have been previously published [ 32 ].…”
Background Factor Xa inhibitors (FXaIs) are increasingly used without having sufficient drug-drug interaction data. Using a microdosed cocktail methodology could support filling the knowledge gap quickly. Methods In a randomised crossover trial, we investigated the drug-drug interactions between six oral azole antifungals and a microdosed FXaI cocktail containing 25 µg rivaroxaban, 25 µg apixaban, and 50 µg edoxaban. Additionally, different enzyme activities were also monitored using a microdosed cocktail approach. The six different azole antifungals were administered in therapeutic doses over a 24 h period, while the microdosed cocktails were administered 1 h after administration of the azole antifungals. Results Ketoconazole and posaconazole were the strongest perpetrators, showing similar increases as apixaban (area under the concentration-time curve ratio [AUCR] 1.64 and 1.62, respectively) and edoxaban (AUCR 2.08 and 2.1, respectively), whereas ketoconazole increased rivaroxaban 2.32-fold but only increased posaconazole 1.37-fold. All other azole antifungals showed less perpetrator effects on the FXaIs. Cytochrome P450 (CYP) 3A inhibition was confirmed using microdosed midazolam, with ketoconazole also the most potent perpetrator (8.42-fold). Conclusion Drug-drug interactions for three victim drugs of the same drug class (FXaIs) with different clearance mechanisms can be studied using a microdosed cocktail approach. Using members of the azole antifungal drug class as perpetrators, multiple interactions can be studied in one trial, and a more detailed insight into the underlying interaction mechanisms is possible. Clinical Trial Registration EudraCT number: 2017-004453-16.
“…The inhibitor ketoconazole has been shown to affect the exposure of isavuconazole. Coadministration of isavuconazole with oral ketoconazole increased isavuconazole AUC and C max by 422% and 9%, respectively [129,130]. Another strong inhibitor of CYP3A4, lopinavir/ritonavir, significantly increased the exposure of isavuconazole.…”
Second generation triazoles are widely used as first-line drugs for the treatment of invasive fungal infections, including aspergillosis and candidiasis. This class, along with itraconazole, voriconazole, posaconazole, and isavuconazole, is characterized by a broad range of activity, however, individual drugs vary considerably in safety, tolerability, pharmacokinetics profiles, and interactions with concomitant medications. The interaction may be encountered on the absorption, distribution, metabolism, and elimination (ADME) step. All triazoles as inhibitors or substrates of CYP isoenzymes can often interact with many drugs, which may result in the change of the activity of the drug and cause serious side effects. Drugs of this class should be used with caution with other agents, and an understanding of their pharmacokinetic profile, safety, and drug-drug interaction profiles is important to provide effective antifungal therapy. The manuscript reviews significant drug interactions of azoles with other medications, as well as with food. The PubMed and Google Scholar bases were searched to collect the literature data. The interactions with anticonvulsants, antibiotics, statins, kinase inhibitors, proton pump inhibitors, non-nucleoside reverse transcriptase inhibitors, opioid analgesics, benzodiazepines, cardiac glycosides, nonsteroidal anti-inflammatory drugs, immunosuppressants, antipsychotics, corticosteroids, biguanides, and anticoagulants are presented. We also paid attention to possible interactions with drugs during experimental therapies for the treatment of COVID-19.
A drug–drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early‐phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three‐cycle, self‐controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1‐hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21‐fold based on maximum plasma concentration (Cmax), 8.37‐fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC0–t), and 11.22‐fold based on area under the curve from zero to infinity (AUC0–∞). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27‐fold based on Cmax, ~0.18‐fold based on AUC0–t, and ~0.18‐fold based on AUC0–∞. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near‐maximal CYP3A levels.
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