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Evaluation of 1β-Hydroxylation of Deoxycholic Acid as a Non-Invasive Urinary Biomarker of CYP3A Activity in the Assessment of Inhibition-Based Drug-Drug Interaction in Healthy Volunteers.

ABSTRACT: In this study, we aimed to evaluate the utility of endogenous 1β-hydroxy-deoxycholic acid/total deoxycholic acid ratio (1β-OH-DCA/ToDCA) in spot urine as a surrogate marker of cytochrome P450 3A (CYP3A) activity in the assessment inhibition-based drug-drug interactions in healthy volunteers. This was accomplished through an open-label, three-treatment parallel-arm study in healthy male volunteers from Zimbabwe. Each group received itraconazole (ITZ; 100 mg once daily; n = 10), fluconazole (FKZ; 50 mg once daily; n = 9), or alprazolam (APZ; 1 mg once daily; n = 8) orally. Midazolam (MDZ), dosed orally and intravenously, was used as a comparator to validate the exploratory measures of CYP3A activity and the effects of known inhibitors. Urinary metabolic ratios of 1β-OH-DCA/ToDCA before and after CYP3A inhibitor treatment showed a similar magnitude of inhibitory effects of the three treatments as that measured by oral MDZ clearance. The maximum inhibition effect of a 75% reduction in the 1β-OH-DCA/ToDCA ratio compared to the baseline was achieved in the ITZ group following six once-daily doses of 100 mg. The correlations of the two markers for CYP3A inhibitor treatment were significant (r_s = 0.53, p < 0.01). The half-life of urinary endogenous 1β-OH-DCA/ToDCA was estimated as four days. These results suggested that 1β-OH-DCA/ToDCA in spot urine is a promising convenient, non-invasive, sensitive, and relatively quickly responsive endogenous biomarker that can be used for CYP3A inhibition-based drug-drug interaction in clinical studies.

SUBMITTER: Li XQ

PROVIDER: S-EPMC8224742 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The 1β-Hydroxy-Deoxycholic Acid to Deoxycholic Acid Urinary Metabolic Ratio: Toward a Phenotyping of CYP3A Using an Endogenous Marker?

Project description:In this study, we assessed the potential use of the 1β-hydroxy-deoxycholic acid (1β-OH-DCA) to deoxycholic acid (DCA) urinary metabolic ratio (UMR) as a CYP3A metric in ten male healthy volunteers. Midazolam (MDZ) 1 mg was administered orally at three sessions: alone (control session), after pre-treatment with fluvoxamine 50 mg (12 h and 2 h prior to MDZ administration), and voriconazole 400 mg (2 h before MDZ administration) (inhibition session), and after a 7-day pre-treatment with the inducer rifampicin 600 mg (induction session). The 1β-OH-DCA/DCA UMR was measured at each session, and correlations with MDZ metrics were established. At baseline, the 1β-OH-DCA/DCA UMR correlated significantly with oral MDZ clearance (r = 0.652, p = 0.041) and Cmax (r = -0.652, p = 0.041). In addition, the modulation of CYP3A was reflected in the 1β-OH-DCA/DCA UMR after the intake of rifampicin (induction ratio = 11.4, p < 0.01). During the inhibition session, a non-significant 22% decrease in 1β-OH-DCA/DCA was observed (p = 0.275). This result could be explained by the short duration of CYP3A inhibitors intake fixed in our clinical trial. Additional studies, particularly involving CYP3A inhibition for a longer period and larger sample sizes, are needed to confirm the 1β-OH-DCA/DCA metric as a suitable CYP3A biomarker.

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Project description:In vitro data support involvement of cytochrome P450 (CYP)2C8 and CYP3A4 in the metabolism of the anaplastic lymphoma kinase inhibitor brigatinib. A 3-arm, open-label, randomized, single-dose, fixed-sequence crossover study was conducted to characterize the effects of the strong inhibitors gemfibrozil (of CYP2C8) and itraconazole (of CYP3A) and the strong inducer rifampin (of CYP3A) on the single-dose pharmacokinetics of brigatinib. Healthy subjects (n = 20 per arm) were administered a single dose of brigatinib (90 mg, arms 1 and 2; 180 mg, arm 3) alone in treatment period 1 and coadministered with multiple doses of gemfibrozil 600 mg twice daily (BID; arm 1), itraconazole 200 mg BID (arm 2), or rifampin 600 mg daily (QD; arm 3) in period 2. Compared with brigatinib alone, coadministration of gemfibrozil with brigatinib did not meaningfully affect brigatinib area under the plasma concentration-time curve (AUC0-inf ; geometric least-squares mean [LSM] ratio [90%CI], 0.88 [0.83-0.94]). Coadministration of itraconazole with brigatinib increased AUC0-inf (geometric LSM ratio [90%CI], 2.01 [1.84-2.20]). Coadministration of rifampin with brigatinib substantially reduced AUC0-inf (geometric LSM ratio [90%CI], 0.20 [0.18-0.21]) compared with brigatinib alone. The treatments were generally tolerated. Based on these results, strong CYP3A inhibitors and inducers should be avoided during brigatinib treatment. If concomitant use of a strong CYP3A inhibitor is unavoidable, the results of this study support a dose reduction of brigatinib by approximately 50%. Furthermore, CYP2C8 is not a meaningful determinant of brigatinib clearance, and no dose modifications are needed during coadministration of brigatinib with CYP2C8 inhibitors.

| S-EPMC7027746 | biostudies-literature

Identification of Appropriate Endogenous Biomarker for Risk Assessment of Multidrug and Toxin Extrusion Protein-Mediated Drug-Drug Interactions in Healthy Volunteers.

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| S-EPMC7891601 | biostudies-literature

Investigation into CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers.

Project description:PurposeMidostaurin (PKC412), a multitargeted tyrosine kinase inhibitor that targets FMS-related tyrosine kinase 3 and KIT, is in clinical trials for the treatment for acute myeloid leukemia and advanced systemic mastocytosis. In vitro studies showed that midostaurin is predominantly metabolized by cytochrome P450 3A4 (CYP3A4) and that midostaurin inhibits and/or induces the same enzyme. Here, we address the clinical relevance of CYP3A4-related drug-drug interactions with midostaurin as either a "victim" or "perpetrator."MethodsThree phase I studies in healthy volunteers evaluated the effects of a CYP3A4 inhibitor (ketoconazole 400 mg daily for 10 days) or CYP3A4 inducer (rifampicin 600 mg daily for 14 days) on concentrations of midostaurin and its metabolites following a single 50-mg dose of midostaurin and the effects of midostaurin as a single dose (100 mg) and multiple doses (50 mg twice daily) on midazolam (a sensitive CYP3A4 probe) concentration. The plasma concentrations of midostaurin and its 2 active metabolites, CGP62221 and CGP52421, were determined using a sensitive liquid chromatography/tandem mass spectrometry method.ResultsInhibition of CYP3A4 by ketoconazole increased midostaurin exposure more than tenfold, and induction of CYP3A4 by rifampicin decreased midostaurin exposure by more than tenfold. Midostaurin did not appreciably affect the concentrations of midazolam or its metabolite, 1'-hydroxymidazolam, at single or multiple doses.ConclusionThe pharmacokinetics of midostaurin and its metabolites was affected substantially by ketoconazole and rifampicin, suggesting that midostaurin is a sensitive CYP3A4 substrate. Midostaurin did not appear to inhibit or induce CYP3A4 in vivo.

| S-EPMC3834177 | biostudies-literature

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