Characterization of the Effect of Upadacitinib on the Pharmacokinetics of Bupropion, a Sensitive Cytochrome P450 2B6 Probe Substrate.

This phase 1 study characterized the effect of multiple doses of upadacitinib, an oral Janus kinase 1 selective inhibitor, on the pharmacokinetics of the cytochrome P450 (CYP) 2B6 substrate bupropion. Healthy subjects (n = 22) received a single oral dose of bupropion 150 mg alone (study period 1) and on day 12 of a 16-day regimen of upadacitinib 30 mg once daily (study period 2). Serial blood samples for measurement of bupropion and hydroxybupropion plasma concentrations were collected in each study period. The central values (90% confidence intervals) for the ratios of change were 0.87 (0.79-0.96) for bupropion maximum plasma concentration (Cmax ), 0.92 (0.87-0.98) for bupropion area under the plasma-concentration time curve from time 0 to infinity (AUCinf ), 0.78 (0.72-0.85) for hydroxybupropion Cmax , and 0.72 (0.67-0.78) for hydroxybupropion AUCinf when administered with, relative to when administered without, upadacitinib. After multiple-dose administration of upadacitinib 30 mg once daily, upadacitinib mean ± SD AUC0-24 was 641 ± 177 ng·h/mL, and Cmax was 83.3 ± 30.7 ng/mL. These results confirm that upadacitinib has no relevant effect on pharmacokinetics of substrates metabolized by CYP2B6.

Application of a physiologically based pharmacokinetic model for the prediction of mirabegron plasma concentrations in a population with severe renal impairment.

We previously verified a physiologically based pharmacokinetic (PBPK) model for mirabegron in healthy subjects using the Simcyp Simulator by incorporating data on the inhibitory effect on cytochrome P450 (CYP) 2D6 and a multi-elimination pathway mediated by CYP3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7 and butyrylcholinesterase (BChE). The aim of this study was to use this PBPK model to assess the magnitude of drug-drug interactions (DDIs) in an elderly population with severe renal impairment (sRI), which has not been evaluated in clinical trials. We first determined the system parameters, and meta-analyses of literature data suggested that the abundance of UGT2B7 and the BChE activity in an elderly population with sRI was almost equivalent to and 20% lower than that in healthy young subjects, respectively. Other parameters, such as the CYP3A4 abundance, for an sRI population were used according to those built into the Simcyp Simulator. Second, we confirmed that the PBPK model reproduced the plasma concentration-time profile for mirabegron in an sRI population (simulated area under the plasma concentration-time curve (AUC) was within 1.5-times that of the observed value). Finally, we applied the PBPK model to simulate DDIs in an sRI population. The PBPK model predicted that the AUC for mirabegron with itraconazole (a CYP3A4 inhibitor) was 4.12-times that in healthy elderly subjects administered mirabegron alone, and predicted that the proportional change in AUC for desipramine (a CYP2D6 substrate) with mirabegron was greater than that in healthy subjects. In conclusion, the PBPK model was verified for the purpose of DDI assessment in an elderly population with sRI.

Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition.

Bupropion hydroxylation is a bioactivation and metabolic pathway, and the standard clinical CYP2B6 probe. This investigation determined the influence of CYP2B6 allelic variants on clinical concentrations and metabolism of bupropion enantiomers. Secondary objectives evaluated the influence of CYP2C19 and P450 oxidoreductase variants. Healthy volunteers in specific cohorts (CYP2B6*1/*1, CYP2B6*1/*6, CYP2B6*6/*6, and also CYP2B6*4 carriers) received single-dose oral bupropion. Plasma and urine bupropion and hydroxybupropion was quantified. Subjects were also genotyped for CYP2C19 and P450 oxidoreductase variants. Hydroxylation of both bupropion enantiomers, assessed by plasma hydroxybupropion/bupropion AUC ratios and urine hydroxybupropion formation clearances, was lower in CYP2B6*6/*6 but not CYP2B6*1/*6 compared with CYP2B6*1/*1 genotypes, and numerically greater in CYP2B6*4 carriers. CYP2C19 and P450 oxidoreductase variants did not influence bupropion enantiomers hydroxylation or plasma concentrations. The results show that clinical hydroxylation of both bupropion enantiomers was equivalently influenced by CYP2B6 allelic variation. CYP2B6 polymorphisms affect S-bupropion bioactivation, which may affect therapeutic outcomes.

The oral bioavailability, excretion and cytochrome P450 inhibition properties of epiberberine: an in vivo and in vitro evaluation.

Epiberberine (EPI) is a novel and potentially effective therapeutic and preventive agent for diabetes and cardiovascular disease. To evaluate its potential value for drug development, a specific, sensitive and robust high-performance liquid chromatography-tandem mass spectrometry assay for the determination of EPI in rat biological samples was established. This assay was used to study the pharmacokinetics, bioavailability and excretion of EPI in rats after oral administration. In addition, a cocktail method was used to compare the inhibition characteristics of EPI on cytochrome P450 (CYP450) isoforms in human liver microsomes (HLMs) and rat liver microsomes (RLMs). The results demonstrated that EPI was rapidly absorbed and metabolized after oral administration (10, 54 or 81 mg/kg) in rats, with Tmax of 0.37-0.42 h and T1/2 of 0.49-2.73 h. The Cmax and area under the curve values for EPI increased proportionally with the dose, and the oral absolute bioavailability was 14.46%. EPI was excreted mainly in bile and feces, and after its oral administration to rats, EPI was eliminated predominantly by the kidneys. A comparison of the current half-maximal inhibitory concentration and Ki values revealed that EPI demonstrated an obvious inhibitory effect on CYP2C9 and CYP2D6. Furthermore, its effect was stronger in HLM than in RLM, more likely to be a result of noncompetitive inhibition.

Use of Human Plasma Samples to Identify Circulating Drug Metabolites that Inhibit Cytochrome P450 Enzymes.

Drug interactions elicited through inhibition of cytochrome P450 (P450) enzymes are important in pharmacotherapy. Recently, greater attention has been focused on not only parent drugs inhibiting P450 enzymes but also on possible inhibition of these enzymes by circulating metabolites. In this report, an ex vivo method whereby the potential for circulating metabolites to be inhibitors of P450 enzymes is described. To test this method, seven drugs and their known plasma metabolites were added to control human plasma at concentrations previously reported to occur in humans after administration of the parent drug. A volume of plasma for each drug based on the known inhibitory potency and time-averaged concentration of the parent drug was extracted and fractionated by high-pressure liquid chromatography-mass spectrometry, and the fractions were tested for inhibition of six human P450 enzyme activities (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Observation of inhibition in fractions that correspond to the retention times of metabolites indicates that the metabolite has the potential to contribute to P450 inhibition in vivo. Using this approach, norfluoxetine, hydroxyitraconazole, desmethyldiltiazem, desacetyldiltiazem, desethylamiodarone, hydroxybupropion, erythro-dihydrobupropion, and threo-dihydrobupropion were identified as circulating metabolites that inhibit P450 activities at a similar or greater extent as the parent drug. A decision tree is presented outlining how this method can be used to determine when a deeper investigation of the P450 inhibition properties of a drug metabolite is warranted.

Physiologically based pharmacokinetic modeling to predict drug-drug interactions involving inhibitory metabolite: a case study of amiodarone.

Evaluation of drug-drug interaction (DDI) involving circulating inhibitory metabolites of perpetrator drugs has recently drawn more attention from regulatory agencies and pharmaceutical companies. Here, using amiodarone (AMIO) as an example, we demonstrate the use of physiologically based pharmacokinetic (PBPK) modeling to assess how a potential inhibitory metabolite can contribute to clinically significant DDIs. Amiodarone was reported to increase the exposure of simvastatin, dextromethorphan, and warfarin by 1.2- to 2-fold, which was not expected based on its weak inhibition observed in vitro. The major circulating metabolite, mono-desethyl-amiodarone (MDEA), was later identified to have a more potent inhibitory effect. Using a combined "bottom-up" and "top-down" approach, a PBPK model was built to successfully simulate the pharmacokinetic profile of AMIO and MDEA, particularly their accumulation in plasma and liver after a long-term treatment. The clinical AMIO DDIs were predicted using the verified PBPK model with incorporation of cytochrome P450 inhibition from both AMIO and MDEA. The closest prediction was obtained for CYP3A (simvastatin) DDI when the competitive inhibition from both AMIO and MDEA was considered, for CYP2D6 (dextromethorphan) DDI when the competitive inhibition from AMIO and the competitive plus time-dependent inhibition from MDEA were incorporated, and for CYP2C9 (warfarin) DDI when the competitive plus time-dependent inhibition from AMIO and the competitive inhibition from MDEA were considered. The PBPK model with the ability to simulate DDI by considering dynamic change and accumulation of inhibitor (parent and metabolite) concentration in plasma and liver provides advantages in understanding the possible mechanism of clinical DDIs involving inhibitory metabolites.

Codeine-related deaths: The role of pharmacogenetics and drug interactions.

The objective of this study was to assess the relationship between genetic polymorphisms and drug interactions on codeine and morphine concentrations in codeine-related deaths (CRD). All CRD in Ontario, Canada between 2006 and 2008 were identified. Post-mortem blood was analyzed for 22 polymorphisms in 5 genes involved in codeine metabolism and response. Sixty-eight CRD were included in this study. The morphine-to-codeine ratio was significantly correlated with the presence of a CYP2D6 inhibitor at varying potencies (p=0.0011). The presence of other central nervous system (CNS) depressants (i.e. benzodiazepines, hypnotics, and/or alcohol) was significantly associated with lower codeine concentration as compared to CRD in which other CNS depressants were not detected (p=0.0002). Individuals who carried the ABCB1 1236T variant had significantly lower morphine concentrations (p=0.004). In this population of individuals whose cause of death was related to codeine, drug interactions and genetic polymorphisms were significantly associated with post-mortem codeine and morphine concentrations.

A phase I open-label study to investigate the potential drug-drug interaction between single-dose dacomitinib and steady-state paroxetine in healthy volunteers.

Dacomitinib is currently in development for the treatment of non-small cell lung cancer. Formation of the major circulating metabolite (PF-05199265) is mediated by cytochrome P450 (CYP) 2D6 and CYP2C9. This phase I, single fixed-sequence, two-period study evaluated the effect of paroxetine, a CYP2D6 inactivator, on dacomitinib pharmacokinetics in healthy volunteers who were extensive CYP2D6 metabolizers. Subjects received a single 45-mg dacomitinib dose alone and in combination with paroxetine (30 mg/day for 10 consecutive days, with dacomitinib administered on day 4) at steady-state levels. Blood samples were collected through 240 hours post-dacomitinib dosing. Dacomitinib exposure (area under the concentration-time curve from 0 to infinity; AUCinf) increased 37%; however a reduction in PF-05199265 AUCinf of approximately 90% was observed during the paroxetine treatment period. The maximum concentration of dacomitinib changed minimally. Adverse events reported with single-dose dacomitinib administered alone or in the presence of steady-state levels of paroxetine were mostly mild, and no serious adverse events were reported. While paroxetine significantly inhibited CYP2D6-mediated metabolism of a single dose of dacomitinib, the modest effect on dacomitinib exposure is unlikely to be clinically relevant when dacomitinib is given daily. Dose adjustment of dacomitinib may therefore not be required upon coadministration with a CYP2D6 inhibitor.