RESUMO
PURPOSE: Esaxerenone is a novel, oral, nonsteroidal treatment for hypertension. Physiologically based pharmacokinetic (PBPK) modelling was performed to predict the drug-drug interaction (DDI) effect of cytochrome P450 (CYP)3A modulators on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment. METHODS: In our PBPK model, the fraction of esaxerenone metabolised by CYP3A was estimated from mass-balance data and verified and optimised by clinical DDI study results with strong CYP3A modulators. The model was also verified by the observed pharmacokinetics after multiple oral dosing and by the effect of hepatic impairment on esaxerenone pharmacokinetics. The model was applied to predict the DDI effects on esaxerenone pharmacokinetics with untested CYP3A modulators in healthy subjects and with strong CYP3A modulators in subjects with hepatic impairment. RESULTS: The PBPK model well described esaxerenone pharmacokinetics after multiple oral dosing. The predicted fold changes in esaxerenone plasma exposure after coadministration with strong CYP3A modulators were comparable with the observed data (1.53-fold with itraconazole and 0.31-fold with rifampicin). Predicted DDIs with untested moderate CYP3A modulators were less than the observed DDI with strong CYP3A modulators. The PBPK model also described the effect of hepatic impairment on esaxerenone plasma exposure. The predicted DDI results with strong CYP3A modulators in subjects with hepatic impairment indicate that, for concomitant use of CYP3A modulators, caution is advised for subjects with hepatic impairment, as is for healthy subjects. CONCLUSION: The PBPK model developed predicted esaxerenone pharmacokinetics and DDIs and informed concurrent use of esaxerenone with CYP3A modulators.
Assuntos
Anti-Hipertensivos/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Falência Hepática/metabolismo , Pirróis/farmacocinética , Sulfonas/farmacocinética , Área Sob a Curva , Simulação por Computador , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Itraconazol/farmacologia , Japão , Taxa de Depuração Metabólica , Modelos Biológicos , Rifampina/farmacologiaRESUMO
Esaxerenone (CS-3150) is a novel, oral, nonsteroidal, selective mineralocorticoid receptor blocker approved for the treatment of hypertension in Japan. Here, the drug-drug interaction (DDI) potential of esaxerenone was evaluated in vitro, and its impact in clinical practice was estimated. Esaxerenone exhibited time-dependent inhibition and induction of CYP3A. When the clinical impacts of esaxerenone on the inhibition and induction of CYP3A were estimated separately by using a mechanistic static model, the predicted area under the curve ratios (AUCRs) of midazolam, a typical CYP3A substrate, were 1.80 and 0.31, respectively, suggesting that the DDI potential of esaxerenone cannot be neglected. Because it was suggested that DDIs mainly occur in the intestine, predictions using concentration-time profiles in each segment of the gastrointestinal tract were performed with GastroPlus, a physiologically based pharmacokinetic (PBPK) modeling software. The predicted AUCR of midazolam was approximately 1.2, which is close to that in a clinical study, despite the difficulty of predicting DDIs for compounds with both inhibition and induction effects. When only inhibition or induction was incorporated into a model, the AUCR of midazolam changed depending on the dosing period and dose level of esaxerenone and the timing of midazolam administration. However, the AUCR calculated by incorporating both effects remained almost constant. This study shows the ability of PBPK models to simulate weak DDIs via intestinal CYP3A and that esaxerenone has low DDI potential as a perpetrator because of the offset of inhibition and induction. SIGNIFICANCE STATEMENT: Weak CYP3A inhibition and/or induction sometimes cause DDIs in the intestine but not the liver. Because strong inhibitors maximally inhibit intestinal CYP3A, the predictability of weak DDIs in the intestine should be evaluated further. Here, we simulate the DDIs of esaxerenone as a perpetrator by using physiologically based pharmacokinetic modeling focusing on the intestine and offset of inhibition and induction.
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Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Modelos Biológicos , Pirróis/farmacocinética , Sulfonas/farmacocinética , Administração Oral , Área Sob a Curva , Simulação por Computador , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Interações Medicamentosas , Glucuronosiltransferase/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/enzimologia , Japão , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Microssomos Hepáticos , Midazolam/farmacocinética , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Pirróis/administração & dosagem , Medição de Risco/métodos , Sulfonas/administração & dosagemRESUMO
A great deal of effort has been being made to improve the accuracy of the prediction of drug-drug interactions (DDIs). In this study, we addressed CYP3A-mediated weak DDIs, in which a relatively high false prediction rate was pointed out. We selected 17 orally administered drugs that have been reported to alter area under the curve (AUC) of midazolam, a typical CYP3A substrate, 0.84-1.47 times. For weak CYP3A perpetrators, the predicted AUC ratio mainly depends on intestinal DDIs rather than hepatic DDIs because the drug concentration in the enterocytes is higher. Thus, DDI prediction using simulated concentration-time profiles in each segment of the digestive tract was made by physiologically based pharmacokinetic (PBPK) modeling software GastroPlus. Although mechanistic static models tend to overestimate the risk to ensure the safety of patients, some underestimation is reported about PBPK modeling. Our in vitro studies revealed that 16 out of 17 tested drugs exhibited time-dependent inhibition (TDI) of CYP3A, and the subsequent DDI simulation that ignored these TDIs provided false-negative results. This is considered to be the cause of past underestimation. Inclusion of the DDI parameters of all the known DDI mechanisms, reversible inhibition, TDI, and induction, which have opposite effects on midazolam AUC, to PBPK model was successful in improving predictability of the DDI without increasing false-negative prediction as trade-off. This comprehensive model-based analysis suggests the importance of the intestine in assessing weak DDIs via CYP3A and the usefulness of PBPK in predicting intestinal DDIs. SIGNIFICANCE STATEMENT: Although drug-drug interaction (DDI) prediction has been extensively performed previously, the accuracy of prediction for weak interactions via CYP3A has not been thoroughly investigated. In this study, we simulate DDIs considering drug concentration-time profile in the enterocytes and discuss the importance and the predictability of intestinal DDIs about weak CYP3A perpetrators.
Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Mucosa Intestinal/enzimologia , Midazolam/farmacocinética , Modelos Biológicos , Administração Oral , Área Sob a Curva , Simulação por Computador , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Interações Medicamentosas , Estudos de Viabilidade , Humanos , Midazolam/administração & dosagem , Medição de Risco/métodosRESUMO
Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23-82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).
Assuntos
Aminopiridinas/uso terapêutico , Neoplasias/tratamento farmacológico , Pirróis/uso terapêutico , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/farmacocinética , Biomarcadores Tumorais , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Ensaios Clínicos Controlados não Aleatórios como Assunto , Prognóstico , Pirróis/farmacocinética , Distribuição Tecidual , Adulto JovemRESUMO
AIMS: To investigate the effects of the strong cytochrome P450 (CYP) 3A inhibitor itraconazole and the strong CYP3A inducer rifampicin on the pharmacokinetics of single-dose esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, in healthy Japanese subjects. METHODS: Two open-label, single-sequence, crossover studies were conducted in healthy Japanese males aged 20-45 years. In Study 1 (n = 20), subjects received a single oral 2.5 mg dose of esaxerenone (Days 1, 13), with itraconazole 200 mg twice daily (Day 8) and once daily (Days 9-16). In Study 2 (n = 12), subjects received a single oral 5 mg dose of esaxerenone (Days 1, 13), with rifampicin 600 mg once daily (Days 8-16). The plasma concentration of esaxerenone and esaxerenone metabolites were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis, and safety was assessed. RESULTS: Esaxerenone exposure increased when coadministered with itraconazole. Geometric least-square mean ratios (90% confidence interval) of peak plasma esaxerenone concentration (Cmax ), area under the plasma concentration-time curve (AUC) from zero until the last measurable concentration (AUClast ) and AUC from zero until infinity (AUCinf ) were 1.13 (1.05, 1.20) ng mL-1 , 1.47 (1.40, 1.54) ng h mL-1 and 1.53 (1.45, 1.62) ng h mL-1 , respectively. Esaxerenone exposure decreased when coadministered with rifampicin. Geometric least-squares mean ratios (90% confidence interval) of esaxerenone Cmax , AUClast and AUCinf were 0.659 (0.599, 0.724), 0.315 (0.300, 0.332) and 0.312 (0.297, 0.328), respectively. CONCLUSION: Itraconazole increased esaxerenone AUCinf by 53.1%, and rifampicin decreased esaxerenone AUCinf by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.
Assuntos
Itraconazol , Rifampina , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP3A , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Itraconazol/efeitos adversos , Japão , Masculino , Pirróis , Receptores de Mineralocorticoides , SulfonasRESUMO
A 1,2,4-oxadiazole ring-containing compound DS-8500a was developed as a novel G protein-coupled receptor 119 agonist. In vivo metabolic fates of [14C]DS-8500a differently radiolabeled in the benzene ring or benzamide side carbon in rats were investigated. Differences in mass balances were observed, primarily because after the oxadiazole ring-opening and subsequent ring-cleavage small-molecule metabolites containing the benzene side were excreted in the urine, while those containing the benzamide side were excreted in the bile. DS-8500a was detected at trace levels in urine and bile, demonstrating extensive metabolism prior to urinary/biliary excretion. At least 16 metabolite structures were proposed in plasma, urine, and bile samples from rats treated with [14C]DS-8500a. Formation of a ring-opened metabolite (reduced DS-8500a) in hepatocytes of humans, monkeys, and rats was confirmed; however, it was not affected by typical inhibitors of cytochrome P450s, aldehyde oxidases, or carboxylesterases in human hepatocytes. Extensive formation of the ring-opened metabolite was observed in human liver microsomes fortified with an NADPH-generating system under anaerobic conditions. These results suggest an in vivo unique reductive metabolism of DS-8500a is mediated by human non-cytochrome P450 enzymes.
Assuntos
Benzamidas/metabolismo , Ciclopropanos/metabolismo , Redes e Vias Metabólicas , Oxidiazóis/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Administração Oral , Anaerobiose , Animais , Benzamidas/administração & dosagem , Benzamidas/sangue , Benzamidas/farmacocinética , Radioisótopos de Carbono/química , Ciclopropanos/administração & dosagem , Ciclopropanos/sangue , Ciclopropanos/farmacocinética , Humanos , Macaca fascicularis , Masculino , Oxidiazóis/administração & dosagem , Oxidiazóis/sangue , Oxidiazóis/farmacocinética , Oxirredução , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismoRESUMO
INTRODUCTION: Bowel urgency (BU) is among the most disruptive of inflammatory bowel disease (IBD) symptoms. However, data on its prevalence and association with disease activity are limited. This real-world study of Japanese patients with IBD evaluated BU prevalence and compared clinical outcomes and health-related quality of life (HRQoL) between patients with and without BU. METHODS: Data were drawn from the Adelphi IBD Disease Specific Programme™, a cross-sectional survey of physicians and their patients with ulcerative colitis (UC) and Crohn's disease (CD). Physicians reported demographic and clinical data, including disease activity measures (Mayo score and CD Activity Index [CDAI]), for consulting patients, who voluntarily completed a patient-reported questionnaire, including HRQoL measures (Short IBD Questionnaire [SIBDQ] and EQ-5D-5L). Outcomes were compared between patients with and without BU using t-, Fisher exact and Mann-Whitney U tests as appropriate. RESULTS: Of 120 UC patients, 27.5% (n = 33) self-reported BU; physicians were unaware of BU in 54.5% (n = 18) of these patients. Patients with BU had higher mean Mayo scores (p < 0.01) and lower mean SIBDQ scores (47.9 vs 56.6, p < 0.01) than patients without BU, with mean EQ-5D-5L scores 0.83 and 0.87, respectively (p = 0.06). Physicians were satisfied with treatment but believed better control could be achieved for 39.4% of patients with BU and 35.6% without. Of 114 CD patients, 17.5% (n = 20) self-reported BU; physicians were unaware of BU in 75.0% (n = 15) of these patients. Patients with BU had higher mean CDAI scores (p < 0.01) and lower mean SIBDQ (48.7 vs 56.2, p < 0.01) and EQ-5D-5L scores (0.81 vs 0.88, p < 0.01) than patients without BU. Physicians were satisfied but believed better control could be achieved for 40.0% of patients with BU vs 19.1% without. CONCLUSIONS: Patients with BU have worse clinical outcomes and HRQoL than patients without, underlining the need for improved physician-patient communication regarding BU and new IBD therapeutic options.
Assuntos
Colite Ulcerativa , Doença de Crohn , Incontinência Fecal , Doenças Inflamatórias Intestinais , Humanos , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Estudos Transversais , Japão/epidemiologia , Qualidade de VidaRESUMO
BACKGROUND/AIMS: Mirikizumab is a p19-directed anti-interleukin-23 antibody with potential efficacy against ulcerative colitis (UC). We evaluated the efficacy and safety of mirikizumab in a Japanese subpopulation with moderately to severely active UC from the LUCENT-1 and LUCENT-2 studies. METHODS: LUCENT-1 and LUCENT-2 were phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab therapy in adults with moderately to severely active UC. LUCENT-1 was a 12-week induction trial where patients were randomized 3:1 to receive intravenous mirikizumab 300 mg or placebo every 4 weeks (Q4W). Patients achieving a clinical response with mirikizumab following the induction study were re-randomized 2:1 to double-blind treatment with either mirikizumab 200 mg or placebo subcutaneously Q4W during the 40-week maintenance study. The primary outcomes were clinical remission at week 12 of LUCENT-1 and week 40 of LUCENT-2. RESULTS: A total of 137 patients enrolled in Japan were randomized to mirikizumab (n = 102) or placebo (n = 35). Compared with placebo, patients who received mirikizumab showed numerically higher clinical remission at week 12 of induction (32.4% [n = 33] vs. 2.9% [n = 1]) and at week 40 of maintenance (48.9% [n = 23] vs. 28.0% [n = 7]). A greater number of patients achieved key secondary endpoints in the mirikizumab group compared with placebo. The frequency of treatment-emergent adverse events was similar across mirikizumab and placebo groups. Efficacy and safety results observed in the Japanese subpopulation were generally consistent with those in the overall population. CONCLUSIONS: Mirikizumab induction and maintenance treatments were effective in Japanese patients with moderately to severely active UC. No new safety concerns were identified.
RESUMO
Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor blocker (ARB). We recently identified carboxymethylenebutenolidase homolog (CMBL) as the responsible enzyme for OM bioactivation in humans. In the present study, we compared the bioactivating properties of OM with those of other prodrug-type ARBs, candesartan cilexetil (CC) and azilsartan medoxomil (AM), by focusing on interspecies differences and tissue specificity. In in-vitro experiments with pooled tissue subcellular fractions of mice, rats, monkeys, dogs, and humans, substantial OM-hydrolase activities were observed in cytosols of the liver, intestine, and kidney in all the species tested except for dog intestine, which showed negligible activity, whereas lung cytosols showed relatively low activities compared with the other tissues. AM-hydrolase activities were well correlated with the OM-hydrolase activities. In contrast, liver microsomes exhibited the highest CC-hydrolase activity among various tissue subcellular fractions in all the species tested. As a result of Western blot analysis with the tissue subcellular fractions, the band intensities stained with anti-human CMBL and carboxylesterase 1 (CES1) antibodies well reflected OM- and AM-hydrolase activities and CC-hydrolase activity, respectively, in animals and humans. Recombinant human CMBL and CES1 showed significant AM- and CC-hydrolase activities, respectively, whereas CC hydrolysis was hardly catalyzed with recombinant carboxylesterase 2 (CES2). In conclusion, OM is bioactivated mainly via intestinal and additionally hepatic CMBL not only in humans but also in mice, rats, and monkeys, while CC is bioactivated via hepatic CES1 rather than intestinal enzymes, including CES2. AM is a substrate for CMBL.
Assuntos
Antagonistas de Receptores de Angiotensina/metabolismo , Carboxilesterase/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Hidrolases/metabolismo , Pró-Fármacos/metabolismo , Animais , Benzimidazóis/metabolismo , Compostos de Bifenilo/metabolismo , Cães , Feminino , Humanos , Hidrólise , Imidazóis/metabolismo , Macaca fascicularis , Masculino , Camundongos , Olmesartana Medoxomila , Oxidiazóis/metabolismo , Ratos , Ratos Sprague-Dawley , Tetrazóis/metabolismo , Distribuição Tecidual/fisiologiaRESUMO
Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor antagonist. OM is rapidly converted into its active metabolite olmesartan by multiple hydrolases in humans, and we recently identified carboxymethylenebutenolidase homolog (CMBL) as one of the OM bioactivating hydrolases. In the present study, we further investigated the interindividual variability of mRNA and protein expression of CMBL and OM-hydrolase activity using 40 individual human liver and 30 intestinal specimens. In the intestinal samples, OM-hydrolase activity strongly correlated with the CMBL protein expression, clearly indicating that CMBL is a major contributor to the prodrug bioactivation in human intestine. The protein and activity were highly distributed in the proximal region (duodenum and jejunum) and decreased to the distal region of the intestine. Although there was high interindividual variability (16-fold) in both the protein and activity in the intestinal segments from the duodenum to colon, the interindividual variability in the duodenum and jejunum was relatively small (3.0- and 2.4-fold, respectively). In the liver samples, the interindividual variability in the protein and activity was 4.1- and 6.8-fold, respectively. No sex differences in the protein and activity were shown in the human liver or intestine. A genetically engineered Y155C mutant of CMBL, which was caused by a single nucleotide polymorphism rs35489000, showed significantly lower OM-hydrolase activity than the wild-type protein although no minor allele was genotyped in the 40 individual liver specimens.
Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Intestinos/enzimologia , Fígado/enzimologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Hidrolases de Éster Carboxílico/genética , Primers do DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Adulto JovemRESUMO
Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor antagonist. The OM-hydrolyzing enzyme responsible for prodrug bioactivation was purified from human plasma through successive column chromatography and was molecularly identified through N-terminal amino acid sequencing, which resulted in a sequence of 20 amino acids identical to that of human paraoxonase 1 (PON1). Two recombinant allozymes of human PON1 (PON1(192QQ) and PON1(192RR)) were constructed and were clearly demonstrated to hydrolyze OM; hydrolysis by the latter allozyme was slightly faster than that by the former. In addition, we evaluated the contribution of PON1 to OM bioactivation in human plasma. Enzyme kinetic studies demonstrated that OM was hydrolyzed more effectively by the recombinant PON1 proteins than by purified albumin. The OM-hydrolyzing activities of the recombinant PON1 proteins and diluted plasma were greatly reduced in the absence of calcium ions. Immunoprecipitation with anti-PON1 IgG completely abolished the OM-hydrolyzing activity in human plasma, whereas the activity was partially inhibited with anti-albumin IgG. The distribution pattern of the OM-hydrolyzing activity in human serum lipoprotein fractions and lipoprotein-deficient serum was examined and showed that most of the OM-hydrolyzing activity was located in the high-density lipoprotein fraction, with which PON1 is closely associated. In conclusion, we identified PON1 as the OM-bioactivating hydrolase in human plasma on a molecular basis and demonstrated that PON1, but not albumin, plays a major role in OM bioactivation in human plasma.
Assuntos
Bloqueadores do Receptor Tipo 2 de Angiotensina II/metabolismo , Anti-Hipertensivos/metabolismo , Arildialquilfosfatase/metabolismo , Imidazóis/metabolismo , Pró-Fármacos/metabolismo , Tetrazóis/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Arildialquilfosfatase/química , Arildialquilfosfatase/genética , Arildialquilfosfatase/isolamento & purificação , Cálcio/metabolismo , Humanos , Hidrólise , Isoenzimas/sangue , Isoenzimas/química , Isoenzimas/isolamento & purificação , Isoenzimas/metabolismo , Cinética , Lipoproteínas HDL/metabolismo , Proteínas Mutantes/sangue , Proteínas Mutantes/química , Proteínas Mutantes/isolamento & purificação , Proteínas Mutantes/metabolismo , Olmesartana Medoxomila , Plasma/enzimologia , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Análise de Sequência de Proteína , Especificidade da Espécie , Especificidade por SubstratoRESUMO
OBJECTIVE: To assess the current status of shared decision making (SDM) in rheumatoid arthritis (RA) clinical practice in Japan from the perspectives of physicians and patients. METHODS: A web-based survey was conducted to recruit patients with RA who were prescribed, for the first time, a conventional synthetic disease-modifying antirheumatic drug (csDMARD) or a biological drug/Janus kinase (JAK) inhibitor, and physicians who prescribed these treatments to patients with RA. The SDM Questionnaire-Physician version (SDM-Q-Doc) and the 9-item SDM Questionnaire (SDM-Q-9) were used to assess the SDM levels of physicians and patients, respectively. The scale ranged from 0 to 100, and higher scores indicated better SDM status. RESULTS: The responses from 107 physicians who treat patients with RA, 107 patients prescribed a csDMARD, and 110 patients prescribed a biological drug/JAK inhibitor were collected. The mean SDM score for SDM-Q-Doc was 74.5 when physicians decided to prescribe a csDMARD and 77.2 when they decided to prescribe a biological drug/JAK inhibitor. However, the mean SDM score for SDM-Q-9 was 62.3 when patients were prescribed csDMARDs and 72.6 when they were prescribed biological drugs/JAK inhibitors. CONCLUSIONS: The results showed differences in SDM level between patients and physicians and, from the patient perspective, between treatment types.
Rheumatoid arthritis (RA) is a long-term disease that causes swelling and pain, mainly in the joints of the hands and feet. Because RA cannot be cured, treatment usually continues for a long time. Shared decision making (SDM) involves people and their doctors deciding on the best treatment together. This study was done to understand how SDM is used for RA treatment in Japan. We sent one survey to 107 doctors who treat RA and a different survey to 217 people with RA. Each survey asked the doctors or the people with RA to score, on a scale of 0 to 100, how involved the person with RA was in making the decision on what treatment to use. A higher score meant more involvement in SDM. Doctors gave higher SDM scores than people with RA did, which meant doctors thought there was more SDM than what people with RA thought. This was true whether the person started treatment with a conventional RA drug or a newer RA drug (biological/JAK inhibitor). However, for both doctors and people with RA, the SDM scores were higher when a newer drug was used than when a conventional drug was used. This may be because the newer drugs are often prescribed for people with more severe RA or because there are more treatment types available. This was the first study to look at SDM in RA treatment in Japan. Increasing SDM will help improve treatment satisfaction in people with RA and increase patient-centered medical care.[Figure: see text].
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Artrite Reumatoide , Produtos Biológicos , Inibidores de Janus Quinases , Médicos , Artrite Reumatoide/tratamento farmacológico , Tomada de Decisões , Tomada de Decisão Compartilhada , Humanos , Internet , Japão , Participação do Paciente , Inquéritos e QuestionáriosRESUMO
Olmesartan medoxomil (OM) is a prodrug type angiotensin II type 1 receptor antagonist widely prescribed as an antihypertensive agent. Herein, we describe the identification and characterization of the OM bioactivating enzyme that hydrolyzes the prodrug and converts to its pharmacologically active metabolite olmesartan in human liver and intestine. The protein was purified from human liver cytosol by successive column chromatography and was identified by mass spectrometry to be a carboxymethylenebutenolidase (CMBL) homolog. Human CMBL, whose endogenous function has still not been reported, is a human homolog of Pseudomonas dienelactone hydrolase involved in the bacterial halocatechol degradation pathway. The ubiquitous expression of human CMBL gene transcript in various tissues was observed. The recombinant human CMBL expressed in mammalian cells was clearly shown to activate OM. By comparing the enzyme kinetics and chemical inhibition properties between the recombinant protein and human tissue preparations, CMBL was demonstrated to be the primary OM bioactivating enzyme in the liver and intestine. The recombinant CMBL also converted other prodrugs having the same ester structure as OM, faropenem medoxomil and lenampicillin, to their active metabolites. CMBL exhibited a unique sensitivity to chemical inhibitors, thus, being distinguishable from other known esterases. Site-directed mutagenesis on the putative active residue Cys(132) of the recombinant CMBL caused a drastic reduction of the OM-hydrolyzing activity. We report for the first time that CMBL serves as a key enzyme in the bioactivation of OM, hydrolyzing the ester bond of the prodrug type xenobiotics.
Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Imidazóis/farmacocinética , Intestinos/enzimologia , Fígado/enzimologia , Pró-Fármacos/farmacocinética , Tetrazóis/farmacocinética , Sequência de Aminoácidos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Biotransformação , Hidrolases de Éster Carboxílico/antagonistas & inibidores , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/isolamento & purificação , Linhagem Celular , Citosol/enzimologia , Primers do DNA/genética , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Imidazóis/química , Técnicas In Vitro , Cinética , Masculino , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Olmesartana Medoxomila , Gravidez , Pró-Fármacos/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Tetrazóis/química , Distribuição TecidualRESUMO
KAI-9803 is composed of a selective δ-protein kinase C (δPKC) inhibitor peptide derived from the δV1-1 portion of δPKC (termed "cargo peptide"), conjugated reversibly to the cell-penetrating peptide 11-amino acid, arginine-rich sequence of the HIV type 1 transactivator protein (TAT47â57; termed "carrier peptide") via a disulfide bond. KAI-9803 administration at the end of ischemia has been found to reduce cardiac damage caused by ischemia-reperfusion in a rat model of acute myocardial infarction. In the study presented here, we examined the TAT47â57-mediated distribution of KAI-9803 in rats after a single intravenous bolus administration (1 mg/kg). ¹4C-KAI-9803 was rapidly delivered to many tissues, including the heart (1.21 µg eq/g tissue), while being quickly cleared from the systemic circulation. The microautoradiography analysis showed that ¹4C-KAI-9803 was effectively delivered into various cells, including cardiac myocytes and cardiac endothelial cells within 1 min after dosing. The tissue distribution of ¹²5I-labeled KAI-9803 was compared to that of ¹²5I-labeled cargo peptide; this comparison demonstrated that the distribution of KAI-9803 to tissues such as the liver, kidney, and heart was facilitated by the reversible conjugation to TAT47â57. In an in vitro cardiomyocyte study, the extent of ¹²5I-KAI-9803 internalization was greater at 37°C than that at 4°C, whereas the internalization of the ¹²5I-cargo peptide at 37°C was not observed, indicating that the uptake of ¹²5I-KAI-9803 into the cardiomyocytes was mediated by the TAT47â57 carrier. Our studies demonstrated that after a single intravenous administration, KAI-9803 can be delivered into the target cells in the liver, kidney, and heart by a TAT47â57-mediated mechanism.
Assuntos
Peptídeos/farmacocinética , Proteína Quinase C-delta/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacocinética , Animais , Autorradiografia/métodos , Peptídeos Penetradores de Células/metabolismo , Células Cultivadas , Produtos do Gene tat/metabolismo , Injeções Intravenosas , Masculino , Miócitos Cardíacos/metabolismo , Peptídeos/administração & dosagem , Proteína Quinase C-delta/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
BACKGROUND AND OBJECTIVE: Esaxerenone showed the potential to inhibit and induce activity against cytochrome P450 (CYP) 3A in in vitro studies. We investigated whether repeated administration of 5 mg/day esaxerenone for 14 days influences the pharmacokinetics of midazolam, a sensitive CYP3A substrate, in healthy Japanese males. METHODS: This single-centre, open-label, single-sequence study had two administration periods: period 1: single oral dose of 2 mg midazolam (day 0); period 2: repeated oral doses of 5 mg/day esaxerenone for 14 days, with a single oral dose of 2 mg midazolam on day 14. Full pharmacokinetic profiles of midazolam and 1-hydroxymidazolam on days 0 and 14 and safety data were obtained. Primary pharmacokinetic endpoints for midazolam were area under the plasma concentration-time curve (AUC) from zero to time of the last measurable concentration (AUClast), AUC from zero to infinity (AUCinf), and peak plasma concentration (Cmax). RESULTS: The study included 28 male subjects. One subject was withdrawn because of a mild adverse event (increased hepatic enzyme levels) that resolved without intervention. Repeated administration of esaxerenone increased midazolam AUClast, AUCinf, and Cmax by about 1.2-fold (1.201, 1.201, and 1.224, respectively) compared with administration of midazolam alone. However, repeated administration of esaxerenone did not affect the elimination half-life of midazolam (2.86 versus 2.63 h with and without esaxerenone). There were no safety concerns associated with concomitant administration of esaxerenone and midazolam. CONCLUSIONS: Esaxerenone 5 mg/day had no clinically significant effect on midazolam pharmacokinetics and was not associated with any safety issues. Esaxerenone can be concomitantly administered with drugs of CYP3A substrates without dose adjustments. CLINICAL TRIAL REGISTRATION: JapiCTI-152832.
Assuntos
Citocromo P-450 CYP3A/efeitos dos fármacos , Midazolam/farmacocinética , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Pirróis/farmacologia , Sulfonas/farmacologia , Administração Oral , Adulto , Área Sob a Curva , Povo Asiático , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Meia-Vida , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacocinética , Masculino , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Midazolam/análogos & derivados , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Sulfonas/administração & dosagem , Sulfonas/efeitos adversos , Adulto JovemRESUMO
Milademetan is a small-molecule inhibitor of murine double minute 2 (MDM2) that is in clinical development for advanced solid tumors and hematological cancers, including liposarcoma and acute myeloid leukemia. Milademetan is a CYP3A and P-glycoprotein substrate and moderate CYP3A inhibitor. The current study aims to understand the drug-drug interaction (DDI) risk of milademetan as a CYP3A substrate during its early clinical development. A clinical DDI study of milademetan (NCT03614455) showed that concomitant administration of single-dose milademetan with the strong CYP3A inhibitor itraconazole or posaconazole increased milademetan mean area under the curve from zero to infinity (AUCinf ) by 2.15-fold (90% confidence interval [CI], 1.98-2.34) and 2.49-fold (90% CI, 2.26-2.74), respectively, supporting that the milademetan dose should be reduced by 50% when concomitantly administered with strong CYP3A inhibitors. A physiologically-based pharmacokinetic (PBPK) model of milademetan was subsequently developed to predict the magnitude of CYP3A-mediated DDI potential of milademetan with moderate CYP3A inhibitors. The PBPK model predicted an increase in milademetan exposure of 1.72-fold (90% CI, 1.69-1.76) with fluconazole, 1.91-fold (90% CI, 1.83-1.99) with erythromycin, and 2.02-fold (90% CI, 1.93-2.11) with verapamil. In addition, it estimated that milademetan's original dose (160 mg once daily) could be resumed from its half-reduced dose 3 days after discontinuation of concomitant strong CYP3A inhibitors. The established PBPK model of milademetan was qualified and considered to be robust enough to support continued development of milademetan.
Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações Medicamentosas , Indóis/farmacocinética , Piridinas/farmacocinética , Pirrolidinas/farmacocinética , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Humanos , Indóis/administração & dosagem , Itraconazol/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Medição de Risco , Triazóis/administração & dosagemRESUMO
The aim of the current study is to identify the human cytochrome P450 (P450) isoforms involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. In the in vitro experiments using cDNA-expressed human P450 isoforms, clopidogrel was metabolized to 2-oxo-clopidogrel, the immediate precursor of its pharmacologically active metabolite. CYP1A2, CYP2B6, and CYP2C19 catalyzed this reaction. In the same system using 2-oxo-clopidogrel as the substrate, detection of the active metabolite of clopidogrel required the addition of glutathione to the system. CYP2B6, CYP2C9, CYP2C19, and CYP3A4 contributed to the production of the active metabolite. Secondly, the contribution of each P450 involved in both oxidative steps was estimated by using enzyme kinetic parameters. The contribution of CYP1A2, CYP2B6, and CYP2C19 to the formation of 2-oxo-clopidogrel was 35.8, 19.4, and 44.9%, respectively. The contribution of CYP2B6, CYP2C9, CYP2C19, and CYP3A4 to the formation of the active metabolite was 32.9, 6.76, 20.6, and 39.8%, respectively. In the inhibition studies with antibodies and selective chemical inhibitors to P450s, the outcomes obtained by inhibition studies were consistent with the results of P450 contributions in each oxidative step. These studies showed that CYP2C19 contributed substantially to both oxidative steps required in the formation of clopidogrel active metabolite and that CYP3A4 contributed substantially to the second oxidative step. These results help explain the role of genetic polymorphism of CYP2C19 and also the effect of potent CYP3A inhibitors on the pharmacokinetics and pharmacodynamics of clopidogrel in humans and on clinical outcomes.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Ticlopidina/análogos & derivados , Anticorpos/imunologia , Anticorpos/farmacologia , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/imunologia , Hidrocarboneto de Aril Hidroxilases/metabolismo , Biocatálise , Biotransformação/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Clopidogrel , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/imunologia , Citocromo P-450 CYP1A2/metabolismo , Inibidores do Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/imunologia , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/genética , Inibidores Enzimáticos/farmacologia , Glutationa/metabolismo , Humanos , Cetoconazol/farmacologia , Cinética , Mefenitoína/análogos & derivados , Mefenitoína/farmacologia , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , NADP/metabolismo , Omeprazol/farmacologia , Oxirredução , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/imunologia , Oxirredutases N-Desmetilantes/metabolismo , Inibidores da Agregação Plaquetária/metabolismo , Inibidores da Agregação Plaquetária/farmacocinética , Sulfafenazol/farmacologia , Teofilina/análogos & derivados , Teofilina/farmacologia , Ticlopidina/metabolismo , Ticlopidina/farmacocinéticaRESUMO
BACKGROUND: To investigate the effects of coadministration of esaxerenone with amlodipine on the pharmacokinetics (PK) of each drug, and of esaxerenone on the PK of digoxin. METHODS: In three open-label, single-sequence, crossover studies, healthy Japanese males received single oral doses of esaxerenone 2.5 mg (Days 1, 15), with amlodipine 10 mg/day (Days 8-18) (Study 1, N = 24); single doses of amlodipine 2.5 mg (Days 1, 21), with esaxerenone 5 mg/day (Days 8-25) (Study 2; N = 20); or digoxin 0.25 mg/day (Days 1-15) with esaxerenone 5 mg/day (Days 11-15) (Study 3; N = 20). PK parameters and safety were assessed. RESULTS: Study 1: esaxerenone peak plasma concentration (Cmax) and time to Cmax were unaltered by amlodipine coadministration, but mean half-life was slightly prolonged from 18.5 to 20.9 h. Geometric least-squares mean (GLSM) ratios for Cmax, area under the plasma concentration-time curve (AUC) from zero to last measurable concentration and from zero to infinity for esaxerenone + amlodipine versus esaxerenone were 0.958, 1.154, and 1.173, respectively. Study 2: corresponding GLSM ratios for amlodipine + esaxerenone versus amlodipine were 1.099, 1.185, and 1.214. Study 3: esaxerenone did not markedly alter digoxin PK. GLSM ratios for Cmax, trough plasma concentration, and AUC during a dosing interval for digoxin versus esaxerenone + digoxin were 1.130, 1.088, and 1.072, respectively. CONCLUSIONS: No drug-drug interactions are expected during combination therapy with esaxerenone and either amlodipine or digoxin, based on a lack of any clinically relevant PK changes. TRIAL REGISTRATION: Studies 1 and 2: JapicCTI-163379 (registered on 20 September 2016); Study 3: JapicCTI-163443 (registered on 24 November 2016).
Assuntos
Anlodipino/farmacocinética , Anti-Hipertensivos/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacocinética , Digoxina/farmacocinética , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Pirróis/farmacocinética , Sulfonas/farmacocinética , Adulto , Anlodipino/sangue , Anti-Hipertensivos/sangue , Povo Asiático , Bloqueadores dos Canais de Cálcio/sangue , Estudos Cross-Over , Digoxina/sangue , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/sangue , Pirróis/sangue , Sulfonas/sangue , Adulto JovemRESUMO
INTRODUCTION: The mineralocorticoid receptor (MR) blocker esaxerenone is a new treatment for hypertension in Japan and under development for treatment of diabetic nephropathy. Hepatic impairment is known to impact the pharmacokinetics (PKs) of other MR blocking drugs. The aim of the present study was to characterise the PKs and safety of a single oral dose of esaxerenone in Japanese subjects with mild-moderate hepatic impairment. METHODS: In this open-label, parallel-group study, subjects with mild (Child-Pugh grade A) or moderate (grade B) hepatic impairment, and healthy controls with normal hepatic function matched by age and BMI (all groups n = 6), received a single 2.5-mg oral dose of esaxerenone. Plasma concentrations were measured by liquid chromatography-tandem mass spectrometry, and PK parameters were calculated using non-compartmental analysis. RESULTS: Geometric least-squares mean (GLSM) ratios (90% confidence intervals [CIs]) for area under the plasma concentration-time curve (up to the last quantifiable time, up to infinity) in subjects with mild hepatic impairment versus normal hepatic function were 0.837 (0.637, 1.099) and 0.824 (0.622, 1.092), respectively. Corresponding values for moderate hepatic impairment versus normal hepatic function were 1.078 (0.820, 1.415) and 1.098 (0.829, 1.454). GLSM ratios (90% CIs) for peak plasma concentration (Cmax) were 0.959 (0.778, 1.182) for mild hepatic impairment versus normal hepatic function and 0.804 (0.653, 0.992) for moderate hepatic impairment versus normal hepatic function. Time to Cmax and clearance values were comparable between groups. The incidence of adverse events (AEs) was 16.7% in the moderate hepatic impairment and normal hepatic function groups. One serious AE (hepatic encephalopathy) occurred in one subject with moderate hepatic impairment. CONCLUSIONS: Mild to moderate hepatic impairment had no clinically relevant effect on esaxerenone exposure. Esaxerenone dosage adjustment based on PKs is unlikely to be needed in patients with mild to moderate hepatic impairment. TRIAL REGISTRATION: JapicCTI-163339. FUNDING: Daiichi Sankyo Co., Ltd.