RESUMO
Nirmatrelvir/ritonavir is a novel drug combination that is authorized by the Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19). Ritonavir is a cytochrome P450 3A inhibitor and a P-glycoprotein inhibitor that increases the plasma concentration of tacrolimus and other medications. We describe the cases of two patients treated with nirmatrelvir/ritonavir: a patient who had undergone kidney transplantation and another with a history of hematopoietic stem cell transplantation. Toxic concentrations of tacrolimus were induced in both. This case series highlights the risk associated with the concomitant administration of tacrolimus and nirmatrelvir/ritonavir.
Assuntos
Tratamento Farmacológico da COVID-19 , Interações Medicamentosas , Transplante de Rim , Ritonavir , Tacrolimo , Humanos , Ritonavir/uso terapêutico , Tacrolimo/uso terapêutico , Tacrolimo/efeitos adversos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Feminino , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Combinação de Medicamentos , COVID-19/virologia , Idoso , Antivirais/uso terapêuticoRESUMO
AIMS: The pharmacokinetics of doravirine has been studied in clinical trials but not in real-world settings. Our study aims to characterize and identify factors influencing doravirine (a CYP3A4 substrate) pharmacokinetics in real-world people with HIV (PWH). METHODS: A total of 174 doravirine concentrations measured in 146 PWH followed up in the therapeutic drug monitoring (TDM) program at the University Hospital of Lausanne (Switzerland) between 2019 and 2023 were included in the analysis. Demographic data, clinical information and comedications were recorded during the routine SHCS visits (every 3-6 months). Population pharmacokinetic analysis and Monte Carlo simulations to investigate the clinical significance of the covariates retained in the final model were performed using NONMEM. RESULTS: A one-compartment model with first-order absorption and linear elimination best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors and, to a lesser extent age, were the only tested covariates to significantly impact doravirine clearance (CL). Potent CYP3A4 inhibitors reduced CL by 50%, and a 30% decrease in CL was observed in an 80-year-old compared with a 55-year-old PWH. The effect of potent CYP3A4 inhibitors was prominent, explaining 59% of between-subject variability in CL. Model-based simulations predicted 2.8-fold and 1.6-fold increases in median steady-state trough and maximum doravirine concentrations, respectively, when a potent CYP3A4 inhibitor was co-administered. CONCLUSIONS: Our findings show that potent CYP3A4 inhibitors and age influence doravirine pharmacokinetics. However, given the good tolerability of doravirine, dosing adjustment of doravirine is probably not mandatory in those situations. TDM remains useful essentially in specific clinical situations, such as hepatic impairment, suspected nonadherence or pregnancy.
Assuntos
Infecções por HIV , Inibidores da Transcriptase Reversa , Triazóis , Humanos , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Piridonas/farmacocinética , Infecções por HIV/tratamento farmacológicoRESUMO
Coronaviruses pose a permanent risk of outbreaks, with three highly pathogenic species and strains (SARS-CoV, MERS-CoV, SARS-CoV-2) having emerged in the last twenty years. Limited antiviral therapies are currently available and their efficacy in randomized clinical trials enrolling SARS-CoV-2 patients has not been consistent, highlighting the need for more potent treatments. We previously showed that cobicistat, a clinically approved inhibitor of Cytochrome P450-3A (CYP3A), has direct antiviral activity against early circulating SARS-CoV-2 strains in vitro and in Syrian hamsters. Cobicistat is a derivative of ritonavir, which is co-administered as pharmacoenhancer with the SARS-CoV-2 protease inhibitor nirmatrelvir, to inhibit its metabolization by CPY3A and preserve its antiviral efficacy. Here, we used automated image analysis for a screening and parallel comparison of the anti-coronavirus effects of cobicistat and ritonavir. Our data show that both drugs display antiviral activity at low micromolar concentrations against multiple SARS-CoV-2 variants in vitro, including epidemiologically relevant Omicron subvariants. Despite their close structural similarity, we found that cobicistat is more potent than ritonavir, as shown by significantly lower EC50 values in monotherapy and higher levels of viral suppression when used in combination with nirmatrelvir. Finally, we show that the antiviral activity of both cobicistat and ritonavir is maintained against other human coronaviruses, including HCoV-229E and the highly pathogenic MERS-CoV. Overall, our results demonstrate that cobicistat has more potent anti-coronavirus activity than ritonavir and suggest that dose adjustments could pave the way to the use of both drugs as broad-spectrum antivirals against highly pathogenic human coronaviruses.
Assuntos
Infecções por Coronavirus , Coronavírus da Síndrome Respiratória do Oriente Médio , Humanos , Antivirais/uso terapêutico , Ritonavir/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Cobicistat/uso terapêuticoRESUMO
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral administration of single doses of brigatinib 30-240 mg, the median time to reach maximum plasma concentration ranged from 1 to 4 h. In patients with advanced malignancies, brigatinib showed dose linearity over the dose range of 60-240 mg once daily. A high-fat meal had no clinically meaningful effect on systemic exposures of brigatinib (area under the plasma concentration-time curve); thus, brigatinib can be administered with or without food. In a population pharmacokinetic analysis, a three-compartment pharmacokinetic model with transit absorption compartments was found to adequately describe brigatinib pharmacokinetics. In addition, the population pharmacokinetic analyses showed that no dose adjustment is required based on body weight, age, race, sex, total bilirubin (< 1.5× upper limit of normal), and mild-to-moderate renal impairment. Data from dedicated phase I trials have indicated that no dose adjustment is required for patients with mild or moderate hepatic impairment, while a dose reduction of approximately 40% (e.g., from 180 to 120 mg) is recommended for patients with severe hepatic impairment, and a reduction of approximately 50% (e.g., from 180 to 90 mg) is recommended when administering brigatinib to patients with severe renal impairment. Brigatinib is primarily metabolized by cytochrome P450 (CYP) 3A, and results of clinical drug-drug interaction studies and physiologically based pharmacokinetic analyses have demonstrated that coadministration of strong or moderate CYP3A inhibitors or inducers with brigatinib should be avoided. If coadministration with a strong or moderate CYP3A inhibitor cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (strong CYP3A inhibitor) or approximately 40% (moderate CYP3A inhibitor), respectively. Brigatinib is a weak inducer of CYP3A in vivo; data from a phase I drug-drug interaction study showed that coadministration of brigatinib 180 mg once daily reduced the oral midazolam area under the plasma concentration-time curve from time zero to infinity by approximately 26%. Brigatinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations in vitro. Exposure-response analyses based on data from the ALTA (ALK in Lung Cancer Trial of AP26113) and ALTA-1L pivotal trials of brigatinib confirm the favorable benefit versus risk profile of the approved titration dosing regimen of 180 mg once daily (after a 7-day lead-in at 90 mg once daily).
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinase do Linfoma Anaplásico , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
INTRODUCTION: Letermovir inhibits cytomegalovirus replication and is approved for the prevention of cytomegalovirus infection in cytomegalovirus seropositive hematopoietic cell transplantation recipients. Studies have found that letermovir coadministration has minimal effect on tacrolimus levels prior to the start of voriconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor. However, data are lacking for hematopoietic cell transplantation recipients receiving letermovir and tacrolimus with moderate CYP 3A4 inhibitors as antifungal prophylaxis. METHODS: In this retrospective single-center analysis, we reviewed the charts of 92 consecutive adult allogeneic hematopoietic cell transplantation recipients receiving letermovir, tacrolimus, and moderate CYP3A4 inhibitors for antifungal prophylaxis. RESULTS: Tacrolimus concentration/dose (C/D) ratios were evaluated for the first 7 days pre-letermovir and for the first and second 7-day periods after letermovir. The tacrolimus mean C/D ratios [(ng/mL)/(mg/kg/day)] increased significantly with the addition of letermovir: 172.99 (95% confidence interval (CI): 158.2-187.78) pre-letermovir, 268.66 (95% CI: 244.34-292.98) first-week letermovir, and 312.19 (95% CI: 279.39-344.99) second-week letermovir (P < 0.001). The average dosages (mg/kg) of tacrolimus also decreased significantly across the three-time intervals (P < 0.001). Only four patients experienced clinically significant cytomegalovirus reactivation which required systemic treatment. CONCLUSION: These results demonstrate a reduction in tacrolimus dosing requirements for patients receiving tacrolimus and letermovir with concomitant moderate CYP3A4 inhibitors. The results of this interaction suggest that frequent monitoring of tacrolimus trough levels is warranted when starting letermovir and that empiric reduction of tacrolimus dosing upon letermovir initiation should be considered.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Tacrolimo , Adulto , Humanos , Tacrolimo/uso terapêutico , Antifúngicos/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Estudos Retrospectivos , Antivirais/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Sistema Enzimático do Citocromo P-450RESUMO
PURPOSE: Non-vitamin K antagonist oral anticoagulants (NOACs) are excreted by P-glycoprotein (P-gp) and some are metabolized by CYP450 enzymes such as CYP3A4. Although fewer drug interactions are present with NOACs, it is unclear whether NOACs should also be preferred over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) using pharmacokinetically interacting drugs. Therefore, the benefit-risk profile of NOACs versus VKAs was investigated in AF patients treated with P-gp and/or CYP450-interacting drugs. METHODS: Using PubMed and Embase, randomized controlled trials and observational studies on the effectiveness and safety of NOACs versus VKAs in AF patients using P-gp and/or CYP450-interacting drugs were included. A meta-analysis was performed, calculating relative risks (RR) and 95% confidence intervals (CI) with the Mantel-Haenszel method. RESULTS: Twelve studies were included, investigating 10,793 NOAC and 10,096 VKA users treated with P-gp/CYP3A4 inhibitors, whereas no studies on P-gp and/or CYP450-inducing drugs were identified. Compared to VKAs, NOACs were associated with a borderline non-significantly lower stroke or systemic embolism (stroke/SE) risk (RR 0.85, 95%CI (0.72-1.01)), significantly lower intracranial bleeding (RR 0.47, 95%CI (0.34-0.65)) and all-cause mortality risks (RR 0.87, 95%CI (0.79-0.95), but significantly higher gastrointestinal bleeding risk (RR 1.74, 95%CI (1.06-2.86)). Among AF patients using amiodarone, NOACs were associated with significantly lower stroke/SE (RR 0.71, 95%CI (0.54-0.93)) and intracranial bleeding risks (RR 0.51, 95%CI (0.29-0.88)), but significantly higher gastrointestinal bleeding risk (RR 2.15, 95%CI (1.24-3.72)) than VKAs. CONCLUSION: The benefit-risk profile of NOACs compared to VKAs was preserved in AF patients using P-gp/CYP3A4 inhibitors, including amiodarone.
Assuntos
Amiodarona , Fibrilação Atrial , Embolia , Acidente Vascular Cerebral , Humanos , Varfarina/efeitos adversos , Anticoagulantes/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Administração Oral , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/prevenção & controle , Hemorragias Intracranianas/induzido quimicamente , Hemorragia Gastrointestinal/induzido quimicamente , Amiodarona/uso terapêuticoRESUMO
The favorable outcomes of venetoclax-based regimens in older adults with acute myeloid leukemia (AML) may result in its regimen becoming the standard treatment. However, the dosage of venetoclax is fixed, irrespective of body surface area (BSA) or weight. Therefore, individualized dosing using therapeutic drug monitoring (TDM) may help optimize treatment in a safe and effective manner. Twelve patients with AML who received venetoclax-based treatment were enrolled in this study. Blood samples were collected before venetoclax administration, and the minimum plasma concentration (Cmin) was evaluated. The concentration of venetoclax was evaluated using a simple, sensitive, and cost-effective assay using high-performance liquid chromatography, as described previously. The median age was 74 (70-85) years. Ten patients received venetoclax in combination with azacitidine and one patient received low-dose cytarabine (LDAC). The patients BSA ranged from 1.345 to 1.912 m2 (median 1.543). The dose of venetoclax was 400 mg with azacitidine, and 600 mg with LDAC. In four patients who were taking CYP3A4 inhibitors, venetoclax was reduced to 50 mg according to the prescribing information. The Cmin ranged from 0.39 to 2.49, and the patient taking itraconazole showed highest Cmin regardless of the reduction of venetoclax. Most patients showed higher Cmin compared to the data from previous clinical trials, and BSA and venetoclax concentrations showed a negative correlation. Many Asian AML patients > 75 years old are petite and receive CYP3A4 inhibitors. Therefore, the TDM of venetoclax may be useful.
Assuntos
Monitoramento de Medicamentos , Leucemia Mieloide Aguda , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Citarabina , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Humanos , Itraconazol , Leucemia Mieloide Aguda/induzido quimicamente , SulfonamidasRESUMO
Certain drugs inherently have unfavourable pharmacokinetic properties; for example, they are poorly absorbed or broken down too quickly in the liver. In some cases, the addition of a pharmacokinetic excipient, thus deliberately causing an interaction, may offer a solution. To date, this concept has been most widely applied in HIV treatment where addition of the CYP3A inhibitors ritonavir and cobicistat greatly increases plasma levels of other HIV medications. For the same reason, ritonavir has been added to the new oral antiviral drug against the SARS CoV-2 virus, nirmatrelvir. In addition to a better and/or longer effect, theoretically lower doses can also be used, resulting in cost savings. Deliberately inducing a pharmacokinetic interaction is not without risk: after all, interactions with other CYP3A substrates can also occur. Nevertheless, we believe that with good interaction management, CYP3A inhibitors can be used safely with benefits for patients and society.
Assuntos
Tratamento Farmacológico da COVID-19 , Infecções por HIV , Citocromo P-450 CYP3A/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Humanos , Ritonavir/farmacologia , Ritonavir/uso terapêuticoRESUMO
PURPOSE: Midostaurin, approved for the treatment of newly diagnosed, FLT3-mutated acute myeloid leukemia (AML), is metabolized by cytochrome P450 3A4 (CYP3A4). Midostaurin with concomitant strong CYP3A4 inhibitors use (e.g., antifungal azoles) may result in drug-drug interactions. This post hoc analysis of RATIFY phase 3 study data evaluated effects of strong CYP3A4 inhibitor use on the exposure and safety of midostaurin. METHODS: Trough concentrations were used to assess midostaurin and metabolite exposure in the presence and absence of strong CYP3A4 inhibitors. Adverse event (AE) frequency was assessed in patients who received concomitant strong CYP3A4 inhibitors vs those who did not. Time to first clinically notable AE (CNAE) was also assessed in patients with high midostaurin plasma exposure vs those of matched placebo controls. RESULTS: Use of concomitant strong CYP3A4 inhibitors was most frequent during the induction phase (60.8%). A 1.44-fold increase in midostaurin plasma exposure was observed in patients with concomitant strong CYP3A4 inhibitor use vs those without. Midostaurin-treated patients who received concomitant strong CYP3A4 inhibitors experienced grade 3/4 infection-related AEs more frequently vs those who did not. Patients with high levels of midostaurin exposure had a shorter median time to first grade 3/4 CNAE vs placebo controls (36 vs 41 days, respectively; P = .012). CONCLUSION: Although concomitantly administered strong CYP3A4 inhibitors increased midostaurin exposure 1.44-fold, no clinically relevant differences in safety were noted. Midostaurin dose adjustment is not necessary with concomitant strong CYP3A4 inhibitors in patients with FLT3-mutated AML; however, caution is advised, and patients should be closely monitored.
Assuntos
Inibidores do Citocromo P-450 CYP3A , Leucemia Mieloide Aguda , Citocromo P-450 CYP3A/genética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Interações Medicamentosas , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Inibidores de Proteínas Quinases , Estaurosporina/efeitos adversos , Estaurosporina/análogos & derivados , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
BACKGROUND: Persons living with human immunodeficiency virus are an underserved population for evidence-based cancer treatment. Paclitaxel and carboplatin (PCb) is an active regimen against a variety of solid tumors, including several seen in excess in patients with HIV infection. We performed a pilot trial to evaluate the safety of full-dose PCb in people living with human immunodeficiency virus and cancer. METHODS: Eligible patients, stratified by concurrent antiretroviral therapy (ART) that included CYP3A4 inhibitors or not, received paclitaxel (175 mg/m2) in combination with carboplatin (target AUC 6) intravenously every 3 weeks for up to 6 cycles. RESULTS: Sixteen evaluable patients received 64 cycles of PCb, including 6 patients treated with CYP3A4 inhibiting ART (ritonavir). The adverse event profile was consistent with the known toxicity profile of PCb, with no differences between the 2 strata. There were 4 partial responses (25%, 95% CI: 7%-52%), and overall, CD4+ lymphocyte count was similar after completion of therapy (median: 310/µL) compared with baseline values (median: 389/µL). Pharmacokinetic studies in 6 patients revealed no significant differences in Cmax or AUCinf for paclitaxel between the 2 cohorts. CONCLUSION: Full doses of PCb chemotherapy are tolerable when given concurrently with ART in people living with human immunodeficiency virus with cancer, including patients receiving CYP3A4 inhibitors. CLINICALTRIALS.GOV IDENTIFIER: NCT01249443.
Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Neoplasias , Síndrome da Imunodeficiência Adquirida/induzido quimicamente , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Paclitaxel/efeitos adversosAssuntos
Tratamento Farmacológico da COVID-19 , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Lactamas/uso terapêutico , Leucina/uso terapêutico , Nitrilas/uso terapêutico , Prolina/uso terapêutico , Ritonavir/uso terapêutico , Inibidores de Protease Viral/uso terapêutico , Administração Oral , Combinação de Medicamentos , Interações Medicamentosas , Humanos , SARS-CoV-2RESUMO
WHAT IS KNOWN AND OBJECTIVES: Although the apixaban Food and Drug Administration (FDA) package insert recommends dose reduction in patients administered dual strong inhibitors of p-glycoprotein (P-gp) and cytochrome P-450 (CYP) 3A4, there are limited published data regarding potential drug-drug interactions between apixaban (Eliquis) and common p-glycoprotein (P-gp) and CYP3A4 inhibitors co-administered with statins. The aim of this study was to investigate the degree of elevation relative to apixaban serum peak and trough concentration after the co-administration of amiodarone, diltiazem and statins (atorvastatin, rosuvastatin and simvastatin). METHODS: Patients prescribed apixaban 5mg twice daily for at least one week were identified from the anticoagulation clinic database and contacted for potential enrolment. A total of 117 volunteers were enrolled with eight excluded due to discontinued use, resulting in 109 volunteers (44 females and 65 males delineated into age groups 40-64 and ≥65 years old) completing the observational study. Fifty-five volunteers were administered apixaban without the P-gp inhibitors amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin and simvastatin). Fifty-four volunteers were administered apixaban with either amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin or simvastatin). Peak and trough concentrations were assessed for each patient utilizing an apixaban anti-Xa assay. RESULTS: Of the combinations studied, the mean apixaban trough concentration upon co-administration of amiodarone without a statin was elevated compared to apixaban alone (experimental 156.83 +/- 79.59 ng/ml vs. control 104.09 +/- 44.56 ng/ml; p = 0.04). The co-administration of diltiazem and rosuvastatin, and the administration of amiodarone without a statin led to greater than 1.5-fold increase in apixaban concentrations (peak experimental 315.19 +/- 157.53 ng/ml vs control 207.6 +/- 83.38 ng/ml; p = 0.08 and trough experimental 182.03 +/- 95.93 ng/ml vs control 112.32 +/- 37.78 ng/ml; p = 0.17) suggesting the need to assess dose adjustment for patients per the FDA package insert. In addition, the aggregated mean peak (p = 0.0056) and trough (p = 0.0089) elevation of CYP3A4 experimental groups (atorvastatin and simvastatin) co-administered apixaban and diltiazem were statistically significant compared with the aggregated non-CYP3A4 control groups (no statin and rosuvastatin). WHAT IS NEW AND CONCLUSION: Herein, we report novel data regarding peak and trough apixaban concentrations after concomitant administration of P-gp and CYP3A4 inhibitors (amiodarone or diltiazem) co-administered with statins (atorvastatin, rosuvastatin or simvastatin). Providers should consider utilizing the apixaban anti-Xa assay or comparative heparin anti-Xa assay to determine if patients require dose reduction to decrease adverse events in high-risk patients prescribed apixaban and concomitant p-glycoprotein and CYP3A4 inhibitors amiodarone or diltiazem with and without a CYP3A4 or non-3A4 statin.
Assuntos
Amiodarona , Inibidores de Hidroximetilglutaril-CoA Redutases , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Idoso , Amiodarona/uso terapêutico , Atorvastatina/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Diltiazem/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Sinvastatina/uso terapêuticoRESUMO
Prostate cancer is the second leading cause of cancer related death in American men. Several therapies have been developed to treat advanced prostate cancer, but these therapies often have severe side effects. To improve the outcome with fewer side effects we focused on the furanocoumarin bergamottin, a natural product found in grapefruit juice and a potent CYP3A inhibitor. Our recent studies have shown that CYP3A5 inhibition can block androgen receptor (AR) signaling, critical for prostate cancer growth. We observed that bergamottin reduces prostate cancer (PC) cell growth by decreasing both total and nuclear AR (AR activation) reducing downstream AR signaling. Bergamottin's role in reducing AR activation was confirmed by confocal microscopy studies and reduction in prostate specific antigen (PSA) levels, which is a marker for prostate cancer. Further studies revealed that bergamottin promotes cell cycle block and accumulates G0/G1 cells. The cell cycle block was accompanied with reduction in cyclin D, cyclin B, CDK4, P-cdc2 (Y15) and P-wee1 (S642). We also observed that bergamottin triggers apoptosis in prostate cancer cell lines as evident by TUNEL staining and PARP cleavage. Our data suggests that bergamottin may suppress prostate cancer growth, especially in African American (AA) patients carrying wild type CYP3A5 often presenting aggressive disease.
Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Furocumarinas/uso terapêutico , Fase G1/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Western Blotting , Fracionamento Celular , Linhagem Celular Tumoral , Citrus paradisi/química , Regulação para Baixo , Sucos de Frutas e Vegetais/análise , Humanos , Masculino , Microscopia Confocal , Receptores Androgênicos/efeitos dos fármacosRESUMO
PURPOSE: To examine the single- and multiple-dose pharmacokinetics (PK), CYP3A inhibition potential of ipatasertib, and effect of food on PK of ipatasertib in patients with refractory solid tumors and a dedicated food effect assessment in healthy subjects. METHODS: The Phase I dose-escalation study enrolled patients with solid tumors in a standard 3 + 3 design with a 1 week washout after the first dose, followed by once-daily dosing on a 3-week-on/1-week-off schedule. In the expansion cohort, the effect of ipatasertib on CYP3A substrate (midazolam) was assessed by examining the change in midazolam exposure when dosed in the absence and presence of steady-state ipatasertib at 600 mg. The effect of food on ipatasertib PK was studied with ipatasertib administered in fed or fasted state (6 patients from Phase I patient study and 18 healthy subjects from the dedicated food effect study). RESULTS: Ipatasertib was generally well tolerated at doses up to 600 mg given daily for 21 days. Ipatasertib showed rapid absorption (tmax, 0.5-3 h), was dose-proportional over a range of 200-800 mg, had a median half-life (range) of 45.0 h (27.8-66.9 h), and had approximately two-fold accumulation following once-daily dosing. Midazolam exposure (AUC0-∞) increased by 2.2-fold in the presence of ipatasertib. PK was comparable in subjects administered ipatasertib in a fed or fasted state. CONCLUSION: Ipatasertib exhibited rapid absorption and was dose-proportional over a broad dose range. Ipatasertib appeared to be a moderate CYP3A inhibitor when administered at 600 mg and could be administered with or without food in clinical studies. TRAIL REGISTRATION: NCT01090960 (registered March 23, 2010); NCT02536391 (registered August 31, 2015).
Assuntos
Antineoplásicos/uso terapêutico , Citocromo P-450 CYP3A/química , Interações Alimento-Droga , Neoplasias/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Estudos de Casos e Controles , Inibidores do Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Ingestão de Alimentos , Feminino , Seguimentos , Voluntários Saudáveis , Humanos , Masculino , Neoplasias/metabolismo , Neoplasias/patologia , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Prognóstico , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Distribuição TecidualRESUMO
Risdiplam (Evrysdi) improves motor neuron function in patients with spinal muscular atrophy (SMA) and has been approved for the treatment of patients ≥2 months old. Risdiplam exhibits time-dependent inhibition of cytochrome P450 (CYP) 3A in vitro. While many pediatric patients receive risdiplam, a drug-drug interaction (DDI) study in pediatric patients with SMA was not feasible. Therefore, a novel physiologically-based pharmacokinetic (PBPK) model-based strategy was proposed to extrapolate DDI risk from healthy adults to children with SMA in an iterative manner. A clinical DDI study was performed in healthy adults at relevant risdiplam exposures observed in children. Risdiplam caused an 1.11-fold increase in the ratio of midazolam area under the curve with and without risdiplam (AUCR)), suggesting an 18-fold lower in vivo CYP3A inactivation constant compared with the in vitro value. A pediatric PBPK model for risdiplam was validated with independent data and combined with a validated midazolam pediatric PBPK model to extrapolate DDI from adults to pediatric patients with SMA. The impact of selected intestinal and hepatic CYP3A ontogenies on the DDI susceptibility in children relative to adults was investigated. The PBPK analysis suggests that primary CYP3A inhibition by risdiplam occurs in the intestine rather than the liver. The PBPK-predicted risdiplam CYP3A inhibition risk in pediatric patients with SMA aged 2 months-18 years was negligible (midazolam AUCR of 1.09-1.18) and included in the US prescribing information of risdiplam. Comprehensive evaluation of the sensitivity of predicted CYP3A DDI on selected intestinal and hepatic CYP3A ontogeny functions, together with PBPK model-based strategy proposed here, aim to guide and facilitate DDI extrapolations in pediatric populations.
Assuntos
Compostos Azo/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Interações Medicamentosas/fisiologia , Modelos Biológicos , Atrofia Muscular Espinal/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Compostos Azo/farmacocinética , Criança , Pré-Escolar , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Midazolam/farmacocinética , Midazolam/uso terapêutico , Atrofia Muscular Espinal/metabolismo , Fármacos Neuromusculares/farmacocinética , Pirimidinas/farmacocinética , Adulto JovemRESUMO
Depot medroxyprogesterone acetate is an injectable hormonal contraceptive, widely used by women of childbearing potential living with HIV and/or tuberculosis. As medroxyprogesterone acetate is a cytochrome P450 (CYP3A4) substrate, drug-drug interactions (DDIs) with antiretroviral or antituberculosis treatment may lead to subtherapeutic medroxyprogesterone acetate concentrations (< 0.1 ng/mL), resulting in contraception failure, when depot medroxyprogesterone is dosed at 12-week intervals. A pooled population pharmacokinetic analysis with 744 plasma medroxyprogesterone acetate concentrations from 138 women treated with depot medroxyprogesterone and antiretroviral/antituberculosis treatment across three clinical trials was performed. Monte Carlo simulations were performed to predict the percentage of participants with subtherapeutic medroxyprogesterone acetate concentrations and to derive alternative dosing strategies. Medroxyprogesterone acetate clearance increased by 24.7% with efavirenz coadministration. Efavirenz plus antituberculosis treatment (rifampicin + isoniazid) increased clearance by 52.4%. Conversely, lopinavir/ritonavir and nelfinavir decreased clearance (28.7% and 15.8%, respectively), but lopinavir/ritonavir also accelerated medroxyprogesterone acetate's appearance into the systemic circulation, thus shortening the terminal half-life. A higher risk of subtherapeutic medroxyprogesterone acetate concentrations at Week 12 was predicted on a typical 60-kg woman on efavirenz (4.99%) and efavirenz with antituberculosis treatment (6.08%) when compared with medroxyprogesterone acetate alone (2.91%). This risk increased in women with higher body weight. Simulations show that re-dosing every 8 to 10 weeks circumvents the risk of subtherapeutic medroxyprogesterone acetate exposure associated with these DDIs. Dosing depot medroxyprogesterone every 8 to 10 weeks should eliminate the risk of subtherapeutic medroxyprogesterone acetate exposure caused by coadministered efavirenz and/or antituberculosis treatment, thus reducing the risk of contraceptive failure.
Assuntos
Antirretrovirais/uso terapêutico , Antituberculosos/uso terapêutico , Contraceptivos Hormonais/farmacocinética , Indutores do Citocromo P-450 CYP3A/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Acetato de Medroxiprogesterona/farmacocinética , Alcinos/uso terapêutico , Benzoxazinas/uso terapêutico , Contraceptivos Hormonais/administração & dosagem , Eficácia de Contraceptivos , Ciclopropanos/uso terapêutico , Preparações de Ação Retardada , Esquema de Medicação , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Isoniazida/uso terapêutico , Lopinavir/uso terapêutico , Acetato de Medroxiprogesterona/administração & dosagem , Nelfinavir/uso terapêutico , Rifampina/uso terapêutico , Ritonavir/uso terapêutico , Tuberculose/tratamento farmacológicoRESUMO
Based on the in vitro profile of bedaquiline against mycobacterial species, it is being investigated for clinical efficacy against pulmonary nontuberculous mycobacteria (PNTM). Being a cytochrome P450 3A substrate, pharmacokinetic interactions of bedaquiline are anticipated with clarithromycin (a cytochrome P450 3A inhibitor), which is routinely used in pulmonary nontuberculous mycobacteria treatment. This phase 1, randomized, crossover study assessed the impact of steady-state clarithromycin (500 mg every 12 hours for 14 days) on the pharmacokinetics of bedaquiline and its metabolite (M2) after single-dose bedaquiline (100 mg; n = 16). Using these data, population pharmacokinetic modeling and simulation analyses were performed to determine the effect of clarithromycin on steady-state bedaquiline exposure. Although no effect was observed on maximum plasma concentration of bedaquiline and time to achieve maximum plasma concentration, its mean plasma exposure increased by 14% after 10 days of clarithromycin coadministration, with slower formation of M2. Simulations showed that bedaquiline plasma trough concentration at steady state was higher (up to 41% until week 48) with clarithromycin coadministration as compared to its monotherapy (400 mg once daily for 2 weeks, followed by 200 mg 3 times a week for 46 weeks; reference regimen). The overall exposure of a simulated bedaquiline regimen (400 mg once dialy for 2 weeks, followed by 200 mg twice a week for 46 weeks) with clarithromycin was comparable (<15% difference) to the monotherapy. Overall, combination of bedaquiline (400 mg once daily for 2 weeks, followed by 200 mg twice a week for 46 weeks) with clarithromycin seems a suitable regimen to be explored for efficacy and safety against pulmonary nontuberculous mycobacteria.
Assuntos
Antibacterianos/farmacologia , Antituberculosos/farmacocinética , Claritromicina/farmacologia , Diarilquinolinas/farmacocinética , Adulto , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Antituberculosos/uso terapêutico , Claritromicina/farmacocinética , Claritromicina/uso terapêutico , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Diarilquinolinas/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas/efeitos dos fármacosRESUMO
PURPOSE: Pamiparib is an investigational, selective, oral poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that has demonstrated PARP-DNA complex trapping and CNS penetration in preclinical models, as well as preliminary anti-tumor activity in early-phase clinical studies. We investigated whether the single-dose pharmacokinetic (PK) profile of pamiparib is altered by coadministration of a strong CYP3A inducer (rifampin) or a strong CYP3A inhibitor (itraconazole) in patients with solid tumors. METHODS: In this open-label, phase 1 study, adults with advanced solid tumors received either oral pamiparib 60 mg (days 1 and 10) and once-daily oral rifampin 600 mg (days 3-11) or oral pamiparib 20 mg (days 1 and 7) and once-daily oral itraconazole 200 mg (days 3-8). Primary endpoints included pamiparib maximum observed concentration (Cmax), and area under the plasma concentration-time curve from zero to last quantifiable concentration (AUC0-tlast) and infinity (AUC0-inf). Secondary endpoints included safety and tolerability. RESULTS: Rifampin coadministration did not affect pamiparib Cmax (geometric least-squares [GLS] mean ratio 0.94; 90% confidence interval 0.83-1.06), but reduced its AUC0-tlast (0.62 [0.54-0.70]) and AUC0-inf (0.57 [0.48-0.69]). Itraconazole coadministration did not affect pamiparib Cmax (1.05 [0.95-1.15]), AUC0-tlast (0.99 [0.91-1.09]), or AUC0-inf (0.99 [0.90-1.09]). There were no serious treatment-related adverse events. CONCLUSIONS: Pamiparib plasma exposure was reduced 38-43% with rifampin coadministration but was unaffected by itraconazole coadministration. Pamiparib dose modifications are not considered necessary when coadministered with CYP3A inhibitors. Clinical safety and efficacy data will be used with these results to recommend dose modifications when pamiparib is coadministered with CYP3A inducers.
Assuntos
Indutores do Citocromo P-450 CYP3A/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Fluorenos/farmacocinética , Fluorenos/uso terapêutico , Itraconazol/uso terapêutico , Neoplasias/tratamento farmacológico , Rifampina/uso terapêutico , Adulto , Idoso , Área Sob a Curva , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Shengmai San (SMS) has been commonly used as a traditional Chinese medicine for the treatment of cardiovascular disorders, of which drug interactions need to be assessed for the safety concern. There is little evidence for the alterations of hepatic and intestinal drug-metabolizing enzymes after repeated SMS treatments to assess drug interactions. AIM OF THE STUDY: The studies aim to illustrate the effects of repeated treatments with SMS on cytochrome P450s (CYPs), reduced nicotinamide adenine dinucleotide (phosphate)-quinone oxidoreductase (NQO), uridine diphosphate-glucuronosyltransferase (UGT), and glutathione S-transferase (GST) using in vivo rat model. MATERIALS AND METHODS: The SMS was prepared using Schisandrae Fructus, Ginseng Radix, and Ophiopogonis Radix (OR) (1:2:2). Chromatographic analyses of decoctions were performed using ultra-performance liquid chromatography (UPLC) and LC-mass spectrometry. Sprague-Dawley rats were orally treated with the SMS and its component herbal decoctions for 2 or 3 weeks. Hepatic and intestinal enzyme activities were determined. CYP3A expression and the kinetics of intestinal nifedipine oxidation (NFO, a CYP3A marker reaction) were determined. RESULTS: Schisandrol A, schisandrin B, ginsenoside Rb1 and ophiopogonin D were identified in SMS. SMS selectively suppressed intestinal, but not hepatic, NFO activity in a dose- and time-dependent manner. Hepatic and intestinal UGT, NQO and GST activities were not affected. A 3-week SMS treatment decreased the maximal velocity of intestinal NFO by 50%, while the CYP3A protein level remained unchanged. Among SMS component herbs, the decoction of OR decreased intestinal NFO activity. CONCLUSIONS: These findings demonstrate that 3-week treatment with SMS and OR suppress intestinal, but not hepatic CYP3A function. It suggested that the potential interactions of SMS with CYP 3A drug substrates should be noticed, especially the drugs whose bioavailability depends heavily on intestinal CYP3A.
Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Intestinos/enzimologia , Fígado/enzimologia , Animais , Biomarcadores/sangue , Ciclo-Octanos/análise , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/análise , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/uso terapêutico , Ginsenosídeos/análise , Glucuronosiltransferase/metabolismo , Glutationa Transferase/metabolismo , Interações Ervas-Drogas , Intestinos/efeitos dos fármacos , Lignanas/análise , Fígado/efeitos dos fármacos , Masculino , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Nifedipino/metabolismo , Oxirredução/efeitos dos fármacos , Compostos Policíclicos/análise , Ratos Sprague-Dawley , Saponinas/química , Espirostanos/químicaRESUMO
An outbreak of coronavirus disease 2019 (COVID-19) that began in Wuhan, China, has spread rapidly to many countries. We herein report four cases of COVID-19 confirmed in Japan among passengers of the cruise ship Diamond Princess and describe the clinical features, clinical course, and progression of chest computed tomographic images, chest radiographs, and treatment. Although these four patients had symptoms that included a fever, malaise, runny nose, and cough, one patient had no symptoms on admission. Two of the four patients needed mechanical ventilation due to respiratory deterioration. One of the patients who required mechanical ventilation was transferred to a higher-level medical institution. Except for that patient, the other three patients were able to return home under their own power. Every patient took lopinavir/ritonavir, which was considered the most effective treatment at the time. We used it after receiving approval from the ethics committee in our hospital. In this case report, we emphasize that some patients need to be carefully monitored, even if their respiratory condition is stable at the initial presentation, as their respiratory status may deteriorate rapidly within a few days after oxygen administration begins.