RESUMO
Tuberculosis (TB) is the deadliest infectious disease worldwide. The design of new treatments for TB is hindered by the large number of candidate drugs, drug combinations, dosing choices, and complex pharmaco-kinetics/dynamics (PK/PD). Here we study the interplay of these factors in designing combination therapies by linking a machine-learning model, INDIGO-MTB, which predicts in vitro drug interactions using drug transcriptomics, with a multi-scale model of drug PK/PD and pathogen-immune interactions called GranSim. We calculate an in vivo drug interaction score (iDIS) from dynamics of drug diffusion, spatial distribution, and activity within lesions against various pathogen sub-populations. The iDIS of drug regimens evaluated against non-replicating bacteria significantly correlates with efficacy metrics from clinical trials. Our approach identifies mechanisms that can amplify synergistic or mitigate antagonistic drug interactions in vivo by modulating the relative distribution of drugs. Our mechanistic framework enables efficient evaluation of in vivo drug interactions and optimization of combination therapies.
Assuntos
Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , Interações Medicamentosas , Transcriptoma/genética , Tuberculose/tratamento farmacológico , Antibacterianos/uso terapêutico , Ensaios Clínicos como Assunto , Simulação por Computador , Granuloma/tratamento farmacológico , Humanos , Cinética , Taxa de Depuração Metabólica/efeitos dos fármacosRESUMO
Metabolic deactivation by cytochrome P450 (CYP) is considered a potential mechanism of anticancer drug resistance. However, this hypothesis is predominantly based on indirect pieces of evidence and/or is influenced by interfering factors such as the use of multienzymatic models. Thus, an experimental approach for its verification is needed. In the present work, we employed HepG2 cells transduced with CYP enzymes involved in docetaxel, paclitaxel and vincristine metabolism to provide mechanistic evidence on their possible roles in resistance to these chemotherapeutic agents. Using MTT proliferation tests, we showed that overexpression of CYP3A4 resulted in decreased antiproliferative activity of 1 µM docetaxel (by 11.2, 23.2 and 22.9% at 24, 48 and 72 h intervals, respectively), while the sensitivity of CYP3A4-transduced cells was restored by co-administration of ketoconazole. Paclitaxel exhibited differential efficacy in CYP2C8- and empty vector-transduced cells (significant differences between 10.9 and 24.4% for 0.01, 0.1 and 1 µM concentrations), but neither montelukast nor clotrimazole was capable of affecting this asymmetry. Finally, the pharmacological activity of vincristine was not influenced by CYP3A4 or CYP3A5 overexpression. In the follow-up caspase activation assays, docetaxel was confirmed to be a victim of CYP3A4-mediated resistance, which is, at least partly, brought by impaired activation of caspases 3/7, 8 and 9. In summary, our data demonstrate that CYP3A4-mediated metabolic deactivation of docetaxel might represent a significant mechanism of pharmacokinetic resistance to this drug. In contrast, the possible role of CYPs in resistance to paclitaxel and vincristine has been disconfirmed. Importantly, the expression of CYP3A4 in HepG2_CYP3A4 cells is comparable to that in primary hepatocytes and HepaRG cells, which suggests that our results might be relevant for in vivo conditions, e.g., for hepatocellular carcinoma. Thus, our data may serve as a valuable in vitro background for future in vivo studies exploring the area of intratumoural metabolism-based drug resistance.
Assuntos
Antineoplásicos/farmacologia , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Citostáticos/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inativação Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/efeitos dos fármacosRESUMO
Intestinal cytochrome P450 3A (CYP3A) plays an important role in oral drug metabolism, but only endogenous metabolic markers for measuring hepatic CYP3A activity were identified. Our study evaluated whether hepatic CYP3A markers reflected intestinal CYP3A activity. An open-label, three-period, six-treatment, one-sequence clinical trial was performed in 16 healthy Korean males. In the control phase, all subjects received a single dose of intravenous (IV) and oral midazolam (1 mg and 5 mg, respectively). Clarithromycin (500 mg) was administered twice daily for 4 days to inhibit hepatic and intestinal CYP3A, and 500 mL of grapefruit juice was given to inhibit intestinal CYP3A. Clarithromycin significantly inhibited total CYP3A activity, and the clearance of IV and apparent clearance of oral midazolam decreased by 0.15- and 0.32-fold, respectively. Grapefruit juice only reduced the apparent clearance of oral midazolam by 0.84-fold, which indicates a slight inhibition of intestinal CYP3A activity. Urinary markers, including 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone, were significantly decreased 0.5-fold after clarithromycin administration but not after grapefruit juice. The fold changes in 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone did not correlate to changes in intestinal availability but did correlate to hepatic availability. In conclusion, endogenous metabolic markers are only useful to measure hepatic, but not intestinal, CYP3A activity.
Assuntos
Citrus paradisi/metabolismo , Claritromicina/urina , Citocromo P-450 CYP3A/urina , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Midazolam/urina , Administração Intravenosa , Administração Oral , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Claritromicina/administração & dosagem , Claritromicina/sangue , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/genética , Interações Alimento-Droga/fisiologia , Voluntários Saudáveis , Humanos , Mucosa Intestinal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Midazolam/administração & dosagem , Midazolam/sangueRESUMO
A computational model was developed to better understand the impact of elevated skin temperatures on transdermal drug delivery and dermal clearance. A simultaneous heat and mass transport model with emphasis on transdermal delivery system (TDS) applications was developed to address transient and steady-state temperature effects on dermal absorption. The model was tested using representative data from nicotine TDS applied to human skin either in vitro or in vivo. The approximately 2-fold increase of nicotine absorption with a 10°C increase in skin surface temperature was consistent with a 50-65 kJ/mol activation energy for diffusion in the stratum corneum, with this layer serving as the primary barrier for nicotine absorption. Incorporation of a dermal clearance component into the model revealed efficient removal of nicotine via the dermal capillaries at both normal and elevated temperatures. Two-compartment pharmacokinetic simulations yielded systemic drug concentrations consistent with the human pharmacokinetic data. Both in vitro skin permeation and in vivo pharmacokinetics of nicotine delivered from a marketed TDS under normal and elevated temperatures can be satisfactorily described by a simultaneous heat and mass transfer computational model incorporating realistic skin barrier properties and dermal clearance components.
Assuntos
Nicotina/administração & dosagem , Nicotina/metabolismo , Modelagem Computacional Específica para o Paciente , Absorção Cutânea/efeitos dos fármacos , Temperatura Cutânea/efeitos dos fármacos , Administração Cutânea , Administração Tópica , Capilares/efeitos dos fármacos , Capilares/metabolismo , Humanos , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Absorção Cutânea/fisiologia , Temperatura Cutânea/fisiologia , Adesivo TransdérmicoRESUMO
Vancomycin (VAN) is an anti-microbial agent used to treat a number of bacterial infections, which has a high incidence of nephrotoxicity. We examined the pharmacokinetics of VAN retrospectively based on trough concentrations at large scale and identified pharmacokinetic differences between Japanese patients having solid malignancy and non-malignancy patients. Data were analyzed from 162 solid malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN. We failed to detect differences in values for VAN clearance or shorter elimination half-lives between these two groups. In contrast, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to solid malignancies in each stage. We conclude that VAN clearance in solid malignancy patients is increased and that the blood concentration of VAN becomes lower than expected. These results suggest that early monitoring of VAN levels in solid malignancy patients might be essential for maintaining desired effects without side-effects.
Assuntos
Antibacterianos/sangue , Monitoramento de Medicamentos/métodos , Neoplasias/sangue , Vancomicina/sangue , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Estudos Retrospectivos , Vancomicina/uso terapêuticoRESUMO
Context: Both nobiletin (NBL) and glycyrrhizin (GL) have anti-inflammatory and antitumor properties. These agents may be co-administered in the clinic. However, the drug-drug interaction between them is not clear.Objective: The drug-drug interaction between GL and NBL was investigated, to clarify the effect of GL on the pharmacokinetics of NBL, and its main mechanism.Materials and methods: The pharmacokinetic profiles of oral administration of NBL (50 mg/kg) in Sprague-Dawley rats of two groups with six each, with or without pre-treatment of GL (100 mg/kg/day for 7 days), were investigated. The effects of GL on the metabolic stability and transport of NBL were also investigated through the rat liver microsome and Caco-2 cell transwell models.Results: The results showed that GL significantly decreased the peak plasma concentration (from 1.74 ± 0.15 to 1.12 ± 0.10 µg/mL) and the t1/2 (7.44 ± 0.65 vs. 5.92 ± 0.68) of NBL, and the intrinsic clearance rate of NBL was increased by the pre-treatment with GL (39.49 ± 2.5 vs. 48.29 ± 3.4 µL/min/mg protein). The Caco-2 cell transwell experiments indicated that GL could increase the efflux ratio of NBL from 1.61 to 2.41.Discussion and conclusion: These results indicated that GL could change the pharmacokinetic profile of NBL, via increasing the metabolism and efflux of NBL in rats. It also suggested that the dose of NBL should be adjusted when co-administrated with GL in the clinic.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacocinética , Flavonas/farmacocinética , Ácido Glicirrízico/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Antineoplásicos/administração & dosagem , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Medicamentos de Ervas Chinesas , Flavonas/administração & dosagem , Ácido Glicirrízico/administração & dosagem , Humanos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Lower clearance of immune checkpoint inhibitors is a predictor of improved overall survival (OS) in patients with advanced cancer. We investigated a novel approach using machine learning to identify a baseline composite cytokine signature via clearance, which, in turn, could be associated with OS in advanced melanoma. Peripheral nivolumab clearance and cytokine data from patients treated with nivolumab in two phase III studies (n = 468 (pooled)) and another phase III study (n = 158) were used for machine-learning model development and validation, respectively. Random forest (Boruta) algorithm was used for feature selection and classification of nivolumab clearance. The 16 top-ranking baseline inflammatory cytokines reflecting immune-cell modulation were selected as a composite signature to predict nivolumab clearance (area under the curve (AUC) = 0.75; accuracy = 0.7). Predicted clearance (high vs. low) via the cytokine signature was significantly associated with OS across all three studies (P < 0.01), regardless of treatment (nivolumab vs. chemotherapy).
Assuntos
Antineoplásicos Imunológicos/sangue , Citocinas/sangue , Aprendizado de Máquina , Melanoma/sangue , Nivolumabe/sangue , Neoplasias Cutâneas/sangue , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Prognóstico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
BACKGROUND: Fat-free mass has gained wide acceptance as a scaler of the maintenance dose rate in obese patients. The choice of fat-free mass as a size scaler for the maintenance dose rate is based on its relationship with drug clearance, on the basis that only lean tissue is sufficiently metabolically active to provide capacity for elimination. For xenobiotics, the majority of biotransformation occurs in the liver and hence fat-free mass is implied to scale linearly with the component of liver that is metabolically active. The liver, like the body, can be assumed to comprise two components, lean mass and fat mass. We expect the lean liver mass (or volume) to be the component that most closely relates to drug clearance. OBJECTIVE: The objective of this study was to investigate the relationship of lean liver volume and fat-free mass. METHODS: Total liver volume and liver fat volume were measured in 100 Indian adults by computed tomography. Lean liver volume was derived as the difference between the two measurements (as liver volume - liver fat volume). Covariate modelling to describe lean liver volume, using NONMEM version 7.3, involved testing the influence of body weight, sex, body surface area and fat-free mass with or without allometric scaling (by estimating the exponent) and the influence of clinical chemistry variables. RESULTS: The final model did not exclude a linear relationship between lean liver volume and fat-free mass, while allometric scaling by body weight0.75 was also supported by the data. While scaling by fat-free mass, the coefficient of proportionality (i.e. lean liver volume per kg fat-free mass) was higher in female (31.25 mL) than male (25.81 mL) subjects. CONCLUSIONS: A model to predict lean liver volume from readily available patient data was developed and evaluated. Fat-free mass plus sex was found to be the best body descriptor to scale lean liver volume. The utility of this model in scaling drug clearance and dose requirements of hepatically cleared drugs needs further exploration.
Assuntos
Fígado/metabolismo , Taxa de Depuração Metabólica/efeitos dos fármacos , Obesidade/metabolismo , Xenobióticos/farmacocinética , Adulto , Idoso , Biotransformação , Composição Corporal , Distribuição da Gordura Corporal , Índice de Massa Corporal , Superfície Corporal , Peso Corporal , Feminino , Humanos , Índia/epidemiologia , Fígado/anatomia & histologia , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Valor Preditivo dos Testes , Prevalência , Tomografia Computadorizada por Raios X/métodosRESUMO
Context: Oridonin has been traditionally used in Chinese treatment of various cancers, but its poor bioavailability limits its therapeutic uses. Verapamil can enhance the absorption of some drugs with poor oral bioavailability. Whether verapamil can enhance the bioavailability of oridonin is still unclear.Objective: This study investigated the effect of verapamil on the pharmacokinetics of oridonin in rats and clarified its main mechanism.Materials and methods: The pharmacokinetic profiles of oral administration of oridonin (20 mg/kg) in Sprague-Dawley rats with two groups of six animals each, with or without pre-treatment of verapamil (10 mg/kg/day for 7 days) were investigated. The effects of verapamil on the transport and metabolic stability of oridonin were also investigated using Caco-2 cell transwell model and rat liver microsomes.Results: The results showed that verapamil could significantly increase the peak plasma concentration (from 146.9 ± 10.17 to 193.97 ± 10.53 ng/mL), and decrease the oral clearance (from 14.69 ± 4.42 to 8.09 ± 3.03 L/h/kg) of oridonin. The Caco-2 cell transwell experiments indicated that verapamil could decrease the efflux ratio of oridonin from 1.67 to 1.15, and the intrinsic clearance rate of oridonin was decreased by the pre-treatment with verapamil (40.06 ± 2.5 vs. 36.09 ± 3.7 µL/min/mg protein).Discussion and conclusions: These results indicated that verapamil could significantly change the pharmacokinetic profile of oridonin in rats, and it might exert these effects through increasing the absorption of oridonin by inhibiting the activity of P-gp, or through inhibiting the metabolism of oridonin in rat liver. In addition, the potential drug-drug interaction should be given special attention when verapamil is used with oridonin. Also, the dose of oridonin should be carefully selected in the clinic.
Assuntos
Diterpenos do Tipo Caurano/metabolismo , Diterpenos do Tipo Caurano/farmacocinética , Verapamil/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Interações Medicamentosas , Humanos , Taxa de Depuração Metabólica/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Verapamil/sangueRESUMO
PURPOSE: Ruxolitinib is metabolized by cytochrome P450 (CYP)3A4 and CYP2C9. Dual inhibitors of these enzymes (like fluconazole) lead to increased ruxolitinib exposure relative to a single pathway inhibition of CYP3A4 or CYP2C9. The magnitude of this interaction, previously assessed via physiologically based pharmacokinetic (PBPK) models, was confirmed in an open-label, phase 1 study in healthy subjects. METHODS: The effect of multiple doses (200 mg) of fluconazole on single-dose (10 mg) PK of ruxolitinib was investigated including evaluation of the safety and tolerability. The PK parameters of ruxolitinib alone (reference) were compared to those of ruxolitinib combined with fluconazole (test). The point estimate and corresponding two-sided 90% confidence interval for the difference between means of test and reference parameters were determined. RESULTS: All enrolled subjects (N = 15) completed the study. When coadministered with fluconazole, geometric means of ruxolitinib PK parameters Cmax, AUClast, and AUCinf increased by 47%, 234%, and 232%, respectively, vs ruxolitinib alone. The median Tmax decreased slightly, apparent clearance decreased approximately threefold, and elimination half-life increased approximately 2.5-fold, upon ruxolitinib administration with fluconazole vs ruxolitinib alone. These results were consistent with the prospective predictions from a SimCYP PBPK model. Adverse events (AEs) were reported in six subjects (none were suspected to be related to ruxolitinib); no death or on-treatment serious AE was reported. CONCLUSIONS: Coadministration of ruxolitinib with fluconazole significantly increased ruxolitinib systemic exposure; however, no AEs were attributed to ruxolitinib. Concomitant use of ruxolitinib with fluconazole (dose ≤ 200 mg) may require dose reduction/modification of ruxolitinib.
Assuntos
Relação Dose-Resposta a Droga , Fluconazol/farmacocinética , Taxa de Depuração Metabólica/efeitos dos fármacos , Pirazóis/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Adulto , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Esquema de Medicação , Interações Medicamentosas , Inibidores Enzimáticos/farmacocinética , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Nitrilas , PirimidinasRESUMO
Sulbactam-durlobactam is being developed for the treatment of infections caused by Acinetobacter baumannii, including those caused by multidrug- and carbapenem-resistant isolates. This was a phase 1 study to evaluate the effects of various degrees of renal impairment, including subjects with end-stage renal disease (ESRD) on hemodialysis (HD), on the pharmacokinetics and safety profile of durlobactam (also known as ETX2514) and sulbactam after single intravenous (i.v.) dose administration. For healthy subjects and those with mild or moderate renal impairment (RI), single 1,000-mg doses each of durlobactam and sulbactam via a 3-h i.v. infusion were administered, and for severe renal impairment, 500-mg doses were administered. For subjects with ESRD and HD, 500-mg i.v. doses each of durlobactam and sulbactam were administered post-HD and pre-HD, with a 1-week washout between doses. Among 34 subjects, decreasing renal function increased systemic exposure (peak plasma concentration [Cmax] and area under the concentration-time curve [AUC]) to durlobactam and sulbactam in a generally linear manner. In healthy subjects and in those with mild or moderate renal impairment, the majority of durlobactam and sulbactam was excreted in the urine, while approximately 40% or less was excreted in urine in subjects with severe renal impairment or ESRD. In subjects with ESRD, hemodialysis was effective at removing both durlobactam and sulbactam from plasma. Renal impairment had no effect of the safety/tolerability profile of durlobactam and sulbactam. In summary, RI and ESRD had a predictable effect on the pharmacokinetic (PK) profile of durlobactam and sulbactam with no adverse effects on the safety/tolerability profile. Durlobactam and sulbactam are cleared to a similar extent by renal elimination and are impacted similarly by renal impairment. The results from this study have been used with population PK modeling and nonclinically derived PK/PD (pharmacodynamic) exposure targets to establish dosage recommendations for durlobactam and sulbactam in patients with various degrees of RI. The dosing regimen of durlobactam-sulbactam will require adjustment in patients with severe renal insufficiency and in those with ESRD.
Assuntos
Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/efeitos adversos , Sulbactam/administração & dosagem , Sulbactam/efeitos adversos , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/patogenicidade , Administração Intravenosa , Idoso , Área Sob a Curva , Compostos Azabicíclicos/uso terapêutico , Feminino , Humanos , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/metabolismo , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/metabolismo , Sulbactam/uso terapêuticoRESUMO
The study examined the effect of doxorubicin (DOX) on the hepatic expression of CYP2C and its activity for metabolizing tolbutamide (TB), a specific CYP2C substrate, in rats and whether the pharmacokinetics of tolbutamide were altered by doxorubicin exposure. The expression level of hepatic CYP2C11 was depressed 1 day after doxorubicin administration (day 1), and this effect on CYP2C11 was augmented on day 4. However, the expression level of hepatic CYP2C6 remained unchanged. The activity of tolbutamide 4-hydroxylation in hepatic microsomes was decreased with time following doxorubicin administration. Regarding the enzyme kinetic parameters for tolbutamide 4-hydroxylation on day 4, the maximum velocity (Vmax ) was significantly lower in the DOX group than that in the control group, while the Michaelis constant (Km ) was unaffected. On pharmacokinetic examination, the total clearance (CLtot ) of tolbutamide on day 4 was increased, despite the decreased metabolic capacity. On the other hand, the serum unbound fraction (fu ) of tolbutamide was elevated with a reduced serum albumin concentration in the DOX group. Contrary to CLtot , CLtot /fu , a parameter approximated to the hepatic intrinsic clearance of unbound tolbutamide, was estimated to be significantly reduced in the DOX group. These findings indicate that the metabolic capacity of CYP2C11 in the liver is depressed time-dependently by down-regulation after doxorubicin exposure in rats, and that the decreased enzyme activity of TB 4-hydroxylation in hepatic microsomes reflects the pharmacokinetic change of unbound tolbutamide, not total tolbutamide, in serum.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Hipoglicemiantes/farmacocinética , Tolbutamida/farmacocinética , Animais , Hidrocarboneto de Aril Hidroxilases/metabolismo , Família 2 do Citocromo P450/metabolismo , Interações Medicamentosas , Hidroxilação/efeitos dos fármacos , Hipoglicemiantes/sangue , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos Sprague-Dawley , Albumina Sérica/metabolismo , Esteroide 16-alfa-Hidroxilase/metabolismo , Tolbutamida/sangueRESUMO
BACKGROUND: Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially renally cleared. We investigated the pharmacokinetics and safety of olaparib in patients with mild or moderate renal impairment to provide dosing recommendations. METHODS: This phase I open-label study assessed the pharmacokinetics, safety and tolerability of single-dose, oral 300-mg olaparib tablets in adults (aged 18-75 years) with solid tumours. Patients had normal renal function, or mild or moderate renal impairment (estimated creatinine clearance ≥ 81, 51-80 or 31-50 mL/min, respectively). Blood was collected for 96 h, and urine samples collected for 24 h post-dose. Patients could continue taking olaparib 300 mg twice daily for a long-term safety assessment. RESULTS: Overall, 44 patients received one or more doses of olaparib and 38 were included in the pharmacokinetic assessment. Patients with mild renal impairment had an area under the curve geometric least-squares mean ratio of 1.24 (90% confidence interval 1.06-1.47) and a geometric least-squares mean maximum plasma concentration ratio of 1.15 (90% confidence interval 1.04-1.27) vs. those with normal renal function. In patients with moderate renal impairment, the geometric least-squares mean ratio for the area under the curve was 1.44 (90% confidence interval 1.10-1.89) and for the maximum plasma concentration was 1.26 (90% confidence interval 1.06-1.48) vs. those with normal renal function. No new safety signals were detected in patients with mild or moderate renal impairment. CONCLUSIONS: In patients with mild renal impairment, the small increase in exposure to olaparib was not considered clinically relevant. In patients with moderate renal impairment, exposure to olaparib increased by 44%; thus, these patients should be carefully monitored and the tablet dose should be adjusted to 200 mg twice daily. CLINICAL TRIALS REGISTRATION: NCT01894256.
Assuntos
Neoplasias/tratamento farmacológico , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Insuficiência Renal/etiologia , Administração Oral , Adulto , Idoso , Feminino , Humanos , Rim/fisiopatologia , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/patologia , Nível de Efeito Adverso não Observado , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , SegurançaRESUMO
Esculetin (ET)-7-O-glucuronide (ET-G) and 4-methylesculetin (4-ME)-7-O-glucuronide (4-ME-G) are the main glucuronide of ET and 4-ME, respectively. The disposition mediated by efflux transporters for glucuronide has significant influence on the pharmacokinetic profile and efficacy of bioactive compounds. In the current study, transporter gene knockout mice and Caco-2 cells were used to explore the effects of breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 2 (MRP2) on the disposition of ET-G and 4-ME-G. After oral or i.v. administration of ET and 4-ME, the area under the plasma concentration-time curve from time 0 to the last data point or infinity values of ET, 4-ME, and their glucuronides (ET-G and 4-ME-G) were remarkably and significantly increased in most Bcrp1-/- and Mrp2-/- mice compared with those in wild-type FVB mice (P < 0.05). These results were accompanied with a significant increase of maximum plasma concentration values (P < 0.05). In Caco-2 monolayers, the efflux and clearance rates of ET-G and 4-ME-G were markedly reduced by the BCRP inhibitor Ko143 and MRP2 inhibitor MK571 on the apical side (P < 0.05). In an intestinal perfusion study, the excretion of ET-G was significantly decreased in perfusate and increased in plasma in Bcrp1-/- mice compared with those in wild-type FVB mice (P < 0.05). The 4-ME-G concentration was also decreased in the bile in transporter gene knockout mice. ET and 4-ME showed good permeability in both Caco-2 monolayers [apparent permeability (Papp ) ≥ 0.59 × 10-5 cm/s] and duodenum (Papp ≥ 1.81). In conclusion, BCRP and MRP2 are involved in excreting ET-G and 4-ME-G. ET and 4-ME are most likely absorbed via passive diffusion in the intestines.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Umbeliferonas/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Área Sob a Curva , Células CACO-2 , Dicetopiperazinas/farmacologia , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Eliminação Hepatobiliar/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/antagonistas & inibidores , Perfusão , Propionatos/farmacologia , Quinolinas/farmacologia , Umbeliferonas/metabolismoRESUMO
It is now established that a drug's pharmacokinetics (PK) absorption, distribution, metabolism, excretion (ADME) and drug-drug interaction (DDI) profile can be modulated by age, disease, and genotype. In order to facilitate subject phenotyping and clinical DDI assessment, therefore, various endogenous compounds (in plasma and urine) have been pursued as drug-metabolizing enzyme and transporter biomarkers. Compared with biomarkers, however, the topic of circulating extracellular vesicles as "liquid biopsy" has received little attention within the ADME community; most organs secrete nanovesicles (e.g., exosomes) into the blood that contain luminal "cargo" derived from the originating organ (proteins, messenger RNA, and microRNA). As such, ADME profiling of plasma exosomes could be leveraged to better define genotype-phenotype relationships and the study of ontogeny, disease, and complex DDIs. If methods to support the isolation of tissue-derived plasma exosomes are successfully developed and validated, it is envisioned that they will be used jointly with genotyping, biomarkers, and modeling tools to greatly progress translational PK-ADME-DDI science.
Assuntos
Interações Medicamentosas/fisiologia , Taxa de Depuração Metabólica/fisiologia , Nanopartículas/metabolismo , Pesquisa Translacional Biomédica/métodos , Adsorção , Biomarcadores/metabolismo , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Humanos , Biópsia Líquida/métodos , Taxa de Depuração Metabólica/efeitos dos fármacos , Nanopartículas/administração & dosagem , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Pesquisa Translacional Biomédica/tendênciasRESUMO
BACKGROUND AND OBJECTIVES: Little is known about the pharmacokinetics of phenobarbital in terminally ill cancer patients. We investigated whether phenobarbital clearance alters depending on the length of survival. METHODS: We retrospectively reviewed the clinical, laboratory, and therapeutic drug monitoring (TDM) records of patients who received parenteral or oral phenobarbital for 21 consecutive days or longer between 2000 and 2016. Patients were divided into non-cancer and cancer groups. Cancer patients were further stratified according to the survival interval after TDM: those who survived > 3 months were classified as long-surviving and the remainders short-surviving cancer patients. Phenobarbital clearance (CLPB) was calculated at steady state. Multiple comparisons of median CLPB were conducted among the three groups. RESULTS: Data were collected from 44 non-cancer patients and 34 cancer patients comprising 24 long-surviving and 10 short-surviving cancer patients. Among 10 short-surviving cancer patients, 4 had hepatic metastasis. Median CLPB (range) in short-surviving cancer patients [0.076 (0.057â0.114) L/kg/day] was significantly (p < 0.05) lower than that in non-cancer patients [0.105 (0.060â0.226) L/kg/day] and in long-surviving cancer patients [0.100 (0.082â0.149) L/kg/day]. CONCLUSION: Terminally ill patients with advanced cancer may have reduced CLPB, thereby TDM is recommended for these patients particularly near the end of life.
Assuntos
Anticonvulsivantes/sangue , Monitoramento de Medicamentos/tendências , Neoplasias/sangue , Fenobarbital/sangue , Assistência Terminal/tendências , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Fenobarbital/farmacocinética , Fenobarbital/uso terapêutico , Estudos Retrospectivos , Assistência Terminal/métodosRESUMO
Context: Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear. Objective: To determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes. Design: Randomized, double-blind, cross-over study. Setting: Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. Patients: Eight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)]. Interventions: Two metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies. Main Outcome Measures: Study one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion. Results: Study one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60-480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0-240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0-360min (P = 0.006) were lower with lixisenatide than with placebo. Conclusions: Lixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance.
Assuntos
Quilomícrons/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Peptídeos/farmacologia , Triglicerídeos/sangue , Glicemia/efeitos dos fármacos , Quilomícrons/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Esvaziamento Gástrico/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Pessoa de Meia-Idade , Peptídeos/uso terapêutico , Período Pós-Prandial/efeitos dos fármacos , Resultado do Tratamento , Triglicerídeos/metabolismoRESUMO
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6, is indicated for metastatic breast cancer treatment. Reversible increases in serum creatinine levels of ~15-40% over baseline have been observed following abemaciclib dosing. This study assessed the in vitro and clinical inhibition of renal transporters by abemaciclib and its metabolites using metformin (a clinically relevant transporter substrate), in a clinical study that quantified glomerular filtration and iohexol clearance. In vitro, abemaciclib inhibited metformin uptake by organic cation transporter 2, multidrug and toxin extrusion (MATE)1, and MATE2-K transporters with a half-maximal inhibitory concentration of 0.4-3.8 µM. Clinically, abemaciclib significantly increased metformin exposure but did not significantly affect measured glomerular filtration rate, serum neutrophil gelatinase-associated lipocalin (NGAL), serum cystatin-C, or the urinary markers of kidney tubular injury, NGAL and kidney injury molecule-1.
Assuntos
Aminopiridinas/farmacologia , Benzimidazóis/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Taxa de Filtração Glomerular/efeitos dos fármacos , Túbulos Renais , Metformina/farmacologia , Antineoplásicos Imunológicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Taxa de Depuração Metabólica/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/metabolismoRESUMO
The use of the Calvert formula to calculate carboplatin doses allows clinicians to achieve the appropriate carboplatin area under the concentration (AUC) curve. Thrombocytopenia is the dose limiting toxicity of carboplatin and optimizing AUC minimizes the risk of thrombocytopenia. Carboplatin clearance directly correlates with glomerular filtration rate (GFR) and, therefore, an accurate estimation of the renal function is needed. The Calvert formula was designed using the GFR measured by 51Cr-EDTA; however, many clinicians substitute estimated creatinine clearance (CrCl) as calculated by the Cockcroft-Gault (C-G) equation. The potential for overestimating AUC occurs when clinicians substitute actual weight in obese patients or use a low serum creatinine when calculating C-G estimated CrCl. In 2010, the National Cancer Institute recommended the GFR value within the Calvert formula should not exceed 125 mL/min, thereby capping the carboplatin dose. However, there are studies demonstrating that certain patients' actual GFR values do exceed 125 mL/min. Therefore, capping the carboplatin dose in these patients may lead to underestimating the carboplatin AUC. A single-center, retrospective study was performed to evaluate the change in platelet count pre- and post-carboplatin exposure in patients with C-G estimated CrCl greater than 125 mL/min receiving capped versus uncapped carboplatin doses. A review of carboplatin dosing strategies is also presented. This study indicated there was a larger mean difference in pre- and post-platelet count in patients receiving uncapped carboplatin compared to patients receiving capped carboplatin with no differences in toxicities. Dose capping this patient population will likely lead to a lower AUC rather than the intended AUC target, which could ultimately lead to substandard outcomes.
Assuntos
Antineoplásicos/administração & dosagem , Carboplatina/administração & dosagem , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Depuração Metabólica/efeitos dos fármacos , Adulto , Idoso , Área Sob a Curva , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Masculino , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Bioavailability of orally administered drugs is partly determined by function of drug transporters in the liver and intestine. Therefore, we explored adenosine triphosphate-binding cassette (ABC) and solute carriers family transporters expression (quantitative polymerase chain reaction) and protein abundance (liquid chromatography tandem mass spectrometry (LC-MS/MS)) in human liver and duodenum, jejunum, ileum, and colon in paired tissue specimens from nine organ donors. The transporter proteins were detected in the liver (permeability-glycoprotein (P-gp), multidrug resistance protein (MRP)2, MRP3, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, organic cation transporter (OCT)1, OCT3, organic anion transporter 2, Na+-taurocholate cotransporting polypeptide, monocarboxylate transporter (MCT)1, and multidrug and toxin extrusion 1) and the intestine (P-gp, multidrug-resistance protein (MRP)2, MRP3, MRP4, BCRP, OATP2B1, OCT1, apical sodium-bile acid transporter (only ileum), MCT1, and peptide transporter (PEPT1)). Significantly higher hepatic gene expression and protein abundance of ABCC2/MRP2, SLC22A1/OCT1, and SLCO2B1/OATP2B1 were found, as compared to all intestinal segments. No correlations between hepatic and small intestinal protein levels were observed. These observations provide a description of drug transporters distribution without the impact of interindividual variability bias and may help in construction of superior physiologically based pharmacokinetic and humanized animal models.