RESUMEN

Olverembatinib (HQP1351) is a BCR-ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug-resistant mutations, such as T315I. In vitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open-label, 2-part, fixed-sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time-concentration curve (AUC)0-last, and AUC0-inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.

Asunto(s)

Inductores del Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Voluntarios Sanos , Itraconazol , Rifampin , Humanos , Masculino , Itraconazol/farmacocinética , Itraconazol/administración & dosificación , Itraconazol/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/farmacología , Adulto , Rifampin/administración & dosificación , Rifampin/farmacocinética , Rifampin/farmacología , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Inductores del Citocromo P-450 CYP3A/farmacocinética , Inductores del Citocromo P-450 CYP3A/farmacología , Femenino , Adulto Joven , Citocromo P-450 CYP3A/metabolismo , Persona de Mediana Edad , Administración Oral , Área Bajo la Curva , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación

RESUMEN

Clarithromycin extended-release (CLA-ER) was used as companion drug to rifampicin (RIF) for Mycobacterium ulcerans infection in the intervention arm of a WHO drug trial. RIF enhances CYP3A4 metabolism, thereby reducing CLA serum concentrations, and RIF concentrations might be increased by CLA co-administration. We studied the pharmacokinetics of CLA-ER at a daily dose of 15 mg/kg combined with RIF at a dose of 10 mg/kg in a subset of trial participants, and compared these to previously obtained pharmacokinetic data. Serial dried blood spot samples were obtained over a period of ten hours, and analyzed by LC-MS/MS in 30 study participants-20 in the RIF-CLA study arm, and 10 in the RIF-streptomycin study arm. Median CLA Cmax was 0.4 mg/L-and median AUC 3.9 mg*h/L, following 15 mg/kg CLA-ER. Compared to standard CLA dosed at 7.5 mg/kg previously, CLA-ER resulted in a non-significant 58% decrease in Cmax and a non-significant 30% increase in AUC. CLA co-administration did not alter RIF Cmax or AUC. Treatment was successful in all study participants. No effect of CLA co-administration on RIF pharmacokinetics was observed. Based on our serum concentration studies, the benefits CLA-ER over CLA immediate release are unclear.

Asunto(s)

Úlcera de Buruli , Claritromicina , Preparaciones de Acción Retardada , Mycobacterium ulcerans , Rifampin , Humanos , Claritromicina/farmacocinética , Claritromicina/administración & dosificación , Masculino , Femenino , Adulto , Rifampin/farmacocinética , Rifampin/administración & dosificación , Rifampin/uso terapéutico , Persona de Mediana Edad , Úlcera de Buruli/tratamiento farmacológico , Úlcera de Buruli/microbiología , Mycobacterium ulcerans/efectos de los fármacos , Preparaciones de Acción Retardada/farmacocinética , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Anciano , Adulto Joven , Área Bajo la Curva , Espectrometría de Masas en Tándem

RESUMEN

The coexistence of TB and diabetes mellitus (DM) (TB-DM) is associated with an increased risk of treatment failure, death, delayed culture conversion, and drug resistance. Because plasma concentrations may influence clinical outcomes, we evaluated the evidence on the pharmacokinetic (PK) of TB drugs in individuals with DM to guide management.We performed a systematic review and meta-analysis through searches of major databases from 1946 to 6 July 2023. PROSPERO (CRD42022323566).Of 4,173 potentially relevant articles, we identified 16 studies assessing rifampicin (RIF) PK, 9 on isoniazid (INH), 8 on pyrazinamide (PZA), and 3 on ethambutol (EMB). Two studies reported on second-line anti-TB drugs. According to our meta-analysis, RIF time to maximum concentration (Tmax) was significantly prolonged in patients with DM compared with non-DM patients. We found no significant differences for RIF Cmax, area under the curve (AUC) 0-24 or drug concentration at 2 h (C2h), INH C2h, PZA C2h, PZA Tmax, and EMB Tmax. Although RIF C2h was slightly reduced in patients with TB-DM, this finding was not statistically significant.This review comprehensively examines the impact of DM on the PK of TB drugs. We observed significant heterogeneity among the studies. Given the association between lower plasma concentrations and poor clinical outcomes among patients with DM, we recommend a higher dose limit to compensate for the larger body weight of patients with DM..

Asunto(s)

Antituberculosos , Diabetes Mellitus , Tuberculosis , Humanos , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Diabetes Mellitus/metabolismo , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Pirazinamida/farmacocinética , Rifampin/farmacocinética , Rifampin/administración & dosificación , Tuberculosis/tratamiento farmacológico

RESUMEN

The intricate process of protein binding orchestrates crucial drug interactions within the bloodstream, facilitating the formation of soluble complexes. This research endeavours to improve the dissolution and oral bioavailability of Rifampicin (RMP) by strategically manipulating drug-protein binding dynamics and the hydrophobic characteristics of human serum albumin (HSA). Various precipitation techniques leveraging methanol, ammonium sulfate, and heat treatment were meticulously employed to tailor the properties of colloidal albumin (HSA NPs). The resultant complexes underwent comprehensive characterization encompassing evaluations of hydrophobicity, size distribution, surface charge, and structural analyses through FTIR, TG-DSC, XRD, and morphological examinations. The findings revealed a significant binding affinity of 78.07 ± 6.6% with native albumin, aligning with prior research. Notably, the complex RMP-HSA NPs-M13, synthesized via the methanolic precipitation method, exhibited the most substantial complexation, achieving a remarkable 3.5-fold increase, followed by the ammonium sulfate (twofold) and heat treatment (1.07-fold) methods in comparison to native albumin binding. The gastric simulated media exhibited accelerated drug release kinetics, with maximal dissolution achieved within two hours, contrasting with the prolonged release observed under intestinal pH conditions. These findings translated into significant improvements in drug permeation, as evidenced by pharmacokinetic profiles demonstrating elevated Cmax, AUC, t1/2, and MRT values for RMP-HSA NPs-M13 compared to free RMP. In summary, this innovative approach underscores the potential of precipitation methods in engineering stable colloidal carrier systems tailored to enhance the oral bioavailability of poorly soluble drugs, offering a pragmatic and scalable alternative to conventional surfactants, polymers, or high-energy methods for complex formation and production.

Asunto(s)

Disponibilidad Biológica , Liberación de Fármacos , Rifampin , Solubilidad , Rifampin/farmacocinética , Rifampin/química , Rifampin/administración & dosificación , Administración Oral , Animales , Humanos , Precipitación Química , Interacciones Hidrofóbicas e Hidrofílicas , Albúmina Sérica Humana/química , Nanopartículas/química , Ratas , Unión Proteica , Masculino , Sulfato de Amonio/química

RESUMEN

Pulmonary Mycobacterium avium-intracellulare complex (MAC) disease is a typical non-tuberculous mycobacterial infection. The incidence of pulmonary MAC is increasing worldwide. This study aimed to clarify the pharmacokinetic parameters of anti-pulmonary MAC disease drugs in silkworms. The pharmacokinetic parameters investigated included maximum concentration, area under the concentration-time curve, total clearance, and volume of distribution at steady-state. In addition, protein-binding rates, fat body transferability, and drug-drug interactions were examined. Antibiotic concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Among the antibiotics investigated, amikacin was not eliminated from silkworms during the 48-h observation period. In contrast, dose-proportional pharmacokinetics were observed in silkworms for all antibiotics tested, except for amikacin. Protein-binding rates in hemolymph for clarithromycin, azithromycin, rifampicin, ethambutol, and amikacin were 39.6 ± 3.0%, 39.5 ± 4.3%, 76.3 ± 3.2%, 20.9 ± 4.2%, and 73.1 ± 4.7%, respectively (mean ± standard deviation). The distribution of antibiotics in the fat bodies of silkworms was related to drug lipophilicity. No drug-drug interactions were observed in the silkworms. The pharmacokinetics of these drugs in silkworms differed significantly from those in humans. Therefore, while it is challenging to predict the pharmacokinetics of these drugs in humans based on silkworm data, the silkworm infection model has facilitated a comprehensive assessment of the relationship between antibiotic exposure and efficacy.

Asunto(s)

Amicacina , Antibacterianos , Bombyx , Complejo Mycobacterium avium , Infección por Mycobacterium avium-intracellulare , Animales , Bombyx/microbiología , Bombyx/metabolismo , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Infección por Mycobacterium avium-intracellulare/microbiología , Antibacterianos/farmacocinética , Complejo Mycobacterium avium/efectos de los fármacos , Amicacina/farmacocinética , Hemolinfa/metabolismo , Claritromicina/farmacocinética , Interacciones Farmacológicas , Etambutol/farmacocinética , Unión Proteica , Rifampin/farmacocinética , Rifampin/farmacología

RESUMEN

BACKGROUND: In South Africa, an estimated 11% of the population have high alcohol use, a major risk factor for TB. Alcohol and other substance use are also associated with poor treatment response, with a potential mechanism being altered TB drug pharmacokinetics. OBJECTIVES: To investigate the impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs in participants with pulmonary TB. METHODS: We prospectively enrolled participants ≥15 years old, without HIV, and initiating drug-susceptible TB treatment in Worcester, South Africa. Alcohol use was measured via self-report and blood biomarkers. Other illicit substances were captured through a urine drug test. Plasma samples were drawn 1 month into treatment pre-dose, and 1.5, 3, 5 and 8 h post-dose. Non-linear mixed-effects modelling was used to describe the pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol. Alcohol and drug use were tested as covariates. RESULTS: The study included 104 participants, of whom 70% were male, with a median age of 37 years (IQR 27-48). Alcohol use was high, with 42% and 28% of participants having moderate and high alcohol use, respectively. Rifampicin and isoniazid had slightly lower pharmacokinetics compared with previous reports, whereas pyrazinamide and ethambutol were consistent. No significant alcohol use effect was detected, other than 13% higher ethambutol clearance in participants with high alcohol use. Methaqualone use reduced rifampicin bioavailability by 19%. CONCLUSION: No clinically relevant effect of alcohol use was observed on the pharmacokinetics of first-line TB drugs, suggesting that poor treatment outcome is unlikely due to pharmacokinetic alterations. That methaqualone reduced rifampicin means dose adjustment may be beneficial.

Asunto(s)

Antituberculosos , Rifampin , Humanos , Masculino , Adulto , Femenino , Antituberculosos/farmacocinética , Sudáfrica , Persona de Mediana Edad , Estudios Prospectivos , Rifampin/farmacocinética , Isoniazida/farmacocinética , Consumo de Bebidas Alcohólicas/efectos adversos , Tuberculosis Pulmonar/tratamiento farmacológico , Trastornos Relacionados con Sustancias , Pirazinamida/farmacocinética , Pirazinamida/administración & dosificación , Etambutol/farmacocinética , Adulto Joven

RESUMEN

Bacterial pneumonia is a common disease with significant health risks. However, the overuse antibiotics in clinics face challenges such as inadequate targeting and limited drug utilization, leading to drug resistance and gut dysbiosis. Herein, a dual-responsive lung inflammatory tissue targeted nanoparticle (LITTN), designed for targeting lung tissue and bacteria, is screened from a series of prepared nanoparticles consisting of permanent cationic lipids, acid-responsive lipids, and reactive oxygen species-responsive and phenylboronic acid-modified lipids with different surface properties. Such nanoparticle is further verified to enhance the adsorption of vitronectin in serum. Additionally, the optimized nanoparticle exhibits more positive charge and coordination of boric acid with cis-diol in the infected microenvironment, facilitating electrostatic interactions with bacteria and biofilm penetration. Importantly, the antibacterial efficiency of dual-responsive rifampicin-loaded LITTN (Rif@LITTN) against methicillin-resistant staphylococcus aureus is 10 times higher than that of free rifampicin. In a mouse model of bacterial pneumonia, the intravenous administration of Rif@LITTN could precisely target the lungs, localize in the lung infection microenvironment, and trigger the responsive release of rifampicin, thereby effectively alleviating lung inflammation and reducing damage. Notably, the targeted delivery of rifampicin helps protect against antibiotic-induced changes in the gut microbiota. This study establishes a new strategy for precise delivery to the lung-infected microenvironment, promoting treatment efficacy while minimizing the impact on gut microbiota. STATEMENT OF SIGNIFICANCE: Intravenous antibiotics play a critical role in clinical care, particularly for severe bacterial pneumonia. However, the inability of antibiotics to reach target tissues causes serious side effects, including liver and kidney damage and intestinal dysbiosis. Therefore, achieving precise delivery of antibiotics is of great significance. In this study, we developed a novel lung inflammatory tissue-targeted nanoparticle that could target lung tissue after intravenous administration and then target the inflammatory microenvironment to trigger dual-responsive antibiotics release to synergistically treat pneumonia while maintaining the balance of gut microbiota and reducing the adverse effects of antibiotics. This study provides new ideas for targeted drug delivery and reference for clinical treatment of pneumonia.

Asunto(s)

Antibacterianos , Disbiosis , Microbioma Gastrointestinal , Nanopartículas , Animales , Antibacterianos/farmacología , Disbiosis/tratamiento farmacológico , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Nanopartículas/química , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/microbiología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Rifampin/farmacología , Rifampin/farmacocinética , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/patología , Sistemas de Liberación de Medicamentos

RESUMEN

PURPOSE: Currently, body weight-based dosing of rifampicin is recommended. But lately, fat-free mass (FFM) was reported to be superior to body weight (BW). The present evaluation aimed to assess the influence of body mass-related covariates on rifampicin's pharmacokinetics (PK) parameters in more detail using non-linear mixed effects modeling (NLMEM). METHODS: Twenty-four healthy Caucasian volunteers were enrolled in a bioequivalence study, each receiving a test and a reference tablet of 600 mg of rifampicin separated by a wash-out period of at least 9 days. Monolix version 2023R1 was used for NLMEM. Monte Carlo simulations (MCS) were performed to visualize the relationship of body size descriptors to the exposure to rifampicin. RESULTS: A one-compartment model with nonlinear (Michaelis-Menten) elimination and zero-order absorption kinetics with a lag time best described the data. The covariate model including fat-free mass (FFM) on volume of distribution (V/F) and on maximum elimination rate (Vmax/F) lowered the objective function value (OFV) by 56.4. The second-best covariate model of sex on V/F and Vmax/F and BW on V/F reduced the OFV by 51.2. The decrease in unexplained inter-individual variability on Vmax/F in both covariate models was similar. For a given dose, MCS showed lower exposure to rifampicin with higher FFM and accordingly in males compared to females with the same BW and body height. CONCLUSION: Our results indicate that beyond BW, body composition as reflected by FFM could also be relevant for optimized dosing of rifampicin. This assumption needs to be studied further in patients treated with rifampicin.

Asunto(s)

Voluntarios Sanos , Modelos Biológicos , Rifampin , Población Blanca , Humanos , Rifampin/farmacocinética , Rifampin/administración & dosificación , Masculino , Femenino , Adulto , Adulto Joven , Equivalencia Terapéutica , Método de Montecarlo , Antibióticos Antituberculosos/farmacocinética , Antibióticos Antituberculosos/administración & dosificación , Peso Corporal , Estudios Cruzados , Dinámicas no Lineales

RESUMEN

BACKGROUND: Pharmacokinetic data of rifampin, when used for tuberculosis preventive treatment (TPT) are not available. We aimed to describe the pharmacokinetics of rifampin used for TPT, at standard and higher doses, and to assess predictors of rifampin exposure. METHODS: A pharmacokinetic sub-study was performed in Bandung, Indonesia among participants in the 2R2 randomized trial, which compared TPT regimens of 2 months of high-dose rifampin at 20 mg/kg/day (2R20) and 30 mg/kg/day (2R30), with 4 months of standard-dose rifampin at 10 mg/kg/day (4R10) in adolescents and adults. Intensive pharmacokinetic sampling was performed after 2-8 weeks of treatment. Pharmacokinetic parameters were assessed non-compartmentally. Total exposure (AUC0-24) and peak concentration (Cmax) between arms were compared using one-way ANOVA and Tukey's post-hoc tests. Multivariable linear regression analyses were used to assess predictors of AUC0-24 and Cmax. RESULTS: We enrolled 51 participants in this study. In the 4R10, 2R20, and 2R30 arms, the geometric mean AUC0-24 was 68.0, 186.8, and 289.9 h⋅mg/L, and Cmax was 18.4, 36.7, and 54.4 mg/L, respectively; high interindividual variabilities were observed. Compared with the 4R10 arm, AUC0-24 and Cmax were significantly higher in the 2R20 and 2R30 arms (P < 0.001). Drug doses, body weight, and female sex were predictors of higher rifampin AUC0-24 and Cmax (P < 0.05). AUC0-24 and Cmax values were much higher than those previously reported in persons with TB disease. CONCLUSIONS: Doubling and tripling the rifampin dose led to three- and four-fold higher exposure compared to standard dose. Pharmacokinetic/pharmacodynamic modelling and simulations are warranted to support trials of shortening the duration of TPT regimens with high-dose rifampin.

Asunto(s)

Rifampin , Tuberculosis , Humanos , Rifampin/farmacocinética , Rifampin/administración & dosificación , Rifampin/uso terapéutico , Femenino , Masculino , Adulto , Adolescente , Adulto Joven , Tuberculosis/prevención & control , Tuberculosis/tratamiento farmacológico , Indonesia , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Antituberculosos/uso terapéutico , Persona de Mediana Edad , Área Bajo la Curva , Quimioprevención/métodos

RESUMEN

The role of transporters in drug clearance is widely acknowledged, directly and indirectly by facilitating tissue/enzyme exposure. Through the latter, transporters also affect volume of distribution. Drug-drug interactions (DDIs) involving organic anion transporting polypeptides (OATPs) 1B1/1B3 and SLCO1B1 pharmacogenetics lead to altered pharmacokinetics of OATP1B substrates; however, several factors may confound direct interpretation of pharmacokinetic parameters from these clinical studies using noncompartmental analysis (NCA). A review of clinical data herein indicates a single dose of OATP1B inhibitor rifampin almost never leads to increased substrate half-life but often a decrease and that most clinical OATP1B substrates are CYP3A4 substrates and/or undergo enterohepatic cycling (EHC). Using hypothetically simple OATP1B substrate physiologically based pharmacokinetic (PBPK) models, simulated effect of rifampin differed from specific OATP1B inhibition due to short rifampin half-life causing dissipation of OATP1B inhibition over time combined with CYP3A4 induction. Calculated using simulated tissue data, volume of distribution indeed decreased with OATP1B inhibition and was expectedly limited to the contribution of liver volume. However, an apparent and counterintuitive effect of rifampin on volume greater than that on clearance resulted for CYP3A4 substrates using NCA. The effect of OATP1B inhibition and rifampin on OATP1B substrate models incorporating EHC plus or minus renal clearance was distinct compared with simpler models. Using PBPK models incorporating reversible lactone metabolism for clinical OATP1B substrates atorvastatin and pitavastatin, DDIs reporting decreased half-life with rifampin were reproduced. These simulations provide an explanation for the distinct change in OATP1B substrate pharmacokinetics observed in clinical studies, including changes in volume of distribution and additional mechanisms. SIGNIFICANCE STATEMENT: Transporters are involved in drug clearance and volume of distribution, and distinct changes in OATP1B substrate pharmacokinetics are observed with OATP1B inhibitor rifampin. Using hypothetical and validated PBPK models and simulations, this study addresses the limitations of single-dose rifampin and complicated clinical OATP1B substrate disposition in evaluating the pharmacokinetic parameters of OATP1B substrates during rifampin drug-drug interactions (DDIs). These models account for change in volume of distribution and identify additional mechanisms underlying apparent pharmacokinetic changes in OATP1B DDIs.

Asunto(s)

Interacciones Farmacológicas , Transportador 1 de Anión Orgánico Específico del Hígado , Modelos Biológicos , Rifampin , Interacciones Farmacológicas/fisiología , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Rifampin/farmacocinética , Rifampin/farmacología , Citocromo P-450 CYP3A/metabolismo , Semivida , Hígado/metabolismo , Inductores del Citocromo P-450 CYP3A/farmacocinética , Inductores del Citocromo P-450 CYP3A/farmacología , Quinolinas

RESUMEN

OBJECTIVES: To develop physiologically based pharmacokinetic (PBPK) models for widely used anti-TB drugs, namely rifampicin, pyrazinamide, isoniazid, ethambutol and moxifloxacin lung pharmacokinetics (PK)-regarding both healthy and TB-infected tissue (cellular lesion and caseum)-in preclinical species and to extrapolate to humans. METHODS: Empirical models were used for the plasma PK of each species, which were connected to multicompartment permeability-limited lung models within a middle-out PBPK approach with an appropriate physiological parameterization that was scalable across species. Lung's extracellular water (EW) was assumed to be the linking component between healthy and infected tissue, while passive diffusion was assumed for the drug transferring between cellular lesion and caseum. RESULTS: In rabbits, optimized unbound fractions in intracellular water of rifampicin, moxifloxacin and ethambutol were 0.015, 0.056 and 0.08, respectively, while the optimized unbound fractions in EW of pyrazinamide and isoniazid in mice were 0.25 and 0.17, respectively. In humans, all mean extrapolated daily AUC and Cmax values of various lung regions were within 2-fold of the observed ones. Unbound concentrations in the caseum were lower than unbound plasma concentrations for both rifampicin and moxifloxacin. For rifampicin, unbound concentrations in cellular rim are slightly lower, while for moxifloxacin they are significantly higher than unbound plasma concentrations. CONCLUSIONS: The developed PBPK approach was able to extrapolate lung PK from preclinical species to humans and to predict unbound concentrations in the various TB-infected regions, unlike empirical lung models. We found that plasma free drug PK is not always a good surrogate for TB-infected tissue unbound PK.

Asunto(s)

Antituberculosos , Pulmón , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Animales , Humanos , Pulmón/metabolismo , Conejos , Ratones , Rifampin/farmacocinética , Rifampin/administración & dosificación , Masculino , Moxifloxacino/farmacocinética , Moxifloxacino/administración & dosificación , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Femenino , Tuberculosis Pulmonar/tratamiento farmacológico

RESUMEN

OBJECTIVES: Twelve weekly doses of rifapentine and isoniazid (3HP regimen) are recommended for TB preventive therapy in children with TB infection. However, they present with variability in the pharmacokinetic profiles. The current study aimed to develop a pharmacokinetic model of rifapentine and isoniazid in 12 children with TB infection using NONMEM. METHODS: Ninety plasma and 41 urine samples were collected at Week 4 of treatment. Drug concentrations were measured using a validated HPLC-UV method. MassARRAY® SNP genotyping was used to investigate genetic factors, including P-glycoprotein (ABCB1), solute carrier organic anion transporter B1 (SLCO1B1), arylacetamide deacetylase (AADAC) and N-acetyl transferase (NAT2). Clinically relevant covariates were also analysed. RESULTS: A two-compartment model for isoniazid and a one-compartment model for rifapentine with transit compartment absorption and first-order elimination were the best models for describing plasma and urine data. The estimated (relative standard error, RSE) of isoniazid non-renal clearance was 3.52 L·h-1 (23.1%), 2.91 L·h-1 (19.6%), and 2.58 L·h-1 (20.0%) in NAT2 rapid, intermediate and slow acetylators. A significant proportion of the unchanged isoniazid was cleared renally (2.7 L·h-1; 8.0%), while the unchanged rifapentine was cleared primarily through non-renal routes (0.681 L·h-1; 3.6%). Participants with the ABCB1 mutant allele had lower bioavailability of rifapentine, while food prolonged the mean transit time of isoniazid. CONCLUSIONS: ABCB1 mutant allele carriers may require higher rifapentine doses; however, this must be confirmed in larger trials. Food did not affect overall exposure to isoniazid and only delayed absorption time.

Asunto(s)

Antituberculosos , Arilamina N-Acetiltransferasa , Isoniazida , Rifampin , Tuberculosis , Humanos , Rifampin/farmacocinética , Rifampin/análogos & derivados , Rifampin/administración & dosificación , Rifampin/uso terapéutico , Isoniazida/farmacocinética , Isoniazida/orina , Isoniazida/administración & dosificación , Isoniazida/uso terapéutico , Masculino , Femenino , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Antituberculosos/uso terapéutico , Niño , Preescolar , Arilamina N-Acetiltransferasa/genética , Tuberculosis/tratamiento farmacológico , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Genotipo , Polimorfismo de Nucleótido Simple , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adolescente , Lactante

RESUMEN

Cytochrome P450 (CYP)3A4 induction by drugs and pesticides plays a critical role in the enhancement of pyrrolizidine alkaloid (PA) toxicity as it leads to increased formation of hepatotoxic dehydro-PA metabolites. Addressing the need for a quantitative analysis of this interaction, we developed a physiologically-based toxicokinetic (PBTK) model. Specifically, the model describes the impact of the well-characterized CYP3A4 inducer rifampicin on the kinetics of retrorsine, which is a prototypic PA and contaminant in herbal teas. Based on consumption data, the kinetics after daily intake of retrorsine were simulated with concomitant rifampicin treatment. Strongest impact on retrorsine kinetics (plasma AUC 24 and C max reduced to 67% and 74% compared to the rifampicin-free reference) was predicted directly after withdrawal of rifampicin. At this time point, the competitive inhibitory effect of rifampicin stopped, while CYP3A4 induction was still near its maximum. Due to the impacted metabolism kinetics, the cumulative formation of intestinal retrorsine CYP3A4 metabolites increased to 254% (from 10 to 25 nmol), while the cumulative formation of hepatic CYP3A4 metabolites was not affected (57 nmol). Return to baseline PA toxicokinetics was predicted 14 days after stop of a 14-day rifampicin treatment. In conclusion, the PBTK model showed to be a promising tool to assess the dynamic interplay of enzyme induction and toxification pathways.

Asunto(s)

Inductores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Modelos Biológicos , Alcaloides de Pirrolicidina , Rifampin , Toxicocinética , Humanos , Masculino , Citocromo P-450 CYP3A/efectos de los fármacos , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Hígado/efectos de los fármacos , Hígado/metabolismo , Alcaloides de Pirrolicidina/toxicidad , Alcaloides de Pirrolicidina/farmacocinética , Rifampin/toxicidad , Rifampin/farmacocinética

RESUMEN

BACKGROUND: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. METHODS: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression. RESULTS: Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events. CONCLUSIONS: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation.

Asunto(s)

Rifampin , Tuberculosis , Rifampin/farmacocinética , Rifampin/administración & dosificación , Humanos , Masculino , Adulto , Femenino , Persona de Mediana Edad , Tuberculosis/tratamiento farmacológico , Adulto Joven , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Resultado del Tratamiento , Adolescente , Relación Dosis-Respuesta a Droga , Anciano

RESUMEN

Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the SLCO gene family of the solute carrier superfamily, are involved in the disposition of many exogenous and endogenous compounds. Preclinical rodent models help assess risks of pharmacokinetic interactions, but interspecies differences in transporter orthologs and expression limit direct clinical translation. An OATP1B transgenic mouse model comprising a rodent Slco1a/1b gene cluster knockout and human SLCO1B1 and SLCO1B3 gene insertions provides a potential physiologically relevant preclinical tool to predict pharmacokinetic interactions. Pharmacokinetics of exogenous probe substrates, pitavastatin and pravastatin, and endogenous OATP1B biomarkers, coproporphyrin-I and coproporphyrin-III, were determined in the presence and absence of known OATP/Oatp inhibitors, rifampin or silymarin (an extract of milk thistle [Silybum marianum]), in wild-type FVB mice and humanized OATP1B mice. Rifampin increased exposure of pitavastatin (4.6- and 2.8-fold), pravastatin (3.6- and 2.2-fold), and coproporphyrin-III (1.6- and 2.1-fold) in FVB and OATP1B mice, respectively, but increased coproporphyrin-I AUC0-24h only (1.8-fold) in the OATP1B mice. Silymarin did not significantly affect substrate AUC, likely because the silymarin flavonolignan concentrations were at or below their reported IC50 values for the relevant OATPs/Oatps. Silymarin increased the Cmax of pitavastatin 2.7-fold and pravastatin 1.9-fold in the OATP1B mice. The data of the OATP1B mice were similar to those of the pitavastatin and pravastatin clinical data; however, the FVB mice data more closely recapitulated pitavastatin clinical data than the data of the OATP1B mice, suggesting that the OATP1B mice are a reasonable, though costly, preclinical strain for predicting pharmacokinetic interactions when doses are optimized to achieve clinically relevant plasma concentrations.

Asunto(s)

Interacciones Farmacológicas , Transportador 1 de Anión Orgánico Específico del Hígado , Ratones Transgénicos , Pravastatina , Rifampin , Silimarina , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Animales , Rifampin/farmacocinética , Ratones , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Humanos , Silimarina/farmacocinética , Pravastatina/farmacocinética , Pravastatina/administración & dosificación , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/genética , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Quinolinas/farmacocinética , Coproporfirinas/metabolismo , Masculino , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo

RESUMEN

BACKGROUND: Pharmacokinetic data on high-dose isoniazid for the treatment of rifampicin-/multidrug-resistant tuberculosis (RR/MDR-TB) are limited. We aimed to describe the pharmacokinetics of high-dose isoniazid, estimate exposure target attainment, identify predictors of exposures, and explore exposure-response relationships in RR/MDR-TB patients. METHODS: We performed an observational pharmacokinetic study, with exploratory pharmacokinetic/pharmacodynamic analyses, in Indonesian adults aged 18-65 years treated for pulmonary RR/MDR-TB with standardized regimens containing high-dose isoniazid (10-15 mg/kg/day) for 9-11 months. Intensive pharmacokinetic sampling was performed after ≥2 weeks of treatment. Total plasma drug exposure (AUC0-24) and peak concentration (Cmax) were assessed using non-compartmental analyses. AUC0-24/MIC ratio of 85 and Cmax/MIC ratio of 17.5 were used as exposure targets. Multivariable linear and logistic regression analyses were used to identify predictors of drug exposures and responses, respectively. RESULTS: We consecutively enrolled 40 patients (median age 37.5 years). The geometric mean isoniazid AUC0-24 and Cmax were 35.4 h·mg/L and 8.5 mg/L, respectively. Lower AUC0-24 and Cmax values were associated (P < 0.05) with non-slow acetylator phenotype, and lower Cmax values were associated with male sex. Of the 26 patients with MIC data, less than 25% achieved the proposed targets for isoniazid AUC0-24/MIC (n = 6/26) and Cmax/MIC (n = 5/26). Lower isoniazid AUC0-24 values were associated with delayed sputum culture conversion (>2 months of treatment) [adjusted OR 0.18 (95% CI 0.04-0.89)]. CONCLUSIONS: Isoniazid exposures below targets were observed in most patients, and certain risk groups for low isoniazid exposures may require dose adjustment. The effect of low isoniazid exposures on delayed culture conversion deserves attention.

Asunto(s)

Antituberculosos , Isoniazida , Pruebas de Sensibilidad Microbiana , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Isoniazida/uso terapéutico , Adulto , Masculino , Femenino , Persona de Mediana Edad , Rifampin/farmacocinética , Rifampin/administración & dosificación , Rifampin/farmacología , Rifampin/uso terapéutico , Indonesia , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Antituberculosos/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto Joven , Adolescente , Anciano , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiología , Mycobacterium tuberculosis/efectos de los fármacos

RESUMEN

The first-generation tyrosine kinase inhibitor imatinib has revolutionized the development of targeted cancer therapy and remains among the frontline treatments, for example, against chronic myeloid leukemia. As a substrate of cytochrome P450 (CYP) 2C8, CYP3A4, and various transporters, imatinib is highly susceptible to drug-drug interactions (DDIs) when co-administered with corresponding perpetrator drugs. Additionally, imatinib and its main metabolite N-desmethyl imatinib (NDMI) act as inhibitors of CYP2C8, CYP2D6, and CYP3A4 affecting their own metabolism as well as the exposure of co-medications. This work presents the development of a parent-metabolite whole-body physiologically based pharmacokinetic (PBPK) model for imatinib and NDMI used for the investigation and prediction of different DDI scenarios centered around imatinib as both a victim and perpetrator drug. Model development was performed in PK-Sim® using a total of 60 plasma concentration-time profiles of imatinib and NDMI in healthy subjects and cancer patients. Metabolism of both compounds was integrated via CYP2C8 and CYP3A4, with imatinib additionally transported via P-glycoprotein. The subsequently developed DDI network demonstrated good predictive performance. DDIs involving imatinib and NDMI were simulated with perpetrator drugs rifampicin, ketoconazole, and gemfibrozil as well as victim drugs simvastatin and metoprolol. Overall, 12/12 predicted DDI area under the curve determined between first and last plasma concentration measurements (AUClast) ratios and 12/12 predicted DDI maximum plasma concentration (Cmax) ratios were within twofold of the respective observed ratios. Potential applications of the final model include model-informed drug development or the support of model-informed precision dosing.

Asunto(s)

Interacciones Farmacológicas , Mesilato de Imatinib , Modelos Biológicos , Humanos , Mesilato de Imatinib/farmacocinética , Mesilato de Imatinib/administración & dosificación , Citocromo P-450 CYP3A/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Masculino , Simulación por Computador , Adulto , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Femenino , Citocromo P-450 CYP2C8/metabolismo , Cetoconazol/farmacocinética , Cetoconazol/farmacología , Persona de Mediana Edad , Rifampin/farmacocinética , Rifampin/administración & dosificación

RESUMEN

AIMS: To develop a semi-mechanistic hepatic compartmental model to predict the effects of rifampicin, a known inducer of CYP3A4 enzyme, on the metabolism of five drugs, in the hope of informing dose adjustments to avoid potential drug-drug interactions. METHODS: A search was conducted for DDI studies on the interactions between rifampicin and CYP substrates that met specific criteria, including the availability of plasma concentration-time profiles, physical and absorption parameters, pharmacokinetic parameters, and the use of healthy subjects at therapeutic doses. The semi-mechanistic model utilized in this study was improved from its predecessors, incorporating additional parameters such as population data (specifically for Chinese and Caucasians), virtual individuals, gender distribution, age range, dosing time points, and coefficients of variation. RESULTS: Optimal parameters were identified for our semi-mechanistic model by validating it with clinical data, resulting in a maximum difference of approximately 2-fold between simulated and observed values. PK data of healthy subjects were used for most CYP3A4 substrates, except for gilteritinib, which showed no significant difference between patients and healthy subjects. Dose adjustment of gilteritinib co-administered with rifampicin required a 3-fold increase of the initial dose, while other substrates were further tuned to achieve the desired drug exposure. CONCLUSIONS: The pharmacokinetic parameters AUCR and CmaxR of drugs metabolized by CYP3A4, when influenced by Rifampicin, were predicted by the semi-mechanistic model to be approximately twice the empirically observed values, which suggests that the semi-mechanistic model was able to reasonably simulate the effect. The doses of four drugs adjusted via simulation to reduce rifampicin interaction.

Asunto(s)

Compuestos de Anilina , Citocromo P-450 CYP3A , Pirazinas , Rifampin , Humanos , Rifampin/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Modelos Epidemiológicos , Interacciones Farmacológicas , Modelos Biológicos

RESUMEN

Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30 mg of avacopan increased the area under the curve (AUC) of midazolam by 1.81-fold and celecoxib by 1.15-fold when administered without food, and twice-daily oral administration of 30 or 60 mg of avacopan increased the AUC of simvastatin by approximately 2.6-3.5-fold and the AUC of the active metabolite ß-hydroxy-simvastatin acid by approximately 1.4-1.7-fold when co-administered with food. Furthermore, the AUC of avacopan increased by approximately 2.19-fold when co-administered with itraconazole and decreased by approximately 13.5-fold when co-administered with rifampin. These findings provide critical insights into the potential drug-drug interactions involving avacopan, which could have significant implications for patient care and treatment planning. (NCT06207682).

Asunto(s)

Citocromo P-450 CYP2C9 , Inhibidores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Voluntarios Sanos , Itraconazol , Midazolam , Rifampin , Simvastatina , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Administración Oral , Área Bajo la Curva , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Interacciones Alimento-Droga , Itraconazol/farmacología , Itraconazol/administración & dosificación , Itraconazol/farmacocinética , Midazolam/farmacocinética , Midazolam/administración & dosificación , Rifampin/farmacología , Rifampin/administración & dosificación , Rifampin/farmacocinética , Simvastatina/farmacocinética , Simvastatina/administración & dosificación , Simvastatina/efectos adversos

RESUMEN

AIMS: To evaluate the effect of the combination of carotegrast methyl with rifampicin, a potent inhibitor of organic anion transporter polypeptide, on the pharmacokinetics (PKs), safety and tolerability of carotegrast methyl. METHODS: In this 2 × 2 crossover study in 20 healthy Japanese adults, 10 subjects received carotegrast methyl 960 mg and rifampicin 600 mg on day 1 and received carotegrast methyl 960 mg on day 8. The subjects in the other sequence received the same treatments but in the opposite order. The 90% confidence interval (CI) of the geometric mean ratio of the Cmax and AUC0-t for carotegrast, the main active metabolite of carotegrast methyl, with/without rifampicin was calculated. If the 90% CI fell within the range of 0.80-1.25, this indicated the absence of any drug-drug interaction. Adverse events (AEs) were monitored. RESULTS: The geometric mean ratios (90% CI) of the Cmax and AUC0-t for carotegrast with/without rifampicin were 4.78 (3.64-6.29) and 5.59 (4.60-6.79), respectively, indicating that carotegrast has a PK interaction with rifampicin. The combination with rifampicin increased the exposure of carotegrast and also that of its metabolites. The incidence of any AEs with/without rifampicin was five (25.0%) and one (5.0%), respectively. CONCLUSIONS: Coadministration of carotegrast methyl with rifampicin significantly increased the exposure of carotegrast compared with carotegrast methyl administration alone. In this single dose study, the incidence of AEs of carotegrast methyl with rifampicin increased compared with carotegrast methyl alone, but the incidence of adverse drug reactions did not increase with combination administration.

Asunto(s)

Área Bajo la Curva , Estudios Cruzados , Interacciones Farmacológicas , Voluntarios Sanos , Rifampin , Humanos , Rifampin/administración & dosificación , Rifampin/efectos adversos , Rifampin/farmacocinética , Masculino , Adulto , Femenino , Adulto Joven , Transportadores de Anión Orgánico/antagonistas & inhibidores