RESUMEN
BACKGROUND: In clinical practice, the vast array of potential drug combinations necessitates swift and accurate assessments of pharmacokinetic drug-drug interactions (DDIs), along with recommendations for adjustments. Current methodologies for clinical DDI evaluations primarily rely on basic extrapolations from clinical trial data. However, these methods are limited in accuracy owing to their lack of a comprehensive consideration of various critical factors, including the inhibitory potency, dosage, and type of the inhibitor, as well as the metabolic fraction and intestinal availability of the substrate. OBJECTIVE: This study aims to propose an efficient and accurate clinical pharmacokinetic-mediated DDI assessment tool, which comprehensively considers the effects of inhibitory potency and dosage of inhibitors, intestinal availability and fraction metabolized of substrates on DDI outcomes. METHODS: This study focuses on DDIs caused by cytochrome P450 3A4 enzyme inhibition, utilizing extensive clinical trial data to establish a methodology to calculate the metabolic fraction and intestinal availability for substrates, as well as the concentration and inhibitory potency for inhibitors ( K i or k inact / K I ). These parameters were then used to predict the outcomes of DDIs involving 33 substrates and 20 inhibitors. We also defined the risk index for substrates and the potency index for inhibitors to establish a clinical DDI risk scale. The training set for parameter calculation consisted of 73 clinical trials. The validation set comprised 89 clinical DDI trials involving 53 drugs. which was used to evaluate the reliability of in vivo values of K i and k inact / K I , the accuracy of DDI predictions, and the false-negative rate of risk scale. RESULTS: First, the reliability of the in vivo K i and k inact / K I values calculated in this study was assessed using a basic static model. Compared with values obtained from other methods, this study values showed a lower geometric mean fold error and root mean square error. Additionally, incorporating these values into the physiologically based pharmacokinetic-DDI model facilitated a good fitting of the C-t curves when the substrate's metabolic enzymes are inhibited. Second, area under the curve ratio predictions of studied drugs were within a 1.5 × margin of error in 81% of cases compared with clinical observations in the validation set. Last, the clinical DDI risk scale developed in this study predicted the actual risks in the validation set with only a 5.6% incidence of serious false negatives. CONCLUSIONS: This study offers a rapid and accurate approach for assessing the risk of pharmacokinetic-mediated DDIs in clinical practice, providing a foundation for rational combination drug use and dosage adjustments.
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Inhibidores del Citocromo P-450 CYP3A , Interacciones Farmacológicas , Humanos , Medición de Riesgo/métodos , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Citocromo P-450 CYP3A/metabolismo , Ensayos Clínicos como Asunto/métodos , Modelos Biológicos , Preparaciones Farmacéuticas/metabolismoRESUMEN
GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C-like (3CL) protease inhibitor that was recently approved for treating mild to moderate coronavirus disease 2019 patients in China. Since cytochrome P450 (CYP) enzymes, primarily CYP3A, are the main metabolic enzymes of GST-HG171, hepatic impairment may affect its pharmacokinetic (PK) profile. Aiming to guide clinical dosing for patients with hepatic impairment, this study, using a non-randomized, open-label, single-dose design, assessed the impact of hepatic impairment on the PK, safety, and tolerability of GST-HG171. Patients with mild and moderate hepatic impairment along with healthy subjects were enrolled (n = 8 each), receiving a single oral dose of 150 mg GST-HG171, with concurrent administration of 100 mg ritonavir to sustain CYP3A inhibition before and after GST-HG171 administration (-12, 0, 12, and 24 hours). Compared to subjects with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for GST-HG171's maximum plasma concentration (Cmax), area under the concentration-time curve up to the last quantifiable time (AUC0-t), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) in subjects with mild hepatic impairment were 1.14 (0.99, 1.31), 1.07 (0.88, 1.30), and 1.07 (0.88, 1.29), respectively. For moderate hepatic impairment, the ratios were 0.87 (0.70, 1.07), 0.82 (0.61, 1.10), and 0.82 (0.61, 1.10), respectively. Hepatic impairment did not significantly alter GST-HG171's peak time (Tmax) and elimination half-life (T1/2). GST-HG171 exhibited good safety and tolerability in the study. Taken together, mild to moderate hepatic impairment minimally impacted GST-HG171 exposure, suggesting no need to adjust GST-HG171 dosage for patients with mild to moderate hepatic impairment in the clinic.Clinical TrialsRegistered at ClinicalTrials.gov (NCT06106113).
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Inhibidores del Citocromo P-450 CYP3A , Hígado , Inhibidores de Proteasas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Área Bajo la Curva , China , Tratamiento Farmacológico de COVID-19 , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/efectos adversos , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Pueblos del Este de Asia , Hígado/efectos de los fármacos , Hepatopatías , Inhibidores de Proteasas/efectos adversos , Inhibidores de Proteasas/farmacocinética , Ritonavir/efectos adversos , Ritonavir/farmacocinéticaRESUMEN
4ß-Hydroxycholesterol (4ß-HC) in plasma has been used as a biomarker to assess CYP3A drug-drug interaction (DDI) potential during drug development. However, due to the long half-life and narrow dynamic range of 4ß-HC, its use has been limited to the identification of CYP3A inducers, but not CYP3A inhibitors. The formation of 1ß-hydroxydeoxycholic acid (1ß-OH DCA) from deoxycholic acid (DCA) is mediated by CYP3A, thus 1ß-OH DCA can potentially serve as an alternative to 4ß-HC for assessment of CYP3A DDI potential. To study this feasibility, we developed a sensitive liquid chromatography-tandem mass spectrometry method for the simultaneous quantitation of 1ß-OH DCA and its glycine and taurine conjugates in human plasma with the lower limit of quantitation of 50 pg/ml, which enabled the quantitation of basal levels and further reduction. The method was applied to a DDI study to assess how 1ß-OH DCA and its glycine and taurine conjugates would respond to CYP3A induction or inhibition. Rifampin induction resulted in an increase of 1ß-OH DCA and its conjugates in plasma, with 6.8-, 7.8-, 8.3-, and 10.3-fold increases of area under the curve from the time of dosing to the last measurable concentration (AUCLST), area under the curve from the time of dosing to 24 hours (AUC24h), C max, and mean concentrations for total 1ß-OH DCA (total of all three forms), respectively. Importantly, inhibition with itraconazole resulted in notable reduction of these biomarkers, with 84%, 85%, 82%, and 81% reductions of AUCLST, AUC24h, C max, and mean concentrations for total 1ß-OH DCA, respectively. These preliminary data demonstrate for the first time that total 1ß-OH DCA in plasma has the potential to serve as a biomarker for CYP3A DDI assessment in early clinical development and may provide key advantages over 4ß-HC. SIGNIFICANCE STATEMENT: The authors have reported the use of total 1ß-hydroxydeoxycholic acid (1ß-OH DCA) (sum of 1ß-OH DCA and its glycine and taurine conjugates) plasma exposure as a biomarker for CYP3A activity. Itraconazole inhibition led to an 81%-85% decrease of total 1ß-OH DCA plasma exposures, whereas rifampin induction led to a 6.8- to 10.3-fold increase of total 1ß-OH DCA plasma exposures. Using 1ß-OH DCA exposures in plasma also provides the benefit of allowing pharmacokinetic and biomarker assessment using the same matrix.
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Biomarcadores , Inductores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Ácido Desoxicólico , Interacciones Farmacológicas , Hidroxicolesteroles , Humanos , Citocromo P-450 CYP3A/metabolismo , Biomarcadores/sangre , Ácido Desoxicólico/sangre , Inductores del Citocromo P-450 CYP3A/farmacología , Hidroxicolesteroles/sangre , Espectrometría de Masas en Tándem/métodos , Masculino , Adulto , Rifampin/farmacología , Rifampin/sangre , Inhibidores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Cromatografía Liquida/métodos , Taurina/sangre , Taurina/análogos & derivadosRESUMEN
Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug-drug interactions (DDIs). ACT-1004-1239 is a potent and selective, first-in-class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism, and excretion (ADME) study results, ACT-1004-1239 is predominantly metabolized by CYP3A4. This study investigated the effect of the strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of single-dose ACT-1004-1239 in healthy male subjects. In the open-label, fixed-sequence DDI study, a total of 16 subjects were treated. Each subject received a single dose of 10 mg ACT-1004-1239 (Treatment A) in the first period followed by concomitant administration of multiple doses of 200 mg itraconazole and a single dose of 10 mg ACT-1004-1239 in the second period. We report a median of difference in tmax (90% confidence interval, CI) of 0.5 h (0.0, 1.0) comparing both treatments. The geometric mean ratio (GMR) (90% CI) of Cmax and AUC0-∞ was 2.16 (1.89, 2.47) and 2.77 (2.55, 3.00), respectively. The GMR (90% CI) of t1/2 was 1.46 (1.26, 1.70). Both treatments were well-tolerated with an identical incidence in subjects reporting treatment-emergent adverse events (TEAE). The most frequently reported TEAEs were headache and nausea. In conclusion, ACT-1004-1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2- to <5-fold), and this should be considered in further clinical studies if CYP3A4 inhibitors are concomitantly administered.
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Inhibidores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Itraconazol , Humanos , Masculino , Itraconazol/farmacocinética , Itraconazol/administración & dosificación , Itraconazol/farmacología , Adulto , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/farmacología , Adulto Joven , Citocromo P-450 CYP3A/metabolismo , Persona de Mediana Edad , Voluntarios Sanos , Área Bajo la CurvaRESUMEN
AIMS: Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre-clinical profiling suggests that time-dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co-administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time-/dose-dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity. METHODS: Open-label, fixed-sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2 mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug-drug interaction. RESULTS: Mean midazolam values of maximum plasma concentration (Cmax) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co-administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in Cmax of midazolam following its co-administrations with two predicted therapeutically relevant doses of Atuliflapon. CONCLUSIONS: Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs.
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Citocromo P-450 CYP3A , Interacciones Farmacológicas , Midazolam , Modelos Biológicos , Midazolam/farmacocinética , Midazolam/administración & dosificación , Humanos , Masculino , Adulto , Citocromo P-450 CYP3A/metabolismo , Adulto Joven , Administración Oral , Área Bajo la Curva , Inhibidores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Relación Dosis-Respuesta a DrogaRESUMEN
A physiologically-based pharmacokinetic (PBPK) model for tipifarnib, which included mechanistic absorption, was built and verified by integrating in vitro data and several clinical data in healthy subjects and cancer patients. The final PBPK model was able to recover the clinically observed single and multiple-dose plasma concentrations of tipifarnib in healthy subjects and cancer patients under several dosing conditions, such as co-administration with a strong CYP3A4 inhibitor and inducer, an acid-reducing agent (proton pump inhibitor and H2 receptor antagonist), and with a high-fat meal. In addition, the model was able to accurately predict the effect of mild or moderate hepatic impairment on tipifarnib exposure. The appropriately verified model was applied to prospectively simulate the liability of tipifarnib as a victim of CYP3A4 enzyme-based drug-drug interactions (DDIs) with a moderate inhibitor and inducer as well as tipifarnib as a perpetrator of DDIs with sensitive substrates of CYP3A4, CYP2B6, CYP2D6, CYP2C9, and CYP2C19 in healthy subjects and cancer patients. The effect of a high-fat meal, acid-reducing agent, and formulation change at the therapeutic dose was simulated. Finally, the model was used to predict the effect of mild, moderate, or severe hepatic, and renal impairment on tipifarnib PK. This multipronged approach of combining the available clinical data with PBPK modeling-guided dosing recommendations for tipifarnib under several conditions. This example showcases the totality of the data approach to gain a more thorough understanding of clinical pharmacology and biopharmaceutic properties of oncology drugs in development.
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Interacciones Farmacológicas , Modelos Biológicos , Neoplasias , Quinolonas , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Quinolonas/farmacocinética , Quinolonas/administración & dosificación , Voluntarios Sanos , Inhibidores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores de la Bomba de Protones/farmacocinética , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/farmacología , Masculino , Interacciones Alimento-Droga , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Citocromo P-450 CYP3A/metabolismo , Antagonistas de los Receptores H2 de la Histamina/farmacocinética , Antagonistas de los Receptores H2 de la Histamina/administración & dosificación , Antagonistas de los Receptores H2 de la Histamina/farmacología , Inductores del Citocromo P-450 CYP3A/farmacología , Simulación por Computador , Biofarmacia , Femenino , AdultoRESUMEN
The purpose of this overview was to perform an exploratory analysis of in-house drug-drug interaction (DDI) studies conducted with investigational drugs and oral midazolam to assess the value of measuring 1-OH-midazolam (1-OHM) in such studies. The perpetrator effect of the investigational drugs on cytochrome P450 3A (CYP3A) was assessed by analyzing both midazolam and 1-OHM in plasma and evaluating their pharmacokinetic parameters. Given the almost exclusive metabolism of the parent drug by CYP3A to the main metabolite 1-OHM, an increase in midazolam and a decrease in 1-OHM exposure in the case of CYP3A inhibition caused by a perpetrator drug would be expected. The opposite would be anticipated in the case of CYP3A induction. For this analysis, the perpetrator potential of eight different investigational drugs was incorporated. Among the 10 studies included, the identified CYP3A inhibitors (n = 4) and inducers (n = 1) were classified based on the data generated with midazolam per se, with 1-OHM levels not contributing to the interpretation of the data as they did not corroborate the findings of the parent compound. Therefore, it was concluded that continued analysis of 1-OHM in plasma may be questionable as it does not add value to the interpretation of the results when performing CYP3A DDI studies with an investigational drug as a perpetrator.
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Inhibidores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Midazolam , Midazolam/farmacocinética , Midazolam/análogos & derivados , Humanos , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inductores del Citocromo P-450 CYP3A/farmacología , Drogas en Investigación/farmacocinética , Drogas en Investigación/farmacología , Drogas en Investigación/administración & dosificaciónRESUMEN
Dasatinib, a second-generation tyrosine kinase inhibitor, is approved for treating chronic myeloid and acute lymphoblastic leukemia. As a sensitive cytochrome P450 (CYP) 3A4 substrate and weak base with strong pH-sensitive solubility, dasatinib is susceptible to enzyme-mediated drug-drug interactions (DDIs) with CYP3A4 perpetrators and pH-dependent DDIs with acid-reducing agents. This work aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model of dasatinib to describe and predict enzyme-mediated and pH-dependent DDIs, to evaluate the impact of strong and moderate CYP3A4 inhibitors and inducers on dasatinib exposure and to support optimized dasatinib dosing. Overall, 63 plasma profiles from perorally administered dasatinib in healthy volunteers and cancer patients were used for model development. The model accurately described and predicted plasma profiles with geometric mean fold errors (GMFEs) for area under the concentration-time curve from the first to the last timepoint of measurement (AUClast) and maximum plasma concentration (Cmax) of 1.27 and 1.29, respectively. Regarding the DDI studies used for model development, all (8/8) predicted AUClast and Cmax ratios were within twofold of observed ratios. Application of the PBPK model for dose adaptations within various DDIs revealed dasatinib dose reductions of 50%-80% for strong and 0%-70% for moderate CYP3A4 inhibitors and a 2.3-3.1-fold increase of the daily dasatinib dose for CYP3A4 inducers to match the exposure of dasatinib administered alone. The developed model can be further employed to personalize dasatinib therapy, thereby help coping with clinical challenges resulting from DDIs and patient-related factors, such as elevated gastric pH.
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Inhibidores del Citocromo P-450 CYP3A , Dasatinib , Interacciones Farmacológicas , Modelos Biológicos , Inhibidores de Proteínas Quinasas , Dasatinib/farmacocinética , Dasatinib/administración & dosificación , Dasatinib/farmacología , Humanos , Inhibidores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inductores del Citocromo P-450 CYP3A/farmacología , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Citocromo P-450 CYP3A/metabolismo , Masculino , Adulto , Área Bajo la Curva , Femenino , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Persona de Mediana EdadRESUMEN
This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.
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Carbolinas , Inhibidores del Citocromo P-450 CYP3A , Interacciones Farmacológicas , Compuestos Heterocíclicos de 4 o más Anillos , Itraconazol , Neoplasias , Humanos , Itraconazol/farmacocinética , Itraconazol/administración & dosificación , Itraconazol/efectos adversos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Neoplasias/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Carbolinas/farmacocinética , Carbolinas/administración & dosificación , Carbolinas/efectos adversos , Adulto , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Área Bajo la Curva , Antineoplásicos/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificaciónRESUMEN
The new adjuvant chemotherapy of docetaxel, epirubicin, and cyclophosphamide has been recommended for treating breast cancer. It is necessary to investigate the potential drug-drug Interactions (DDIs) since they have a narrow therapeutic window in which slight differences in exposure might result in significant differences in treatment efficacy and tolerability. To guide clinical rational drug use, this study aimed to evaluate the DDI potentials of docetaxel, cyclophosphamide, and epirubicin in cancer patients using physiologically based pharmacokinetic (PBPK) models. The GastroPlus™ was used to develop the PBPK models, which were refined and validated with observed data. The established PBPK models accurately described the pharmacokinetics (PKs) of three drugs in cancer patients, and the predicted-to-observed ratios of all the PK parameters met the acceptance criterion. The PBPK model predicted no significant changes in plasma concentrations of these drugs during co-administration, which was consistent with the observed clinical phenomenon. Besides, the verified PBPK models were then used to predict the effect of other Cytochrome P450 3A4 (CYP3A4) inhibitors/inducers on these drug exposures. In the DDI simulation, strong CYP3A4 modulators changed the exposure of three drugs by 0.71-1.61 fold. Therefore, patients receiving these drugs in combination with strong CYP3A4 inhibitors should be monitored regularly to prevent adverse reactions. Furthermore, co-administration of docetaxel, cyclophosphamide, or epirubicin with strong CYP3A4 inducers should be avoided. In conclusion, the PBPK models can be used to further investigate the DDI potential of each drug and to develop dosage recommendations for concurrent usage by additional perpetrators or victims.
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Ciclofosfamida , Citocromo P-450 CYP3A , Docetaxel , Interacciones Farmacológicas , Epirrubicina , Modelos Biológicos , Humanos , Epirrubicina/farmacocinética , Epirrubicina/administración & dosificación , Docetaxel/farmacocinética , Docetaxel/administración & dosificación , Ciclofosfamida/farmacocinética , Ciclofosfamida/administración & dosificación , Femenino , Citocromo P-450 CYP3A/metabolismo , Persona de Mediana Edad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Adulto , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Taxoides/farmacocinética , Taxoides/administración & dosificación , Simulación por Computador , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Inductores del Citocromo P-450 CYP3A/farmacología , Inductores del Citocromo P-450 CYP3A/farmacocinética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificaciónRESUMEN
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).
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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 adversosRESUMEN
This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict changes in the pharmacokinetics (PK) and pharmacodynamics (PD, PDE4 inhibition) of roflumilast (ROF) and ROF N-oxide when co-administered with eight CYP3A4/1A2 perpetrators. The population PBPK model of ROF and ROF N-oxide has been successfully developed and validated based on the four clinical PK studies and five clinical drug-drug interactions (DDIs) studies. In PK simulations, every ratio of prediction to observation for PK parameters fell within the range 0.7 to 1.5. In DDI simulations, except for tow peak concentration ratios (Cmax) of ROF with rifampicin (prediction: 0.63 vs. observation: 0.19) and with cimetidine (prediction: 1.07 vs. observation: 1.85), the remaining predicted ratios closely matched the observed ratios. Additionally, the PBPK model suggested that co-administration with the three perpetrators (cimetidine, enoxacin, and fluconazole) may use with caution, with CYP3A4 strong inhibitor (ketoconazole and itraconazole) or with dual CYP3A41A2 inhibitor (fluvoxamine) may reduce to half-dosage or use with caution, while co-administration with CYP3A4 strong or moderate inducer (rifampicin, efavirenz) should avoid. Overall, the present PBPK model can provide recommendations for adjusting dosing regimens in the presence of DDIs.
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Citocromo P-450 CYP3A , Rifampin , Rifampin/farmacología , Cimetidina , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Interacciones Farmacológicas , Óxidos , Modelos BiológicosRESUMEN
Oxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the dose is excreted unchanged into the urine. Oxymorphone, the metabolite primarily formed by CYP2D6, has a 40- to 60-fold higher mu-opioid receptor affinity than the parent compound. While CYP2D6-mediated gene-drug-interactions (GDIs) and drug-drug interactions (DDIs) are well-studied, they only account for a portion of the variability in oxycodone and oxymorphone exposure. The combined impact of CYP2D6-mediated GDIs and DDIs, CYP3A4-mediated DDIs, and UGT2B7 GDIs is not fully understood yet and hard to study in head-to-head clinical trials given the relatively large number of scenarios. Instead, we propose the use of a physiologically-based pharmacokinetic model that integrates available information on oxycodone's metabolism to characterize and predict the impact of DDIs and GDIs on the exposure of oxycodone and its major, pharmacologically-active metabolite oxymorphone. To this end, we first developed and verified a PBPK model for oxycodone and its metabolites using published clinical data. The verified model was then applied to determine the dose-exposure relationship of oxycodone and oxymorphone stratified by CYP2D6 and UGT2B7 phenotypes respectively, and administered perpetrators of CYP-based drug interactions. Our simulations demonstrate that the combination of CYP2D6 UM and a UGT2B7Y (268) mutation may lead to a 2.3-fold increase in oxymorphone exposure compared to individuals who are phenotyped as CYP2D6 NM / UGT2B7 NM. The extent of oxymorphone exposure increases up to 3.2-fold in individuals concurrently taking CYP3A4 inhibitors, such as ketoconazole. Inhibition of the CYP3A4 pathway results in a relative increase in the partial metabolic clearance of oxycodone to oxymorphone. Oxymorphone is impacted to a higher extent by GDIs and DDIs than oxycodone. We predict oxymorphone exposure to be highest in CYP2D6 UMs/UGT2B7 PMs in the presence of ketoconazole (strong CYP3A4 index inhibitor) and lowest in CYP2D6 PMs/UGT2B7 NMs in the presence of rifampicin (strong CYP3A4 index inducer) covering a 55-fold exposure range.
Asunto(s)
Oxicodona , Oximorfona , Humanos , Oxicodona/farmacocinética , Oximorfona/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Cetoconazol/farmacología , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inductores del Citocromo P-450 CYP3A , Inhibidores de Disociación de Guanina Nucleótido , Glucuronosiltransferasa/genéticaRESUMEN
Mosunetuzumab is a CD3/CD20 bispecific antibody. As an on-target effect, transient elevation of interleukin-6 (IL-6) occurs in early treatment cycles. A physiologically-based pharmacokinetic (PBPK) model was developed to assess potential drug interaction caused by IL-6 enzyme suppression on cytochrome P450 3A (CYP3A) during mosunetuzumab treatment. The model's performance in predicting IL-6 CYP3A suppression and subsequent drug-drug interactions (DDIs) was verified using existing clinical data of DDIs caused by chronic and transient IL-6 elevation. Sensitivity analyses were performed for a complete DDI risk assessment. The IL-6 concentration- and time-dependent CYP3A suppression during mosunetuzumab treatment was simulated using PBPK model with incorporation of in vitro IL-6 inhibition data. At clinically approved doses/regimens, the DDI at maximum CYP3A suppression was predicted to be a midazolam maximum drug concentration in plasma (Cmax ) and area under the plasma drug concentration-time curve (AUC) ratio of 1.17 and 1.37, respectively. At the 95th percentile of IL-6 concentration level or when gut CYP3A suppression was considered, the predicted DDI risk for mosunetuzumab remained low (<2-fold). The PBPK-based DDI predictions informed the mosunetuzumab product label to monitor, in early cycles, the concentrations and toxicities for sensitive CYP3A substrates with narrow therapeutic windows.
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Antineoplásicos , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP3A/metabolismo , Interleucina-6 , Citocinas , Interacciones Farmacológicas , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Modelos BiológicosRESUMEN
Encorafenib, a potent BRAF kinase inhibitor undergoes significant metabolism by CYP3A4 (83%) and CYP2C19 (16%) and also a substrate of P-glycoprotein (P-gp). Because of this, encorafenib possesses potential for enzyme-transporter related interactions. Clinically, its drug-drug interactions (DDIs) with CYP3A4 inhibitors (posaconazole, diltiazem) were reported and hence there is a necessity to study DDIs with multiple enzyme inhibitors, inducers, and P-gp inhibitors.USFDA recommended clinical CYP3A4, CYP2C19, P-gp inhibitors, CYP3A4 inducers were selected and prospective DDIs were simulated using physiologically based pharmacokinetic modelling (PBPK). Impact of dose (50 mg vs. 300 mg) and staggering of administrations (0-10 h) on the DDIs were predicted.PBPK models for encorafenib, perpetrators simulated PK parameters within twofold prediction error. Clinically reported DDIs with posaconazole and diltiazem were successfully predicted.CYP2C19 inhibitors did not result in significant DDI whereas strong CYP3A4 inhibitors resulted in DDI ratio up to 4.5. Combining CYP3A4, CYP2C19 inhibitors yielded DDI equivalent CYP3A4 alone. Strong CYP3A4 inducers yielded DDI ratio up to 0.3 and no impact of P-gp inhibitors on DDIs was observed. The DDIs were not impacted by dose and staggering of administration. Overall, this work indicated significance of PBPK modelling for evaluating clinical DDIs with enzymes, transporters and interplay.
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Inhibidores del Citocromo P-450 CYP3A , Diltiazem , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP2C19 , Estudios Prospectivos , Inductores del Citocromo P-450 CYP3A/farmacología , Interacciones Farmacológicas , Modelos BiológicosRESUMEN
Encorafenib, a potent BRAF kinase inhibitor gets significantly metabolised by CYP3A4 (83%) and CYP2C19 (16%) and is a substrate for P-glycoprotein (P-gp). Due to significant metabolism by CYP3A4, encorafenib exposure can increase in hepatic and renal impairment and may lead to altered magnitude of drug-drug interactions (DDI). Hence, it is necessary to assess the exposures & DDI's in impaired population.Physiologically based pharmacokinetic modelling (PBPK) was utilised to determine the exposures of encorafenib in hepatic and renal impairment along with altered DDI's. Prospective DDI's were predicted with USFDA recommended clinical CYP3A4, CYP2C19, P-gp inhibitors and CYP3A4 inducers.PBPK models for encorafenib, perpetrators simulated PK parameters within 2-folds error. Encorafenib exposures significantly increased in hepatic as compared to renal impairment because of reduced CYP3A4 levels.Hepatic impairment caused changes in inhibition and induction DDI's, when compared to healthy population. Renal impairment did not cause significant changes in DDIs except for itraconazole. P-gp, CYP2C19 inhibitors did not result in altered DDI's. The DDI's were found to have insignificant correlation with relative exposure increase of perpetrators in case of impairment. Overall, this work signifies use of PBPK modelling for DDI's evaluations in hepatic and renal impairment populations.
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Inhibidores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A/metabolismo , Estudios Prospectivos , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Interacciones Farmacológicas , Inhibidores de Proteínas Quinasas , Modelos BiológicosRESUMEN
Itraconazole is a potent inhibitor of cytochrome P450 3A4 (CYP3A4), associated with numerous drug-drug interactions (DDI). PUR1900, a dry powder formulation of itraconazole for oral inhalation, results in high lung and low systemic exposure. This project used physiologically based pharmacokinetic (PBPK) modeling to assess the DDI potential of inhaled PUR1900, using midazolam as a "victim drug." The basic and mechanistic static models evaluated the DDI potential of PUR1900, assuming 5 mg of midazolam coadministration at steady-state itraconazole exposure. Subsequently, Simcyp® PBPK simulation software and pharmacokinetic data from a Phase 1 clinical trial with PUR1900 (NCT03479411) were used to optimize an existing itraconazole PBPK model. The model was applied to investigate the potential for CYP3A4 DDI when 5 mg of midazolam is co-administered with inhaled PUR1900 at a steady state in a virtual healthy population at PUR1900 doses up to 40 mg per day. The basic static and mechanistic static models suggested a strong likelihood for DDI with inhaled PUR1900. The PBPK model was consistent with PUR1900 Phase 1 trial data. The geometric mean Cmax and AUC ratios of midazolam at a maximum dose of 40 mg PUR1900 were 1.14 and 1.26, respectively, indicating a minimal likelihood of DDI with inhaled PUR1900. The low systemic exposure of itraconazole when administered as PUR1900 results in minimal to no CYP3A4 inhibition, reducing the concern of drug-drug interactions. As the risk of CYP3A4 DDI is predicted to be significantly lower when itraconazole is administered via oral inhalation as PUR1900, it is likely that PUR1900 can be safely used for the treatment of pulmonary fungal infections in patients taking pharmaceuticals currently contraindicated with oral itraconazole.
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Itraconazol , Midazolam , Humanos , Itraconazol/farmacocinética , Midazolam/farmacocinética , Modelos Biológicos , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A , Interacciones FarmacológicasRESUMEN
The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) and is therefore recommended for use in clinical drug-drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P-gp, it is susceptible to DDIs involving these proteins. Physiologically-based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug-drug(-gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P-gp perpetrators as well as CYP2D6 and P-gp victims. The quinidine parent-metabolite model including 3-hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1-600 mg). The model covers efflux transport via P-gp and metabolic transformation to either 3-hydroxyquinidine or unspecified metabolites via CYP3A4. The 3-hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with greater than 90% of predicted pharmacokinetic parameters within two-fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with greater than 90% of predicted DD(G)I pharmacokinetic parameter ratios within two-fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims, and targets, to support investigations of DD(G)Is.
Asunto(s)
Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Quinidina , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Interacciones Farmacológicas , Modelos Biológicos , Inhibidores del Citocromo P-450 CYP3A/farmacocinéticaRESUMEN
Vonoprazan is metabolized extensively through CYP3A and is an in vitro time-dependent inhibitor of CYP3A. A tiered approach was applied to understand the CYP3A victim and perpetrator drug-drug interaction (DDI) potential for vonoprazan. Mechanistic static modeling suggested vonoprazan is a potential clinically relevant CYP3A inhibitor. Thus, a clinical study was conducted to evaluate the impact of vonoprazan on the exposure of oral midazolam, an index substrate for CYP3A. A physiologically-based pharmacokinetic (PBPK) model for vonoprazan was also developed using in vitro data, drug- and system-specific parameters, and clinical data and observations from a [14 C] human absorption, distribution, metabolism, and excretion study. The PBPK model was refined and verified using data from a clinical DDI study with the strong CYP3A inhibitor, clarithromycin, to confirm the fraction metabolized by CYP3A, and the oral midazolam clinical DDI data assessing vonoprazan as a time-dependent inhibitor of CYP3A. The verified PBPK model was applied to simulate the anticipated changes in vonoprazan exposure due to moderate and strong CYP3A inducers (efavirenz and rifampin, respectively). The clinical midazolam DDI study indicated weak inhibition of CYP3A, with a less than twofold increase in midazolam exposure. PBPK simulations projected a 50% to 80% reduction in vonoprazan exposure when administered concomitantly with moderate or strong CYP3A inducers. Based on these results, the vonoprazan label was revised and states that lower doses of sensitive CYP3A substrates with a narrow therapeutic index should be used when administered concomitantly with vonoprazan, and co-administration with moderate and strong CYP3A inducers should be avoided.