RESUMEN
Glofitamab is a novel T cell bispecific antibody developed for treatment of relapsed-refractory diffuse large B cell lymphoma and other non-Hodgkin's lymphoma indications. By simultaneously binding human CD20-expressing tumor cells and CD3 on T cells, glofitamab induces tumor cell lysis, in addition to T-cell activation, proliferation, and cytokine release. Here, we describe physiologically-based pharmacokinetic (PBPK) modeling performed to assess the impact of glofitamab-associated transient increases in interleukin 6 (IL-6) on the pharmacokinetics of several cytochrome P450 (CYP) substrates. By refinement of a previously described IL-6 model and inclusion of in vitro CYP suppression data for CYP3A4, CYP1A2, and 2C9, a PBPK model was established in Simcyp to capture the induced IL-6 levels seen when glofitamab is administered at the intended dose and dosing regimen. Following model qualification, the PBPK model was used to predict the potential impact of CYP suppression on exposures of various CYP probe substrates. PBPK analysis predicted that, in the worst-case, the transient elevation of IL-6 would increase exposures of CYP3A4, CYP2C9, and CYP1A2 substrates by less than or equal to twofold. Increases for CYP3A4, CYP2C9, and CYP1A2 substrates were projected to be 1.75, 1.19, and 1.09-fold following the first administration and 2.08, 1.28, and 1.49-fold following repeated administrations. It is recommended that there are no restrictions on concomitant treatment with any other drugs. Consideration may be given for potential drug-drug interaction during the first cycle in patients who are receiving concomitant CYP substrates with a narrow therapeutic index via monitoring for toxicity or for drug concentrations.
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Anticuerpos Biespecíficos , Citocromo P-450 CYP1A2 , Linfoma no Hodgkin , Humanos , Interleucina-6 , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Interacciones Farmacológicas , Linfocitos T/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Linfoma no Hodgkin/tratamiento farmacológico , Modelos BiológicosRESUMEN
INTRODUCTION: Emicizumab is a humanized bispecific antibody approved for the routine prophylaxis of bleeding episodes in patients with hemophilia A (PwHA) regardless of the presence of factor VIII (FVIII) inhibitors. It mimics the cofactor function of missing activated FVIII by bridging activated factor IX and factor X, thereby restoring hemostasis. AREAS COVERED: This review covers the clinical pharmacology of emicizumab and the translation of its pharmacokinetics (PK) and pharmacodynamics (PD) to clinical efficacy and safety. The PK of emicizumab is linear, with an approximately 1-month half-life. Once-weekly to every-4-week subcutaneous (SC) administrations maintain effective trough concentrations throughout the dosing intervals, associated with a coagulation potential analogous to that in patients with mild hemophilia A. In combination with activated prothrombin complex concentrate, and to a lesser extent with recombinant activated factor VII, emicizumab exerts a synergistic effect, whereas combination with FVIII may result in a non-additive coagulation potential at normal FVIII activity. EXPERT OPINION: The translation of emicizumab PK/PD into clinical effects was demonstrated in several phase III studies, which showed remarkable bleed control and a favorable safety profile in PwHA. These emicizumab attributes, together with the convenience of use (infrequent SC injections), offer a novel paradigm for the management of PwHA.
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Anticuerpos Biespecíficos , Hemofilia A , Humanos , Hemofilia A/tratamiento farmacológico , Hemorragia/prevención & control , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Monoclonales HumanizadosRESUMEN
PURPOSE: Entrectinib is an anti-cancer agent that inhibits TRKA/B/C, ROS1, and ALK. Secondary pharmacokinetic (PK) exposure parameters for entrectinib derived from a previously described population PK model were used to characterize exposure-response relationships in patients treated with entrectinib. METHODS: Data were pooled from Phase 1 and 2 studies of entrectinib (600-800 mg/day in adults, 250-750 mg/m2/day in children) in 293 patients with NTRK-, ROS1-, or ALK-positive, locally advanced or metastatic tumors. Efficacy was evaluated by the changes in sum of target lesion diameters and best overall response defined by RECIST1.1. A longitudinal nonlinear mixed-effect model described the relationship between entrectinib exposure and tumor size data in patients with ROS1-positive non-small-cell lung cancer (NSCLC) or NTRK fusion-positive solid tumors. The relationship between exposure and treatment-emergent (TEAEs) or serious (SAEs) adverse events was assessed by logistic regression in all patients for whom secondary PK parameter estimates were derived. RESULTS: Among the 89 patients with evaluable efficacy data included in the exposure-efficacy analysis, 73% (65/89) achieved a complete or partial response. Entrectinib exposure distribution was similar in responders and non-responders. Model-described tumor shrinkage rates were 8-12 times greater than growth rates in both ROS-1-positive NSCLC patients and NTRK fusion-positive solid tumor patients, with no relationship between exposure and these rates. The probability of experiencing a Grade ≥ 3 TEAE or SAE increased with exposure, primarily at doses > 600 mg/day. CONCLUSION: These analyses supported that entrectinib at 600 mg/day provides an acceptable benefit-risk ratio in adults with NTRK-, ROS1-, or ALK-positive tumors, considered as rare disease.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Primarias Secundarias , Adulto , Benzamidas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Niño , Humanos , Indazoles , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas ReceptorasRESUMEN
Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib-failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one-compartment models with sequential zero/first-order input and first-order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment-naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression-free survival in treatment-naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of treatment as a significant covariate, with an optimal response achieved for concentrations above 1040 nmol/L. With 600 mg twice daily (b.i.d.), 92% of global patients are above this threshold concentration, compared with only 43% of patients with 300 mg b.i.d. In Japan, where the body weight distribution is lower, the approved 300 mg b.i.d. dose brings about 70% of Japanese patients above this threshold. Logistic regression analyses found no significant relationship between the combined alectinib-M4 molar concentration and first occurrence of adverse events. These pharmacometric results were used to expedite and facilitate regulatory approvals of 600 mg b.i.d. for first-line ALK-positive NSCLC in the United States and European Union in 2017 and in China in 2018.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Quinasa de Linfoma Anaplásico , Teorema de Bayes , Carbazoles , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , PiperidinasRESUMEN
The pharmacokinetics (PK) of RO7049389, a new hepatitis B virus (HBV) core protein allosteric modulator of class I, and of its active metabolite M5 were studied in fasted and fed conditions after single and multiple once-a-day and twice-a-day doses in healthy subjects and patients with HBV. The nonlinearity of the pharmacokinetics, the large variability, the small sample size per dose arms, the higher plasma exposure in Asians, and the heterogeneity in patient baseline characteristics seen in phase I studies made the ethnic sensitivity assessment and the selection of the recommended phase II dose difficult. A population PK model, simultaneously modeling RO7049389 and M5, was developed to characterize the complex PK, quantify ethnicity (i.e., Asian vs. non-Asian) and gender effects on the PK of RO7049389 and M5, and infer the quantity of RO7049389 in liver relative to plasma. Exposures in the liver are of particular importance for dose selection since the liver is the site of action of the compound. The model described and reproduced the population PK profiles as well as the between-subject variability of RO7049389 and its metabolite. It could show that the PK is similar between healthy subjects and in HBV patients, once the ethnicity and gender effects are accounted for. The model predicts that, despite a large difference in the plasma exposure of RO7049389 between Asians and non-Asians, the exposure in the liver is comparable, allowing the use of the same dose to treat Asian and non-Asian patients. This model provides a valuable basis to develop this new anti-HBV drug and to define optimal dosing.
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Antivirales/farmacocinética , Hepatitis B/tratamiento farmacológico , Adulto , Transporte Biológico , Relación Dosis-Respuesta a Droga , Ayuno , Femenino , Voluntarios Sanos , Hepatitis B/etnología , Humanos , Hígado , Masculino , Modelos Biológicos , Grupos Raciales , Factores SexualesRESUMEN
Plasma drug concentration and electrocardiogram (ECG) data from a drug-drug interaction (DDI) study employing the metabolic inhibitor itraconazole have been used as part of a prospectively defined pharmacokinetic/pharmacodynamic modelling strategy to quantify the potential for QT interval prolongation from basmisanil, an investigational compound. ECG data were collected on multiple days during repeat dosing treatment regimens, thereby allowing the capture of QT data across a wide range of drug concentrations in each study participant and encompassing both "therapeutic" and "supra-therapeutic" exposures. The data were used to develop a non-linear mixed effect concentration-QT (C-QT) model that differentiated drug-induced QT prolongation from other factors altering QT interval duration. Food effects were accounted by quantitating their influences on the parameters describing the diurnal variation of QT. The final model demonstrated that itraconazole does not cause QT prolongation, while for basmisanil, the 1-sided upper 95% CI of the QT interval at 240 mg (the highest dose tested in ongoing phase 2 studies) with DDI, was below the 10 ms threshold considered to be of clinical significance by regulatory authorities. The empirical modelling was complemented with a human mechanistic cardiac single cell model that was used to simulate the change in action potential duration as a function of drug concentration. The results of the two approaches were in agreement, suggesting that the effect of basmisanil on QT interval duration can be attributed to the effect on hERG alone. The C-QT model for basmisanil can be used to derive the QT interval corrected changes in heart rate (QTc) and thus inform cardiac safety strategy in later development without the need for a separate, dedicated study.
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Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Antagonistas de Receptores de GABA-A/farmacocinética , Itraconazol/farmacocinética , Síndrome de QT Prolongado/diagnóstico , Adulto , Estudios Cruzados , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Interacciones Farmacológicas , Electrocardiografía/efectos de los fármacos , Femenino , Antagonistas de Receptores de GABA-A/administración & dosificación , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Itraconazol/administración & dosificación , Síndrome de QT Prolongado/inducido químicamente , Masculino , Persona de Mediana Edad , Modelos Biológicos , Análisis de la Célula Individual , Adulto JovenRESUMEN
PURPOSE: Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3-39.0) for alectinib 600 mg twice daily (BID). We investigated exposure-response relationships from final pooled phase II OS and safety data to assess alectinib dose selection. METHODS: A semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (Ctrough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between Ctrough,ss and incidence of adverse events (AEs: serious and Grade ≥ 3). RESULTS: Overall, 92% of patients (n = 207/225) had Ctrough,ss data and were included in the analysis. No statistically significant relationship was found between Ctrough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between Ctrough,ss and AEs. CONCLUSION: Alectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC.