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The current demand for pharmacometricians outmatches the supply provided by academic institutions and considerable investments are made to develop the competencies of these scientists on-the-job. Even with the observed increase in academic programs related to pharmacometrics, this need is unlikely to change in the foreseeable future, as the demand and scope of pharmacometrics applications keep expanding. Further, the field of pharmacometrics is changing. The field largely started when Lewis Sheiner and Stuart Beal published their seminal papers on population pharmacokinetics in the late 1970's and early 1980's and has continued to grow in impact and use since its inception. Physiological-based pharmacokinetics and systems pharmacology have grown rapidly in scope and impact in the last decade and machine learning is just on the horizon. While all these methodologies are categorized as pharmacometrics, no one person can be an expert in everything. So how do you train future pharmacometricians? Leading experts in academia, industry, contract research organizations, clinical medicine, and regulatory gave their opinions on how to best train future pharmacometricians. Their opinions were collected and synthesized to create some general recommendations.
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Farmacología , Humanos , Farmacocinética , Selección de ProfesiónRESUMEN
The International Society of Pharmacometrics (ISoP) Mentorship Program (IMP) aims to help professionals at all career stages to transition into the pharmacometrics field, move to a different role/area within pharmacometrics, or expand their skillsets. The program connects mentees at various stages of their careers with mentors based on established criteria for mentor-mentee matching. Pairing mentees with appropriate mentors ensures strong alignment between mentees' interests and mentors' expertise as this is critical to the success and continuation of the relationship between the mentor and mentee. Once mentors and mentees are connected, they are strongly encouraged to meet at least once per month for an hour. The mentor and mentee have the freedom to tailor their sessions to their liking, including frequency, duration, and topics they choose to focus on. Mentees are encouraged to clearly define their goals to help direct their mentor-mentee relationship and conversations. Mentees and mentors alike are given the opportunity to provide feedback about the program to the ISoP Education Committee through surveys and testimonials. Due to the program's infancy, structured guidelines for mentor-mentee sessions are still being developed and instituted using the program evaluation described in this paper.
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Tutoría , Mentores , Humanos , Retroalimentación , Evaluación de Programas y Proyectos de Salud , Encuestas y CuestionariosRESUMEN
The development of innate and/or acquired resistance to human epidermal growth factor receptor type-2 (HER2)-targeted therapy in HER2-positive breast cancer (HER2 + BC) is a major clinical challenge that needs to be addressed. One of the main mechanisms of resistance includes aberrant activation of the HER2 and phosphatidylinositol 3-kinase/AKT8 virus oncogene cellular homolog/mammalian target of rapamycin (PI3K/Akt/mTOR) pathways. In the present work, we propose to use a triple combination therapy to combat this resistance phenomenon. Our strategy involves evaluation of two targeted small molecule agents, everolimus and dasatinib, with complementary inhibitory circuitries in the PI3K/Akt/mTOR pathway, along with a standard cytotoxic agent, paclitaxel. Everolimus inhibits mTOR, while dasatinib inhibits Src, which is a protein upstream of Akt. An over-activation of these two proteins has been implicated in approximately 50% of HER2 + BC cases. Hence, we hypothesize that their simultaneous inhibition may lead to enhanced cell-growth inhibition. Moreover, the potent apoptotic effects of paclitaxel may help augment the overall cytotoxicity of the proposed triple combination in HER2 + BC cells. To this end, we investigated experimentally and assessed computationally the in vitro pharmacodynamic drug-drug interactions of the various dual and triple combinations to assess their subsequent combinatorial effects (synergistic/additive/antagonistic) in a HER2-therapy resistant BC cell line, JIMT-1. Our proposed triple combination therapy demonstrated synergism in JIMT-1 cells, thus corroborating our hypothesis. This effort may form the basis for further investigation of the triple combination therapy in vivo at a mechanistic level in HER2-therapy resistant BC cells.
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Antineoplásicos , Neoplasias de la Mama , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Dasatinib/farmacología , Dasatinib/uso terapéutico , Interacciones Farmacológicas , Resistencia a Antineoplásicos , Everolimus/farmacología , Everolimus/uso terapéutico , Femenino , Humanos , Paclitaxel/farmacología , Fosfatidilinositol 3-Quinasas/farmacología , Fosfatidilinositol 3-Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/farmacología , Receptor ErbB-2 , Serina-Treonina Quinasas TOR/metabolismo , Trastuzumab/uso terapéuticoRESUMEN
Pharmacometrics is a constantly evolving field that plays a major role in decision making in drug development and clinical monitoring. Scientists in Pharmacometrics, especially in their early phases of career, are often faced with the challenge of identifying adequate resources for self-training and education. Hence, the ISoP Education Committee through its working group dedicated to Central Indexing and knowledge Dissemination has built a database of worldwide educational programs and most common references in Pharmacometrics.
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HER2-positive breast cancer (BC) is a rapidly growing and aggressive BC subtype that predominantly affects younger women. Despite improvements in patient outcomes with anti-HER2 therapy, primary and/or acquired resistance remain a major clinical challenge. Here, we sought to use a quantitative systems pharmacological (QSP) approach to evaluate the efficacy of lapatinib (LAP), abemaciclib (ABE) and 5-fluorouracil (5-FU) mono- and combination therapies in JIMT-1 cells, a HER2+ BC cell line exhibiting intrinsic resistance to trastuzumab. Concentration-response relationships and temporal profiles of cellular viability were assessed upon exposure to single agents and their combinations. To quantify the nature and intensity of drug-drug interactions, pharmacodynamic cellular response models were generated, to characterize single agent and combination time course data. Temporal changes in cell-cycle phase distributions, intracellular protein signaling, and JIMT-1 cellular viability were quantified, and a systems-based protein signaling network model was developed, integrating protein dynamics to drive the observed changes in cell viability. Global sensitivity analyses for each treatment arm were performed, to identify the most influential parameters governing cellular responses. Our QSP model was able to adequately characterize protein dynamic and cellular viability trends following single and combination drug exposure. Moreover, the model and subsequent sensitivity analyses suggest that the activation of the stress pathway, through pJNK, has the greatest impact over the observed declines of JIMT-1 cell viability in vitro. These findings suggest that dual HER2 and CDK 4/6 inhibition may be a promising novel treatment strategy for refractory HER2+ BC, however, proof-of-concept in vivo studies are needed to further evaluate the combined use of these therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Humanos , Lapatinib/farmacología , Lapatinib/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Farmacología en Red , Mapas de Interacción de Proteínas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2/análisis , Receptor ErbB-2/metabolismo , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Doxorubicin (DOX) is one of the most effective anticancer drugs to treat various forms of cancers; however, its therapeutic utility is severely limited by its associated cardiotoxicity. Despite the enormous amount of research conducted in this area, the exact molecular mechanisms underlying DOX toxic effects on the heart are still an area that warrants further investigations. In this study, we reviewed literature to gather the best-known molecular pathways related to DOX-induced cardiotoxicity (DIC). They include mechanisms dependent on mitochondrial dysfunction such as DOX influence on the mitochondrial electron transport chain, redox cycling, oxidative stress, calcium dysregulation, and apoptosis pathways. Furthermore, we discuss the existing strategies to prevent and/or alleviate DIC along with various techniques available for therapeutic drug monitoring (TDM) in cancer patients treated with DOX. Finally, we propose a stepwise flowchart for TDM of DOX and present our perspective at curtailing this deleterious side effect of DOX.
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Antibióticos Antineoplásicos/efectos adversos , Doxorrubicina/efectos adversos , Cardiopatías/inducido químicamente , Animales , Cardiotoxicidad , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Cardiopatías/metabolismo , Humanos , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Estrés OxidativoRESUMEN
The emergence of human epidermal growth factor receptor type-2 (HER2) therapy resistance in HER2-positive (HER2+) breast cancer (BC) poses a major clinical challenge. The primary mechanisms of resistance include aberrant activation of the HER2 and phosphatidylinositol 3-kinase/mammalian target of rapamycin/AKT8 virus oncogene cellular homolog (PI3K/Akt/mTOR) pathways. The existence of feedback loops in this pathway may engender resistance to targeted therapies such as everolimus, an mTOR inhibitor, resulting in a more aggressive form of refractory HER2+ BC. Here, we hypothesize that a triple and sequential combination therapy of paclitaxel, a potent cytotoxic agent, before concomitant administration of dasatinib, a SRC proto-oncogene nonreceptor tyrosine kinase (Src) family kinase inhibitor, with everolimus, restores sensitivity to treatment in refractory HER2+ BC. This was assessed by a combination of experimental and computational approaches. Quantitative systems pharmacological (QSP), pharmacokinetics (PK), and pharmacodynamics (PD) studies were conducted in static and three-dimensional and dynamic (3DD) cell culture systems using a HER2+ cell line resistant to HER2 therapy, JIMT-1. The dynamic responses in cellular viability and key signaling proteins in the HER2 and PI3K/Akt/mTOR pathways were measured upon treatments with single drugs, combinations, and appropriate controls. A QSP-PK/PD model was developed and used to optimize the sequence and interdose interval of the three agents in the combination. The proposed sequential combination therapy demonstrated strong cytotoxic effects in JIMT-1 cells, and our models predicted the usefulness of this combination over prolonged durations in the 3DD setting. Our combined experimental and QSP-PK/PD modeling approach may serve as a useful screening tool in predicting clinical efficacy of combination therapies in oncology. Nonetheless, further in vivo human xenograft tumor studies are warranted.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Simulación por Computador , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Terapia Molecular Dirigida , Receptor ErbB-2/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Interacciones Farmacológicas , Humanos , Proto-Oncogenes MasRESUMEN
PURPOSE: Trastuzumab combined with Doxorubicin (DOX) demonstrates significant clinical activity in human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC). However, emergence of treatment resistance and trastuzumab associated cardiotoxicity remain clinical challenges. In an effort to improve patient outcome, we have developed and evaluated novel tri-functional immunoliposomes (TFIL) that target HER2-receptors on BC cells and CD3-receptors on T-lymphocytes, and deliver DOX. METHODS: Trastuzumab (anti-HER2) and OKT-3 (anti-CD3) antibodies were conjugated to liposomes using a micelle-transfer method. Cytotoxicity of targeted immunoliposomes loaded with DOX was examined in vitro on HER2-positive BC cells (BT474), with peripheral blood monocytic cells (PBMC) as immune effector cells. RESULTS: TFIL demonstrated high antibody-liposome conjugation ratios (100-130 µg protein/µmol phospholipid) and cargo capacity (0.21 mol:mol drug:lipid), highly efficient DOX loading (>90%), a particle size favorable for extended circulation (~150 nm), and good stability (up to 3 months at 4°C). In the presence of PBMCs, TFIL showed complete killing of BT474 cells, and were superior to mono-targeted trastuzumab-bearing liposomes, non-targeted liposomes, and free Trastuzumab and DOX. CONCLUSIONS: Novel anti-HER2xCD3 + DOX TFIL show promise as a means to both engage immune cells against HER2 positive breast cancer cells and deliver chemotherapy, and have the potential to improve clinical outcomes.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Preparaciones de Acción Retardada/administración & dosificación , Doxorrubicina/administración & dosificación , Composición de Medicamentos/métodos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Leucocitos Mononucleares , Liposomas , Muromonab-CD3/administración & dosificación , Trastuzumab/administración & dosificaciónRESUMEN
Dysregulation of mTOR pathway is common in hepatocellular carcinoma (HCC). A translational quantitative systems pharmacology (QSP), pharmacokinetic (PK), and pharmacodynamic (PD) model dissecting the circuitry of this pathway was developed to predict HCC patients' response to everolimus, an mTOR inhibitor. The time course of key signaling proteins in the mTOR pathway, HCC cells viability, tumor volume (TV) and everolimus plasma and tumor concentrations in xenograft mice, clinical PK of everolimus and progression free survival (PFS) in placebo and everolimus-treated patients were extracted from literature. A comprehensive and multiscale QSP/PK/PD model was developed, qualified, and translated to clinical settings. Model fittings and simulations were performed using Monolix software. The S6-kinase protein was identified as critical in the mTOR signaling pathway for describing everolimus lack of efficacy in HCC patients. The net growth rate constant (kg) of HCC cells was estimated at 0.02 h-1 (2.88%RSE). The partition coefficient of everolimus into the tumor (kp) was determined at 0.06 (12.98%RSE). The kg in patients was calculated from the doubling time of TV in naturally progressing HCC patients, and was determined at 0.004 day-1. Model-predicted and observed PFS were in good agreement for placebo and everolimus-treated patients. In conclusion, a multiscale QSP/PK/PD model elucidating everolimus lack of efficacy in HCC patients was successfully developed and predicted PFS reasonably well compared to observed clinical findings. This model may provide insights into clinical response to everolimus-based therapy and serve as a valuable tool for the clinical translation of efficacy for novel mTOR inhibitors.
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Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Everolimus/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Hepáticas/metabolismo , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Tyrosine kinase inhibitors (TKIs) are targeted therapies rapidly becoming favored over conventional cytotoxic chemotherapeutics. Our study investigates two FDA approved TKIs, DASATINIB; indicated for IMATINIB-refractory chronic myeloid leukemia, and SORAFENIB; indicated for hepatocellular carcinoma and advanced renal cell carcinoma. Limited but crucial evidence suggests that these agents can have cardiotoxic side effects ranging from hypertension to heart failure. A greater understanding of the underlying mechanisms of this cardiotoxicity are needed as concerns grow and the capacity to anticipate them is lacking. The objective of this study was to explore the mitochondrial-mediated cardiotoxic mechanisms of the two selected TKIs. This was achieved experimentally using immortalized human cardiomyocytes, AC16 cells, to investigate dose- and time-dependent cell killing, along with measurements of temporal changes in key signaling proteins involved in the intrinsic apoptotic and autophagy pathways upon exposure to these agents. Quantitative systems pharmacology (QSP) models were developed to capture the toxicological response in AC16 cells using protein dynamic data. The developed QSP models captured well all the various trends in protein signaling and cellular responses with good precision on the parameter estimates, and were successfully qualified using external data sets. An interplay between the apoptotic and autophagic pathways was identified to play a major role in determining toxicity associated with the investigated TKIs. The established modeling platform showed utility in elucidating the mechanisms of cardiotoxicity of SORAFENIB and DASATINIB. It may be useful for other small molecule targeted therapies demonstrating cardiac toxicities, and may aid in informing alternate dosing strategies to alleviate cardiotoxicity associated with these therapies.
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Cardiotoxicidad/etiología , Mitocondrias/efectos de los fármacos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Línea Celular , Humanos , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/efectos adversos , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Breast cancer (BC) is the most common cancer in women, and the second most frequent cause of cancer-related deaths in women worldwide. It is a heterogeneous disease composed of multiple subtypes with distinct morphologies and clinical implications. Quantitative systems pharmacology (QSP) is an emerging discipline bridging systems biology with pharmacokinetics (PK) and pharmacodynamics (PD) leveraging the systematic understanding of drugs' efficacy and toxicity. Despite numerous challenges in applying computational methodologies for QSP and mechanism-based PK/PD models to biological, physiological, and pharmacological data, bridging these disciplines has the potential to enhance our understanding of complex disease systems such as BC. In QSP/PK/PD models, various sources of data are combined including large, multi-scale experimental data such as -omics (i.e. genomics, transcriptomics, proteomics, and metabolomics), biomarkers (circulating and bound), PK, and PD endpoints. This offers a means for a translational application from pre-clinical mathematical models to patients, bridging the bench to bedside paradigm. Not only can these models be applied to inform and advance BC drug development, but they also could aid in optimizing combination therapies and rational dosing regimens for BC patients. Here, we review the current literature pertaining to the application of QSP and pharmacometrics-based pharmacotherapy in BC including bottom-up and top-down modeling approaches. Bottom-up modeling approaches employ mechanistic signal transduction pathways to predict the behavior of a biological system. The ones that are addressed in this review include signal transduction and homeostatic feedback modeling approaches. Alternatively, top-down modeling techniques are bioinformatics reconstruction techniques that infer static connections between molecules that make up a biological network and include (1) Bayesian networks, (2) co-expression networks, and (3) module-based approaches. This review also addresses novel techniques which utilize the principles of systems biology, synthetic lethality and tumor priming, both of which are discussed in relationship to novel drug targets and existing BC therapies. By utilizing QSP approaches, clinicians may develop a platform for improved dose individualization for subpopulation of BC patients, strengthen rationale in treatment designs, and explore mechanism elucidation for improving future treatments in BC medicine.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Farmacología/métodos , Biología de Sistemas/métodos , Humanos , Modelos BiológicosRESUMEN
The fetal/neonatal hematopoietic system must generate enough blood cells to meet the demands of rapid growth. This unique challenge might underlie the high incidence of thrombocytopenia among preterm neonates. In this study, neonatal platelet production and turnover were investigated in newborn mice. Based on a combination of blood volume expansion and increasing platelet counts, the platelet mass increased sevenfold during the first 2 weeks of murine life, a time during which thrombopoiesis shifted from liver to bone marrow. Studies applying in vivo biotinylation and mathematical modeling showed that newborn and adult mice had similar platelet production rates, but neonatal platelets survived 1 day longer in circulation. This prolonged lifespan fully accounted for the rise in platelet counts observed during the second week of murine postnatal life. A study of pro-apoptotic and anti-apoptotic Bcl-2 family proteins showed that neonatal platelets had higher levels of the anti-apoptotic protein Bcl-2 and were more resistant to apoptosis induced by the Bcl-2/Bcl-xL inhibitor ABT-737 than adult platelets. However, genetic ablation or pharmacologic inhibition of Bcl-2 alone did not shorten neonatal platelet survival or reduce platelet counts in newborn mice, indicating the existence of redundant or alternative mechanisms mediating the prolonged lifespan of neonatal platelets.
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Plaquetas/fisiología , Recuento de Plaquetas , Trombopoyesis/fisiología , Animales , Animales Recién Nacidos , Apoptosis/fisiología , Compuestos de Bifenilo/farmacología , Plaquetas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Humanos , Recién Nacido , Hígado/citología , Volúmen Plaquetario Medio , Megacariocitos/fisiología , Megacariocitos/ultraestructura , Ratones , Nitrofenoles/farmacología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Bazo/citología , Sulfonamidas/farmacología , Trombopoyesis/efectos de los fármacosRESUMEN
Cancer is a complex disease that is characterized by an uncontrolled growth and spread of abnormal cells. Drug development in oncology is particularly challenging and is associated with one of the highest attrition rates of compounds despite substantial investments in resources. Pharmacokinetic and pharmacodynamic (PK/PD) modeling seeks to couple experimental data with mathematical models to provide key insights into factors controlling cytotoxic effects of chemotherapeutics and cancer progression. PK/PD modeling of anti-cancer compounds is equally challenging, partly based on the complexity of biological and pharmacological systems. However, reliable mechanistic and systems PK/PD models for anti-cancer agents have been developed and successfully applied to: (1) provide insights into fundamental mechanisms implicated in tumor growth, (2) assist in dose selection for first-in-human phase I studies (e.g., effective dose, escalating doses, and maximal tolerated doses), (3) design and optimize combination drug regimens, (4) design clinical trials, and (5) establish links between drug efficacy and safety and the concentrations of measured biomarkers. In this commentary, classes of relevant mechanism-based and systems PK/PD models of anti-cancer agents that have shown promise in translating preclinical data and enhancing stages of the drug development process are reviewed. Specific features of such models are discussed including their strengths and limitations along with a prospectus of using these models alone or in combination for cancer therapy.
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Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Progresión de la Enfermedad , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Análisis de Supervivencia , Distribución TisularRESUMEN
Cisplatin is widely used for the treatment of various types of cancer. However, cisplatin-induced nephrotoxicity (CIN) is frequently observed in patients receiving cisplatin therapy which poses a challenge in its clinical utility. Currently used clinical biomarkers for CIN are not adequate for early detection of nephrotoxicity, hence there is a need to identify potential early biomarkers in predicting CIN. In the current study, a combination of in vitro toxicodynamic (TD) modeling and untargeted global metabolomics approach was used to identify novel potential metabolite biomarkers for early detection of CIN. In addition, we investigated the protective role of cimetidine (CIM), an inhibitor of the organic cation transporter 2 (OCT2), in suppressing CIN. We first characterized the time-course of nephrotoxic effects of cisplatin (CIS) and the protective effects of CIM in a human pseudo-immortalized renal proximal tubule epithelial cell line (RPTEC), SA7K cell line. Secondly, we used a mathematical cell-level, in vitro TD modeling approach to quantitatively characterize the time-course effects of CIS and CIM as single agents and combination in SA7K cells. Based on the experimental and modeling results, we selected relevant concentrations of CIS and CIM for our metabolomics study. With the help of PCA (Principal Component Analysis) and PLS-DA (Projection to Latent Structure - Discriminate Analysis) analyses, we confirmed global metabolome changes for different groups (CIS, CIM, CIS+CIM vs control) in SA7K cells. Based on the criterion of a p-value ≤ 0.05 and a fold change ≥ 2 or ≤ 0.5, we identified 20 top metabolites that were significantly changed during the early phase i.e. within first 12 h of CIS treatment. Finally, pathway analysis was conducted that revealed the key metabolic pathways that were most impacted in CIN.
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Antineoplásicos , Cisplatino , Humanos , Cisplatino/toxicidad , Antineoplásicos/toxicidad , Cimetidina/farmacología , Riñón/metabolismo , BiomarcadoresRESUMEN
Sotatercept, a soluble fusion protein comprising the extracellular domain of activin receptor type IIA linked to the Fc portion of human IgG1, is a first-in-class activin signaling inhibitor under development for the treatment of pulmonary arterial hypertension (PAH). We evaluated antidrug antibody (ADA) development and determined the effects of immunogenicity on the pharmacokinetics (PKs), efficacy, and safety of sotatercept in STELLAR, a multicenter, double-blind phase III trial (NCT04576988) wherein participants with PAH were randomized 1:1 to receive sotatercept (starting dose 0.3; target dose 0.7 mg/kg) or placebo subcutaneously every 3 weeks in combination with background therapies for ≤ 72 weeks. ADA-positive (ADA-POS) participants were identified and characterized for neutralizing antibodies (NAbs). PKs, efficacy, and safety were evaluated by ADA and NAb status. Of 162 evaluable participants, 42 (25.9%) were ADA-POS through week 24, of whom 11 (6.8%) were also NAb-POS. Median onset of ADAs was 3.29 weeks (interquartile range (IQR): 3.14-6.14), and median duration was 6 weeks (IQR: 3.14-17.86). No clinically meaningful differences were found across subgroups that were ADA-NEG, ADA-POS/NAb-NEG, and ADA-POS/NAb-POS, in terms of PKs (sotatercept trough concentration over time, mean postdose trough concentration at the end of treatment, and clearance), efficacy (changes from baseline in 6-minute walk distance, pulmonary vascular resistance, and N-terminal pro-B-type natriuretic peptide levels), and safety (incidence of hypersensitivity, anaphylactic reactions, and administration site reactions). We conclude that ADA incidence from sotatercept treatment was 25.9% and did not meaningfully affect the PKs, efficacy, or safety of sotatercept in participants with PAH.
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Antineoplásicos , Hipertensión Arterial Pulmonar , Humanos , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Proteínas Recombinantes de Fusión/efectos adversos , Anticuerpos Neutralizantes , Resultado del TratamientoRESUMEN
Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on-target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies. This review assesses dose selection and the role of quantitative clinical pharmacology in the development of the first eight approved TCEs. Model informed drug development (MIDD) strategies can be used at every stage to guide TCE development. Mechanistic modeling approaches allow for (1) efficacious yet safe first-in-human dose selection as compared with in vitro minimum anticipated biological effect level (MABEL) approach; (2) rapid escalation and reducing number of patients with subtherapeutic doses through model-based adaptive design; (3) virtual testing of different step-up dosing regimens that may not be feasible to be evaluated in the clinic; and (4) selection and justification of the optimal clinical step-up and full treatment doses. As the knowledge base around TCEs continues to grow, the relevance and utilization of MIDD strategies for supporting the development and dose optimization of these molecules are expected to advance, optimizing the benefit-risk profile for cancer patients.
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Sotatercept is a breakthrough, first-in-class biologic, that is FDA-approved for the treatment of pulmonary arterial hypertension (PAH). A population pharmacokinetic (PopPK) model was developed using data from two phase 1 studies in healthy participants, and two phase 2 studies and one phase 3 study in participants with PAH. The pooled sotatercept PK data encompassed single intravenous (IV) or subcutaneous (SC) doses ranging from 0.01 to 3.0 mg/kg, as well as multiple SC doses ranging from 0.03 to 1.0 mg/kg, with PK samples collected up to a maximum of ~150 weeks following Q3W and Q4W dosing regimens. The final PopPK analysis included 350 participants, with 30 and 320 participants receiving sotatercept IV and SC, respectively. A two-compartment model with a first-order absorption rate constant and a linear disposition from central compartment well-described sotatercept PK. The estimated bioavailability is ~66%; bioavailability, clearance (CL), and central volume (VC) have low to moderate inter-individual variability. Time-varying body weight and baseline albumin concentration were statistically significant predictors of PK; CL and VC were predicted to increase with increasing body weight, while CL was predicted to decrease with increasing baseline albumin concentration. However, the magnitude of covariate effects is not predicted to meaningfully alter the disposition of sotatercept. Altogether, the PopPK modeling results demonstrate favorable PK characteristics (low to moderate variability and typical bioavailability), supporting sotatercept as a SC biological agent for the treatment of patients with PAH.
Asunto(s)
Modelos Biológicos , Hipertensión Arterial Pulmonar , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Adulto Joven , Voluntarios Sanos , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/administración & dosificación , Disponibilidad Biológica , Anciano , Inyecciones Subcutáneas , AdolescenteRESUMEN
The transition from intravenous (i.v.) to subcutaneous (s.c.) administration of biologics is a critical strategy in drug development aimed at improving patient convenience, compliance, and therapeutic outcomes. Focusing on the increasing role of model-informed drug development (MIDD) in the acceleration of this transition, an in-depth overview of the essential clinical pharmacology, and regulatory considerations for successful i.v. to s.c. bridging for biologics after the i.v. formulation has been approved are presented. Considerations encompass multiple aspects beginning with adequate pharmacokinetic (PK) and pharmacodynamic (i.e., exposure-response) evaluations which play a vital role in establishing comparability between the i.v. and s.c. routes of administrations. Selected key recommendations and points to consider include: (i) PK characterization of the s.c. formulation, supported by the increasing preclinical understanding of the s.c. absorption, and robust PK study design and analyses in humans; (ii) a thorough characterization of the exposure-response profiles including important metrics of exposure for both efficacy and safety; (iii) comparability studies designed to meet regulatory considerations and support approval of the s.c. formulation, including noninferiority studies with PK and/or efficacy and safety as primary end points; and (iv) comprehensive safety package addressing assessments of immunogenicity and patients' safety profile with the new route of administration. Recommendations for successful bridging strategies are evolving and MIDD approaches have been used successfully to accelerate the transition to s.c. dosing, ultimately leading to improved patient experiences, adherence, and clinical outcomes.