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This study evaluated venetoclax population pharmacokinetics (popPK) in patients with treatment-naïve acute myeloid leukemia and assessed the relationship between venetoclax exposure and clinical response for venetoclax in combination with either a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). A total of 771 patients who received venetoclax from 5 Phase 1-3 studies were included in the popPK model. Exposure-response analyses included data from 575 patients for venetoclax/placebo plus HMA and 279 patients for venetoclax/placebo plus LDAC. The popPK model successfully characterized venetoclax plasma concentrations over time and confirmed venetoclax exposure did not vary significantly with age, weight, sex, mild to moderate hepatic impairment, or mild to severe renal impairment. Asian patients had 67% higher mean relative bioavailability than non-Asian patients, however the range of exposures in Asian patients was similar to non-Asian patients. For all efficacy endpoints with both treatment combinations, efficacy was higher in the venetoclax treatment groups compared with the respective control arm of placebo plus azacitidine or LDAC. Within patients who received venetoclax, no significant exposure-efficacy relationships were identified for either treatment combination, indicating that the beneficial effects of venetoclax were already maximized in the dose ranges studied. There was no apparent effect of venetoclax exposure on treatment-emergent Grade ≥3 thrombocytopenia or infections for either combination. Rates of treatment-emergent Grade ≥3 neutropenia were higher in the venetoclax treatment arms compared with the respective control arms; however, within patients who received venetoclax, there was only a shallow relationship or no apparent relationship with venetoclax exposure for venetoclax plus HMA or LDAC, respectively. Along with the efficacy and safety data previously published, the exposure-response analyses support the venetoclax dose regimens of 400 mg once daily (QD) plus HMA and 600 mg QD plus LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Sulfonamidas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêuticoRESUMO
The finding of medial arterial calcification (MAC) on cone beam computed tomographic scans is more common than many clinicians realize. Medial arterial calcification is a specific pattern of vascular calcification that has been associated with diabetes mellitus. When MAC is identified on a scan, the clinician must refer the patient for evaluation of cardiovascular accident risk and for serologic evaluation to detect undiagnosed type 2 diabetes mellitus. This case report describes a patient with undiagnosed type 2 diabetes mellitus that was later confirmed by hemoglobin A1c levels after incidental detection of MAC on cone beam computed tomography. The article also reviews the literature on MAC and its relationship with diabetes and discusses radiographic features of MAC that are often unrecognized by clinicians.
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Diabetes Mellitus Tipo 2 , Tomografia Computadorizada de Feixe Cônico Espiral , Tomografia Computadorizada de Feixe Cônico , Diabetes Mellitus Tipo 2/complicações , Hemoglobinas Glicadas , HumanosRESUMO
PURPOSE: The established two-analyte integrated population pharmacokinetic model was applied to assess the impact of intrinsic/extrinsic factors on the pharmacokinetics (PK) of polatuzumab vedotin (pola) in patients with non-Hodgkin lymphoma (NHL) following bodyweight-based dosing. METHODS: Model simulations based on individual empirical Bayes estimates were used to evaluate the impact of intrinsic/extrinsic factors as patient subgroups on Cycle 6 exposures. Intrinsic factors included bodyweight, age, sex, hepatic and renal functions. Extrinsic factors included rituximab/obinutuzumab or bendamustine combination with pola and manufacturing process. The predicted impact on exposures along with the established exposure-response relationships were used to assess clinical relevance. RESULTS: No clinically meaningful differences in Cycle 6 pola exposures were found for the following subgroups: bodyweight 100-146 kg versus 38-<100 kg, age ≥ 65 years versus <65 years, female versus male, mild hepatic impairment versus normal, mild-to-moderate renal impairment versus normal. Co-administration of rituximab/obinutuzumab or bendamustine, and change in the pola manufacturing process, also had no meaningful impact on PK. CONCLUSIONS: In patients with NHL, bodyweight-based dosing is adequate, and no further dose adjustment is recommended for the heavier subgroup (100-146 kg). In addition, no dose adjustments are recommended for other subgroups based on intrinsic/extrinsic factors evaluated.
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Anticorpos Monoclonais/farmacocinética , Antineoplásicos Imunológicos/farmacocinética , Imunoconjugados/farmacocinética , Linfoma não Hodgkin/tratamento farmacológico , Modelos Biológicos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Peso Corporal , Ensaios Clínicos como Assunto , Simulação por Computador , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Imunoconjugados/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Adulto JovemRESUMO
Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from healthy-volunteer studies. Semi-mechanistic models predict well for tumors with static, increasing, or decreasing growth over time, but they were not considered adequate for predicting tumor sizes in medullary thyroid cancer patients, among whom an early reduction in tumor size was followed by a late stabilization phase in those receiving cabozantinib. A semi-empirical tumor model adequately predicted tumor profiles that were assumed to have a net growth rate constant that was piecewise continuous in the regions of 0-110 and 110-280 days. Emax models relating average concentration to average change in tumor size predicted that an average concentration of 79 and 58 ng/ml, respectively, would yield 50% of the maximum possible tumor reduction during the first 110 days of dosing and during the subsequent 110-280 days of dosing. Simulations of tumor responses showed that daily doses of 60 mg or greater are expected to provide a similar tumor reduction. Both model evaluation of observed data and simulation results suggested that the two protocol-defined cabozantinib dose reductions from 140 to 100 mg/day and from 100 to 60 mg/day are not projected to result in a marked reduction in target lesion regrowth.
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Anilidas/farmacocinética , Antineoplásicos/farmacocinética , Carcinoma Neuroendócrino/tratamento farmacológico , Modelos Biológicos , Piridinas/farmacocinética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Anilidas/farmacologia , Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/patologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Humanos , Piridinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias da Glândula Tireoide/patologia , Carga Tumoral/efeitos dos fármacosRESUMO
Metabolism and excretion of cabozantinib, an oral inhibitor of receptor tyrosine kinases, was studied in 8 healthy male volunteers after a single oral dose of 175 mg cabozantinib l-malate containing (14)C-cabozantinib (100 µCi/subject). Total mean radioactivity recovery within 48 days was 81.09%; radioactivity was eliminated in feces (53.79%) and urine (27.29%). Cabozantinib was extensively metabolized with 17 individual metabolites identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in plasma, urine, and feces. Relative plasma radioactivity exposures (analyte AUC0-t/total AUC0-t for cabozantinib+major metabolites) were 27.2, 25.2, 32.3, 7, and 6% for cabozantinib and major metabolites monohydroxy sulfate (EXEL-1646), 6-desmethyl amide cleavage product sulfate (EXEL-1644), N-oxide (EXEL-5162), and amide cleavage product (EXEL-5366), respectively. Comparable relative plasma exposures determined by LC-MS/MS analysis were 32.4, 13.8, 45.9, 4.9, and 3.1%, respectively. These major metabolites each possess in vitro inhibition potencies ≤1/10th of parent cabozantinib against the targeted kinases MET, RET, and VEGFR2/KDR. In an in vitro cytochrome P450 (CYP) panel, cabozantinib and EXEL-1644 both inhibited most potently CYP2C8 (Kiapp = 4.6 and 1.1 µM, respectively). In an in vitro drug transporter panel, cabozantinib inhibited most potently MATE1 and MATE2-K (IC50 = 5.94 and 3.12 µM, respectively) and was a MRP2 substrate; EXEL-1644 inhibited most potently OAT1, OAT3, OATP1B1, MATE1, and OATP1B3 (IC50 = 4.3, 4.3, 6.1, 16.7, and 20.6 µM, respectively) and was a substrate of MRP2, OAT3, OATP1B1, OATP1B3, and possibly P-gp. Therefore, cabozantinib appears to be the primary pharmacologically active circulating analyte, whereas both cabozantinib and EXEL-1644 may represent potential for drug-drug interactions.
Assuntos
Anilidas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/farmacocinética , Adulto , Anilidas/toxicidade , Animais , Área Sob a Curva , Ductos Biliares/metabolismo , Ductos Biliares/fisiologia , Biotransformação , Proteínas Sanguíneas/metabolismo , Proteínas de Transporte/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Eritrócitos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Inibidores de Proteínas Quinases/toxicidade , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/toxicidade , Ratos , Distribuição Tecidual , Adulto JovemRESUMO
Autologous chimeric antigen receptor T-cell (CAR-T) therapies have garnered unprecedented clinical success with multiple regulatory approvals for the treatment of various hematological malignancies. However, there are still several clinical challenges that limit their broad utilization for aggressive disease conditions. To address some of these challenges, allogeneic cell therapies are evaluated as an alternative approach. As compared with autologous products, they offer several advantages, such as a more standardized "off the shelf" product, reduced manufacturing complexity, and no requirement of bridging therapy. As with autologous CAR-T therapies, allogeneic cell therapies also present clinical pharmacology challenges due to their in vivo living nature, unique pharmacokinetics or cellular kinetics (CKs), and complex dose-exposure-response relationships that are impacted by various patient- and product-related factors. On top of that, allogeneic cell therapies present additional unique challenges, including attenuated in vivo persistence and graft-vs.-host disease risk as compared with autologous counterparts. This review draws comparison between autologous and allogeneic cell therapies, summarizing key engineering aspects unique to allogeneic cell therapy. Clinical pharmacology learnings from emerging clinical data of allogeneic cell therapy programs are also highlighted, with particular emphasis on CK, dose-exposure-response relationship, lymphodepletion regimen, repeat dosing, and patient- and product-related factors that can impact CK and patient outcomes. There are specific unique challenges and opportunities arising from the development of allogeneic cell therapies, especially in optimizing lymphodepletion and establishing a regimen for repeat dosing. This review highlights how clinical pharmacologists are well positioned to help address these challenges by leveraging novel clinical pharmacology and modeling and simulation approaches.
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Farmacologia Clínica , Humanos , Farmacologia Clínica/métodos , Imunoterapia Adotiva/métodos , Transplante Homólogo , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Receptores de Antígenos Quiméricos/imunologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , AnimaisRESUMO
Despite recent progress in adoptive T cell therapy for cancer, understanding and predicting the kinetics of infused T cells remains a challenge. Multiple factors can impact the distribution, expansion, and decay or persistence of infused T cells in patients. We have developed a novel quantitative systems pharmacology (QSP) model of TCR-transgenic T cell therapy in patients with solid tumors to describe the kinetics of endogenous T cells and multiple memory subsets of engineered T cells after infusion. These T cells undergo lymphodepletion, proliferation, trafficking, differentiation, and apoptosis in blood, lymph nodes, tumor site, and other peripheral tissues. Using the model, we generated patient-matched digital twins that recapitulate the circulating T cell kinetics reported from a clinical trial of TCR-engineered T cells targeting E7 in patients with metastatic HPV-associated epithelial cancers. Analyses of key parameters influencing cell kinetics and differences among digital twins identify stem cell-like memory T cells (Tscm) cells as an important determinant of both expansion and persistence and suggest that Tscm-related differences contribute significantly to the observed variability in cellular kinetics among patients. We simulated in silico clinical trials using digital twins and predict that Tscm enrichment in the infused product improves persistence of the engineered T cells and could enable administration of a lower dose. Finally, we verified the broader relevance of the QSP model, the digital twins, and findings on the importance of Tscm enrichment by predicting kinetics for two patients with pancreatic cancer treated with KRAS G12D targeting T cell therapy. This work offers insight into the key role of Tscm biology on T cell kinetics and provides a quantitative framework to evaluate cellular kinetics for future efforts in the development and clinical application of TCR-engineered T cell therapies.
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Linfócitos T CD4-Positivos , Receptores de Antígenos de Linfócitos T , Humanos , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
In oncology drug development, tumor dynamics modeling is widely applied to predict patients' overall survival (OS) via parametric models. However, the current modeling paradigm, which assumes a disease-specific link between tumor dynamics and survival, has its limitations. This is particularly evident in drug development scenarios where the clinical trial under consideration contains patients with tumor types for which there is little to no prior institutional data. In this work, we propose the use of a pan-indication solid tumor machine learning (ML) approach whereby all three tumor metrics (tumor shrinkage rate, tumor regrowth rate and time to tumor growth) are simultaneously used to predict patients' OS in a tumor type independent manner. We demonstrate the utility of this approach in a clinical trial of cancer patients treated with the tyrosine kinase inhibitor, pralsetinib. We compared the parametric and ML models and the results showed that the proposed ML approach is able to adequately predict patient OS across RET-altered solid tumors, including non-small cell lung cancer, medullary thyroid cancer as well as other solid tumors. While the findings of this study are promising, further research is needed for evaluating the generalizability of the ML model to other solid tumor types.
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Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure-response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody-conjugated (acMMAE)/unconjugated MMAE area under the concentration-time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression-free and event-free survival (both p = 0.01). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.
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Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Linfoma Difuso de Grandes Células B , Prednisona , Rituximab , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Doxorrubicina/farmacocinética , Doxorrubicina/análogos & derivados , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Ciclofosfamida/farmacocinética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prednisona/administração & dosagem , Prednisona/farmacocinética , Prednisona/uso terapêutico , Rituximab/farmacocinética , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Adulto , Área Sob a Curva , Modelos Biológicos , Imunoconjugados/farmacocinética , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Relação Dose-Resposta a Droga , Intervalo Livre de ProgressãoRESUMO
The favorable benefit-risk profile of polatuzumab vedotin, as demonstrated in a pivotal Phase Ib/II randomized study (GO29365; NCT02257567), coupled with the need for effective therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), prompted the need to accelerate polatuzumab vedotin development. An integrated, fit-for-purpose clinical pharmacology package was designed to support regulatory approval. To address key clinical pharmacology questions without dedicated clinical pharmacology studies, we leveraged non-clinical and clinical data for polatuzumab vedotin, published clinical data for brentuximab vedotin, a similar antibody-drug conjugate, and physiologically based pharmacokinetic and population pharmacokinetic modeling approaches. We review strategies and model-informed outcomes that contributed to regulatory approval of polatuzumab vedotin plus bendamustine and rituximab in R/R DLBCL. These strategies made polatuzumab vedotin available to patients earlier than previously possible; depending on the strength of available data and the regulatory/competitive environment, they may also prove useful in accelerating the development of other agents.
Assuntos
Imunoconjugados , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Farmacologia Clínica , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológicoRESUMO
Pharmacogenomics (PGx), the study of inherited genomic variation and drug response or safety, is a vital tool in precision medicine. In oncology, testing to identify PGx variants offers patients the opportunity for customized treatments that can minimize adverse effects and maximize the therapeutic benefits of drugs used for cancer treatment and supportive care. Because individuals of shared ancestry share specific genetic variants, PGx factors may contribute to outcome disparities across racial and ethnic categories when genetic ancestry is not taken into account or mischaracterized in PGx research, discovery, and application. Here, we examine how the current scientific understanding of the role of PGx in differential oncology safety and outcomes may be biased toward a greater understanding and more complete clinical implementation of PGx for individuals of European descent compared with other genetic ancestry groups. We discuss the implications of this bias for PGx discovery, access to care, drug labeling, and patient and provider understanding and use of PGx approaches. Testing for somatic genetic variants is now the standard of care in treatment of many solid tumors, but the integration of PGx into oncology care is still lacking despite demonstrated actionable findings from PGx testing, reduction in avoidable toxicity and death, and return on investment from testing. As the field of oncology is poised to expand and integrate germline genetic variant testing, it is vital that PGx discovery and application are equitable for all populations. Recommendations are introduced to address barriers to facilitate effective and equitable PGx application in cancer care.
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Testes Farmacogenômicos , Medicina de Precisão , Humanos , Farmacogenética , Testes Genéticos , OncologiaRESUMO
Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral foretinib once daily. Dose escalation was planned as a conventional "3+3" design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P<0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P<0.03). The MTD of foretinib bisphosphate salt was determined to be 80 mg once daily.
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Anilidas/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Adulto , Idoso , Anilidas/efeitos adversos , Anilidas/farmacocinética , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Humanos , Hipertensão/induzido quimicamente , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-met/sangue , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
Alectinib, approved as 150 mg capsules for the treatment of adults with advanced ALK-positive non-small cell lung cancer, is being assessed in children with ALK-positive solid and central nervous system tumors. An ad hoc pediatric-friendly suspension of alectinib, prepared from capsule contents, is under investigation as an alternative formulation for children who cannot swallow capsules. This randomized, crossover, relative bioavailability, and food effect study evaluated alectinib administered as an oral suspension versus capsule formulation following conventional venipuncture and capillary microsampling. A total of 28 healthy adult subjects received a 600 mg single dose of alectinib in two groups: fasted (n = 14) and mixed fed (n = 14; seven receiving high-fat meal and seven receiving low-fat meal). Combined alectinib + M4 (active metabolite) exposure was higher for suspension versus capsule, with geometric mean ratio (GMR) of 2.6 for area under the concentration-time curve extrapolated to infinity (AUC0-∞ ) and 3.0 for maximum observed concentration (Cmax ) under fasted conditions, and 1.7 for both parameters for mixed fed. The suspension showed increased alectinib + M4 AUC0-∞ following a high-fat meal versus fasted conditions (GMR 1.7 [90% confidence interval 1.4-2.2]). Alectinib AUC0-∞ and Cmax measured in venous and capillary samples were generally similar for the suspension and capsule. Single oral doses of 600 mg alectinib suspension and capsule were well tolerated, with no safety concerns. Based on these findings, the oral suspension of alectinib appears suitable for use in pediatric studies after appropriate dose adjustment relative to the capsule.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Criança , Disponibilidade Biológica , Flebotomia , Voluntários Saudáveis , Cápsulas , Receptores Proteína Tirosina Quinases , Administração OralRESUMO
With the promise of a potentially "single dose curative" paradigm, CAR-T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies. Both CAR-T and TCR-T cell therapies have also made great progress toward the successful treatment of solid tumor indications. The field is rapidly evolving with recent advancements including the clinical development of "off-the-shelf" allogeneic CAR-T therapies that can overcome the long and difficult "vein-to-vein" wait time seen with autologous CAR-T therapies. There are unique clinical pharmacology, pharmacometric, bioanalytical, and immunogenicity considerations and challenges in the development of these CAR-T and TCR-T cell therapies. Hence, to help accelerate the development of these life-saving therapies for the patients with cancer, experts in this field came together under the umbrella of International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) to form a joint working group between the Clinical Pharmacology Leadership Group (CPLG) and the Translational and ADME Sciences Leadership Group (TALG). In this white paper, we present the IQ consortium perspective on the best practices and considerations for clinical pharmacology and pharmacometric aspects toward the optimal development of CAR-T and TCR-T cell therapies.
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Neoplasias , Farmacologia Clínica , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T , Neoplasias/terapia , Imunoterapia Adotiva/efeitos adversosRESUMO
This ethnic sensitivity analysis used data from the phase III POLARIX study (NCT03274492) to assess polatuzumab vedotin pharmacokinetics (PKs) in Asian versus non-Asian patients with previously untreated diffuse large B-cell lymphoma and examined the appropriateness of extrapolating global study findings to Asian patients. PK and population PK (PopPK) analyses assessed polatuzumab vedotin analyte exposures by ethnicity (Asian [n = 84] vs. non-Asian [n = 345] patients) and region (patients enrolled from Asia [n = 80] vs. outside Asia [n = 349]). In patients from Asia versus outside Asia, observed mean antibody-conjugated monomethyl auristatin E (acMMAE) concentrations were comparable (1.2% lower at cycle [C]1 postdose, 4.4% higher at C4 predose; and 6.8% lower at C4 postdose in patients from Asia). Observed mean unconjugated MMAE was lower in patients from Asia by 6.5% (C1 postdose), 20.0% (C4 predose), and 15.3% (C4 postdose). In the PopPK analysis, C6 area under the curve and peak plasma concentrations were also comparable for acMMAE (6.3% and 3.0% lower in Asian vs. non-Asian patients, respectively) and lower for unconjugated MMAE by 19.1% and 16.7%, respectively. By region, C6 mean acMMAE concentrations were similar, and C6 mean unconjugated MMAE concentrations were lower, in patients enrolled from Asia versus outside Asia, by 3.9%-7.0% and 17.3%-19.7%, respectively. In conclusion, polatuzumab vedotin PKs were similar between Asian and non-Asian patients by ethnicity and region, suggesting PKs are not sensitive to Asian ethnicity and dose adjustments are not required in Asian patients to maintain efficacy and safety.
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Imunoconjugados , Linfoma Difuso de Grandes Células B , Humanos , Anticorpos Monoclonais/farmacocinética , Ásia , Imunoconjugados/farmacocinética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Ensaios Clínicos Fase III como AssuntoRESUMO
Ipatasertib is a selective, small molecule Akt inhibitor that is currently being developed for the treatment of metastatic castration-resistant prostate cancer. Darolutamide is an androgen receptor (AR) inhibitor that is approved for the treatment of non-metastatic castration-resistant prostate cancer. Ipatasertib is metabolized by CYP3A4 to form a less active metabolite M1 (G-037720). Ipatasertib is also a weak time-dependent CYP3A4 inhibitor. Darolutamide is a mild CYP3A4 inducer and is metabolized into an active keto-darolutamide metabolite via CYP3A4. In this Phase 1b open-label, single sequence crossover study, ipatasertib pharmacokinetics safety and tolerability were evaluated in combination with darolutamide in metastatic castration-resistant prostate cancer (n = 15 patients). Specifically, the effect of 600 mg BID of darolutamide on 400 mg QD ipatasertib was evaluated in this study. Based on pharmacokinetic analysis, a mild reduction in ipatasertib AUC0-24 h,ss and Cmax,ss exposures was observed (~8% and ~21%, respectively) when administered in combination with darolutamide, which is considered not clinically meaningful. M1 exposures were similar with and without darolutamide administration. Darolutamide and keto-darolutamide exposures in combination with ipatasertib were similar to previously reported exposures for single agent darolutamide. Overall, the combination appears to be well-tolerated in the metastatic castration-resistant prostate cancer indication with very few AEs.
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Ipatasertib, an AKT inhibitor, in combination with prednisone and abiraterone, is under evaluation for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Hyperglycemia is an on-target effect of ipatasertib. An open-label, single-arm, single-sequence, signal-seeking study (n = 25 mCRPC patients) was conducted to evaluate the glucose changes across four different treatment periods: ipatasertib alone, ipatasertib-prednisone combination, ipatasertib-prednisone-abiraterone combination (morning dose), and ipatasertib-prednisone-abiraterone combination (evening dose). Continuous glucose monitoring (CGM) was used in this study to compare the dynamic glucose changes across the different treatment periods. Four key parameters: average glucose, peak glucose and % time in range (70-180 and >180 mg/dl) were evaluated for this comparison. Ipatasertib-prednisone-abiraterone combination when administered in the morning after an overnight fast significantly increased average glucose, peak glucose and % time in range >180 mg/dl compared to ipatasertib monotherapy. Ipatasertib, when co-administered with abiraterone, increased ipatasertib and M1 (G-037720) metabolite exposures by approximately 1.5- and 2.2-fold, respectively. Exposure-response analysis results show that increased exposures of ipatasertib in combination with abiraterone are associated with increased glucose levels. When ipatasertib-prednisone-abiraterone combination was administered as an evening dose compared to a morning dose, lowered peak glucose and improved % time in range was observed. The results from this study suggest that dosing ipatasertib after an evening meal followed by overnight fasting can be an effective strategy for managing increased glucose levels.
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Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glicemia , Automonitorização da Glicemia , Glucose/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do TratamentoRESUMO
Adoptive cell therapies (ACTs) have shown transformative efficacy in oncology with five US Food and Drug Administration (FDA) approvals for chimeric antigen receptor (CAR) T-cell therapies in hematological malignancies, and promising activity for T cell receptor T-cell therapies in both liquid and solid tumors. Clinical pharmacology can play a pivotal role in optimizing ACTs, aided by modeling and simulation toolboxes and deep understanding of the underlying biological and immunological processes. Close collaboration and multilevel data integration across functions, including chemistry, manufacturing, and control, biomarkers, bioanalytical, and clinical science and safety teams will be critical to ACT development. As ACT is comprised of alive, polyfunctional, and heterogeneous immune cells, its overall physicochemical and pharmacological property is vastly different from other platforms/modalities, such as small molecule and protein therapeutics. In this review, we first describe the unique kinetics of T cells and the appropriate bioanalytical strategies to characterize cellular kinetics. We then assess the distinct aspects of clinical pharmacology for ACTs in comparison to traditional small molecule and protein therapeutics. Additionally, we provide a review for the five FDA-approved CAR T-cell therapies and summarize their properties, cellular kinetic characteristics, dose-exposure-response relationship, and potential baseline factors/variables in product, patient, and regimen that may affect the safety and efficacy. Finally, we probe into existing empirical and mechanistic quantitative techniques to understand how various modeling and simulation approaches can support clinical pharmacology strategy and propose key considerations to be incorporated and explored in future models.
Assuntos
Neoplasias , Farmacologia Clínica , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T , Linfócitos TRESUMO
INTRODUCTION: Outcomes remain poor in patients with diffuse large B cell lymphoma (DLBCL) who overexpress BCL-2 protein. We present population pharmacokinetics (PopPK) and exposure-response (ER) analyses for venetoclax (a selective BCL-2 inhibitor) administered with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed/refractory (R/R) and previously untreated (1L) non-Hodgkin lymphoma (NHL) from the phase 1b/2 CAVALLI study, to confirm dose selection for future studies. METHODS: Analyses included 216 patients with R/R or 1L NHL treated for eight 21-day cycles with 400-800 mg venetoclax (cycle 1: days 4-10; cycles 2-8: days 1-10) in combination with R for eight cycles and CHOP for 6-8 cycles. A legacy PopPK model for venetoclax was used to describe the observed data and provide post hoc PK parameters. Venetoclax steady-state exposure (AUCss) was used to predict clinical efficacy, safety, or tolerability. To isolate the effect of venetoclax, ER analyses referenced data from the R-CHOP arm of a historical control study, GOYA, in 1L DLBCL. RESULTS: There was no significant association between venetoclax AUCss and progression-free survival or complete response either for all-comers or the BCL-2-immunohistochemistry-positive subpopulation. No statistically significant trends were observed with venetoclax AUCss and the key grade ≥ 3 adverse events and serious adverse events. Similar dose intensities were observed for venetoclax and R-CHOP components across venetoclax exposures, suggesting venetoclax did not impact delivery of the R-CHOP backbone. CONCLUSIONS: The PopPK and ER analyses, in addition to the positive benefit-risk observed in the clinical data, support the selection of 800 mg venetoclax given with R-CHOP for future studies in BCL-2-immunohistochemistry-positive patients with 1L DLBCL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02055820.
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Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linfoma Difuso de Grandes Células B , Sulfonamidas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
INTRODUCTION: This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study. METHODS: Parameter estimates and uncertainty, which were estimated by a previously developed population PK (popPK) model, were used as informative priors for this analysis. They were re-estimated, and then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using data from CLL14, with steady-state nominal venetoclax exposure (CmeanSS,nominal) as the predictor variable. Exposure-safety analyses were conducted using logistic regression for selected treatment-emergent grade ≥ 3 adverse events (AEs) and serious AEs (SAEs). Dose intensities were summarized by tertiles of CmeanSS,nominal. RESULTS: PK data from 274 patients (CLL14, n = 194; GP28331, n = 80) were included. The final model provided good fit of the observed data. Obinutuzumab co-administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥ 3 neutropenia, grade ≥ 3 thrombocytopenia, grade ≥ 3 infections, and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles. CONCLUSION: PopPK and exposure-efficacy, exposure-safety, and exposure-tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab for 1L treatment in patients with CLL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT02242942 and NCT02339181.