RESUMEN
The current regulatory path for new drug registration in East Asian countries has led to significant delay of the new medicines in these countries. A unified regulatory path and allowance of mutual usage of clinical data in East Asian countries would lead to cost saving in drug development and expedite the new drug registration in these countries. The objectives of the present analysis are to compare the approval dates of a selection of products developed by Pfizer in the United States and East Asian countries (China, Japan, Korea) and compare the pharmacokinetics and recommended doses of these products in East Asian countries. Eighteen products (20 drugs, 2 products with 2 combination drugs) with exposure data available in at least 2 of the 3 East Asian countries across different therapeutic areas were included in the analyses. The results showed that most products had delayed approval in East Asian countries (up to 8 years) after US or EU approval. No distinct differences were observed in the drug exposure and recommended doses for the selected products in East Asian countries. These results together with literature data of genetic similarity of the East Asian populations support the mutual usage of the clinical data in the East Asian countries for expedited regulatory submission and approval.
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Aprobación de Drogas , Asia Oriental , China , Japón , República de Corea , Estados UnidosRESUMEN
Exposure-response (E-R) analyses are an integral component of understanding the benefit/risk profile of novel oncology therapeutics. These analyses are typically conducted using data from the treatment arm to characterize the relationship between drug exposure (low vs. high) and efficacy or safety outcomes. For example, outcomes of patients with lower exposure in the treatment arm (e.g., Q1) might be compared to outcomes of those with higher drug exposure (Q2, Q3, and Q4). Outcomes from the lowest exposure quartile may be also compared to the control arm to evaluate whether the Q1 subgroup derived clinical benefit. However, the sample size and the distribution of patient baseline characteristics and disease risk factors are not balanced in such a comparison (Q1 vs. control), which may bias the analysis and causal interpretation of clinical benefit in the Q1 subgroup. Herein, we report the use of case-control matching to account for this bias and better understand the E-R relationship for avelumab in urothelial carcinoma, a PD-L1 inhibitor approved for the treatment of several cancers. Data from JAVELIN-100 was utilized which is a phase III study of avelumab in first-line maintenance treatment in patients with urothelial carcinoma; this clinical study demonstrated superiority of avelumab versus best-supportive care leading to approval in the United States, Europe, and other countries. A post hoc case-control matching method was implemented to compare the efficacy outcome between Q1 avelumab subgroup and matched patients extracted from the control arm with similar baseline characteristics, which showed a clinically relevant difference in overall survival in favor of the Q1 avelumab subgroup. This analysis demonstrates the importance of accounting for imbalance in important baseline covariates when comparing efficacy outcomes between subgroups within the treatment arm versus the control arm.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inducido químicamente , Estudios de Casos y ControlesRESUMEN
Oncology therapies shifted from chemotherapy to molecularly targeted agents and finally to the era of immune-oncology agents. In contrast to cytotoxic agents, molecularly targeted agents are more selective, exhibit a wider therapeutic window, and may maximally modulate tumor growth at doses lower than the maximum tolerated dose (MTD). However, first-in-patient oncology studies for molecularly targeted agents continued to evaluate escalating doses using limited number of patients per dose cohort assessing dose-limiting toxicities to identify the MTD which is commonly selected for further development adopting a 'more is better' approach that led to several post-marketing requirement (PMR) studies to evaluate alternative, typically lower, doses or dosing frequencies to optimize the benefit-risk profile. In this review, post-marketing dose optimization efforts were reviewed including those required by a regulatory pathway or voluntarily conducted by the sponsor to improve efficacy, safety, or method of administration. Lessons learned and future implications from this deep dive review are discussed considering the evolving regulatory landscape on dose optimization for oncology compounds.
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Antineoplásicos , Neoplasias , Humanos , Terapia Molecular Dirigida/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Oncología Médica , Dosis Máxima Tolerada , Relación Dosis-Respuesta a DrogaRESUMEN
AIM: This phase I study investigated talazoparib pharmacokinetics (PK) and safety in patients with advanced solid tumours and varying degrees of hepatic function. METHODS: Patients with advanced solid tumours and normal hepatic function or varying degrees of hepatic impairment (mild, moderate or severe, based on National Cancer Institute Organ Dysfunction Working Group classification) received talazoparib 0.5 mg once daily for 22 calendar days. Plasma and urine samples after single and multiple doses were collected and analysed for talazoparib using validated assays. Plasma PK data from all patients were analysed using the population PK method. Plasma and urine PK parameters in PK-evaluable patients were calculated using noncompartmental analysis (NCA). Safety was monitored in all enrolled patients. RESULTS: Thirty-eight patients were enrolled; 37 had ≥1 PK concentration, among which 17 were evaluable for NCA. Population PK analysis (n = 37) indicated no significant impact of hepatic function on apparent clearance (CL/F) of talazoparib. Baseline creatinine clearance was the only significant covariate on CL/F (α = 0.05). NCA of data (n = 17) showed no clear trend for increase in exposure on day 22 with worsening hepatic function. Talazoparib protein binding was comparable in patients with varying hepatic function. Talazoparib was generally well tolerated, and the safety profile observed in this study was consistent with the known safety profile of the drug. CONCLUSIONS: Hepatic impairment (mild, moderate or severe) has no impact on the PK of talazoparib. No dose modification is recommended for patients with advanced solid tumours and various degrees of hepatic impairment, and this labelling language has been approved by the US Food and Drug Administration and the European Medicines Agency.
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Hepatopatías , Neoplasias , Ftalazinas , Humanos , Hepatopatías/complicaciones , Hepatopatías/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Ftalazinas/efectos adversos , Ftalazinas/farmacocinéticaRESUMEN
Patients with cancer and advanced hepatic impairment (HI) (i.e., moderate and severe impairment) are often excluded from first-in-patient, phase II, and phase III studies. Thus, dose recommendations for this subgroup of patients are often derived using a combination of dedicated phase I studies conducted in participants without cancer and a population pharmacokinetic (PK) modeling approach. A standardized risk-based approach to guide the evaluation of HI in patients with cancer is needed. In this review, we evaluated available oncology drug approvals by the US Food and Drug Administration (FDA) from 1999 to 2019, identified strategies utilized by sponsors to characterize the effect of HI on the PK of oncology drugs, and assessed regulatory expectations for each strategy. Finally, we constructed a decision tree that complements current FDA guidance to enable efficient evaluation of the effect of HI on PK and provide guidance for dose recommendations.
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Hepatopatías , Neoplasias , Aprobación de Drogas , Humanos , Preparaciones Farmacéuticas , Estados Unidos , United States Food and Drug AdministrationRESUMEN
This report examined the benefits and risks of palbociclib plus endocrine therapy (ET) in men with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib was evaluated using three independent data sources: real-world data from pharmacy and medical claims, a de-identified real-world data source derived from electronic health records (EHRs), and a global safety database. From medical and pharmacy records, 1,139 men with MBC were identified; in the first-line setting, median duration of treatment was longer with palbociclib plus ET (n = 37, 8.5 months, 95% confidence interval (CI), 4.4-13.0) than ET alone (n = 214, 4.3 months, 95% CI, 3.0-5.7) and specifically, was longer with palbociclib plus letrozole (n = 26, 9.4 months, 95% CI, 4.4-14.0) than letrozole alone (n = 63, 3.0 months, 95% CI, 1.8-4.8). In the EHR-derived database, 59 men received treatment for MBC; real-world response across all lines of therapy in the metastatic setting was reported in 4 of 12 patients (33.3%) in the palbociclib plus ET group vs. 1 of 8 (12.5%) patients in the ET group. Review of the global safety database did not identify any new safety signals in palbociclib-treated men. Real-world data indicated that men with MBC benefit from palbociclib plus ET, with a safety profile consistent with previous observations in women with MBC. Collective data on palbociclib in women and men in this report, including clinical trial data, real-world data, and a well-established risk/benefit profile, led to US approval of an expansion of the palbociclib indication to include men with MBC.
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Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama Masculina/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Piperazinas/uso terapéutico , Piridinas/uso terapéutico , Reclamos Administrativos en el Cuidado de la Salud , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de la Aromatasa/efectos adversos , Inhibidores de la Aromatasa/uso terapéutico , Bases de Datos Factuales , Registros Electrónicos de Salud , Humanos , Estimación de Kaplan-Meier , Letrozol/efectos adversos , Letrozol/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Observacionales como Asunto , Piperazinas/efectos adversos , Piridinas/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: Pharmacokinetic (PK) studies suggest that talazoparib is primarily eliminated unchanged via renal excretion. The current study investigated how varying degrees of renal impairment may affect the PK of talazoparib, and evaluated the safety and tolerability of talazoparib, in patients with advanced solid tumors with/without renal impairment. METHODS: Patients with advanced solid tumors and normal renal function or different degrees of renal impairment measured by estimated glomerular filtration rate (eGFR: mild = 60-89, moderate = 30-59, severe = 15-29 mL/min/1.73 m2) were enrolled in this open-label, non-randomized, phase I study. Talazoparib was administered orally at 0.5 mg/day for 22 days. Primary PK parameters included the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) and maximum observed plasma concentration (Cmax) at steady state (Day 22). Safety and tolerability were also investigated. RESULTS: Thirty-four patients were enrolled. At Day 22, compared with patients with normal renal function (n = 9), patients with mild (n = 9), moderate (n = 8), or severe (n = 8) renal impairment had a 12.2%, 43.0%, and 163.3% increase in talazoparib AUC0-24, and a 11.1%, 31.6%, and 89.3% increase in talazoparib Cmax, respectively. Talazoparib was generally well tolerated, and overall there were no notable differences in the treatment-emergent adverse event profile across renal function groups. CONCLUSIONS: Exposure to talazoparib increased with worsening renal impairment. Overall, this study confirms current dosing recommendations in patients with mild and moderate renal impairment (1 mg/day and 0.75 mg/day, respectively) and indicates that a lower starting dose of 0.5 mg/day should be considered for patients with severe renal impairment. CLINICAL TRIALS REGISTRATION: NCT02997163.
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Neoplasias , Insuficiencia Renal , Área Bajo la Curva , Tasa de Filtración Glomerular , Humanos , Neoplasias/tratamiento farmacológico , Ftalazinas/efectos adversosRESUMEN
Guidance from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recommends using Child-Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI). Therefore, dosing recommendations for oncology compounds for patients with HI are commonly based on Child-Pugh classification. In oncology clinical practice, National Cancer Institute classification (NCIc), is commonly used for evaluating hepatic function and dosing decisions for oncology patients. This work evaluated the discordance between the 2 systems and the impact on dosing recommendations. The classification system in HI studies was reviewed for FDA-approved oncology compounds. Discordance between Child-Pugh and NCIc was evaluated for sunitinib, dacomitinib, palbociclib, bosutinib, and axitinib. Pharmacokinetic (PK) analyses were conducted based on Child-Pugh classification and NCIc. Review of 117 approved oncology compounds showed prevalent use of Child-Pugh classification for dedicated HI studies in noncancer subjects. NCIc is commonly used in cancer patient studies. NCIc tended to classify subjects as less impaired versus Child-Pugh (64.9%, 73.7%, and 61.5% of subjects with mild, moderate, and severe HI, respectively, via Child-Pugh were classified as at least 1 category less impaired via NCIc). PK analyses by NCIc were consistent with Child-Pugh for sunitinib, dacomitinib, and palbociclib. For bosutinib, NCIc showed less impact of HI than Child-Pugh; an opposite trend was observed for axitinib. The impact of this considerable discordance between the 2 systems on dosing decisions bears consideration. When Child-Pugh is used for HI study enrollment, exploratory PK analyses based on NCIc should be conducted. Prescribers should attempt to use the same classification system in the product label for dosing decisions.
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Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Hepatopatías/epidemiología , Pruebas de Función Hepática/normas , National Cancer Institute (U.S.)/normas , Neoplasias/epidemiología , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias/tratamiento farmacológico , Estados Unidos , United States Food and Drug Administration/normasRESUMEN
BACKGROUND: Palbociclib is indicated for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). OBJECTIVE: Exposure-response analyses were conducted to evaluate efficacy in Asian versus non-Asian patients and in patients with versus without dose reduction in PALOMA-2. PATIENTS AND METHODS: PALOMA-2 compared palbociclib plus letrozole versus placebo plus letrozole in patients with ABC. Population pharmacokinetic analysis provided apparent palbociclib clearance (CL/F) for each patient. The time-varying exposure metric, Cavg,t, was calculated using average dose intensity and CL/F at the time of each progression-free survival (PFS) event. A Cox proportional model characterized PFS and palbociclib Cavg,t relationships. Significant prognostic factors for PFS were identified by univariate analysis, which were subsequently included in multivariate analyses, in addition to the Cavg,t effect on PFS. PFS profiles in Asian/non-Asian patients and patients with/without dose reduction were simulated and compared using observed palbociclib exposures and established exposure-response relationships. RESULTS: Patients (n = 421) received palbociclib plus letrozole (Asian = 64, non-Asian = 357; no dose reduction = 272, dose reduction = 149). Based on univariate analyses, significant prognostic factors were Ki67 score, age, and baseline aspartate aminotransferase (BAST), tumor size, alkaline phosphatase, and albumin levels. In multivariate analysis, only Ki67 and BAST remained significant. Palbociclib exposure did not significantly affect PFS in either univariate (P = 0.12) or multivariate (P = 0.44) analyses. CONCLUSIONS: This analysis suggests that palbociclib exposure has no impact on PFS when the dose reduction algorithm from palbociclib clinical trials is used. There is no difference in efficacy between Asians and non-Asians, despite the higher level of dose reductions in Asians. PFIZER: NCT01740427.
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Neoplasias de la Mama/tratamiento farmacológico , Reducción Gradual de Medicamentos/métodos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Resultado del TratamientoRESUMEN
In the phase 3 EMBRACA trial, treatment with the poly(ADP-ribose) polymerase inhibitor, talazoparib, led to significantly improved progression-free survival (PFS) compared with chemotherapy (hazard ratio, 0.54; 95% confidence interval, 0.41-0.71; P < .0001). We conducted an exposure-efficacy analysis using EMBRACA data from 285 patients who were treated with talazoparib and had available pharmacokinetic parameters to evaluate the effect of talazoparib exposure (time-varying average talazoparib concentration [Cavg,t ]) and other baseline variables on PFS. Graphical examination of the relationship between Cavg,t and PFS and a Cox proportional model were used. Exposure-response analyses showed that higher talazoparib exposure, absence of visceral disease, lower baseline lactate dehydrogenase levels, and disease-free interval >12 months were independent covariates associated with longer PFS. The association of talazoparib exposure with PFS (higher exposure, longer PFS) suggests the recommended starting dose of 1 mg once daily (the maximum tolerated dose) is appropriate.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Mutación de Línea Germinal , Ftalazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/sangre , Relación Dosis-Respuesta a Droga , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Ftalazinas/sangre , Inhibidores de Poli(ADP-Ribosa) Polimerasas/sangre , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Factores de Tiempo , Resultado del TratamientoRESUMEN
Poly(ADP-ribose) polymerase inhibitors, such as talazoparib, may affect hematopoiesis. This analysis characterized the relationship between talazoparib exposure and the most common grade ≥ 3 hematopoietic adverse events (AEs) leading to dose modification in the phase 2 (ABRAZO) and phase 3 (EMBRACA) trials. The relationship between time-varying average talazoparib concentration (Cavg,t ), along with other baseline variables, and grade ≥ 3 anemia, thrombocytopenia, and neutropenia were evaluated both by graphical examination and using univariate and multivariate Cox proportional hazard models. The results indicated that higher Cavg,t was associated with a higher risk of anemia and thrombocytopenia. A trend toward an association between higher Cavg,t and neutropenia was observed, although not statistically significant. Higher risk of all tested safety end points was associated with lower baseline hemoglobin. Higher risk of neutropenia was associated with lower baseline absolute neutrophil count and lower body weight. These findings support the proposed management of AEs through talazoparib dosing modification.
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Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Mutación de Línea Germinal , Ftalazinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Cálculo de Dosificación de Drogas , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Persona de Mediana Edad , Mutación , Neutropenia/inducido químicamente , Ftalazinas/administración & dosificación , Ftalazinas/sangre , Ftalazinas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/sangre , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Pronóstico , Modelos de Riesgos Proporcionales , Trombocitopenia/inducido químicamenteRESUMEN
Understanding transporter-mediated drug-drug interactions (DDIs) for investigational agents is important during drug development to assess DDI liability, its clinical relevance, and to determine appropriate DDI management strategies. P-glycoprotein (P-gp) is an efflux transporter that influences the pharmacokinetics (PK) of various compounds. Assessing transporter induction in vitro is challenging and is not always predictive of in vivo effects, and hence there is a need to consider clinical DDI studies; however, there is no clear guidance on when clinical evaluation of transporter induction is required. Furthermore, there is no proposed list of index transporter inducers to be used in clinical studies. This review evaluated DDI studies with known P-gp inducers to better understand the mechanism and site of P-gp induction, as well as the magnitude of induction effect on the exposure of P-gp substrates. Our review indicates that P-gp and cytochrome P450 (CYP450) enzymes are co-regulated via the pregnane xenobiotic receptor (PXR) and the constitutive androstane receptor (CAR). The magnitude of the decrease in substrate drug exposure by P-gp induction is generally less than that of CYP3A. Most P-gp inducers reduced total bioavailability with a minor impact on renal clearance, despite known expression of P-gp at the apical membrane of the kidney proximal tubules. Rifampin is the most potent P-gp inducer, resulting in an average reduction in substrate exposure ranging between 20 and 67%. For other inducers, the reduction in P-gp substrate exposure ranged from 12 to 42%. A lower reduction in exposure of the P-gp substrate was observed with a lower dose of the inducer and/or if the administration of the inducer and substrate was simultaneous, i.e. not staggered. These findings suggest that clinical evaluation of the impact of P-gp inducers on the PK of investigational agents that are substrates for P-gp might be warranted only for compounds with a relatively steep exposure-efficacy relationship.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Interacciones Farmacológicas , Preparaciones Farmacéuticas , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Proteínas de Transporte de MembranaRESUMEN
Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to treat cancers associated with somatic BRCA mutations and germline genetic aberrations involved in the DNA damage response. The efficacy, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profile of talazoparib, a potent small-molecule PARP inhibitor, was established in 4 clinical studies in cancer patients (2 phase 1 studies PRP-001 and PRP-002, the phase 2 ABRAZO trial, and the phase 3 EMBRACA trial). The current study aimed to describe the population PK of talazoparib and identify covariates that affect talazoparib PK in patients with advanced cancers using pooled data from these 4 studies. Talazoparib PK was well characterized by a 2-compartment model with first-order absorption and absorption lag time. Based on covariate analysis, no dose adjustment for talazoparib is required based on a patient's age, sex, baseline body weight, Asian race, the presence of mild renal or hepatic impairment, or use of acid-reducing agents. A reduced 0.75-mg daily dose is recommended for patients taking a potent P-glycoprotein inhibitor and those with moderate renal impairment. Insufficient data were available to establish dosing recommendations for patients with severe renal and moderate or severe hepatic impairment. The PK of a single 1-mg talazoparib capsule is comparable with 4 0.25-mg capsules. Talazoparib can be taken with or without food. These data provide support for dosing recommendations and labeling information for talazoparib.
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Antineoplásicos/farmacocinética , Neoplasias/tratamiento farmacológico , Ftalazinas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/sangre , Antineoplásicos/orina , Disponibilidad Biológica , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Estadificación de Neoplasias , Neoplasias/diagnóstico , Ftalazinas/administración & dosificación , Ftalazinas/sangre , Ftalazinas/orina , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/sangre , Inhibidores de Poli(ADP-Ribosa) Polimerasas/orina , Adulto JovenRESUMEN
The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Electrocardiografía/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/fisiopatología , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Letrozol , Persona de Mediana Edad , Nitrilos/administración & dosificación , Nitrilos/sangre , Nitrilos/farmacocinética , Piperazinas/administración & dosificación , Piperazinas/sangre , Piperazinas/farmacocinética , Piridinas/administración & dosificación , Piridinas/sangre , Piridinas/farmacocinética , Triazoles/administración & dosificación , Triazoles/sangre , Triazoles/farmacocinéticaRESUMEN
This study aims at evaluating the utility of the population pharmacokinetics approach in therapeutic protein drug-drug-interaction (DDI) assessment. Simulations were conducted for 2 representative victim drugs, methotrexate and trastuzumab, using a parallel-group design with and without the interaction drug. The effect of a perpetrator on the exposure of the victim drug is described as the ratio of clearance/apparent clearance of the victim drug given with or without the perpetrator. The power of DDI assessment was calculated as the percentage of runs with 90% confidence interval of the estimated DDI effect within 80% to 125% for the scenarios of no DDI, benchmarked with the noncompartmental approach with intensive sampling. The impact of the number of subjects, the number of sampling points per subject, sampling time error, and model misspecification on the power of DDI determination were evaluated. Results showed that with equal numbers of subjects in each arm, the population pharmacokinetics approach with sparse sampling may need about the same or a higher number of subjects compared to a noncompartmental approach in order to achieve similar power. Increasing the number of subjects, even if only in the study drug alone arm, can increase the power. Sampling or dosing time error had notable impacts on the power for methotrexate but not for trastuzumab. Model misspecification had no notable impacts on the power for trastuzumab. Overall, the population pharmacokinetics approach with sparse sampling built in phase 2/3 studies allows appropriate DDI assessment with adequate study design and analysis and can be considered as an alternative to dedicated DDI studies.
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Interacciones Farmacológicas , Modelos Biológicos , Área Bajo la Curva , Simulación por Computador , Humanos , Metotrexato/farmacocinética , Trastuzumab/farmacocinéticaRESUMEN
PURPOSE: This phase I study estimated the effect of food on bioavailability of palbociclib (IBRANCE®), and a selective inhibitor of cyclin-dependent kinase 4/6 approved for oncology indications has pH-dependent solubility and high permeability. METHODS: In this randomized, four-sequence, four-period crossover study, 28 healthy volunteers received a single 125-mg dose of palbociclib (free-base capsule) following an overnight fast or (1) after a high-fat/-calorie meal, (2) after a low-fat/-calorie meal, and (3) between two moderate-fat/standard-calorie meals. Pharmacokinetic samples were collected predose and serially ≤144 h postdose; palbociclib concentrations were measured using validated high-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic data were analyzed using a noncompartmental approach based on a mixed-effects model. RESULTS: Median time to maximum concentration was 8 h for all conditions. Exposure (AUCinf and C max) increased slightly in the fed versus fasted conditions; ratios (90% CIs) of the adjusted geometric mean relative to the fasted condition ranged from 111.8 (104.3-119.9%) to 120.6% (112.6-129.1%) for AUCinf and from 124.0 (108.4-141.9%) to 137.8% (120.6-157.5%) for C max due mainly to three subjects with significantly lower exposure (low liers) in the fasted condition. Pharmacokinetic variability was reduced in the fed (AUCinf, 23-27%; C max, 21-24%) versus fasted (AUCinf, 39%; C max, 73%) conditions. In a supplemental analysis excluding the three low liers, food intake did not affect palbociclib exposure. CONCLUSIONS: Food intake modestly increased palbociclib exposure while greatly reducing pharmacokinetic variability. For subjects with normal absorption, food intake did not affect palbociclib exposure. Thus, palbociclib should be administered with food. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01904747.
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Antineoplásicos/farmacocinética , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/farmacocinética , Piperazinas/farmacocinética , Piridinas/farmacocinética , Adolescente , Adulto , Antineoplásicos/efectos adversos , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/efectos adversos , Ingestión de Energía , Ayuno/metabolismo , Femenino , Interacciones Alimento-Droga , Voluntarios Sanos , Humanos , Absorción Intestinal , Masculino , Comidas , Persona de Mediana Edad , Piperazinas/efectos adversos , Piridinas/efectos adversos , Adulto JovenRESUMEN
PURPOSE: Rucaparib is a potent Poly (ADP-ribose) Polymerase (PARP) inhibitor currently under clinical development. The objectives of this analysis were to establish population PK and PK/PD models for rucaparib, and to evaluate the predictability of PARP activity in PBL for PARP activity in tumor tissues. EXPERIMENTAL DESIGN: Rucaparib concentrations and PARP activity in human PBLs and tumor issues were obtained from 32 patients with solid tumors in a Phase 1 First-in-Patient study. Simulations were conducted to evaluate different dosing regimens. RESULTS: A 3-compartment PK model best described the PK of rucaparib. An Emax model best described the exposure and PARP inhibition relationship. The maximum PARP inhibition (Imax) achieved in PBLs and in tumors were 90.9% and 90.0% of the baseline PARP activity, and the IC50 values were 1.05 ng/mL and 1.10 ng/mL, respectively. PAR polymer baseline value was found to be a covariate of Emin. CONCLUSION: Population PK and PK/PD models have been established to describe population PK of rucaparib and the relationship between rucaparib plasma concentration and PARP inhibition in both PBLs and tumor issues. Results from this trial indicated that PARP inhibition in PBLs can be used as a substitute for PARP inhibition in melanoma tumor tissues.
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Indoles/farmacocinética , Linfocitos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Poli(ADP-Ribosa) Polimerasas/sangre , Biomarcadores/sangre , Simulación por Computador , Esquema de Medicación , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Indoles/sangre , Infusiones Intravenosas , Linfocitos/enzimología , Modelos Biológicos , Neoplasias/sangre , Neoplasias/enzimología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/sangreRESUMEN
Assessment of pharmacokinetic (PK) based drug-drug interactions (DDI) is essential for ensuring patient safety and drug efficacy. With the substantial increase in therapeutic proteins (TP) entering the market and drug development, evaluation of TP-drug interaction (TPDI) has become increasingly important. Unlike for small molecule (e.g., chemical-based) drugs, conducting TPDI studies often presents logistical challenges, while the population PK (PPK) modeling may be a viable approach dealing with the issues. A working group was formed with members from the pharmaceutical industry and the FDA to assess the utility of PPK-based TPDI assessment including study designs, data analysis methods, and implementation strategy. This paper summarizes key issues for consideration as well as a proposed strategy with focuses on (1) PPK approach for exploratory assessment; (2) PPK approach for confirmatory assessment; (3) importance of data quality; (4) implementation strategy; and (5) potential regulatory implications. Advantages and limitations of the approach are also discussed.
Asunto(s)
Modelos Biológicos , Proteínas/farmacocinética , Proteínas/uso terapéutico , Interacciones Farmacológicas , HumanosRESUMEN
The investigation of therapeutic protein drug-drug interactions has proven to be challenging. In May 2012, a roundtable was held at the American Association of Pharmaceutical Scientists National Biotechnology Conference to discuss the challenges of preclinical assessment and in vitro to in vivo extrapolation of these interactions. Several weeks later, a 2-day workshop co-sponsored by the U.S. Food and Drug Administration and the International Consortium for Innovation and Quality in Pharmaceutical Development was held to facilitate better understanding of the current science, investigative approaches and knowledge gaps in this field. Both meetings focused primarily on drug interactions involving therapeutic proteins that are pro-inflammatory cytokines or cytokine modulators. In this meeting synopsis, we provide highlights from both meetings and summarize observations and recommendations that were developed to reflect the current state of the art thinking, including a four-step risk assessment that could be used to determine the need (or not) for a dedicated clinical pharmacokinetic interaction study.
Asunto(s)
Investigación Biomédica/normas , Biotecnología/normas , Industria Farmacéutica/normas , Interacciones Farmacológicas , United States Food and Drug Administration/normas , Animales , Investigación Biomédica/tendencias , Biotecnología/tendencias , California , Industria Farmacéutica/tendencias , Educación/normas , Educación/tendencias , Humanos , Estados Unidos , United States Food and Drug Administration/tendenciasRESUMEN
Biologics, including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones, have unique characteristics compared to small molecules. This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective, the determination of a starting dose for first-in-human (FIH) studies, and dosing regimen optimisation for phase II/III clinical trials. Subsequently, typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised, including drug-drug interactions, QTc prolongation, immunogenicity, and studies in specific populations. The relationships between the molecular structure of biologics, their pharmacokinetic and pharmacodynamic characteristics, and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram.