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1.
Leuk Lymphoma ; : 1-10, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31549889

RESUMO

Exposure-response relationships from a phase 1b (M13-365) and phase 3 (MURANO) study were investigated to assess benefit/risk of venetoclax 400 mg daily plus rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Dose intensities were summarized by tertiles of predicted venetoclax steady-state average concentrations based on nominal venetoclax dose (CmeanSS,nominal) for tolerability; exposure-safety analyses used logistic regression. Exposure-progression-free survival (PFS) relationships were assessed using MURANO data, with CmeanSS,nominal as a grouping factor. Covariates were demographics, geographic region, study, baseline disease characteristics, ECOG performance status, responsiveness to prior therapy, and chromosomal abnormalities. There was no significant effect of covariates on grade ≥3 neutropenia/infection or PFS, and no relationship between venetoclax exposure and these endpoints, or venetoclax or rituximab dose intensity. These results support the recommended venetoclax 400 mg daily dose in combination with rituximab in patients with R/R CLL or small lymphocytic leukemia.

2.
J Clin Neurosci ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31521472

RESUMO

Thrombolysis-induced haemorrhagic transformation is the most challenging preventable complication in thrombolytic therapy. This condition is often associated with poor functional outcome and long-term disease burden. Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are controversially suggested to either increase or decrease the odds of better primary outcomes compared to treatment without statins after thrombolysis in patients or animals; statins are thought to act by influencing lipid levels, the inflammatory response, blood brain barrier permeability and cell apoptosis. Statins are the cornerstone of secondary prevention of cardiovascular and cerebrovascular diseases. However, the role of statins in acute phase stroke, and the necessity of their use, remains unclear. Currently, whether statins can increase the risk of haemorrhagic transformation is of great concern for patients treated with tissue plasminogen activator (t-PA). Herein, we thoroughly summarize the recent advances that address whether the administration of statins in ischaemic stroke increases haemorrhagic transformation in patients or animals who received thrombolysis at an early stage and the related mechanisms. This review will provide more clinical and preclinical evidence to address questions regarding the exercise of caution in the use of high dose statins in patients who received thrombolysis and if low dose statins may be beneficial in decreasing thrombolysis-induced haemorrhagic transformation.

3.
PLoS Biol ; 17(9): e3000436, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31498797

RESUMO

Bats harbor many zoonotic viruses, including highly pathogenic viruses of humans and other mammals, but they are typically asymptomatic in bats. To further understand the antiviral immunity of bats, we screened and identified a series of bat major histocompatibility complex (MHC) I Ptal-N*01:01-binding peptides derived from four different bat-borne viruses, i.e., Hendra virus (HeV), Ebola virus (EBOV), Middle East respiratory syndrome coronavirus (MERS-CoV), and H17N10 influenza-like virus. The structures of Ptal-N*01:01 display unusual peptide presentation features in that the bat-specific 3-amino acid (aa) insertion enables the tight "surface anchoring" of the P1-Asp in pocket A of bat MHC I. As the classical primary anchoring positions, the B and F pockets of Ptal-N*01:01 also show unconventional conformations, which contribute to unusual peptide motifs and distinct peptide presentation. Notably, the features of bat MHC I may be shared by MHC I from various marsupials. Our study sheds light on bat adaptive immunity and may benefit future vaccine development against bat-borne viruses of high impact on humans.

5.
J Voice ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31383515

RESUMO

BACKGROUND: Vibration is commonly used to relax tension in the limb and truck muscle. Vibration used directly on the muscle concerned and vertical vibration used on the whole-body through a foot platform have been reported in the literature to be useful to release muscle tension. AIM: The present study investigated the effect of indirect whole-body vibration (WBV) and direct localized perilaryngeal vibration (LPV) on the phonatory functions of nondysphonic individuals with vocal fatigue. METHODS: Forty-four subjects (mean age = 21.67 years) with normal voice, were randomly assigned to either the WBV group, the LPV group, or the Control (sham hand-held vibratory device) group. They performed karaoke singing for at least 95 minutes. They then received either WBV through a Turbosonic vibratory machine, LPV with a Novofan vibrator, or a sham vibrator for 10 minutes. The highest pitch produced, and self-reported vocal fatigue score were taken before singing, after singing, and after the intervention. Data were analyzed separately for the gender subgroups. RESULTS: All subject groups showed significant reduction of vocal function (highest pitch production, and vocal fatigue score) after singing. Following the vibrational interventions, both the WBV and LPV groups showed significantly recovery in the highest pitch production and the perception of vocal fatigue (P < 0.002) than the Control groups. CONCLUSION: Vibrational therapy, whether it is localized vibration on the peri-laryngeal muscles, or whole-body vibration, is more effective than voice rest per se in relieving vocal fatigue. Vibrational methods are recommended for treating vocal fatigue.

6.
Front Immunol ; 10: 1709, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396224

RESUMO

Human leukocyte antigen (HLA) alleles have a high degree of polymorphism, which determines their peptide-binding motifs and subsequent T-cell receptor recognition. The simplest way to understand the cross-presentation of peptides by different alleles is to classify these alleles into supertypes. A1 and A3 HLA supertypes are widely distributed in humans. However, direct structural and functional evidence for peptide presentation features of key alleles (e.g., HLA-A*30:01 and -A*30:03) are lacking. Herein, the molecular basis of peptide presentation of HLA-A*30:01 and -A*30:03 was demonstrated by crystal structure determination and thermostability measurements of complexes with T-cell epitopes from influenza virus (NP44), human immunodeficiency virus (RT313), and Mycobacterium tuberculosis (MTB). When binding to the HIV peptide, RT313, the PΩ-Lys anchoring modes of HLA-A*30:01, and -A*30:03 were similar to those of HLA-A*11:01 in the A3 supertype. However, HLA-A*30:03, but not -A*30:01, also showed binding with the HLA*01:01-favored peptide, NP44, but with a specific structural conformation. Thus, different from our previous understanding, HLA-A*30:01 and -A*30:03 have specific peptide-binding characteristics that may lead to their distinct supertype-featured binding peptide motifs. Moreover, we also found that residue 77 in the F pocket was one of the key residues for the divergent peptide presentation characteristics of HLA-A*30:01 and -A*30:03. Interchanging residue 77 between HLA-A*30:01 and HLA-A*30:03 switched their presented peptide profiles. Our results provide important recommendations for screening virus and tumor-specific peptides among the population with prevalent HLA supertypes for vaccine development and immune interventions.

7.
Cancer Discov ; 9(9): 1268-1287, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31263025

RESUMO

Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS-NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC. SIGNIFICANCE: NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer.This article is highlighted in the In This Issue feature, p. 1143.

8.
Nat Prod Res ; : 1-5, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31305144

RESUMO

In the course of searching for cytotoxic metabolites from insects associated actinomyces, two new natural p-terphenyl glycosides, strepantibin D (1) and strepantibin E (2), along with terferol (3), actinomycin D (4), actinomycin V (5) and actinomycin V0ß (6), were identified from the fermentation medium of a Streptomyces sp. which was obtained from the larva body of mud dauber wasp. Strepantibin D (1), previously reported as a synthetic derivative of terfestatin A, is firstly isolated as a natural p-terphenyl in this research. Strepantibin D (1) and terferol (3) showed medium cytotoxic activity against breast cancer cells MCF-7, MDA-MB-231 and BT-474. Actinomycins (4-6), especially actinomycin V (5), displayed remarkable cytotoxicity against breast cancer cells, with IC50 values ranging from 0.83 nM to 369.90 nM.

9.
Nat Med ; 25(8): 1205-1212, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31332393

RESUMO

Exclusive breastfeeding (EBF)-giving infants only breast-milk (and medications, oral rehydration salts and vitamins as needed) with no additional food or drink for their first six months of life-is one of the most effective strategies for preventing child mortality1-4. Despite these advantages, only 37% of infants under 6 months of age in Africa were exclusively breastfed in 20175, and the practice of EBF varies by population. Here, we present a fine-scale geospatial analysis of EBF prevalence and trends in 49 African countries from 2000-2017, providing policy-relevant administrative- and national-level estimates. Previous national-level analyses found that most countries will not meet the World Health Organization's Global Nutrition Target of 50% EBF prevalence by 20256. Our analyses show that even fewer will achieve this ambition in all subnational areas. Our estimates provide the ability to visualize subnational EBF variability and identify populations in need of additional breastfeeding support.

10.
Plant Physiol ; 181(1): 262-275, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31289214

RESUMO

Magnesium (Mg) is a relatively mobile element that is remobilized in plants under Mg-limited conditions through transport from old to young tissues. However, the physiological and molecular mechanisms underlying Mg remobilization in plants remain poorly understood. In this study, we investigated Mg remobilization in rice (Oryza sativa) as facilitated through a Mg dechelatase gene involved in chlorophyll degradation, STAY-GREEN (OsSGR). We first observed that mid-aged leaves of rice are more susceptible to Mg deficiency. Expression of OsSGR was specifically upregulated by Mg deficiency, and the response was more pronounced in mid-aged leaves. Knockout of OsSGR exhibited the stay-green phenotype, which hindered the mobility of Mg from mid-aged leaves to young developing leaves. This decline in Mg mobility was associated with inhibited growth of developing leaves in mutants under Mg-limited conditions. Furthermore, Mg deficiency enhanced reactive oxygen species (ROS) generation in mid-aged leaves. ROS levels, particularly hydrogen peroxide, in turn, positively regulated OsSGR expression, probably through chloroplast-to-nucleus signaling, which triggers chlorophyll degradation to protect mid-aged leaves from photodamage. Taken together, these results show that OsSGR-mediated chlorophyll degradation contributes to not only internal remobilization of Mg from mid-aged leaves to developing leaves, but also photooxidative protection of mid-aged leaves under Mg-limited conditions. ROS appear to act as feedback regulators of OsSGR expression to precisely govern chlorophyll degradation in mid-aged leaves where Mg and photosynthetic capacities are relatively high.

11.
PLoS One ; 14(7): e0220306, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31348821

RESUMO

BACKGROUND: Lung cancer is the leading cause of death caused by malignant tumors. PD-L1(programmed cell death protein-1) has shown tremendous achievement in treating NSCLC. We sought to find the relationship between CTCs in the pulmonary vein and postoperative PFS, besides we detected PD-L1 in CTCs. METHOD: We enrolled 112 NSCLC patients. CTC tests were performed at four time points (preoperative, pulmonary vein, intraoperative and postoperative) on every NSCLC patient who received surgery. The RNA of PD-L1 was tested by FISH. The levels of the PD-L1 mRNA and protein in tissue samples were detected. RESULTS: The CTCs in the PV were the highest (P< 0.001), and CTCs in the PPA were the lowest (P< 0.001). The PFS in the group with PV CTCs≥ 16/5 ml was shorter than that in the group with PV CTCs< 16/5 ml (11.1 months vs 21.2 months, respectively; P< 0.001). The PFS in the group with PPA CTCs≥ 3/5 ml was shorter than that in the group with CTCs< 3/5 ml (14.8 months vs 20.7 months, respectively; P< 0.001). The CTCs in stage I were lower than those in stage II-IV (P = 0.025). No linear relationship was found between the CTCs and tumor size (P> 0.05) or LN metastasis (P> 0.05). In total, fifty-two (50.5%) patients had positive PD-L1 expression in CTC. In PD-L1-positive CTC patients, the value of PD-L1 tissue expression was higher than that in PD-L1-negative CTC patients (P = 0.0153). CONCLUSION: CTCs in the pulmonary vein can be an effective prognosis indicator of NSCLC patients.

12.
World Neurosurg ; 131: 21-26, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31362106

RESUMO

BACKGROUND: During endovascular treatment of complex intracranial dural arteriovenous fistulas (DAVFs) of the transverse sigmoid sinus, it can be difficult to preserve the patency of the dural sinus. We have described the details of the transvenous balloon-assisted technique using Copernic RC balloon as a treatment option for patients with complex DAVFs of the transverse sigmoid sinus. CASE DESCRIPTION: In these 2 cases, the Copernic RC balloon was navigated into the internal jugular vein and placed at the distal end of the DAVFs in the transverse sinus. After the balloon was fully inflated, a transarterial glue embolization or transvenous Onyx tunnel technique was performed, with complete exclusion of the fistula and patency of the transverse sigmoid sinus. No immediate or delayed postoperative complications occurred. CONCLUSION: Transvenous Copernic RC balloon-assisted embolization of DAVFs in the transverse and sigmoid sinuses is safe and can offer complete occlusion of DAVFs and remission of clinical symptoms.

13.
CPT Pharmacometrics Syst Pharmacol ; 8(8): 606-615, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207190

RESUMO

Peripheral neuropathy (PN) is a common long-term debilitating toxicity of antimicrotubule agents. PN was the most frequent adverse event resulting in dose modifications and/or discontinuation of treatment for valine-citrulline-monomethylauristatin E antibody-drug conjugates (ADCs) developed at Genentech. A pooled time-to-event analysis across eight ADCs (~700 patients) was performed to evaluate the relationship between the ADC exposure and the risk for developing a clinically significant (grade ≥ 2) PN. In addition, the impact of demographic and pathophysiological risk factors on the risk for PN was explored. The time-to-event analysis suggested that the development of PN risk increased with ADC exposure, treatment duration, body weight, and previously reported PN. This model can be used to inform clinical strategies such as adaptations to dosing regimen and/or treatment duration as well as inform clinical eligibility to reduce the incidence of grade ≥ 2 PN.

14.
FEBS Open Bio ; 9(8): 1450-1459, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237075

RESUMO

The majority of human CD8 cytotoxic T lymphocytes express αß T-cell receptors that recognize peptide-MHC class I complexes. Considerable attention has been devoted to TCR ß repertoires, but study of TCR α chains has been limited. To gain a better understanding of the features of CDR3α and CDR3ß in paired samples, we comprehensively analyzed 776 unique paired αß TCR CDR3 regions in this study. We found that (I) the CDR3 length among paired αß TCRs had a fairly narrow distribution due to random assortment of CDR3 length in alpha and beta chains; (II) nucleotide deletions among CDR3 regions were positively correlated with insertions in both α and ß TCRs; (III) the CDR3 loops of both α and ß chains contained an abundance of charged/polar residues and the CDR3 base regions contained a conserved motif; and (IV) the occurrence of Gly was CDR3 length- and position-dependent in both chains, whereas the frequency of Ser at positions 106 and 107 was positively correlated with CDR3 length in TCR ß. Overall, the amino acids in CDR3 loop regions were significantly different between TCR α and ß, which suggests a distinct role for each chain in the recognition of antigen-MHC complexes. Here, we have provided detailed information on CDR3 in paired TCRs expressed on human CD8+ T cells and established the basis of a reference set for αß TCR repertoires in healthy humans.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31233831

RESUMO

STUDY OBJECTIVE: The purpose of this study was to determine if there are any genetic changes with whole-exome sequencing associated with distal vaginal atresia. DESIGN: This was a retrospective genetics study of 5 patients who presented with distal vaginal atresia who were recruited between 2017 and 2018. Whole-exome sequencing was performed in each subject with distal vaginal atresia. Sanger sequencing was used to confirm the potential causative genetic mutation. SETTING: Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. PARTICIPANTS AND MAIN OUTCOME MEASURES: The main outcome measure was the rare mutations potentially associated with distal vaginal atresia in 5 patients. RESULTS: A truncating mutation c.266delC (p.P89Rfs*5) in the T-box transcription factor 6 (TBX6) gene, which is highly expressed in the human vagina, was identified in 1 patient using whole-exome sequencing. The deletion of the 16p11.2 region containing the TBX6 locus has also been reported previously to have the clinical feature of Müllerian agenesis. This mutation was paternally inherited by the patient. This truncating mutation was absent from all of the databases we checked, suggesting that the variant is rare and pathogenic. CONCLUSION: We showed, to our knowledge, for the first time, that the mutation in TBX6 might be associated with human distal vaginal atresia.

16.
Opt Express ; 27(13): 17876-17886, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31252740

RESUMO

The reflection Airy distribution (RAD) of a Fabry-Pérot (F-P) resonator is deduced with the consideration of the mode coupling between the cavity resonance field and the initial back-reflected field at the input F-P resonator facet, as well as the influence of the loss/gain factor. A waveguide loss/gain measurement method is proposed based on the measurement of the finesse of the RAD, which is intrinsically free from the influence of the coupling loss and the substrate scattering noise. The waveguide loss can be measured with a simple single-facet coupling setup, considerably reducing the coupling difficulty and the complexity of the measurement system while achieving the same or better measurement accuracy as that of the transmission F-P method.

17.
Org Lett ; 21(13): 5138-5142, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31247759

RESUMO

Here, we describe an Se-auxiliary mediated ligation protocol capable of rapid native chemical ligations at sterically hindered junctions, followed by in situ auxiliary cleavage under neutral conditions without affecting unprotected Cys residues. This auxiliary, which is prepared from phenyl acetaldehyde in one step, can be conveniently attached to the N-terminal region of a peptide via a reductive amination or coupling reaction. We demonstrated this methodology by synthesizing two protein samples.

18.
Clin Pharmacokinet ; 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31209657

RESUMO

BACKGROUND: Venetoclax is a selective B-cell lymphoma-2 (BCL-2) inhibitor approved for use as monotherapy or with rituximab in patients with chronic lymphocytic leukemia (CLL). The objectives of the current analysis of observed data from adult patients randomized to venetoclax-rituximab in the phase III MURANO study were to characterize venetoclax pharmacokinetics (PKs) using a Bayesian approach, evaluate whether a previously developed population PK model for venetoclax can describe the PKs of venetoclax when administered with rituximab, and to determine post hoc estimates of PK parameters for the exposure-response analysis. METHODS: Parameter estimates and uncertainty estimated by a population PK model were used as priors. Additional covariate effects (CLL risk status, geographic region, and 17p deletion [del(17p)] status) were added to the model. The updated model was used to describe venetoclax PKs after repeated dosing in combination with rituximab, and to determine post hoc estimates of PK parameters for exposure-response analysis. RESULTS: The PK analysis included 600 quantifiable venetoclax PK samples from 182 patients in the MURANO study. Model evaluation using standard diagnostic plots, visual predictive checks, and normalized prediction distribution error plots indicated no model deficiencies. There was no significant relationship between venetoclax apparent clearance (CL/F) and bodyweight, age, sex, mild and moderate hepatic and renal impairment, or coadministration of weak cytochrome P450 3A inhibitors. The chromosomal abnormality del(17p) and CLL risk status had no apparent effect on the PKs of venetoclax. A minimal increase in venetoclax CL/F (approximately 7%) was observed after coadministration with rituximab. CL/F was 30% lower in patients from Central and Eastern Europe (n = 60) or Asia (n = 4) compared with other regions (95% confidence interval [CI] 21-39%). Apparent central volume of distribution was 30% lower (95% CI 22-38%) in females (n = 56) compared with males (n = 126). No clinically significant impact of region or sex was observed on key safety and efficacy outcomes. CONCLUSIONS: The Bayesian model successfully characterized venetoclax PKs over time and confirmed key covariates affecting PKs in the MURANO study. The model was deemed appropriate for further use in simulations and for generating individual patient PK parameters for subsequent exposure-response evaluation.

19.
Clin Transl Sci ; 12(5): 534-544, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31115997

RESUMO

Prediction of human pharmacokinetics (PK) based on preclinical information for antibody-drug conjugates (ADCs) provide important insight into first-in-human (FIH) study design. This retrospective analysis was conducted to identify an appropriate scaling method to predict human PK for ADCs from animal PK data in the linear range. Different methods for projecting human clearance (CL) from animal PK data for 11 ADCs exhibiting linear PK over the tested dose ranges were examined: multiple species allometric scaling (CL vs. body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent, and scaling from only cynomolgus monkey PK data. Two analytes of interest for ADCs, namely total antibody and conjugate (measured as conjugated drug or conjugated antibody), were assessed. Percentage prediction errors (PEs) and residual sum of squares (RSS) were compared across methods. Human CL was best estimated using cynomolgus monkey PK data alone and an allometric scaling exponent of 1.0 for CL. This was consistently observed for both conjugate and total antibody analytes. Other scaling methods either underestimated or overestimated human CL, or produced larger average absolute PEs and RSS. Human concentration-time profiles were also reasonably predicted from the cynomolgus monkey data using species-invariant time method with a fixed exponent of 1.0 for CL and 1.0 for volume of distribution. In conclusion, results from this retrospective analysis of 11 ADCs indicate that allometric scaling of CL with an exponent of 1.0 using cynomolgus monkey PK data alone can successfully project human PK profiles of an ADC within linear range.

20.
Cancer Chemother Pharmacol ; 84(1): 175-185, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102024

RESUMO

PURPOSE: The phase III MARIANNE study investigated single-agent trastuzumab emtansine (T-DM1) and combination T-DM1 plus pertuzumab as the first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Pharmacokinetic properties of T-DM1 and pertuzumab in these patients and the potential for drug-drug interactions (DDIs) were assessed. METHODS: Pharmacokinetic samples of T-DM1-related analytes (T-DM1 conjugate, total trastuzumab, DM1) and pertuzumab were analyzed. Observed pharmacokinetic data were summarized for all analytes. Historical population pharmacokinetic models for T-DM1 conjugate and pertuzumab in HER2-positive MBC were used to derive empirical Bayes estimates of pharmacokinetic parameters. RESULTS: In MARIANNE (N = 375), mean ± standard deviation population pharmacokinetic model-predicted Cycle 1 Cmax for T-DM1 conjugate was 74.4 ± 10.1 µg/mL, Cycle 1 Ctrough was 1.34 ± 0.802 µg/mL, and area under the concentration-time curve from time zero to infinity after first dose (AUCinf) was 338 ± 69.5 µg*day/mL. These values were similar to other T-DM1 studies. Pharmacokinetics of T-DM1 conjugate and other analytes (total trastuzumab, DM1) were similar with or without pertuzumab. In the pertuzumab plus T-DM1 arm, mean model-predicted Cycle 1 pertuzumab Cmax, Ctrough, and AUCinf were 276 ± 50.0 µg/mL, 64.8 ± 17.9 µg/mL, and 4470 ± 1360 µg*day/mL, respectively. These values were similar to other pertuzumab studies. CONCLUSIONS: Based on the population pharmacokinetic analysis of T-DM1 conjugate and pertuzumab, pharmacokinetics are similar across different lines of treatment and stages of disease including previously untreated MBC patients, and no DDIs were identified for combined use of T-DM1 and pertuzumab.

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