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Article ; Online: Physiologically-based pharmacokinetic model of sparsentan to evaluate drug-drug interaction potential.

Patel, Nikunjkumar K / Chen, Kuan-Fu / Chen, Shang-Chiung / Liu, Kai

CPT: pharmacometrics & systems pharmacology

2023 Volume 13, Issue 2, Page(s) 317–329

Abstract: Sparsentan is a dual endothelin/angiotensin II receptor antagonist indicated to reduce proteinuria in patients with primary IgA nephropathy at high risk of disease progression. In vitro data indicate that sparsentan is likely to inhibit or induce various ...

Abstract	Sparsentan is a dual endothelin/angiotensin II receptor antagonist indicated to reduce proteinuria in patients with primary IgA nephropathy at high risk of disease progression. In vitro data indicate that sparsentan is likely to inhibit or induce various CYP enzymes at therapeutic concentrations. Sparsentan as a victim and perpetrator of CYP3A4 mediated drug-drug interactions (DDIs) has been assessed clinically. A mechanistic, bottom-up, physiologically-based pharmacokinetic (PK) model for sparsentan was developed based on in vitro data of drug solubility, formulation dissolution and particle size, drug permeability, inhibition and induction of metabolic enzymes, and P-glycoprotein (P-gp) driven efflux. The model was verified using clinical PK data from healthy adult volunteers administered single and multiple doses in the fasted and fed states for a wide range of sparsentan doses. The model was also verified by simulation of clinically observed DDIs. The verified model was then used to test various DDI simulations of sparsentan as a perpetrator and victim of CYP3A4 using an expanded set of inducers and inhibitors with varying potency. Additional perpetrator and victim DDI simulations were performed using probes for CYP2C9 and CYP2C19. Simulations were conducted to predict the effect of complete inhibition of P-gp inhibition on sparsentan absorption and clearance. The predictive simulations indicated that exposure of sparsentan could increase greater than two-fold if co-administered with a strong CYP3A4 inhibitor, such as itraconazole. Other potential DDI interactions as victim or perpetrator were all within two-fold of control. The effect of complete P-gp inhibition on sparsentan PK was negligible.
MeSH term(s)	Adult ; Humans ; Cytochrome P-450 CYP3A/metabolism ; Models, Biological ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; Drug Interactions ; Spiro Compounds ; Sulfonamides
Chemical Substances	Cytochrome P-450 CYP3A (EC 1.14.14.1) ; sparsentan (9242RO5URM) ; Cytochrome P-450 CYP3A Inhibitors ; Spiro Compounds ; Sulfonamides
Language	English
Publishing date	2023-12-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13086
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Article ; Online: Population pharmacokinetic analysis of sparsentan in healthy volunteers and patients with focal segmental glomerulosclerosis.

Wada, Russell / Kleijn, Huub Jan / Zhang, Lu / Chen, Shang-Chiung

CPT: pharmacometrics & systems pharmacology

2023 Volume 12, Issue 8, Page(s) 1080–1092

Abstract: Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was ... ...

Abstract	Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and co-medications as covariates on sparsentan PKs. Blood samples were collected from 236 healthy volunteers, 16 subjects with hepatic impairment, and 194 primary and genetic FSGS patients enrolled in nine studies ranging from phase I to phase III. Sparsentan plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry with a lower limit of quantitation of 2 ng/mL. Modeling was conducted with the first-order conditional estimation with η-ϵ interaction (FOCE-1) method in NONMEM. A total of 20 covariates were tested using a univariate forward addition and stepwise backward elimination analysis with significance level of p < 0.01 and p < 0.001, respectively. A two-compartment model with first-order absorption and an absorption lag time with proportional plus additive residual error (2 ng/mL) described sparsentan PKs. A 32% increase of clearance due to CYP3A auto-induction occurred at steady-state. Covariates retained in the final model included formulation, cytochrome P450 (CYP) 3A4 inhibitor co-administration, sex, race, creatinine clearance, and serum alkaline phosphatase. Moderate and strong CYP3A4 inhibitors comedications increased area under the concentration-time curve by 31.4% and 191.3%, respectively. This population PK model of sparsentan suggests that dose adjustments may be warranted for patients taking moderate and strong CYP3A4 inhibitors concomitantly, but other covariates analyzed may not require dose adjustments.
MeSH term(s)	Humans ; Glomerulosclerosis, Focal Segmental/drug therapy ; Cytochrome P-450 CYP3A Inhibitors ; Healthy Volunteers ; Spiro Compounds
Chemical Substances	sparsentan (9242RO5URM) ; Cytochrome P-450 CYP3A Inhibitors ; Spiro Compounds
Language	English
Publishing date	2023-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12996
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Article ; Online: Effect of Multiple Doses of Sparsentan on the Single-Dose Pharmacokinetics of Dapagliflozin: An Open-Label Drug-Drug Interaction Study in Healthy Adults.

Chen, Shang-Chiung / Cai, Danlin / Winnett, Claire / Nguyen, Mai / Verma, Neeraj / Liu, Kai / Preciado, Priscila

Clinical pharmacology in drug development

2023 Volume 12, Issue 5, Page(s) 535–541

Abstract: Sparsentan is a single-molecule dual antagonist of the endothelin type A receptor and angiotensin II type 1 receptor under investigation for the treatment of focal segmental glomerulosclerosis and immunoglobulin A nephropathy. Dapagliflozin, a sodium- ... ...

Abstract	Sparsentan is a single-molecule dual antagonist of the endothelin type A receptor and angiotensin II type 1 receptor under investigation for the treatment of focal segmental glomerulosclerosis and immunoglobulin A nephropathy. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has recently been indicated in chronic kidney disease. Sparsentan may be considered for concomitant use with dapagliflozin. The purpose of this open-label, 1-sequence crossover study was to determine whether drug-drug interactions between sparsentan and dapagliflozin affect dapagliflozin pharmacokinetics (PK). In addition, exposure to the inactive metabolite of dapagliflozin, dapagliflozin-3-O-glucuronide, was used to evaluate the effect of sparsentan on the primary metabolizing enzyme of dapagliflozin, uridine 5'-diphospho-glucuronosyltransferase 1A9. The study included 22 healthy adults treated with 10 mg of dapagliflozin on day 1, and 800 mg/day of sparsentan on days 5-14, with a 10-mg dose of dapagliflozin coadministered on day 11. PK samples were taken for dapagliflozin, dapagliflozin-3-O-glucuronide, and sparsentan before and after treatment throughout the study. Steady-state concentrations of sparsentan following daily dosing did not affect the PK of single-dose dapagliflozin in healthy adults. Dapagliflozin-3-O-glucuronide PK suggests a minimal effect of sparsentan on metabolism of dapagliflozin by uridine 5'-diphospho-glucuronosyltransferase 1A9. No deaths, serious adverse events, or unusual safety signals occurred. Results suggest dapagliflozin PK is not affected by sparsentan daily dosing.
MeSH term(s)	Adult ; Humans ; Hypoglycemic Agents ; Cross-Over Studies ; Glucuronides ; Drug Interactions ; Glucuronosyltransferase
Chemical Substances	Hypoglycemic Agents ; sparsentan (9242RO5URM) ; dapagliflozin (1ULL0QJ8UC) ; Glucuronides ; Glucuronosyltransferase (EC 2.4.1.17)
Language	English
Publishing date	2023-02-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.1231
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Article ; Online: Impact of Physiologically Based Pharmacokinetics, Population Pharmacokinetics and Pharmacokinetics/Pharmacodynamics in the Development of Antibody-Drug Conjugates.

Li, Chunze / Chen, Shang-Chiung / Chen, Yuan / Girish, Sandhya / Kaagedal, Matts / Lu, Dan / Lu, Tong / Samineni, Divya / Jin, Jin Y

Journal of clinical pharmacology

2020 Volume 60 Suppl 1, Page(s) S105–S119

Abstract: Antibody-drug conjugates are important molecular entities in the treatment of cancer, with 8 antibody-drug conjugates approved by the US Food and Drug Administration since 2000 and many more in early- and late-stage clinical development. These conjugates ...

Abstract	Antibody-drug conjugates are important molecular entities in the treatment of cancer, with 8 antibody-drug conjugates approved by the US Food and Drug Administration since 2000 and many more in early- and late-stage clinical development. These conjugates combine the target specificity of monoclonal antibodies with the potent anticancer activity of small-molecule therapeutics. The complex structure of antibody-drug conjugates poses unique challenges to pharmacokinetic (PK) and pharmacodynamic (PD) characterization because it requires a quantitative understanding of the PK and PD properties of multiple different molecular species (eg, conjugate, total antibody, and unconjugated payload) in different tissues. Quantitative clinical pharmacology using mathematical modeling and simulation provides an excellent approach to overcome these challenges, as it can simultaneously integrate the disposition, PK, and PD of antibody-drug conjugates and their components in a quantitative manner. In this review, we highlight diverse quantitative clinical pharmacology approaches, ranging from system models (eg, physiologically based pharmacokinetic [PBPK] modeling) to mechanistic and empirical models (eg, population PK/PD modeling for single or multiple analytes, exposure-response modeling, platform modeling by pooling data across multiple antibody-drug conjugates). The impact of these PBPK and PK/PD models to provide insights into clinical dosing justification and inform drug development decisions is also highlighted.
MeSH term(s)	Computer Simulation ; Dose-Response Relationship, Drug ; Drug Development ; Drug Interactions ; Humans ; Immunoconjugates/pharmacokinetics ; Immunoconjugates/pharmacology ; Immunologic Factors/pharmacokinetics ; Immunologic Factors/pharmacology ; Models, Biological
Chemical Substances	Immunoconjugates ; Immunologic Factors
Language	English
Publishing date	2020-11-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.1720
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Article ; Online: Clinical pharmacology of vc-MMAE antibody-drug conjugates in cancer patients: learning from eight first-in-human Phase 1 studies.

Li, Chunze / Zhang, Cindy / Li, Zao / Samineni, Divya / Lu, Dan / Wang, Bei / Chen, Shang-Chiung / Zhang, Rong / Agarwal, Priya / Fine, Bernard M / Girish, Sandhya

mAbs

2020 Volume 12, Issue 1, Page(s) 1699768

Abstract: vc-MMAE antibody-drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile valine-citrulline (vc) linker. The objective of this study was to characterize the ... ...

Abstract	vc-MMAE antibody-drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile valine-citrulline (vc) linker. The objective of this study was to characterize the pharmacokinetics (PK) and explore exposure-response relationships of eight vc-MMAE ADCs, against different targets and for diverse tumor indications, using data from eight first-in-human Phase 1 studies. PK parameters of the three analytes, namely antibody-conjugated MMAE (acMMAE), total antibody, and unconjugated MMAE, were estimated using non-compartmental approaches and compared across the eight vc-MMAE ADCs. Relationships between analytes were assessed by linear regression. Exposure-response relationships were explored with key efficacy (objective response rate) and safety (Grade 2+ peripheral neuropathy) endpoints. PK profiles of acMMAE, total antibody and unconjugated MMAE following the first dose of 2.4 mg/kg were comparable across the eight ADCs; the exposure differences between molecules were small relative to the inter-subject variability. acMMAE exposure was strongly correlated with total antibody exposure for all the eight ADCs, but such correlation was less evident between acMMAE and unconjugated MMAE exposure. For multiple ADCs evaluated, efficacy and safety endpoints appeared to correlate well with acMMAE exposure, but not with unconjugated MMAE over the doses tested. PK of vc-MMAE ADCs was well characterized and demonstrated remarkable similarity at 2.4 mg/kg across the eight ADCs. Results from analyte correlation and exposure-response relationship analyses suggest that measurement of acMMAE analyte alone might be adequate for vc-MMAE ADCs to support the clinical pharmacology strategy used during late-stage clinical development.
MeSH term(s)	Antimitotic Agents ; Antineoplastic Agents, Immunological/pharmacokinetics ; Clinical Trials, Phase I as Topic ; Humans ; Immunoconjugates/pharmacokinetics ; Immunotherapy/methods ; Neoplasms/immunology ; Neoplasms/therapy
Chemical Substances	Antimitotic Agents ; Antineoplastic Agents, Immunological ; Immunoconjugates
Language	English
Publishing date	2020-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2537838-7
ISSN	1942-0870 ; 1942-0862
ISSN (online)	1942-0870
ISSN	1942-0862
DOI	10.1080/19420862.2019.1699768
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Article ; Online: A phase I study of pharmacokinetics of trastuzumab emtansine in Chinese patients with locally advanced inoperable or metastatic human epidermal growth factor receptor 2-positive breast cancer who have received prior trastuzumab-based therapy.

Ji, Dongmei / Shen, Weina / Zhang, Jian / Cao, Junning / Li, Wenhua / Lam, Lisa H / Wu, Fan / Wang, Bei / Li, Zao / Sun, Guofang / Hu, Xichun / Chen, Shang-Chiung

Medicine

2020 Volume 99, Issue 44, Page(s) e22886

Abstract: Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that retains the antitumor effects of trastuzumab while also delivering the cytotoxic antimicrotubule agent, DM1, directly to tumor cells that overexpress human epidermal growth ... ...

Abstract	Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that retains the antitumor effects of trastuzumab while also delivering the cytotoxic antimicrotubule agent, DM1, directly to tumor cells that overexpress human epidermal growth factor receptor 2. The pharmacokinetic (PK) profile of T-DM1 has been well characterized in Western, Asian, and Japanese patients; this single-center, phase I study (NCT03153163) examined the PK of T-DM1 and safety specifically in Chinese patients. Methods: Patients with locally advanced or metastatic breast cancer, previously treated with trastuzumab and a taxane, received open-label T-DM1 at 3.6 mg/kg every 3 weeks. Serum T-DM1 and total trastuzumab, and plasma DM1 were evaluated, and PK parameters were calculated using standard noncompartmental approaches. Adverse events (AEs) were assessed, and immunogenicity was evaluated by measuring antidrug antibodies to T-DM1. Results: Among 11 Chinese patients, mean (±standard deviation) PK parameters (maximum serum concentration, 77.6 ± 17.4 μg/mL; clearance 11.0 ± 2.6 mL/d/kg; terminal half-life 3.8 ± 1.0 days) were similar to those previously reported in Western and Japanese patients. One patient transiently developed antidrug antibodies, which did not appear to influence safety or PK. T-DM1 was generally well tolerated. Grade 3-4 AEs occurred in 7 patients (63.6%) and serious AEs occurred in 4 patients (36.4%). Platelet count decrease was the most common all-grade AE (10/11; 90.9%), grade 3-4 AE (5/11; 45.5%), and serious AE (3/11; 27.3%), but did not appear to be associated with any clinically significant bleeding events. Conclusions: T-DM1 PK in Chinese patients was consistent with those in global and Asian populations, supporting its use in patients with advanced human epidermal growth factor receptor 2-positive breast cancer following progression on trastuzumab and a taxane. The safety profile of T-DM1 was consistent with prior experience.
MeSH term(s)	Antineoplastic Agents, Immunological/administration & dosage ; Antineoplastic Agents, Immunological/adverse effects ; Antineoplastic Agents, Immunological/pharmacokinetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/immunology ; Breast Neoplasms/pathology ; China ; Drug Monitoring/methods ; Female ; Humans ; Middle Aged ; Neoplasm Staging ; Receptor, ErbB-2/analysis ; Trastuzumab/administration & dosage ; Trastuzumab/adverse effects ; Trastuzumab/pharmacokinetics ; Treatment Outcome
Chemical Substances	Antineoplastic Agents, Immunological ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK)
Language	English
Publishing date	2020-11-24
Publishing country	United States
Document type	Clinical Trial ; Clinical Trial, Phase I ; Journal Article
ZDB-ID	80184-7
ISSN	1536-5964 ; 0025-7974
ISSN (online)	1536-5964
ISSN	0025-7974
DOI	10.1097/MD.0000000000022886
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Article ; Online: Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC).

Chen, Shang-Chiung / Kagedal, Matts / Gao, Yuying / Wang, Bei / Harle-Yge, Marie-Laurence / Girish, Sandhya / Jin, Jin / Li, Chunze

Cancer chemotherapy and pharmacology

2017 Volume 80, Issue 6, Page(s) 1147–1159

Abstract: Purpose: Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T- ...

Abstract	Purpose: Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T-DM1 PK and evaluate the impact of patient characteristics on T-DM1 PK in previously treated patients with HER2-positive advanced gastric cancer (AGC). Methods: Following T-DM1 weekly or every three weeks dosing, T-DM1 concentration measurements (n = 780) were collected from 136 patients in the GATSBY (NCT01641939) study and analyzed using nonlinear mixed effects modeling. The influence of demographic, baseline laboratory, and disease characteristics on T-DM1 PK was examined. Results: T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment. The final population model estimated linear clearance (CL) of 0.79 L/day, volume of distribution in the central compartment (V Conclusions: In a HER2-positive AGC population, T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Baseline body weight and trastuzumab concentration were identified as significant covariates for T-DM1 PK in a HER2-positive AGC population.
Language	English
Publishing date	2017-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-017-3443-1
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Article ; Online: Correction to: Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC).

Chen, Shang-Chiung / Kagedal, Matts / Gao, Yuying / Wang, Bei / Harle-Yge, Marie-Laurence / Girish, Sandhya / Jin, Jin / Li, Chunze

Cancer chemotherapy and pharmacology

2017 Volume 81, Issue 2, Page(s) 421–422

Abstract: The online version of the original article can be. ...

Abstract	The online version of the original article can be.
Language	English
Publishing date	2017-12-11
Publishing country	Germany
Document type	Journal Article ; Published Erratum
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-017-3488-1
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Article ; Online: Pharmacokinetics of trastuzumab emtansine (T-DM1) as a single agent or in combination with pertuzumab in HER2-positive breast cancer patients with recurrent or locally advanced metastatic breast cancer.

Lu, Dan / Li, Chunze / Riggs, Matthew / Polhamus, Daniel / French, Jonathan / Agarwal, Priya / Chen, Shang-Chiung / Vadhavkar, Shweta / Patre, Monika / Strasak, Alexander / Quartino, Angelica / Jin, Jin Yan / Girish, Sandhya

Cancer chemotherapy and pharmacology

2019 Volume 84, Issue 1, Page(s) 175–185

Abstract: 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). ... ...

Abstract	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 C 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.
MeSH term(s)	Ado-Trastuzumab Emtansine/administration & dosage ; Ado-Trastuzumab Emtansine/pharmacokinetics ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antineoplastic Agents, Immunological/administration & dosage ; Antineoplastic Agents, Immunological/pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Area Under Curve ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Drug Interactions ; Female ; Humans ; Models, Biological ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Receptor, ErbB-2/metabolism
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antineoplastic Agents, Immunological ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; pertuzumab (K16AIQ8CTM) ; Ado-Trastuzumab Emtansine (SE2KH7T06F)
Language	English
Publishing date	2019-05-17
Publishing country	Germany
Document type	Clinical Trial, Phase III ; Comparative Study ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-019-03852-z
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Article: Nano-scale liquid chromatography/mass spectrometry and on-the-fly orthogonal array optimization for quantification of therapeutic monoclonal antibodies and the application in preclinical analysis

Duan, Xiaotao / Dai, Lipeng / Chen, Shang-Chiung / Balthasar, Joseph P / Qu, Jun

Journal of chromatography. 2012 Aug. 17, v. 1251

2012

Abstract: Therapeutic monoclonal antibodies (mAbs) constitute a group of highly effective agents for treating various refractory diseases. Nonetheless it is challenging to achieve selective and accurate quantification of mAb in pharmaceutical matrices, which is ... ...

Abstract	Therapeutic monoclonal antibodies (mAbs) constitute a group of highly effective agents for treating various refractory diseases. Nonetheless it is challenging to achieve selective and accurate quantification of mAb in pharmaceutical matrices, which is required by PK studies. Liquid chromatography/mass spectrometry under selected reaction monitoring mode (LC/SRM-MS) is emerging as an attractive alternative to immunoassays because of the high specificity and multiplexing capacity it provides, but may fall short in terms of sensitivity, reliability and quantitative accuracy. Moreover, the strategy for optimization of the MS conditions for many candidates of signature peptides (SP) and the selection of the optimal SP for quantification remains elusive. In this study, we employed a suite of technical advances to overcome these difficulties, which include: (i) a nano-LC/SRM-MS approach to achieve high analytical sensitivity, (ii) a high-resolution nano-LC/LTQ/Orbitrap for confident identification of candidate peptides, (iii) an on-the-fly orthogonal array optimization (OAO) method for the high-throughput, accurate and reproducible optimization for numerous candidate peptides in a single LC/MS run without using synthesized peptides, (iv) a comprehensive evaluation of stability of candidates in matrix using the optimized SRM parameters, (v) the use of two unique SP for quantification of one mAb to gauge possible degradation/modification in biological system and thus enhancing data reliability (e.g. rejection of data if the deviation between the two SP is greater than 25%) and (vi) the utilization of purified target protein as the calibrator to eliminate the risk of severe negative biases that could occur when a synthesized peptide is used as calibrator. To show a proof of concept, this strategy is applied in the quantification of cT84.66, a chimeric, anti-CEA antibody, in preclinical mouse models. A low detection limit of the mAb down to 3.2ng/mL was achieved, which is substantially more sensitive than established immunoassay methods for anti-CEA antibodies. The quantitative method showed good linearity (within the range of 12.9ng/mL to 32.3μg/mL in plasma), accuracy and precision. Additionally, the ultra-low sample consumption (2μL plasma per preparation) permits the acquisition of an entire set of time course data from the same mouse, which represents a prominent advantage for PK study using small-animal models. The developed method enabled an accurate PK investigation of cT84.66 in mice following intravenous and subcutaneous administrations at relatively low doses over an extended period of time. The strategy employed in this study can be easily adapted to the sensitive and accurate analysis of other mAb and therapeutic proteins.
Keywords	animal models ; biopharmaceuticals ; chimerism ; detection limit ; immunoassays ; intravenous injection ; liquid chromatography ; mass spectrometry ; mice ; monitoring ; monoclonal antibodies ; peptides ; risk
Language	English
Dates of publication	2012-0817
Size	p. 63-73.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	218139-3
ISSN	0021-9673 ; 0378-4355 ; 0376-737X
ISSN	0021-9673 ; 0378-4355 ; 0376-737X
DOI	10.1016/j.chroma.2012.06.007
Database	NAL-Catalogue (AGRICOLA)

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