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Population pharmaco...
Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors.
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Schmidt, Keith T (författare)
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Huitema, Alwin D R (författare)
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- Dorlo, Thomas P C (författare)
- Netherlands Cancer Institute
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Peer, Cody J (författare)
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Cordes, Lisa M (författare)
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Sciuto, Linda (författare)
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Wroblewski, Susan (författare)
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Pommier, Yves (författare)
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Madan, Ravi A (författare)
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Thomas, Anish (författare)
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Figg, William D (författare)
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(creator_code:org_t)
- 2020-09-08
- 2020
- Engelska.
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 86:4, s. 475-486
- Relaterad länk:
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https://link.springe...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
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- PURPOSE: NLG207 (formerly CRLX101) is a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model.METHODS: From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling.RESULTS: The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%).CONCLUSION: The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- Drug release
- NLMEM
- Nanoparticle
- Population pharmacokinetics
- Topoisomerase I
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- art (ämneskategori)
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- Av författaren/redakt...
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Schmidt, Keith T
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Huitema, Alwin D ...
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Dorlo, Thomas P ...
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Peer, Cody J
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Cordes, Lisa M
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Sciuto, Linda
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visa fler...
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Wroblewski, Susa ...
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Pommier, Yves
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Madan, Ravi A
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Thomas, Anish
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Figg, William D
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visa färre...
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