Population Pharmacokinetic Analysis of Lanreotide Autogel®/Depot in the Treatment of Neuroendocrine Tumors: Pooled Analysis of Four Clinical Trials

Buil-Bruna, Núria; Garrido, María J.; Dehez, Marion; Manon, Amandine; Nguyen, Thi Xuan Quyen; Gomez-Panzani, Edda; Trocóniz, Iñaki F.

doi:10.1007/s40262-015-0329-4

Cited by 9 publications

(6 citation statements)

References 14 publications

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“…1b successfully described LAN time profiles, CgA dynamics, and PFS. LAN concentrations were adequately described by the population PK model (23). The estimated half-life of LAN was 0.59 h, and the model predicted trough (predose) value (2.5th-97.5th prediction intervals corresponding to the 120-mg dose administered subcutaneously every 4 weeks) was 6 (3-11) ng/mL.…”

Section: Model Evaluationmentioning

confidence: 92%

“…The LAN pharmacokinetic properties were characterized as part of a pooled analysis of four clinical trial including patients with functioning and nonfunctioning GEP-NETs (23). The popPK model selected consisted on a onecompartment disposition model with an absorption process characterized by two parallel absorption pathways, following first-and zero-order kinetics, and was used to predict the corresponding serum profiles in LAN to develop the models for CgA dynamics and PFS using the model parameters represented in Supplementary Table S1.…”

Section: Lanreotide Pharmacokineticsmentioning

confidence: 99%

“…As shown in ref. (23), the selected population pharmacokinetic model provided a good descript of the concentrations vs. time data (non-and steady state).…”

Section: Model Evaluationmentioning

confidence: 99%

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Establishing the Quantitative Relationship Between Lanreotide Autogel®, Chromogranin A, and Progression-Free Survival in Patients with Nonfunctioning Gastroenteropancreatic Neuroendocrine Tumors

Buil-Bruna

Dehez

Manon

et al. 2016

AAPS J

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The objective of this work was to establish the quantitative relationship between Lanreotide Autogel® (LAN) on serum chromogranin A (CgA) and progression-free survival (PFS) in patients with nonfunctioning gastroenteropancreatic neuroendocrine tumors (GEP-NETs) through an integrated pharmacokinetic/pharmacodynamic (PK/PD) model. In CLARINET, a phase III, randomized, double-blind, placebo-controlled study, 204 patients received deep subcutaneous injections of LAN 120 mg (n = 101) or placebo (n = 103) every 4 weeks for 96 weeks. Data for 810 LAN and 1298 CgA serum samples (n = 632 placebo and n = 666 LAN) were used to develop a parametric time-to-event model to relate CgA levels and PFS (76 patients experienced disease progression: n = 49 placebo and n = 27 LAN). LAN serum profiles were described by a one-compartment disposition model. Absorption was characterized by two parallel pathways following first- and zero-order kinetics. As PFS data were considered informative dropouts, CgA and PFS responses were modeled jointly. The LAN-induced decrease in CgA levels was described by an inhibitory E MAX model. Patient age and target lesions at baseline were associated with an increment in baseline CgA. Weibull model distribution showed that decreases in CgA from baseline reduced the hazard of disease progression significantly (P < 0.001). Covariates of tumor location in the pancreas and tumor hepatic tumor load were associated with worse prognosis (P < 0.001). We established a semimechanistic PK/PD model to better understand the effect of LAN on a surrogate endpoint (serum CgA) and ultimately the clinical endpoint (PFS) in treatment-naive patients with nonfunctioning GEP-NETs.

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Section: Model Evaluationmentioning

confidence: 92%

Section: Lanreotide Pharmacokineticsmentioning

confidence: 99%

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Establishing the Quantitative Relationship Between Lanreotide Autogel®, Chromogranin A, and Progression-Free Survival in Patients with Nonfunctioning Gastroenteropancreatic Neuroendocrine Tumors

Buil-Bruna

Dehez

Manon

et al. 2016

AAPS J

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“…However, the effect of any other systemic therapy could be ruled out since these patients were not included. In addition, from in vitro studies it is known that SSA inhibits cell growth within a short period of time and pharmacokinetic studies with humans revealed similar results [47, 48]. A control collective would be desirable.…”

Section: Discussionmentioning

confidence: 99%

Treatment with somatostatin analogs induces differentially expressed let-7c-5p and mir-3137 in small intestine neuroendocrine tumors

et al. 2019

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Background Distant metastases frequently occur in gastroenteropancreatic neuroendocrine tumors. If hepatic surgery is not feasible, patients are treated with somatostatin analogs. However, the underlying mechanisms of action of this treatment remain to be defined. The aim of the present study was to analyze the micro-RNA expression profile inter-individually before and after the treatment with somatostatin analogs. Material and methods Tumor specimens of all included patients ( n = 8) before and after the onset of a therapy with somatostatin analogs were analyzed and a micro-RNA expression profile (754 micro-RNAs) of each probe was generated. This analysis in an intra-individual setting was selected to avoid bias from inter-individual differences. The micro-RNA expression profiles were validated by qPCR. Patients with any other systemic treatment were excluded from the present study. Results Eight patients were included in the present study of which all had neuroendocrine tumors of the small intestine with diffuse hepatic metastases. Grouped analyses revealed that 15 micro-RNAs were differentially expressed (3 up- and 12 downregulated) after the exposure to somatostatin analogs. Additionally, let-7c-5p and mir-3137 are concordantly regulated in the inter-individually analysis. Conclusions This is the first study analyzing the individual micro-RNA expression profile before and after a therapy with somatostatin analogs. Data from this study reveal that somatostatin analogs may in part exert their beneficial effects through an alteration in the micro-RNA expression profile.

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“…The absorption model used to estimate the corresponding absorption parameters allowing afterwards computation of metrics is represented in the work from [ 3 ] and comprises three non-simultaneous absorption mechanisms, two of them following 1 st order kinetics and the third one following a 0 th order process. This model is considered of a sufficient complexity to deal with almost any absorption profile that can take place after administration of SR formulations [ 16 , 17 ]. A schematic representation of the structural model with the corresponding ordinary differential equations is provided in S1 Fig .…”

Section: Methodsmentioning

confidence: 99%

Optimal dynamic control approach in a multi-objective therapeutic scenario: Application to drug delivery in the treatment of prostate cancer

et al. 2018

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Numerous problems encountered in computational biology can be formulated as optimization problems. In this context, optimization of drug release characteristics or dosing schedules for anticancer agents has become a prominent area not only for the development of new drugs, but also for established drugs. However, in complex systems, optimization of drug exposure is not a trivial task and cannot be efficiently addressed through trial-error simulation exercises. Finding a solution to those problems is a challenging task which requires more advanced strategies like optimal control theory. In this work, we perform an optimal control analysis on a previously developed computational model for the testosterone effects of triptorelin in prostate cancer patients with the goal of finding optimal drug-release characteristics. We demonstrate how numerical control optimization of non-linear models can be used to find better therapeutic approaches in order to improve the final outcome of the patients.

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Population Pharmacokinetic Analysis of Lanreotide Autogel®/Depot in the Treatment of Neuroendocrine Tumors: Pooled Analysis of Four Clinical Trials

Abstract: Using two mechanisms of absorption, the pharmacokinetics of lanreotide Autogel were well-described in patients with GEP-NET. None of the patient characteristics tested were of clinical relevance to potential dose adjustment in clinical practice.

Cited by 9 publications

References 14 publications

Establishing the Quantitative Relationship Between Lanreotide Autogel®, Chromogranin A, and Progression-Free Survival in Patients with Nonfunctioning Gastroenteropancreatic Neuroendocrine Tumors

Establishing the Quantitative Relationship Between Lanreotide Autogel®, Chromogranin A, and Progression-Free Survival in Patients with Nonfunctioning Gastroenteropancreatic Neuroendocrine Tumors

Treatment with somatostatin analogs induces differentially expressed let-7c-5p and mir-3137 in small intestine neuroendocrine tumors

Optimal dynamic control approach in a multi-objective therapeutic scenario: Application to drug delivery in the treatment of prostate cancer

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