Intra-monocyte Pharmacokinetics of Imiglucerase Supports a Possible Personalized Management of Gaucher Disease Type 1

Berger, Juliette; Vigan, Marie; Pereira, Bruno; Nguyễn, Thu Thủy; Froissart, Roseline; Belmatoug, Nadia; Dalbiès, Florence; Masseau, A.; Rosé, Christian; Serratrice, J.; Pers, Yves-Marie; Bertchansky, Ivan; Camou, Fabrice; Bengherbia, Monia; Bourgne, Céline; Caillaud, Catherine; Pettazzoni, Magali; Berrahal, Amina; Stirnemann, Jérôme; Mentré, France; Berger, Marc

doi:10.1007/s40262-018-0708-8

Cited by 6 publications

(4 citation statements)

References 53 publications

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“…Plasma and leukocyte GBA 1 half‐lives were 0.48 and 3.42 hours, respectively, which are in agreement with previous estimations of GBA 1 in plasma 35,36 . A GCase half‐life of 8.6 hours has been described using a population PK/PD model in blood monocytes 22 . Previous studies in rats indicate that after ERT administration, 54,55 enzyme activity decreases rapidly in plasma, since it is bound by the mannose‐6‐phosphate receptors of the monocyte–macrophage system with a biphasic decay with short t 1/2 of 45 minutes in serum 56 .…”

Section: Discusionsupporting

confidence: 89%

“…35,36 A GCase half-life of 8.6 hours has been described using a population PK/PD model in blood monocytes. 22 Previous studies in rats indicate that after ERT administration, 54,55 receptors of the monocyte-macrophage system with a biphasic decay with short t 1/2 of 45 minutes in serum. 56 Additionally, this rapid decrease of GBA 1 could be explained by regular proteolytic breakdown in lysosomes.…”

Section: Efficacy Count Data Modellingmentioning

confidence: 99%

“…[16][17][18] Pharmacokinetic-biomarker analyses based on GCase activity in leukocytes have demonstrated a good correlation with clinical response to ERT [19][20][21] and a pharmacokinetic/pharmacodynamic (PK/PD) model in intra-monocyte GBA 1 data allowed better understanding of its properties. 22 Moreover, ERT is effective in improving bone marrow involvement, but no exposure-response relationship of ERT in bone marrow has been established so far. 23,24 The relationship between GCase activity and clinical response to ERT, defined by Pastores criteria, only measures pain grade as bone involvement.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative assessment of the exposure–efficacy relationship of glucocerebrosidase using Markovian elements in Gaucher patients treated with enzyme replacement therapy

Gras-Colomer

Mangas‐Sanjuán

Martínez‐Gómez

et al. 2022

Brit J Clinical Pharma

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The aims of this study are (i) to develop a population pharmacokinetic model of enzyme activity in Gaucher-type 1 (GD1) patients after intravenous administration of enzyme replacement therapy (ERT), and (ii) to establish an exposure-efficacy relationship for bone marrow infiltration to propose dose adjustments according to patient covariate values.Methods: A prospective follow-up, semi-experimental multi-centre study was conducted in four hospitals to evaluate the pharmacokinetics, efficacy and safety of ERT in GD1 patients. Twenty-five individuals with 266 glucocerebrosidase (GCase) observations in plasma and leukocytes and 14 individuals with 68 Spanish magnetic resonance imaging (S-MRI) observations were enrolled. Results: A two concatenated compartment model with zero-order endogenous production and first-order distribution (CL 1 = 3.85 Â 10 À1 L/d) and elimination (CL 2 = 1.25 L/d) allowed GCase observations in plasma and leukocytes to be described, respectively. An exponential time dependency (k T = 6.14 Â 10 À1 d À1 ) effect on CL 1 was incorporated. The final exposure-efficacy model was a longitudinal logistic regression model with a first-order Markov element. An E max function (EC 50 = 15.73 U/L and E max = 2.33) linked steady-state concentrations of GCase in leukocytes to the probability of transition across the different S-MRI stages. Conclusion: A population pharmacokinetic model successfully characterized the leukocyte activity-time profiles of GCase following intravenous administration of ERT in GD1 patients together with an exposure-efficacy relationship in bone marrow using Markovian elements. The information obtained from this study could be of high clinical relevance in individualization of ERT in GD1 patients, as this could lead to anticipative decision-making regarding clinical response in bone and optimal dosing strategy.The authors confirm that the Principal Investigator for this paper is Elena Gras-Colomer and that she had direct clinical responsibility for patients.

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Section: Discusionsupporting

confidence: 89%

Section: Efficacy Count Data Modellingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantitative assessment of the exposure–efficacy relationship of glucocerebrosidase using Markovian elements in Gaucher patients treated with enzyme replacement therapy

Gras-Colomer

Mangas‐Sanjuán

Martínez‐Gómez

et al. 2022

Brit J Clinical Pharma

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“…tissues; the second phase is slower and associated with the elimination of the drug [45]. The twophase decay model is typical for certain types of drug administration, such as IP and IV [46][47][48], where the elimination half-life is given by the slow phase rather than the time it takes the plasma concentration to reach 50% of the administered dose as in a simpler one-phase decay model [45]. Our data show that the rate of biological elimination for N-TIMP2-PAT200 is significantly slower than that of N-TIMP2 (p<0.0001); the halflife was extended approximately 3.5-fold, from 2.5 hours to 8.5 hours for the N-TIMP2-PAT200.…”

Section: Measurement Of N-timp2 Construct Half-life In Micementioning

confidence: 99%

Improving Circulation Half-Life of Therapeutic Candidate N-TIMP2 by Unfolded Peptide Extension

Shirian,

Hockla,

Gleba

et al. 2024

Preprint

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Matrix Metalloproteinases (MMPs) are drivers of many diseases including cancer and are established targets for drug development. Tissue inhibitors of metalloproteinases (TIMPs) are human proteins that inhibit MMPs and are being pursued for the development of anti-MMP therapeutics. TIMPs possess many attractive properties of a drug candidate, such as complete MMP inhibition, low toxicity and immunogenicity, high tissue permeability and others. A major challenge with TIMPs, however, is their formulation and delivery, as these proteins are quickly cleared from the bloodstream due to their small size. In this study, we explore a new method for plasma half-life extension for the N-terminal domain of TIMP2 (N-TIMP2) through appending it with a long intrinsically unfolded tail containing a random combination of Pro, Ala, and Thr (PATylation). We design, produce and explore two PATylated N-TIMP2 constructs with a tail length of 100- and 200-amino acids (N-TIMP2-PAT100and N-TIMP2-PAT200, respectively). We demonstrate that both PATylated N-TIMP2 constructs possess apparent higher molecular weights compared to the wild-type protein and retain high inhibitory activity against MMP-9. Furthermore, when injected into mice, N-TIMP2-PAT200exhibited a significant increase in plasma half-life compared to the non-PATylated variant, enhancing the therapeutic potential of the protein. Thus, we establish that PATylation could be successfully applied to TIMP-based therapeutics and offers distinct advantages as an approach for half-life extension, such as fully genetic encoding of the gene construct, mono-dispersion, and biodegradability. Furthermore, PATylation could be easily applied to N-TIMP2 variants engineered to possess high affinity and selectivity toward individual MMP family members, thus creating attractive candidates for drug development against MMP-related diseases.

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Manifestaciones osteoarticulares de las esfingolipidosis en adultos

Chalès

Guggenbuhl

Cador-Rousseau

et al. 2020

EMC - Aparato Locomotor

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Intra-monocyte Pharmacokinetics of Imiglucerase Supports a Possible Personalized Management of Gaucher Disease Type 1

Cited by 6 publications

References 53 publications

Quantitative assessment of the exposure–efficacy relationship of glucocerebrosidase using Markovian elements in Gaucher patients treated with enzyme replacement therapy

Quantitative assessment of the exposure–efficacy relationship of glucocerebrosidase using Markovian elements in Gaucher patients treated with enzyme replacement therapy

Improving Circulation Half-Life of Therapeutic Candidate N-TIMP2 by Unfolded Peptide Extension

Manifestaciones osteoarticulares de las esfingolipidosis en adultos

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