34 results on '"De Meulder M"'
Search Results
2. Development and validation of a liquid chromatographic–tandem mass spectrometric method for the determination of galantamine in human heparinised plasma
- Author
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Verhaeghe, T, Diels, L, de Vries, R, De Meulder, M, and de Jong, J
- Published
- 2003
- Full Text
- View/download PDF
3. Antiviral and lung protective activity of a novel RSV fusion inhibitor in a mouse model
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Olszewska, W., Ispas, G., Schnoeller, C., Sawant, D., van de Casteele, T., Nauwelaers, D., van Kerckhove, B., Roymans, D., de Meulder, M., Rouan, M.C., van Remoortere, P., Bonfanti, J.F., van Velsen, F., Koul, A, Vanstockem, M., Andries, Koen, Sowinski, P., Wang, B., Openshaw, P., and Verloes, R.
- Subjects
Pharmacology. Therapy - Abstract
Respiratory syncytial virus (RSV) causes bronchiolitis in young children and common colds in adults. There is no licensed vaccine, and prophylactic treatment with palivizumab is very expensive and limited to high risk infants. Ribavirin is used as an antiviral treatment in infants and immunosuppressed patients, and its use is limited due to side effects, toxicity to the recipient and staff and evidence of marginal clinical efficacy. We therefore studied the in vivo kinetics, antiviral and protective properties of a novel candidate for RSV disease treatment. The drug is a small molecule (TMC353121) discovered by screening for fusion inhibitory properties against RSV in a cellular infection model. The pharmacokinetics of TMC353121 was studied in BALB/c mice and antiviral effects determined by testing viral loads in lung tissue by quantitative RT-PCR and plaque assay after intranasal RSV infection. At doses between 0.2510 mg·kg−1, TMC353121 significantly reduced viral load, BAL cell accumulation and the severity of lung histopathological change after infection. Treatment remained effective if started within 48 hours post-infection, but was ineffective thereafter. Therefore, TMC353121 is a novel potent antiviral drug, in vivo reducing RSV replication and inhibiting consequential lung inflammation, with a great potential for further clinical development.
- Published
- 2011
4. Toelichting Erkenning Vlaamse Gebarentaal. Document toegevoegd aan de petitie waarin gevraagd wordt om de erkenning van de Vlaamse Gebarentaal
- Author
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Adriaenssens, J., De Meulder, M., Smessaert, I., Van Herreweghe, M., Van Mulders, K., Vermeerbergen, Myriam, Heyerick, I., Verstraete, F., Centre for Linguistics, and Vrije Universiteit Brussel
- Published
- 2005
5. Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model
- Author
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Olszewska, W., primary, Ispas, G., additional, Schnoeller, C., additional, Sawant, D., additional, Van de Casteele, T., additional, Nauwelaers, D., additional, Van Kerckhove, B., additional, Roymans, D., additional, De Meulder, M., additional, Rouan, M. C., additional, Van Remoortere, P., additional, Bonfanti, J. F., additional, Van Velsen, F., additional, Koul, A., additional, Vanstockem, M., additional, Andries, K., additional, Sowinski, P., additional, Wang, B., additional, Openshaw, P., additional, and Verloes, R., additional
- Published
- 2010
- Full Text
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6. Effect of Carbamazepine on the Pharmacokinetics of Erdafitinib in Healthy Participants.
- Author
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Jaiprasart P, Hellemans P, Jiao JJ, Dosne AG, De Meulder M, De Zwart L, Brees L, and Zhu W
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- Humans, Adult, Male, Female, Young Adult, Middle Aged, Cytochrome P-450 CYP3A Inducers pharmacology, Cytochrome P-450 CYP2C9 metabolism, Pyrazoles pharmacokinetics, Pyrazoles adverse effects, Pyrazoles administration & dosage, Pyrazoles pharmacology, Quinoxalines pharmacokinetics, Quinoxalines adverse effects, Quinoxalines administration & dosage, Quinoxalines pharmacology, Administration, Oral, Receptors, Fibroblast Growth Factor antagonists & inhibitors, Drug Interactions, Healthy Volunteers, Carbamazepine pharmacology, Carbamazepine pharmacokinetics, Carbamazepine administration & dosage, Area Under Curve, Cytochrome P-450 CYP3A metabolism
- Abstract
Erdafitinib, a selective and potent oral pan-FGFR inhibitor, is metabolized mainly through CYP2C9 and CYP3A4 enzymes. This phase 1, open-label, single-sequence, drug-drug interaction study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of erdafitinib alone and when co-administered with steady state oral carbamazepine, a dual inducer of CYP3A4 and CYP2C9, in 13 healthy adult participants (NCT04330248). Compared with erdafitinib administration alone, carbamazepine co-administration decreased total and free maximum plasma concentrations of erdafitinib (C
max ) by 35% (95% CI 30%-39%) and 22% (95% CI 17%-27%), respectively. The areas under the concentration-time curve over the time interval from 0 to 168 hours, to the last quantifiable data point, and to time infinity (AUC168h , AUClast , AUCinf ), were markedly decreased for both total erdafitinib (56%-62%) and free erdafitinib (48%-55%). The safety profile of erdafitinib was consistent with previous clinical studies in healthy participants, with no new safety concerns when administered with or without carbamazepine. Co-administration with carbamazepine may reduce the activity of erdafitinib due to reduced exposure. Concomitant use of strong CYP3A4 inducers with erdafitinib should be avoided., (© 2024 Janssen Research & Development, LLC. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)- Published
- 2024
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7. Effect of Erdafitinib on the Pharmacokinetics of Midazolam and Metformin in Patients With Advanced Solid Tumors Harboring FGFR Gene Alterations.
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Zhu W, Baig M, Naini V, De Meulder M, Akapame S, De Zwart L, Haddish-Berhane N, and Triantos S
- Abstract
Erdafitinib, an oral pan-FGFR inhibitor, is used in locally advanced or metastatic urothelial carcinoma for adults with FGFR3 genetic alterations and whose disease progressed following prior systemic therapy. This drug-drug interaction substudy evaluated the effect of erdafitinib on the pharmacokinetics of midazolam (cytochrome P450 3A4 substrate), and metformin (organic cation transporter 2 substrate). Twenty-five patients with advanced solid tumors harboring FGFR gene alterations received pretreatment with single doses of midazolam and metformin, followed by a daily dose of erdafitinib. Drug-drug interaction assessments were performed at erdafitinib steady state following coadministration of single doses of midazolam and metformin, respectively. Geometric mean ratios for maximum plasma concentration and area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, and AUC from time 0 to infinity were estimated using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). The 90% confidence intervals of geometric mean ratios for maximum plasma concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity of midazolam (86.3%, 88.5%, and 82.1%), 1-OH midazolam (99.8%, 97.4%, and 101.5%), and metformin (108.7%, 119.0%, and 113.9%) were either contained or slightly outside the 80%-125% interval and not considered clinically meaningful. Adverse events were consistent with the known erdafitinib safety profile; no new safety signals emerged. Thus, repeated dosing of erdafitinib had no clinically meaningful effect on the pharmacokinetics of midazolam or metformin., (© 2024 Janssen Research & Development, LLC. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
- Published
- 2024
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8. Correction to: Pharmacokinetics of Nasal Esketamine in Patients with Allergic Rhinitis with and Without Nasal Decongestant Pretreatment and in Healthy Subjects with and Without Nasal Corticosteroid Pretreatment.
- Author
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Zannikos P, Solanki B, De Meulder M, Badorrek P, Hohlfeld JM, and Singh J
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- 2023
- Full Text
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9. Pharmacokinetics of Nasal Esketamine in Patients with Allergic Rhinitis with and Without Nasal Decongestant Pretreatment and in Healthy Subjects with and Without Nasal Corticosteroid Pretreatment.
- Author
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Zannikos P, Solanki B, De Meulder M, Badorrek P, Hohlfeld JM, and Singh J
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- Adult, Humans, Administration, Intranasal, Adrenal Cortex Hormones, Double-Blind Method, Healthy Volunteers, Mometasone Furoate, Nasal Decongestants, Nasal Sprays, Oxymetazoline pharmacokinetics, Depressive Disorder, Major, Rhinitis, Allergic drug therapy
- Abstract
Background and Objectives: Nasal esketamine is indicated for the treatment of adults with treatment-resistant depression and depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Primary objectives of this study were to evaluate the effect of nasal decongestant pretreatment in patients with allergic rhinitis and the impact of daily nasal corticosteroid administration by healthy subjects on nasal esketamine pharmacokinetics., Methods: Patients with allergic rhinitis self-administered 56 mg of nasal esketamine after pretreatment with nasal oxymetazoline (0.05%) at 1 h before esketamine and without oxymetazoline pretreatment. They were exposed to grass pollen in an allergen challenge chamber to induce allergic rhinitis symptoms at approximately 2 h before each esketamine administration until 1 h after. Healthy subjects self-administered esketamine (56 mg) before and after administration for 16 consecutive days of mometasone (200 µg), with the second esketamine dose administered 1 h after the last mometasone dose. The plasma pharmacokinetics of esketamine and noresketamine were assessed after each esketamine administration. The tolerability of esketamine, including effects on dissociative and potential psychotomimetic symptoms and level of sedation and suicidal ideation and behavior, was evaluated., Results: The rate of esketamine absorption was slightly greater in patients exhibiting symptoms of allergic rhinitis (decrease in median t
max from 32 min to 22 min). Increases in esketamine Cmax and AUC were also small (mean, ≤ 21%). The pharmacokinetics of esketamine was not affected by oxymetazoline or mometasone pretreatment. Esketamine was well tolerated when it was administered with or without pretreatment of oxymetazoline or mometasone., Conclusions: Patients exhibiting symptoms of rhinitis may receive nasal esketamine spray without dose adjustment. In addition, esketamine may be administered 1 h after using a nasal decongestant or corticosteroid., Trial Registration: The study was registered in the Clinical Trials (NCT02154334) and EudraCT (2014-000534-38) registries., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)- Published
- 2023
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10. Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE).
- Author
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Saad F, Chi KN, Shore ND, Graff JN, Posadas EM, Lattouf JB, Espina BM, Zhu E, Yu A, Hazra A, De Meulder M, Mamidi RNVS, Bradic B, Francis P, Hayreh V, and Rezazadeh Kalebasty A
- Subjects
- Aged, Aged, 80 and over, Androstenes therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Humans, Indazoles therapeutic use, Male, Middle Aged, Piperidines therapeutic use, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Prednisone therapeutic use, Prostatic Neoplasms, Castration-Resistant metabolism, Thiohydantoins therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Indazoles adverse effects, Indazoles pharmacokinetics, Piperidines adverse effects, Piperidines pharmacokinetics, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Poly(ADP-ribose) Polymerase Inhibitors pharmacokinetics, Prostatic Neoplasms, Castration-Resistant drug therapy, Receptors, Androgen metabolism
- Abstract
Purpose: To assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: BEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer., Results: Thirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib-apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation., Conclusions: These results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib-AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC., Trial Registration No: NCT02924766 (ClinicalTrials.gov).
- Published
- 2021
- Full Text
- View/download PDF
11. Population Pharmacokinetics of Paliperidone Palmitate (Once-Monthly Formulation) in Japanese, Korean, and Taiwanese Patients With Schizophrenia.
- Author
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Shimizu H, Neyens M, De Meulder M, Gopal S, Tsukamoto Y, Samtani MN, and Remmerie B
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- Adult, Aged, Antipsychotic Agents administration & dosage, Antipsychotic Agents blood, Antipsychotic Agents therapeutic use, Body Mass Index, Case-Control Studies, Dopamine D2 Receptor Antagonists, Female, Half-Life, Humans, Injections, Intramuscular, Japan epidemiology, Male, Middle Aged, Paliperidone Palmitate administration & dosage, Paliperidone Palmitate blood, Paliperidone Palmitate therapeutic use, Predictive Value of Tests, Republic of Korea epidemiology, Serotonin 5-HT2 Receptor Antagonists, Taiwan epidemiology, Treatment Outcome, Antipsychotic Agents pharmacokinetics, Paliperidone Palmitate pharmacokinetics, Schizophrenia drug therapy
- Abstract
The paliperidone pharmacokinetics after intramuscular administration of once-monthly paliperidone palmitate in Japanese patients were studied in 3 phase 1 studies and in 2 phase 3 studies performed in Japan, Korea, and Taiwan. These data (Japanese, n = 509; Korean, n = 31; Taiwanese, n = 47) were used to describe the paliperidone palmitate pharmacokinetics in Japanese, to compare with non-Japanese, and to validate the historical population pharmacokinetic (Pop-PK) model for paliperidone palmitate, developed using data from studies in patients with schizophrenia outside Japan. The final historical Pop-PK model, including all significant patient covariates of Japanese studies, was used to simulate paliperidone plasma concentration-time data using nonlinear mixed effects, followed by comparison with actual data. Visual predictive checks displayed considerable overlap between predicted and actual plasma concentrations; the majority of observations were within the 90% prediction interval. Japanese, Korean, and Taiwanese patients had comparable plasma concentrations. Covariate distributions demonstrated comparatively lower median body mass index in Japanese, Korean, and Taiwanese patients versus rest-of-world population. Prediction errors for the data set used for external validation were within cutoff values, confirming accuracy/precision of the model. Paliperidone pharmacokinetics were adequately predicted for Japanese studies using the historical Pop-PK model, confirming its robustness. Pharmacokinetics in Japanese, Korean, and Taiwanese patients with schizophrenia were comparable with rest-of-world population., (© 2019 Janssen Pharmaceutical. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)
- Published
- 2020
- Full Text
- View/download PDF
12. Effect of Fluconazole and Itraconazole on the Pharmacokinetics of Erdafitinib in Healthy Adults: A Randomized, Open-Label, Drug-Drug Interaction Study.
- Author
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Poggesi I, Li LY, Jiao J, Hellemans P, Rasschaert F, de Zwart L, Snoeys J, De Meulder M, Mamidi RNVS, and Ouellet D
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- Adult, Area Under Curve, Cytochrome P-450 CYP2C9 genetics, Drug Combinations, Female, Healthy Volunteers, Humans, Male, Middle Aged, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors blood, Protein Kinase Inhibitors urine, Pyrazoles adverse effects, Pyrazoles blood, Pyrazoles urine, Quinoxalines adverse effects, Quinoxalines blood, Quinoxalines urine, Receptors, Fibroblast Growth Factor antagonists & inhibitors, Cytochrome P-450 Enzyme Inhibitors pharmacology, Drug Interactions, Fluconazole pharmacology, Itraconazole pharmacology, Protein Kinase Inhibitors pharmacokinetics, Pyrazoles pharmacokinetics, Quinoxalines pharmacokinetics
- Abstract
Background and Objectives: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated., Methods: In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1-11, or Treatment C (itraconazole 200 mg/day orally) on days 1-11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (C
max ), area under the curve (AUC) from time 0 to 168 h (AUC168h ), AUC from time 0 to the last quantifiable concentration (AUClast ), and AUC from time 0 to infinity (AUC∞ ) were calculated from individual plasma concentration-time data using standard non-compartmental methods., Results: Coadministration of erdafitinib with fluconazole increased Cmax of erdafitinib by approximately 21%, AUC168h by 38%, AUClast by 49%, and AUC∞ by 48% while coadministration with itraconazole resulted in no change in erdafitinib Cmax and increased AUC168h by 20%, AUClast by 33% and AUC∞ by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults., Conclusion: Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential., Trial Registration: ClinicalTrials.gov identifier number: NCT03135106.- Published
- 2020
- Full Text
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13. Integrating Duodenal Sampling in a Human Mass Balance Study to Quantify the Elimination Pathways of JNJ-53718678, a Respiratory Syncytial Virus Fusion Protein Inhibitor.
- Author
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Remmerie B, van den Boer M, Van Looy T, Wynant I, Rusch S, Huntjens D, De Meulder M, and Stevens M
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- Adult, Animals, Area Under Curve, Cytochrome P-450 CYP3A metabolism, Humans, Male, Metabolic Clearance Rate, Metabolic Networks and Pathways, Imidazolidines metabolism, Indoles metabolism, Respiratory Syncytial Viruses metabolism
- Abstract
Introduction: The study objective was to characterize the excretion and metabolic profile of the respiratory syncytial virus fusion protein inhibitor, JNJ-53718678. Prior animal and in vitro studies suggested three main elimination pathways: N-glucuronidation to M8; CYP(3A4) metabolism leading to circulating metabolites M5, M12, M19 and M37; and JNJ-53718678 biliary excretion. To gain insight into the relative contribution of JNJ-53718678 and M8 biliary excretion, duodenal fluid sampling was incorporated into this mass balance study., Methods: A single oral dose of 500 mg
14 C-JNJ-53718678 was administered to six healthy male subjects. Four hours after study drug intake, gallbladder contraction was stimulated and duodenal fluid samples were collected. JNJ-53718678, its key circulating metabolites and total radioactivity (TR) were quantified in plasma, feces, urine and duodenal fluid. Safety was monitored throughout., Results: JNJ-53718678 and M12 represented 47.4% and 17.8%, respectively, of TR area under the curve (AUC)∞ in plasma. M37 (9.6%), M19 (5.2%), M5 (4.3%) and M8 (1.4%) were minor metabolites; 70.6% of TR was recovered in feces and 19.9% in urine. Duodenal fluid concentrations (% of TR) were highest for JNJ-53718678 (11.6%) followed by M8 (10.4%), M5 (5.9%) and M12 (1.1%). In feces, 10-16% of TR was JNJ-53718678, 5-8% M5, < 1% M12 and < 1% M8. N-glucuronidation to M8 and direct biliary excretion of JNJ-53718678 represented 7% and 8% of drug clearance, respectively. JNJ-53718678 was safe and well tolerated., Conclusions: JNJ-53718678 is primarily eliminated through CYP3A4-mediated metabolism. By integrating duodenal sampling, N-glucuronidation was confirmed as another metabolic pathway despite the low amount of M8 excreted in urine and feces., Trial Registration: Eudract no. 2016-002664-14.- Published
- 2020
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14. Comparison of Capillary and Venous Drug Concentrations After Administration of a Single Dose of Risperidone, Paliperidone, Quetiapine, Olanzapine, or Aripiprazole.
- Author
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Remmerie B, De Meulder M, Weiner S, and Savitz A
- Subjects
- Adolescent, Adult, Antipsychotic Agents adverse effects, Aripiprazole pharmacokinetics, Benzodiazepines pharmacokinetics, Blood Specimen Collection methods, Female, Fingers, Half-Life, Humans, Male, Middle Aged, Olanzapine, Paliperidone Palmitate pharmacokinetics, Quetiapine Fumarate pharmacokinetics, Risperidone pharmacokinetics, Young Adult, Antipsychotic Agents blood, Capillaries metabolism, Veins metabolism
- Abstract
Risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole are antipsychotic drugs approved for treating various psychiatric disorders, including schizophrenia. The objective of this randomized, parallel-group, open-label study was to compare finger-stick-based capillary with corresponding venous whole-blood and plasma concentrations for these drugs after administration of a single dose to healthy volunteers. All whole-blood and plasma drug concentrations were measured with validated liquid chromatography-tandem mass spectrometry methods. Capillary and venous concentrations (both in plasma and whole blood) were in close agreement, although a time-dependent difference was observed, most obviously for olanzapine and paliperidone, with slightly higher capillary versus venous drug concentrations during the first hours after administering a single dose. The observed difference between capillary and venous plasma drug concentrations is expected not to be relevant in clinical practice, considering the wide window of therapeutic concentrations and the wide range of drug concentrations in the patient population for a given dose. Based on these results, finger-stick-based capillary drug concentrations have been shown to approximate venous drug concentrations., (© 2016, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)
- Published
- 2016
- Full Text
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15. Comparison of Capillary and Venous Plasma Drug Concentrations After Repeated Administration of Risperidone, Paliperidone, Quetiapine, Olanzapine, or Aripiprazole.
- Author
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Remmerie B, De Meulder M, Ariyawansa J, and Savitz A
- Subjects
- Adolescent, Adult, Antipsychotic Agents adverse effects, Aripiprazole pharmacokinetics, Benzodiazepines pharmacokinetics, Blood Specimen Collection methods, Female, Fingers, Half-Life, Humans, Male, Middle Aged, Olanzapine, Paliperidone Palmitate pharmacokinetics, Quetiapine Fumarate pharmacokinetics, Risperidone pharmacokinetics, Schizophrenia drug therapy, Schizophrenia metabolism, Young Adult, Antipsychotic Agents blood, Capillaries metabolism, Veins metabolism
- Abstract
Quantification of blood levels of antipsychotic drugs may be useful for managing medication therapy. This open-label, parallel-group study was performed to compare finger-stick-based capillary with corresponding venous plasma concentrations for risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole and their major metabolites after repeated dosing in patients with schizophrenia or related illnesses. Finger-stick-based capillary and venous blood samples were collected at various times within a dosing interval. All drug concentration measurements in the derived plasma samples were performed with validated liquid chromatography-tandem mass spectrometry methods. Finger-stick-based capillary and venous plasma drug concentrations after repeated dosing were generally similar. Olanzapine capillary plasma concentrations, however, were on average approximately 20% higher than venous concentrations, with a trend for a relatively greater difference occurring shortly after dosing. In addition, smaller capillary-venous differences were observed for extended-release and long-acting intramuscular formulations and for aripiprazole, a drug with a long half-life, compared with drugs administered as an immediate-release formulation (risperidone, olanzapine). After repeated dosing, plasma derived from finger-stick-based blood was observed to be predictive of the venous concentrations. Capillary sampling may be an appropriate alternative to venous sampling to readily evaluate systemic drug concentrations., (© 2016, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)
- Published
- 2016
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16. Drug-Drug Interaction Studies of Paliperidone and Divalproex Sodium Extended-Release Tablets in Healthy Participants and Patients with Psychiatric Disorders.
- Author
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Remmerie B, Ariyawansa J, De Meulder M, Coppola D, and Berwaerts J
- Subjects
- Adult, Antimanic Agents administration & dosage, Antipsychotic Agents administration & dosage, Delayed-Action Preparations administration & dosage, Delayed-Action Preparations metabolism, Drug Interactions physiology, Drug Therapy, Combination, Female, Follow-Up Studies, Healthy Volunteers, Humans, Male, Middle Aged, Paliperidone Palmitate administration & dosage, Tablets, Valproic Acid administration & dosage, Antimanic Agents blood, Antipsychotic Agents blood, Mental Disorders blood, Mental Disorders drug therapy, Paliperidone Palmitate blood, Valproic Acid blood
- Abstract
The objective of these 2 phase 1, open-label, 2-treatment, single-sequence studies was to evaluate the effect of repeated oral doses of divalproex sodium extended-release (ER) on the pharmacokinetics (PK) of a single dose of paliperidone ER in healthy participants (study 1), and the effect of multiple doses of paliperidone ER on the steady-state PK of valproic acid (VPA) in patients with psychiatric disorders (study 2), respectively. In study 1 healthy participants received, in a fixed sequential order, treatment A, paliperidone ER 12 mg (day 1); treatment B, VPA 1000 mg (2 × 500 mg divalproex sodium ER) once daily (days 5 to 18) and paliperidone ER 12 mg (day 15). In study 2 patients received treatment A, VPA (days 1-7); treatment B, VPA + paliperidone ER 12 mg (days 8-12). Divalproex sodium ER doses (study 2) were individualized such that systemic therapeutic VPA exposure from prior treatment was maintained on entry into the study. PK assessments were performed at prespecified time points (paliperidone days 1 and 15 [study 1]; VPA days 7 and 12 [study 2]). The oral bioavailability of paliperidone was increased by an estimated 51% (Cmax ) and 51%-52% (AUCs) when coadministered with divalproex sodium ER. No effect on the steady-state plasma concentration of VPA was observed following repeated coadministration with paliperidone ER: the 90%CI around the VPA exposure ratios for the 2 treatments was within the 80%-125% bioequivalence criteria for Cmax,ss and AUCτ . Both VPA and paliperidone ER were well tolerated, and no new safety concerns were identified., (© 2015, The American College of Clinical Pharmacology.)
- Published
- 2016
- Full Text
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17. The effect of macrophage and angiogenesis inhibition on the drug release and absorption from an intramuscular sustained-release paliperidone palmitate suspension.
- Author
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Darville N, van Heerden M, Mariën D, De Meulder M, Rossenu S, Vermeulen A, Vynckier A, De Jonghe S, Sterkens P, Annaert P, and Van den Mooter G
- Subjects
- Animals, Antipsychotic Agents administration & dosage, Antipsychotic Agents pharmacokinetics, Antipsychotic Agents pharmacology, Delayed-Action Preparations administration & dosage, Delayed-Action Preparations pharmacokinetics, Delayed-Action Preparations pharmacology, Drug Liberation, Injections, Intramuscular, Liposomes, Macrophages drug effects, Macrophages metabolism, Male, Neovascularization, Pathologic metabolism, Paliperidone Palmitate pharmacokinetics, Paliperidone Palmitate pharmacology, Prodrugs pharmacokinetics, Prodrugs pharmacology, Rats, Wistar, Sunitinib, Suspensions, Angiogenesis Inhibitors administration & dosage, Clodronic Acid administration & dosage, Indoles administration & dosage, Paliperidone Palmitate administration & dosage, Prodrugs administration & dosage, Pyrroles administration & dosage
- Abstract
The intramuscular (IM) administration of long-acting injectable (LAI) aqueous nano-/microsuspensions elicits a chronic granulomatous injection site reaction, which recently has been hypothesized to drive the (pro)drug dissolution and systemic absorption resulting in flip-flop pharmacokinetics. The goal of this mechanistic study was to investigate the effects of the local macrophage infiltration and angiogenesis on the systemic drug exposure following a single IM administration of a paliperidone palmitate (PP) LAI nano-/microsuspension in the rat. Liposomal clodronate (CLO) and sunitinib (SNT) were co-administered to inhibit the depot infiltration and nano-/microparticle phagocytosis by macrophages, and the neovascularization of the depot, respectively. Semi-quantitative histopathology of the IM administration sites at day 1, 3, 7, 14, 21 and 28 after dosing with PP-LAI illustrated that CLO significantly decreased the rate and extent of the granulomatous inflammatory reaction. The macrophage infiltration was slowed down, but only partially suppressed by CLO and this translated in paliperidone (PAL) plasma concentration-time profiles that resembled those observed upon injection of PP-LAI only, albeit with a lower PAL input rate and delayed maximum plasma concentration (CMAX). Conversely, SNT treatment completely suppressed the granulomatous reaction, besides effectively inhibiting the neovascularization of the PP-LAI depot. This resulted in an even slower systemic PAL input with delayed and lower maximum PAL CMAX. The reduced PP-LAI lymph node retention after CLO and SNT treatment, as well as pharmacokinetic drug-drug interactions were rejected as possible sources of the observed pharmacokinetic differences. The biphasic PAL plasma concentration-time profiles could best be described by an open first-order disposition model with parallel fast (first-order) and slow (sequential zero-first-order) absorption. The correlation of the pharmacokinetic data with the histopathological findings indicated that the macrophage infiltration, with subsequent phagocytosis of an important fraction of the PP-LAI dose, actively contributed to the observed PAL plasma exposures by promoting the prodrug dissolution and conversion to the active. An initial fast PP dissolution of individual nano-/microcrystals present in the interstitium was followed by a second, slower, but dominating input process that was driven by the PAL formation rate in the infiltrated portions of the LAI depot. The present work provides new fundamental insights into the influence of the local tissue response to IM LAI (pro)drug suspensions on the systemic drug exposure. This knowledge might support the future development of predictive in vitro and in silico models, which could help guide the LAI formulation design., (Copyright © 2016 Elsevier B.V. All rights reserved.)
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- 2016
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18. Development and validation of HILIC-ESI/MS/MS methods for simultaneous quantitation of several antipsychotics in human plasma and blood.
- Author
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De Meulder M, Waldron MP, Li L, Peay MG, Tingler MJ, Hidy BJ, Verhaeghe T, and Jenkins RG
- Subjects
- Antipsychotic Agents pharmacokinetics, Antipsychotic Agents standards, Blood Chemical Analysis standards, Calibration, Half-Life, Humans, Point-of-Care Systems, Reproducibility of Results, Antipsychotic Agents blood, Blood Chemical Analysis methods, Chromatography, High Pressure Liquid standards, Spectrometry, Mass, Electrospray Ionization standards
- Abstract
Background: Knowledge of antipsychotic drug levels at point of care (POC) may significantly aid therapeutic decision-making. To support the development of future POC devices and to validate the use of fingerstick capillary blood sampling, two robust hydrophilic interaction LC-ESI/MS/MS methods were developed and validated. Two PK studies were completed evaluating the correlation between fingerstick blood and plasma concentrations with corresponding venous blood and plasma concentrations for several commonly prescribed atypical antipsychotics and selected metabolites. Sensitive and reliable LC-MS/MS bioanalytical assays were developed to support these studies., Results: Three methods, requiring only 25-μl matrix volumes, were developed using supported liquid extraction with hydrophilic interaction LC-MS/MS detection and validated according to regulatory guidance., Conclusion: Robust and efficient LC-MS/MS assays were established and were effective in providing antipsychotic drug matrix comparator results in the intended clinical studies.
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- 2016
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19. Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: A phase-1, single-dose, randomized, open-label study.
- Author
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Ravenstijn P, Remmerie B, Savitz A, Samtani MN, Nuamah I, Chang CT, De Meulder M, Hough D, and Gopal S
- Subjects
- Adolescent, Adult, Aged, Antipsychotic Agents administration & dosage, Antipsychotic Agents blood, Biological Availability, Delayed-Action Preparations administration & dosage, Dose-Response Relationship, Drug, Female, Humans, Injections, Intramuscular, Male, Middle Aged, Paliperidone Palmitate adverse effects, Paliperidone Palmitate blood, Psychotic Disorders drug therapy, Young Adult, Antipsychotic Agents adverse effects, Antipsychotic Agents pharmacokinetics, Delayed-Action Preparations pharmacokinetics, Paliperidone Palmitate administration & dosage, Paliperidone Palmitate pharmacokinetics, Schizophrenia blood, Schizophrenia drug therapy
- Abstract
This multicenter, randomized, open-label, parallel-group, phase-1 study assessed the pharmacokinetics (PK), safety, and tolerability of the investigational intramuscular paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia or schizoaffective disorder. A total of 328 patients (men or women, aged 18-65 years) were enrolled in 1 of 4 separately conducted panels (A to D). Each panel had 2 single-dose treatment periods (period 1, 1 mg intramuscular paliperidone immediate release [IR]; period 2, intramuscular PP3M 75-525 mg eq) separated by a washout of 7-21 days. Overall, 245 of 308 (79.5%) PP3M-dosed patients completed the study. Because the PK studies of panels A and C were compromised by incomplete injection in some patients, PK data from only panels B and D are presented. Safety data from all panels are presented. Peak paliperidone plasma concentration was achieved between 23 and 34 days, and apparent half-life was ∼2-4 months. Mean plasma AUC∞ and Cmax of paliperidone appeared to be dose-proportional. Relative bioavailability in comparison with paliperidone was ∼100% independent of the dose and injection site. Headache and nasopharyngitis were the most common (>7%) treatment-emergent adverse events. Overall, safety and tolerability were similar to those of the 1-month formulation. Results support a once-every-3-months dosing interval in patients with schizophrenia or schizoaffective disorder., (© 2015, The American College of Clinical Pharmacology.)
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- 2016
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20. Modeling the Time Course of the Tissue Responses to Intramuscular Long-acting Paliperidone Palmitate Nano-/Microcrystals and Polystyrene Microspheres in the Rat.
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Darville N, van Heerden M, Erkens T, De Jonghe S, Vynckier A, De Meulder M, Vermeulen A, Sterkens P, Annaert P, and Van den Mooter G
- Subjects
- Animals, Cytokines analysis, Cytokines metabolism, Delayed-Action Preparations, Injections, Intramuscular, Lymph Nodes chemistry, Lymph Nodes metabolism, Male, Microspheres, Muscle, Skeletal chemistry, Muscle, Skeletal metabolism, Organ Specificity drug effects, Paliperidone Palmitate pharmacology, Polystyrenes chemistry, Rats, Rats, Wistar, Vascular Endothelial Growth Factor A analysis, Vascular Endothelial Growth Factor A metabolism, Nanoparticles administration & dosage, Paliperidone Palmitate administration & dosage, Paliperidone Palmitate pharmacokinetics
- Abstract
Long-acting injectable (LAI) drug suspensions consist of drug nano-/microcrystals suspended in an aqueous vehicle and enable prolonged therapeutic drug exposure up to several months. The examination of injection site reactions (ISRs) to the intramuscular (IM) injection of LAI suspensions is relevant not only from a safety perspective but also for the understanding of the pharmacokinetics. The aim of this study was to perform a multilevel temporal characterization of the local and lymphatic histopathological/immunological alterations triggered by the IM injection of an LAI paliperidone palmitate suspension and an analog polystyrene suspension in rats and identify critical time points and parameters with regard to the host response. The ISRs showed a moderate to marked chronic granulomatous inflammation, which was mediated by multiple cyto-/chemokines, including interleukin-1β, monocyte Chemoattractant Protein-1, and vascular endothelial growth factor. Lymphatic uptake and lymph node retention of nano-/microparticles were observed, but the contribution to the drug absorption was negligible. A simple image analysis procedure and empirical model were proposed for the accurate evaluation of the depot geometry, cell infiltration, and vascularization. This study was designed as a reference for the evaluation and comparison of future LAIs and to support the mechanistic modeling of the formulation-physiology interplay regulating the drug absorption from LAIs., (© The Author(s) 2015.)
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- 2016
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21. Pharmacokinetic profile after multiple deltoid or gluteal intramuscular injections of paliperidone palmitate in patients with schizophrenia.
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Rossenu S, Cleton A, Hough D, Crauwels H, Vandebosch A, Berwaerts J, Eerdekens M, Herben V, De Meulder M, Remmerie B, and Francetic I
- Subjects
- Adolescent, Adult, Aged, Antipsychotic Agents adverse effects, Antipsychotic Agents blood, Area Under Curve, Buttocks, Croatia, Deltoid Muscle, Drug Monitoring methods, Female, Humans, Injections, Intramuscular, Male, Metabolic Clearance Rate, Middle Aged, Paliperidone Palmitate adverse effects, Paliperidone Palmitate blood, Schizophrenia blood, Schizophrenia diagnosis, Schizophrenic Psychology, Treatment Outcome, Young Adult, Antipsychotic Agents administration & dosage, Antipsychotic Agents pharmacokinetics, Paliperidone Palmitate administration & dosage, Paliperidone Palmitate pharmacokinetics, Schizophrenia drug therapy
- Abstract
Paliperidone palmitate (PP) is a once-monthly long-acting injectable antipsychotic approved for the treatment of schizophrenia in many countries. To evaluate the different injection-site options, we compared the pharmacokinetic profile of paliperidone after multiple injections of PP 100 mg eq. (156 mg of PP, equivalent to 100 mg of paliperidone) on days 1, 8, 36, and 64 into the deltoid (n = 24) or gluteal muscle (n = 25) in patients with schizophrenia. After four injections in the deltoid muscle, paliperidone exposure was higher for AUCτ and Cmax , compared with the gluteal muscle (geometric mean AUCτ -based ratio: 120% [90% CI: 93.1-154.7%], and geometric mean Cmax -based ratio: 130% [90% CI: 100.6-168.9%]). The mean [SD] fluctuation index was higher, with a larger interpatient variability, after deltoid-injections (75.9% [30.9%]) than gluteal-injections (58.5% [14.3%]). The median tmax was similar for both sites. PP was generally tolerable in patients, with more favorable local-site tolerability for gluteal-injection. In conclusion, to achieve therapeutic-concentrations quickly, the first-two injections of PP are best administered into the deltoid muscle, whereas thereafter maintenance-injections can be administered either in the deltoid or gluteal muscle., (© 2014, The American College of Clinical Pharmacology.)
- Published
- 2015
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22. Safety, Tolerability and Pharmacokinetic and Pharmacodynamic Learnings from a Double-Blind, Randomized, Placebo-Controlled, Sequential Group First-in-Human Study of the TRPV1 Antagonist, JNJ-38893777, in Healthy Men.
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Manitpisitkul P, Mayorga A, Shalayda K, De Meulder M, Romano G, Jun C, and Moyer JA
- Subjects
- Adolescent, Adult, Area Under Curve, Azepines adverse effects, Azepines pharmacokinetics, Chemistry, Pharmaceutical, Double-Blind Method, Humans, Male, Middle Aged, Piperidines adverse effects, Piperidines pharmacokinetics, Tablets, Tandem Mass Spectrometry, Young Adult, Azepines administration & dosage, Piperidines administration & dosage, TRPV Cation Channels antagonists & inhibitors
- Abstract
Background and Objective: Nociceptive and neuropathic pain, one of common reasons of disability and loss of quality life, are often undertreated due to safety concerns with current therapies. This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-38893777, a potent and selective transient receptor potential vanilloid 1 (TRPV1) channel antagonist in healthy men., Methods: In a single-center, double-blind, placebo-controlled, sequential group, single-ascending-dose phase 1 study, 80 healthy men (18-45 years old; body mass index 18.5 to <30 kg/m(2)), randomized to two groups, received either JNJ-38893777 (n = 6) or placebo (n = 2) in a dose-escalation manner. The study was designed in two parts: Part 1, an early tablet formulation was administered under fasting conditions at 5, 15, 45, 125, 250, or 500 mg; Part 2, a new tablet formulation was administered in a fasting state (250 mg) and a high-fat fed state (250 mg, 375 mg, or 500 mg). Serial plasma and urine samples (collected over 120 h post-dose) were analyzed using LC-MS/MS for pharmacokinetic evaluations., Results: JNJ-38893777 concentrations peaked from 3.0 to 5.5 h (median) post-administration, and then declined multi-exponentially with a prolonged terminal phase. Renal clearance was negligible. Maximum concentration (C max) and area under the concentration-time curve from time zero to infinity (AUC∞) of the early formulation increased with increasing doses but less than dose-proportionally over 5-500 mg (fasted) doses. The new tablet formulation showed no improvements in the fasting state but showed an 11- to 22-fold increase in JNJ-38893777 exposure; interindividual variability reduced from 73-85% to 23-24%, and a significant increase (P < 0.05) in heat pain detection threshold (~3 °C) was observed in the fed state. Mild to moderate adverse events were observed, with no evidence of exposure dependence up to 500 mg (fed). Concentration-related increases in body temperature or changes in Fridericia-corrected QT interval (QTcF) were not observed., Conclusion: JNJ-38893777 was tolerated at single doses up to 500 mg (fed) and is suitable for further clinical development.
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- 2015
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23. Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease.
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Vite CH, Bagel JH, Swain GP, Prociuk M, Sikora TU, Stein VM, O'Donnell P, Ruane T, Ward S, Crooks A, Li S, Mauldin E, Stellar S, De Meulder M, Kao ML, Ory DS, Davidson C, Vanier MT, and Walkley SU
- Subjects
- 2-Hydroxypropyl-beta-cyclodextrin, Aging pathology, Alanine Transaminase blood, Animals, Ataxia blood, Ataxia complications, Ataxia pathology, Auditory Threshold, Calbindins metabolism, Cats, Cell Death, Fluorescent Antibody Technique, G(M2) Ganglioside metabolism, Inflammation complications, Inflammation pathology, Injections, Subcutaneous, Liver pathology, Liver Diseases blood, Liver Diseases complications, Liver Diseases pathology, Lung pathology, Niemann-Pick Disease, Type C blood, Niemann-Pick Disease, Type C complications, Purkinje Cells metabolism, Staining and Labeling, Survival Analysis, beta-Cyclodextrins administration & dosage, Cisterna Magna pathology, Cisterna Magna physiopathology, Niemann-Pick Disease, Type C drug therapy, Niemann-Pick Disease, Type C physiopathology, Purkinje Cells pathology, beta-Cyclodextrins therapeutic use
- Abstract
Niemann-Pick type C1 (NPC) disease is a lysosomal storage disease caused by mutations in the NPC1 gene, leading to an increase in unesterified cholesterol and several sphingolipids, and resulting in hepatic disease and progressive neurological disease. We show that subcutaneous administration of the pharmaceutical excipient 2-hydroxypropyl-β-cyclodextrin (HPβCD) to cats with NPC disease ameliorated hepatic disease, but doses sufficient to reduce neurological disease resulted in pulmonary toxicity. However, direct administration of HPβCD into the cisterna magna of presymptomatic cats with NPC disease prevented the onset of cerebellar dysfunction for greater than a year and resulted in a reduction in Purkinje cell loss and near-normal concentrations of cholesterol and sphingolipids. Moreover, administration of intracisternal HPβCD to NPC cats with ongoing cerebellar dysfunction slowed disease progression, increased survival time, and decreased the accumulation of brain gangliosides. An increase in hearing threshold was identified as a potential adverse effect. These studies in a feline animal model have provided critical data on efficacy and safety of drug administration directly into the central nervous system that will be important for advancing HPβCD into clinical trials., (Copyright © 2015, American Association for the Advancement of Science.)
- Published
- 2015
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24. A single-dose, open-label, parallel, randomized, dose-proportionality study of paliperidone after intramuscular injections of paliperidone palmitate in the deltoid or gluteal muscle in patients with schizophrenia.
- Author
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Cleton A, Rossenu S, Crauwels H, Berwaerts J, Hough D, Gopal S, Eerdekens M, Vandebosch A, Remmerie B, De Meulder M, and Rosso CM
- Subjects
- Adult, Antipsychotic Agents adverse effects, Antipsychotic Agents blood, Buttocks, Female, Humans, Injections, Intramuscular, Isoxazoles adverse effects, Isoxazoles blood, Male, Middle Aged, Muscle, Skeletal, Paliperidone Palmitate, Psychiatric Status Rating Scales, Pyrimidines adverse effects, Pyrimidines blood, Schizophrenia drug therapy, Shoulder, Antipsychotic Agents administration & dosage, Antipsychotic Agents pharmacokinetics, Isoxazoles administration & dosage, Isoxazoles pharmacokinetics, Pyrimidines administration & dosage, Pyrimidines pharmacokinetics, Schizophrenia metabolism
- Abstract
Paliperidone palmitate (PP) is a long-acting injectable (LAI) antipsychotic, developed for monthly intramuscular (i.m.) administration into deltoid/gluteal muscle, approved for the treatment of schizophrenia in many countries. To assess the options for i.m. injection sites, dose-proportionality of PP was investigated after injection of a single dose (25-150 mg eq.) of PP in either gluteal (n = 106) or deltoid (n = 95) muscle of schizophrenic patients. Overall, mean (geometric) area under plasma concentration-time curve from time zero to infinity (AUC∞ ) of paliperidone increased proportionally with increasing PP doses, regardless of injection site. Mean maximum plasma concentration (Cmax ) was slightly less than dose-proportional for both injection sites at PP doses >50 mg eq. Mean Cmax was higher after injection in the deltoid compared with the gluteal muscle, except for the 100 mg eq. dose, while AUC∞ for both injection sites was comparable at all doses. Median time to reach Cmax (tmax ) ranged from 13-14 days after deltoid and 13-17 days after gluteal injection across all doses. Single PP injections in deltoid and gluteal muscles in the dose range of 25-150 mg eq. were generally tolerable both locally and systemically., (© 2014, The American College of Clinical Pharmacology.)
- Published
- 2014
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25. Intramuscular administration of paliperidone palmitate extended-release injectable microsuspension induces a subclinical inflammatory reaction modulating the pharmacokinetics in rats.
- Author
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Darville N, van Heerden M, Vynckier A, De Meulder M, Sterkens P, Annaert P, and Van den Mooter G
- Subjects
- Animals, Delayed-Action Preparations, Immunohistochemistry, Injections, Intramuscular, Isoxazoles administration & dosage, Isoxazoles chemistry, Male, Microscopy, Electron, Transmission, Nanoparticles, Paliperidone Palmitate, Palmitates administration & dosage, Palmitates chemistry, Particle Size, Prodrugs administration & dosage, Prodrugs chemistry, Rats, Wistar, Surface Properties, Suspensions, Tissue Distribution, Inflammation metabolism, Inflammation pathology, Isoxazoles pharmacokinetics, Models, Biological, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Palmitates pharmacokinetics, Prodrugs pharmacokinetics
- Abstract
The present study aims at elucidating the intricate nature of the drug release and absorption following intramuscular (i.m.) injection of sustained-release prodrug nanocrystals/microcrystals. A paliperidone palmitate (PPP) long-acting suspension was characterized with regard to particle size (Dv,50 = 1.09 μm) and morphology prior to i.m. injection in rats. The local disposition was rigorously investigated by means of (immuno)histochemistry and transmission electron microscopy while the concurrent multiphasic pharmacokinetics was linked to the microanatomy. A transient (24 h) trauma-induced inflammation promptly evolved into a subclinical but chronic granulomatous inflammatory reaction initiated by the presence of solid material. The dense inflammatory envelope (CD68(+) macrophages) led to particle agglomeration with subsequent drop in dissolution rate beyond 24 h postinjection. This was associated with a decrease in apparent paliperidone (PP) absorption (near-zero order) until 96 h and a delayed time of occurrence of observed maximum drug plasma concentration (168 h). The infiltrating macrophages phagocytosed large fractions of the depot, thereby influencing the (pro)drug release. Radial angiogenesis (CD31(+)) was observed throughout the inflammatory rim from 72 h onwards and presumably contributed to the sustained systemic PP concentrations by maintaining a sufficient absorptive capacity. No solid-state transitions of the retrieved formulation were recorded with X-ray diffraction analysis. In summary, the initial formulation-driven prodrug (PPP) dissolution and drug (PP) absorption were followed by a complex phase determined by the relative contribution of formulation factors and dynamic physiological variables., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)
- Published
- 2014
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26. Development and validation of sensitive LC-MS/MS assays for quantification of HP-β-CD in human plasma and CSF.
- Author
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Jiang H, Sidhu R, Fujiwara H, De Meulder M, de Vries R, Gong Y, Kao M, Porter FD, Yanjanin NM, Carillo-Carasco N, Xu X, Ottinger E, Woolery M, Ory DS, and Jiang X
- Subjects
- Chromatography, Liquid methods, Female, Humans, Male, 2-Hydroxypropyl-beta-cyclodextrin blood, 2-Hydroxypropyl-beta-cyclodextrin cerebrospinal fluid, Mass Spectrometry methods
- Abstract
2-Hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of Niemann-Pick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. Development of a sensitive quantitative LC-MS/MS assay to monitor the pharmacokinetics (PKs) of HP-β-CD required for clinical trials has been challenging owing to the dispersity of the HP-β-CD. To support a phase 1 clinical trial for ICV delivery of HP-β-CD in NPC1 patients, novel methods for quantification of HP-β-CD in human plasma and cerebrospinal fluid (CSF) using LC-MS/MS were developed and validated: a 2D-LC-in-source fragmentation-MS/MS (2D-LC-IF-MS/MS) assay and a reversed phase ultra performance LC-MS/MS (RP-UPLC-MS/MS) assay. In both assays, protein precipitation and "dilute and shoot" procedures were used to process plasma and CSF, respectively. The assays were fully validated and in close agreement, and allowed determination of PK parameters for HP-β-CD. The LC-MS/MS methods are ∼100-fold more sensitive than the current HPLC assay, and were successfully employed to analyze HP-β-CD in human plasma and CSF samples to support the phase 1 clinical trial of HP-β-CD in NPC1 patients., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2014
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27. Recommendations from the European Bioanalysis Forum on method establishment for tissue homogenates.
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Timmerman P, Mokrzycki N, Delrat P, De Meulder M, Erbach E, Lentheric I, McIntosh M, and Dzygiel P
- Subjects
- Calibration, Data Collection, Documentation, Europe, Humans, Pharmaceutical Preparations isolation & purification, Social Control, Formal, Chemistry Techniques, Analytical, Histocytological Preparation Techniques methods
- Abstract
Tissue analysis has always been a difficult discipline of bioanalysis. Differences in scientific approaches or level of adherence to regulated guidelines have led to a growing ambiguity on how to perform tissue analysis, an ambiguity that starts with the question of if we analyze tissue or tissue homogenates. The European Bioanalysis Forum (EBF) is proposing a recommendation on how to perform method establishment and analysis of tissue homogenates. The recommendation is based on broad discussions and survey data from the EBF community and, as for many EBF recommendations, focuses on finding the right balance between science, technology and regulations.
- Published
- 2014
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28. Feedback from a European Bioanalysis Forum survey on bioanalysis of drugs in tissues.
- Author
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Mokrzycki N, Delrat P, De Meulder M, Erbach E, Lenthéric I, McIntosh M, Dzygiel P, and Timmerman P
- Subjects
- Animals, Cryopreservation, Europe, Humans, Laboratories, Research Design, Biological Assay statistics & numerical data, Data Collection
- Abstract
Tissue analysis has always been a difficult discipline of bioanalysis. Laboratories that perform bioanalysis in tissue are facing a lot of challenges and questions before starting experiments, from a scientific/technical point of view regarding more regulated aspects. Actually, literature is poor regarding the more technical and scientific aspects but also beyond that no clear guidance is available on this topic and laboratories performing tissue analysis face real ambiguity regarding regulatory requirements, always with the risk of under- or over-validation of the assay. For all of these reasons bioanalysis in tissue became a frequently discussed topic within the European Bioanalytical Forum (EBF) organization. The EBF then decided to treat this as a specific topic, and carried out a survey that was done in two steps between 2012 and 2013. This paper represents an exhaustive summary of the result of this survey that includes themost important aspects of tissue bioanalysis. This survey provided the team a good starting point for their discussions and resulted in an EBF recommendation paper published separately.
- Published
- 2014
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29. Understanding Deafhood: in search of its meanings.
- Author
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Kusters A and De Meulder M
- Subjects
- Cochlear Implantation psychology, Deafness therapy, Hearing Aids psychology, Humans, Music, Taboo, Deafness psychology, Feminism, Persons With Hearing Impairments psychology, Philosophy
- Abstract
The authors argue that Deafhood (a term coined by Dr. Paddy Ladd) is an open-ended concept with an essentialist core. They describe how deaf people who have attended their Deafhood lectures and workshops have perceived different aspects of the Deafhood concept, and compare the basic tenets of Deafhood and criticisms on Deafhood to theories and criticisms on feminist essentialisms. The authors find that the vagueness and wideness of the Deafhood concept is one of its strengths, though they also find that it is in some respects problematic to combine and unite ontology and liberation theory in one concept. They further suggest that the ontological aspects of Deafhood need to be foregrounded. The question of essentialism inherent in the Deafhood concept is also briefly discussed with regard to hearing people, the use of spoken language, and the use of amplification technology and cochlear implants.
- Published
- 2013
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30. Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model.
- Author
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Olszewska W, Ispas G, Schnoeller C, Sawant D, Van de Casteele T, Nauwelaers D, Van Kerckhove B, Roymans D, De Meulder M, Rouan MC, Van Remoortere P, Bonfanti JF, Van Velsen F, Koul A, Vanstockem M, Andries K, Sowinski P, Wang B, Openshaw P, and Verloes R
- Subjects
- Animals, Bronchoalveolar Lavage Fluid virology, Female, Lung virology, Lung Diseases drug therapy, Lung Diseases virology, Mice, Mice, Inbred BALB C, Respiratory Syncytial Virus Infections drug therapy, Treatment Outcome, Viral Load drug effects, Virus Replication drug effects, Antiviral Agents therapeutic use, Benzimidazoles therapeutic use, Lung drug effects, Pyridines therapeutic use, Respiratory Syncytial Viruses drug effects, Virus Internalization drug effects
- Abstract
Respiratory syncytial virus (RSV) causes bronchiolitis in young children and common colds in adults. There is no licensed vaccine, and prophylactic treatment with palivizumab is very expensive and limited to high-risk infants. Ribavirin is used as an antiviral treatment in infants and immunosuppressed patients, and its use is limited due to side-effects, toxicity to the recipient and staff, and evidence of marginal clinical efficacy. Therefore, we studied the in vivo kinetics, and the antiviral and protective properties of a novel candidate for RSV disease treatment. The drug is a small molecule (TMC353121) discovered by screening for fusion inhibitory properties against RSV in a cellular infection model. The pharmacokinetics of TMC353121 was studied in BALB/c mice and antiviral effects determined by testing viral loads in lung tissue by quantitative RT-PCR and plaque assay after intranasal RSV infection. At doses of 0.25-10 mg · kg(-1), TMC353121 significantly reduced viral load, bronchoalveolar lavage cell accumulation and the severity of lung histopathological change after infection. Treatment remained effective if started within 48 h of infection, but was ineffective thereafter. Therefore, TMC353121 is a novel potent antiviral drug, in vivo reducing RSV replication and inhibiting consequential lung inflammation, with a great potential for further clinical development.
- Published
- 2011
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31. Pharmacokinetics-pharmacodynamics of a respiratory syncytial virus fusion inhibitor in the cotton rat model.
- Author
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Rouan MC, Gevers T, Roymans D, de Zwart L, Nauwelaers D, De Meulder M, van Remoortere P, Vanstockem M, Koul A, Simmen K, and Andries K
- Subjects
- Animals, Antiviral Agents blood, Benzimidazoles blood, Bronchoalveolar Lavage Fluid chemistry, Female, Male, Pyridines blood, Rats, Rats, Sprague-Dawley, Respiratory Syncytial Virus Infections virology, Respiratory Syncytial Viruses genetics, Reverse Transcriptase Polymerase Chain Reaction, Sigmodontinae, Antiviral Agents pharmacokinetics, Antiviral Agents therapeutic use, Benzimidazoles pharmacokinetics, Benzimidazoles therapeutic use, Pyridines pharmacokinetics, Pyridines therapeutic use, Respiratory Syncytial Virus Infections drug therapy, Respiratory Syncytial Viruses drug effects
- Abstract
Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, young children, elderly persons, and severely immunocompromised patients. Effective postinfection treatments are not widely available, and currently there is no approved vaccine. TMC353121 is a potent RSV fusion inhibitor in vitro, and its ability to reduce viral loads in vivo was demonstrated in cotton rats following prophylactic intravenous administration. Here, the pharmacokinetics of TMC353121 in the cotton rat, which is semipermissive for RSV replication, were further explored to build a pharmacokinetic-pharmacodynamic (PK-PD) model and to estimate the plasma drug levels needed for significant antiviral efficacy. TMC353121 reduced the viral titers in bronchoalveolar lavage fluid in a dose-dependent manner after a single subcutaneous administration and intranasal RSV inoculation 24 h after compound administration. The viral titer reduction and plasma TMC353121 concentration at the time of RSV inoculation were well described using a simple E(max) model with a maximal viral titer reduction (E(max)) of 1.5 log(10). The plasma drug level required to achieve 50% of the E(max) (200 ng/ml) was much higher than the 50% inhibitory concentration observed in vitro in HeLaM cells (0.07 ng/ml). In conclusion, this simple PK-PD approach may be useful in predicting efficacious exposure levels for future RSV inhibitors.
- Published
- 2010
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32. Single- and multiple-dose pharmacokinetics and dose proportionality of the psychotropic agent paliperidone extended release.
- Author
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Boom S, Talluri K, Janssens L, Remmerie B, De Meulder M, Rossenu S, van Osselaer N, Eerdekens M, and Cleton A
- Subjects
- Adolescent, Adult, Antipsychotic Agents administration & dosage, Antipsychotic Agents adverse effects, Delayed-Action Preparations pharmacokinetics, Female, Humans, Isoxazoles administration & dosage, Isoxazoles adverse effects, Male, Middle Aged, Paliperidone Palmitate, Pyrimidines administration & dosage, Pyrimidines adverse effects, Random Allocation, Antipsychotic Agents pharmacokinetics, Dose-Response Relationship, Drug, Isoxazoles pharmacokinetics, Pyrimidines pharmacokinetics
- Abstract
Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D(2)- and serotonergic 5-HT(2A)-receptor antagonist that is registered for the treatment of schizophrenia. The controlled rate of release of paliperidone from the ER formulation is designed to have a slower absorption rate, which results in gradual ascending plasma concentrations with observed maximum plasma concentrations occurring at 24 hours after dosing on the first dosing day. On subsequent treatment days, the ER formulation provides minimal fluctuations in plasma concentrations. Paliperidone is eliminated with a terminal half-life of approximately 24 hours. Steady state is achieved after 4 daily doses. Paliperidone ER exhibits time-invariant pharmacokinetics. It shows a 3.5-fold accumulation upon steady state, mainly caused by the controlled release characteristics of the formulation. Paliperidone ER displays dose proportionality over the dose range of 3 to 15 mg; the 90% confidence intervals of the pairwise dose comparisons are all included in the 80% to 125% bioequivalence limits.
- Published
- 2009
- Full Text
- View/download PDF
33. Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals.
- Author
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Yilmaz A, Izadkhashti A, Price RW, Mallon PW, De Meulder M, Timmerman P, and Gisslén M
- Subjects
- Adult, Chromatography, Liquid, Darunavir, Drug Therapy, Combination, Female, HIV Infections blood, HIV Infections cerebrospinal fluid, HIV Infections virology, HIV Protease Inhibitors therapeutic use, HIV-1 drug effects, Humans, Male, Mass Spectrometry, Middle Aged, Reverse Transcriptase Inhibitors therapeutic use, Ritonavir blood, Ritonavir cerebrospinal fluid, Ritonavir therapeutic use, Sulfonamides therapeutic use, Treatment Outcome, Young Adult, HIV Infections drug therapy, HIV Protease Inhibitors blood, HIV Protease Inhibitors cerebrospinal fluid, Sulfonamides blood, Sulfonamides cerebrospinal fluid
- Abstract
Darunavir is the most recently licensed protease inhibitor currently used in treatment-experienced HIV-infected individuals. Our objective was to determine darunavir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing ritonavir-boosted darunavir. Darunavir concentrations were determined by liquid chromatography tandem mass spectrometry in 14 paired CSF and plasma samples from eight HIV-1-infected individuals. The lower limit of quantification was 5.0 ng/ml. All of the 14 CSF samples had detectable darunavir concentrations with a median darunavir concentration of 34.2 ng/ml (range 15.9-212.0 ng/ml). The median (range) plasma darunavir concentration was 3930 (1800-12900) ng/ml. All CSF samples had detectable darunavir concentrations. Most of them exceeded or were in the same range as levels needed to inhibit replication of wild type virus, making it probable that darunavir, at least to some extent, contributes to the suppression of HIV replication in the central nervous system.
- Published
- 2009
- Full Text
- View/download PDF
34. Validated LC-MS/MS methods for the determination of risperidone and the enantiomers of 9-hydroxyrisperidone in human plasma and urine.
- Author
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De Meulder M, Remmerie BM, de Vries R, Sips LL, Boom S, Hooijschuur EW, van de Merbel NC, and Timmerman PM
- Subjects
- Humans, Isoxazoles blood, Isoxazoles pharmacokinetics, Isoxazoles urine, Paliperidone Palmitate, Pyrimidines blood, Pyrimidines pharmacokinetics, Pyrimidines urine, Risperidone blood, Risperidone pharmacokinetics, Risperidone urine, Sensitivity and Specificity, Chromatography, Liquid methods, Isoxazoles chemistry, Pyrimidines chemistry, Risperidone chemistry, Tandem Mass Spectrometry methods
- Abstract
Two liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods are described, one for the quantitative determination of risperidone and the enantiomers of its active metabolite 9-hydroxyrisperidone (paliperidone) in human plasma and the other for the determination of the enantiomers of 9-hydroxyrisperidone in human urine. The plasma method is based on solid-phase extraction of 200 microl of sample on a mixed-mode sorbent, followed by separation on a cellulose-based LC column with a 13.5-min mobile phase gradient of hexane, isopropanol and ethanol. After post-column addition of 10 mM ammonium acetate in ethanol/water, detection takes place by ion-spray tandem mass spectrometry in the positive ion mode. Method validation results show that the method is sufficiently selective towards the enantiomers of 7-hydroxyrisperidone and capable of quantifying the analytes with good precision and accuracy in the concentration range of 0.2-100 ng/ml. An accelerated (run time of 4.3 min) and equally valid method for the enantiomers of 9-hydroxyrisperidone alone in plasma is obtained by increasing the mobile phase flow-rate from 1.0 to 2.0 ml/min and slightly adapting the gradient conditions. The urine method is based on the same solid-phase extraction and chromatographic approach as the accelerated plasma method. Using 100 microl of sample, (+)- and (-)-9-hydroxyrisperidone can be quantified in the concentration range 1-2000 ng/ml. The accelerated method for plasma and the method for urine can be used only when paliperidone is administered instead of risperidone, as there is insufficient separation of the 9-hydroxy enantiomers from the 7-hydroxy enantiomers, the latter ones being present only after risperidone administration.
- Published
- 2008
- Full Text
- View/download PDF
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