32 results on '"Kamerling IMC"'
Search Results
2. Fosfomycin: Pharmacological, Clinical and Future Perspectives
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Dijkmans, AC, Zacarias, NVO, Burggraaf, J, Mouton, Johan, Wilms, EB, Nieuwkoop, C, Touw, DJ, Stevens, J, Kamerling, IMC, Dijkmans, AC, Zacarias, NVO, Burggraaf, J, Mouton, Johan, Wilms, EB, Nieuwkoop, C, Touw, DJ, Stevens, J, and Kamerling, IMC
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- 2017
3. Levofloxacin-Induced QTc Prolongation Depends on the Time of Drug Administration
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Kervezee, L, primary, Gotta, V, additional, Stevens, J, additional, Birkhoff, W, additional, Kamerling, IMC, additional, Danhof, M, additional, Meijer, JH, additional, and Burggraaf, J, additional
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- 2016
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4. Enhanced tolerability of the 5-hydroxytryptophane challenge test combined with granisetron
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Jacobs, GE, primary, Kamerling, IMC, additional, de Kam, ML, additional, DeRijk, RH, additional, van Pelt, J., additional, Zitman, FG, additional, and van Gerven, JMA, additional
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- 2008
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5. Safety, reactogenicity and immunogenicity of an intranasal seasonal influenza vaccine adjuvanted with gram-positive matrix (GEM) particles (FluGEM): A randomized, double-blind, controlled, ascending dose study in healthy adults and elderly.
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van der Plas JL, Haijema BJ, Leenhouts K, Paul Zoeteweij J, Burggraaf J, and Kamerling IMC
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- Humans, Adult, Male, Female, Middle Aged, Double-Blind Method, Young Adult, Adolescent, Immunogenicity, Vaccine, Adjuvants, Vaccine administration & dosage, Aged, Immunoglobulin A blood, Healthy Volunteers, Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic adverse effects, Netherlands, Immunity, Mucosal, Vaccination methods, Influenza Vaccines immunology, Influenza Vaccines administration & dosage, Influenza Vaccines adverse effects, Administration, Intranasal, Antibodies, Viral blood, Influenza, Human prevention & control, Influenza, Human immunology, Hemagglutination Inhibition Tests
- Abstract
Background: Intranasal administration of respiratory vaccines offers many advantages such as eliciting both systemic and mucosal immunity at the point of viral entry. Immunogenicity of intranasal vaccination can be improved through the use of adjuvants. Bacteria-like particles derived fromLactococcus lactishave the potential to serve as a vaccine adjuvant.This clinical study investigated the safety, reactogenicity and immunogenicity of intranasal seasonal influenza vaccine adjuvanted with gram-positive matrix particles (FluGEM®)., Methods: This was a first-in-human, randomized, double-blind, controlled, dose-escalation study performed at the Centre for Human Drug Research (CHDR), the Netherlands. Participants aged 18-49 were randomized in a 3:1 ratio to receive FluGem® in ascending doses (two-dose regimens) together with a standard trivalent inactivated influenza vaccine or unadjuvanted TIV only. Primary outcomes were safety and tolerability. Secondary outcomes were serum hemagglutination inhibition (HI) antibody titers and mucosal IgA. The most immunogenic dose was used in an additionalelderly cohort (>65 years)., Results: Ninty participants were included. Intranasal FluGem®was safe and well tolerated. The majority of adverse events were mild (97.4 %) with (un)solicited adverse events comparable across all dose levels and control groups. All groups showed geometric mean increases ≥ 2.5-fold. Seroconversion (≥40 % participants) was achieved at both day 21 (single-dose) and 42 (two-dose) for the 1.25 mg dose and on day 42 (two-dose only) for the 2.5 mg dose. Highest geometric mean IgA increases were observed in the 1.25 mg group on day 21. Immunogenicity was less pronounced in elderly., Conclusions: Intranasal vaccination of FluGEM®was safe and tolerable in healthy adult volunteers aged 18-49 years and 65 and older. Highest immunogenicity was observed for 1.25 mg and 2.5 mg doses (compared to 5 mg) suggesting a potential non-linear dose-response relationship.More research is needed to further investigate the capabilities of bacteria-like peptides as adjuvants., Competing Interests: Declaration of competing interest Kees Leenhouts and Bert-Jan Haijema were former employees of Mucosis BV. The study was sponsored by Mucosis BV. For the other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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6. Safety and immunogenicity of Ad26.COV2.S in adults: A randomised, double-blind, placebo-controlled Phase 2a dose-finding study.
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Cárdenas V, Le Gars M, Truyers C, Ruiz-Guiñazú J, Struyf F, Colfer A, Bonten M, Borobia A, Reisinger EC, Kamerling IMC, Douoguih M, and Sadoff J
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- Humans, Adult, Double-Blind Method, Male, Middle Aged, Female, Young Adult, Adolescent, Ad26COVS1 immunology, Antibodies, Neutralizing blood, Antibodies, Neutralizing immunology, Aged, Immunization Schedule, Vaccination methods, Immunologic Memory, Spike Glycoprotein, Coronavirus immunology, Immunity, Humoral, Immunity, Cellular immunology, Antibodies, Viral blood, Antibodies, Viral immunology, COVID-19 prevention & control, COVID-19 immunology, SARS-CoV-2 immunology, Immunogenicity, Vaccine, COVID-19 Vaccines immunology, COVID-19 Vaccines administration & dosage, COVID-19 Vaccines adverse effects
- Abstract
Background: A single dose of Ad26.COV2.S is well-tolerated and effective in preventing moderate-to-severe disease outcomes due to COVID-19. We evaluated the impact of dose level, number of doses, and dose interval on immunogenicity, reactogenicity, and safety of Ad26.COV2.S in adults. Anamnestic responses were also explored., Methods: This randomised, double-blind, placebo-controlled, Phase 2a study was conducted in adults aged 18-55 years and ≥ 65 years (NCT04535453). Four dose levels (1.25 × 10
10 , 2.5 × 1010 , 5 × 1010 , and 1 × 1011 viral particles [vp], single and 2-dose schedules, and dose intervals of 56 and 84 days, were assessed. Four or 6 months post-primary vaccination, Ad26.COV2.S 1.25 × 1010 vp was given to evaluate anamnestic responses. Humoral and cell-mediated immune responses were measured. Reactogenicity and safety were assessed in all participants., Results: All Ad26.COV2.S schedules induced humoral responses with evidence of a dose response relationship. A single dose of Ad26.COV2.S (5 × 1010 vp) induced antibody and cellular immune responses that persisted for up to at least 6 months. In the 2-dose regimens, antibody responses were higher than 1-dose regimens at comparable dose levels, and the magnitude of the immune response increased when the interval between doses was increased (84 days vs 56 days). Rapid, marked immune responses were observed in all groups after vaccine antigen exposure indicating immune memory. Durable immune responses were observed in all groups for up to at least 6 months post-antigen exposure. Strong and consistent correlations between neutralising and binding antibodies were observed CD4 + and CD8 + T cell responses were similar after all regimens. Reactogenicity within 7 days post-vaccination tended to be dose-related., Conclusion: The study supports the primary, single dose schedule with Ad26.COV2.S at 5 × 1010 vp and homologous booster vaccination after a 6 month interval. Rapid and marked responses to vaccine antigen exposure indicate induction of immune memory by 1- and 2-dose primary vaccination., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Vicky Cardenas reports financial support was provided by Johnson & Johnson. Mathieu Le Gars reports financial support was provided by Johnson & Johnson. Carla Truyers reports financial support was provided by Johnson & Johnson. Javier Ruiz-Guinazu reports financial support was provided by Johnson & Johnson. Frank Struyf reports financial support was provided by Johnson & Johnson. Alicia Colfer reports financial support was provided by Johnson & Johnson. Macaya Douoguih reports financial support was provided by Johnson & Johnson. Jerald Sadoff reports financial support was provided by Johnson & Johnson. Marc Bonten reports a relationship with Shionogi, Merck, GSK and Janssen Vaccines that includes: consulting or advisory. Marc Bonten reports a relationship with Sanofi that includes: board membership. Frank Struyf reports a relationship with GSK that includes: equity or stocks. Marc Bonten reports a relationship with Johnson & Johnson, Merck, Sanofi that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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7. Immunogenicity and reactogenicity of intradermal mRNA-1273 SARS-CoV-2 vaccination: a non-inferiority, randomized-controlled trial.
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Prins MLM, Roozen GVT, Pothast CR, Huisman W, van Binnendijk R, den Hartog G, Kuiper VP, Prins C, Janse JJ, Lamers OAC, Koopman JPR, Kruithof AC, Kamerling IMC, Dijkland RC, de Kroon AC, Azimi S, Feltkamp MCW, Kuijer M, Jochems SP, Heemskerk MHM, Rosendaal FR, Roestenberg M, Visser LG, and Roukens AHE
- Abstract
Fractional dosing can be a cost-effective vaccination strategy to accelerate individual and herd immunity in a pandemic. We assessed the immunogenicity and safety of primary intradermal (ID) vaccination, with a 1/5th dose compared with the standard intramuscular (IM) dose of mRNA-1273 in SARS-CoV-2 naïve persons. We conducted an open-label, non-inferiority, randomized controlled trial in the Netherlands between June and December 2021. One hundred and fifty healthy and SARS-CoV-2 naïve participants, aged 18-30 years, were randomized (1:1:1) to receive either two doses of 20 µg mRNA-1273 ID with a standard needle (SN) or the Bella-mu® needle (BM), or two doses of 100 µg IM, 28 days apart. The primary outcome was non-inferiority in seroconversion rates at day 43 (D43), defined as a neutralizing antibody concentration threshold of 465 IU/mL, the lowest response in the IM group. The non-inferiority margin was set at -15%. Neutralizing antibody concentrations at D43 were 1789 (95% CI: 1488-2150) in the IM and 1263 (951-1676) and 1295 (1020-1645) in the ID-SN and ID-BM groups, respectively. The absolute difference in seroconversion proportion between fractional and standard-dose groups was -13.95% (-24.31 to -3.60) for the ID-SN and -13.04% (-22.78 to -3.31) for the ID-BM group and exceeded the predefined non-inferiority margin. Although ID vaccination with 1/5th dose of mRNA-1273 did not meet the predefined non-inferior criteria, the neutralizing antibody concentrations in these groups are far above the proposed proxy for protection against severe disease (100 IU/mL), justifying this strategy in times of vaccine scarcity to accelerate mass protection against severe disease., (© 2024. The Author(s).)
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- 2024
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8. Causal chemoprophylactic activity of cabamiquine against Plasmodium falciparum in a controlled human malaria infection: a randomised, double-blind, placebo-controlled study in the Netherlands.
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van der Plas JL, Kuiper VP, Bagchus WM, Bödding M, Yalkinoglu Ö, Tappert A, Seitzinger A, Spangenberg T, Bezuidenhout D, Wilkins J, Oeuvray C, Dhingra SK, Thathy V, Fidock DA, Smidt LCA, Roozen GVT, Koopman JPR, Lamers OAC, Sijtsma J, van Schuijlenburg R, Wessels E, Meij P, Kamerling IMC, Roestenberg M, and Khandelwal A
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- Adult, Humans, Plasmodium falciparum, Netherlands, Healthy Volunteers, Double-Blind Method, Malaria, Falciparum drug therapy, Malaria, Falciparum prevention & control, Malaria, Falciparum parasitology, Antimalarials
- Abstract
Background: Cabamiquine is a novel antimalarial that inhibits Plasmodium falciparum translation elongation factor 2. We investigated the causal chemoprophylactic activity and dose-exposure-response relationship of single oral doses of cabamiquine following the direct venous inoculation (DVI) of P falciparum sporozoites in malaria-naive, healthy volunteers., Methods: This was a phase 1b, randomised, double-blind, placebo-controlled, adaptive, dose-finding, single-centre study performed in Leiden, Netherlands. Malaria-naive, healthy adults aged 18-45 years were divided into five cohorts and randomly assigned (3:1) to receive cabamiquine or placebo. Randomisation was done by an independent statistician using codes in a permuted block schedule with a block size of four. Participants, investigators, and study personnel were masked to treatment allocation. A single, oral dose regimen of cabamiquine (200, 100, 80, 60, or 30 mg) or matching placebo was administered either at 2 h (early liver-stage) or 96 h (late liver-stage) after DVI. The primary endpoints based on a per-protocol analysis set were the number of participants who developed parasitaemia within 28 days of DVI, time to parasitaemia, number of participants with documented parasite blood-stage growth, clinical symptoms of malaria, and exposure-efficacy modelling. The impact of cabamiquine on liver stages was evaluated indirectly by the appearance of parasitaemia in the blood. The Clopper-Pearson CI (nominal 95%) was used to express the protection rate. The secondary outcomes were safety and tolerability, assessed in those who had received DVI and were administered one dose of the study intervention. The trial was prospectively registered on ClinicalTrials.gov (NCT04250363)., Findings: Between Feb 17, 2020 and April 29, 2021, 39 healthy participants were enrolled (early liver-stage: 30 mg [n=3], 60 mg [n=6], 80 mg [n=6], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=6]; late liver-stage: 60 mg [n=3], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=3]). A dose-dependent causal chemoprophylactic effect was observed, with four (67%) of six participants in the 60 mg, five (83%) of six participants in the 80 mg, and all three participants in the 100 and 200 mg cabamiquine dose groups protected from parasitaemia up to study day 28, whereas all participants in the pooled placebo and 30 mg cabamiquine dose group developed parasitaemia. A single, oral dose of 100 mg cabamiquine or higher provided 100% protection against parasitaemia when administered during early or late liver-stage malaria. The median time to parasitaemia in those with early liver-stage malaria was prolonged to 15, 22, and 24 days for the 30, 60, and 80 mg dose of cabamiquine, respectively, compared with 10 days for the pooled placebo. All participants with positive parasitaemia showed documented blood-stage parasite growth, apart from one participant in the pooled placebo group and one participant in the 30 mg cabamiquine group. Most participants did not exhibit any malaria symptoms in both the early and late liver-stage groups, and those reported were mild in severity. A positive dose-exposure-efficacy relationship was established across exposure metrics. The median maximum concentration time was 1-6 h, with a secondary peak observed between 6 h and 12 h in all cabamiquine dose groups (early liver-stage). All cabamiquine doses were safe and well tolerated. Overall, 26 (96%) of 27 participants in the early liver-stage group and ten (83·3%) of 12 participants in the late liver-stage group reported at least one treatment-emergent adverse event (TEAE) with cabamiquine or placebo. Most TEAEs were of mild severity, transient, and resolved without sequelae. The most frequently reported cabamiquine-related TEAE was headache. No dose-related trends were observed in the incidence, severity, or causality of TEAEs., Interpretation: The results from this study show that cabamiquine has a dose-dependent causal chemoprophylactic activity. Together with previously demonstrated activity against the blood stages combined with a half-life of more than 150 h, these results indicate that cabamiquine could be developed as a single-dose monthly regimen for malaria prevention., Funding: The healthcare business of Merck KGaA, Darmstadt, Germany., Competing Interests: Declaration of interests MB, ÖY, AT, AS, and AK are employed by the healthcare business of Merck KGaA, Darmstadt, Germany (the study sponsor). DB is employed by Merck Pty in Modderfontein, South Africa. CO and TS are employed by the Global Health Institute of Merck, Ares Trading in Eysins, Switzerland. WMB is a former (retired) employee of the Merck Institute for Pharmacometrics, Merck Serono in Lausanne, Switzerland. JW received funding for consulting with the healthcare business of Merck during the course of this study. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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9. Immunosuppression by hydroxychloroquine: mechanistic proof in in vitro experiments but limited systemic activity in a randomized placebo-controlled clinical pharmacology study.
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In 't Veld AE, Grievink HW, van der Plas JL, Eveleens Maarse BC, van Kraaij SJW, Woutman TD, Schoonakker M, Klarenbeek NB, de Kam ML, Kamerling IMC, Jansen MAA, and Moerland M
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- Humans, Toll-Like Receptor 7, Toll-Like Receptor 9, Immunosuppression Therapy, Cytokines, Hydroxychloroquine pharmacology, Hydroxychloroquine therapeutic use, Pharmacology, Clinical
- Abstract
Based on its wide range of immunosuppressive properties, hydroxychloroquine (HCQ) is used for the treatment of several autoimmune diseases. Limited literature is available on the relationship between HCQ concentration and its immunosuppressive effect. To gain insight in this relationship, we performed in vitro experiments in human PBMCs and explored the effect of HCQ on T and B cell proliferation and Toll-like receptor (TLR)3/TLR7/TLR9/RIG-I-induced cytokine production. In a placebo-controlled clinical study, these same endpoints were evaluated in healthy volunteers that were treated with a cumulative dose of 2400 mg HCQ over 5 days. In vitro, HCQ inhibited TLR responses with IC
50 s > 100 ng/mL and reaching 100% inhibition. In the clinical study, maximal HCQ plasma concentrations ranged from 75 to 200 ng/mL. No ex vivo HCQ effects were found on RIG-I-mediated cytokine release, but there was significant suppression of TLR7 responses and mild suppression of TLR3 and TLR9 responses. Moreover, HCQ treatment did not affect B cell and T cell proliferation. These investigations show that HCQ has clear immunosuppressive effects on human PBMCs, but the effective concentrations exceed the circulating HCQ concentrations under conventional clinical use. Of note, based on HCQ's physicochemical properties, tissue drug concentrations may be higher, potentially resulting in significant local immunosuppression. This trial is registered in the International Clinical Trials Registry Platform (ICTRP) under study number NL8726., (© 2023. The Author(s).)- Published
- 2023
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10. Viral clearance, pharmacokinetics and tolerability of ensovibep in patients with mild to moderate COVID-19: A phase 2a, open-label, single-dose escalation study.
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Prins MLM, van der Plas JL, Vissers MFJM, Berends CL, Tresch G, Soergel M, Fernández E, van den Berge N, Duijsings D, Zitt C, Stavropoulou V, Zimmermann M, Drake RF, Burggraaf J, Groeneveld GH, and Kamerling IMC
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- Humans, SARS-CoV-2, Recombinant Fusion Proteins, Antibodies, Viral, Double-Blind Method, COVID-19
- Abstract
Aim: To assess viral clearance, pharmacokinetics, tolerability and symptom evolution following ensovibep administration in symptomatic COVID-19 outpatients., Methods: In this open-label, first-in-patient study a single dose of either 225 mg (n = 6) or 600 mg (n = 6) of ensovibep was administered intravenously in outpatients with mild-to-moderate COVID-19 symptoms. Pharmacokinetic profiles were determined (90-day period). Pharmacodynamic assessments consisted of viral load (qPCR and cultures) and symptom questionnaires. Immunogenicity against ensovibep and SARS-CoV-2-neutralizing activity were determined. Safety and tolerability were assessed throughout a 13-week follow-up., Results: Both doses showed similar pharmacokinetics (first-order) with mean half-lives of 14 (SD 5.0) and 13 days (SD 5.7) for the 225- and 600-mg groups, respectively. Pharmacologically relevant serum concentrations were maintained in all subjects for at least 2 weeks postdose, regardless of possible immunogenicity against ensovibep. Viral load changes from baseline at day 15 were 5.1 (SD 0.86) and 5.3 (SD 2.2) log
10 copies/mL for the 225- and 600-mg doses, respectively. COVID-19 symptom scores decreased from 10.0 (SD 4.1) and 11.3 (SD 4.0) to 1.6 (SD 3.1) and 3.3 (SD 2.4) in the first week for the 225- and 600-mg groups, respectively. No anti-SARS-CoV-2 neutralizing activity was present predose and all patients had SARS-CoV-2 antibodies at day 91. Adverse events were of mild-to-moderate severity, transient and self-limiting., Conclusion: Single-dose intravenous administration of 225 or 600 mg of ensovibep appeared safe and well tolerated in patients with mild-to-moderate COVID-19. Ensovibep showed favourable pharmacokinetics in patients and the pharmacodynamic results warrant further research in a larger phase 2/3 randomized-controlled trail., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2023
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11. Administration of an adeno-associated viral vector expressing interferon-β in patients with inflammatory hand arthritis, results of a phase I/II study.
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Vrouwe JPM, Meulenberg JJM, Klarenbeek NB, Navas-Cañete A, Reijnierse M, Ruiterkamp G, Bevaart L, Lamers RJ, Kloppenburg M, Nelissen RGHH, Huizinga TWJ, Burggraaf J, and Kamerling IMC
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- Aged, Cohort Studies, Female, Genetic Therapy adverse effects, Humans, Interferon-beta biosynthesis, Middle Aged, Arthritis therapy, Dependovirus metabolism, Genetic Therapy methods, Genetic Vectors, Hand Joints, Interferon-beta administration & dosage
- Abstract
Objective: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-β, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA., Methods: In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 × 10
12 -1.2 × 1013 genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-β immune responses were evaluated. A data review committee provided safety recommendations., Results: Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-β, nor IFN-β antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose., Conclusion: Single IA doses of 0.6 × 1012 or 1.2 × 1012 ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation., Trial Registration: NCT02727764., (Copyright © 2021. Published by Elsevier Ltd.)- Published
- 2022
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12. First-in-human trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324, a dual enkephalinase inhibitor for pain management.
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Moss LM, Berends CL, van Brummelen EMJ, Kamerling IMC, Klaassen ES, Bergmann K, Ville V, Juarez-Perez V, Benichou AC, and Groeneveld GJ
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- Area Under Curve, Dose-Response Relationship, Drug, Double-Blind Method, Healthy Volunteers, Humans, Male, Neprilysin, Pain Management
- Abstract
Aim: Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR-324 belongs to the DENKI pharmacological class. This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324 in healthy male participants., Methods: This was a randomised, double-blind, placebo-controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004-11.475 mg h
-1 of STR-324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two-group, partial crossover design with four treatment periods separated by 1 month wash-out, and in part 2, 48 participants divided into three groups received either the active drug (1.25-11.25 mg h-1 ) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated., Results: No clinically relevant changes in safety parameters were observed. All treatment-emergent adverse events were mild and transient. The pharmacokinetics of STR-324 could not be determined due to most concentrations being below quantifiable limits. STR-324 metabolite concentrations were measurable, showing dose proportionality of Cmax and AUCinf with an estimated t1/2 of 0.2-0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose-dependent., Conclusion: STR-324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h-1 . Although pharmacokinetic characterisation of STR-324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed., Trial Registry: EudraCT (2014-002402-21) and toetsingonline.nl (63085)., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2022
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13. Safety, tolerability and pharmacokinetic characterisation of DACRA KBP-042 in healthy male subjects.
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Henriksen K, Broekhuizen K, de Boon WMI, Karsdal MA, Bihlet AR, Christiansen C, Dillingh MR, de Kam M, Kumar R, Burggraaf J, and Kamerling IMC
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- Calcitonin analogs & derivatives, Dose-Response Relationship, Drug, Double-Blind Method, Humans, Male, Receptors, Calcitonin agonists, Amylin Receptor Agonists pharmacology
- Abstract
There is a need for antidiabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was (a) to evaluate safety and tolerability, (b) to evaluate pharmacokinetics and (c) to assess indications of receptor engagement of single ascending doses of KBP-042, a dual amylin and calcitonin receptor agonist (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 (evening), 40 ug) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after 4 hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20 μg and above. Doses of 5-40 μg KBP-042 behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 μg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses., (© 2021 British Pharmacological Society.)
- Published
- 2021
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14. Accelerating vaccine trial conduct in a pandemic with a hot spot-based inclusion strategy using trial and epidemic simulation.
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van der Plas JL, van Esdonk MJ, Kamerling IMC, and Cohen AF
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- Humans, SARS-CoV-2 immunology, Time Factors, COVID-19 prevention & control, Clinical Trials as Topic organization & administration, Pandemics, Vaccine Efficacy
- Abstract
Clinical development of vaccines in a pandemic situation should be rigorous but expedited to tackle the pandemic threat as fast as possible. We explored the effects of a novel vaccine trial strategy that actively identifies and enrolls subjects in local areas with high infection rates. In addition, we assessed the practical requirements needed for such a strategy. Clinical trial simulations were used to assess the effects of utilizing these so-called "hot spot strategy" compared to a traditional vaccine field trial. We used preset parameters of a pandemic outbreak and incorporated realistic aspects of conducting a trial in a pandemic setting. Our simulations demonstrated that incorporating a hot spot strategy shortened the duration of the vaccine trial considerably, even if only one hot spot was identified during the clinical trial. The active hot spot strategy described in this paper has clear advantages compared to a "wait-and-see" approach that is used in traditional vaccine efficacy trials. Completion of a clinical trial can be expedited by adapting to resurgences and outbreaks that will occur in a population during a pandemic. However, this approach requires a speed of response that is unusual for a traditional phase III clinical trial. Therefore, several recommendations are made to help accomplish rapid clinical trial setup in areas identified as local outbreaks. The described model and hot spot vaccination strategy can be adjusted to disease-specific transmission characteristics and could therefore be applied to any future pandemic threat., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2021
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15. An exploratory first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone at a 2- and 1-week interval in patients with metastatic castration resistant prostate cancer.
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Vrouwe JPM, Kamerling IMC, van Esdonk MJ, Metselaar JM, Stuurman FE, van der Pluijm G, Burggraaf J, and Osanto S
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- Adenocarcinoma secondary, Aged, Bone Neoplasms secondary, Dexamethasone pharmacokinetics, Dexamethasone therapeutic use, Drug Delivery Systems, Humans, Liposomes, Male, Middle Aged, Prostatic Neoplasms, Castration-Resistant pathology, Adenocarcinoma drug therapy, Bone Neoplasms drug therapy, Dexamethasone administration & dosage, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients. In this exploratory first-in-man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2-week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy. Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1-2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter-related urosepsis). No infusion-related adverse events occurred. One patient had upsloping glucose levels ≤9.1 mmol/L. Trough plasma concentrations of liposomal- and free dexamethasone were below the lower limit of quantification (LLOQ) in part A, and above LLOQ in three patients in part B (t
1/2 ~50 h for liposomal dexamethasone), trough concentrations of liposomal- and free dexamethasone increased toward the end of the study. In seven of nine patients (78%) patients, stable disease was observed in bone and/or CT scans at follow-up, and in one (part B) of these seven patients a >50% PSA biochemical response was observed. Bi- and once weekly administrations of IV liposomal dexamethasone were well-tolerated. Weekly dosing enabled trough concentrations of liposomal- and free dexamethasone >LLOQ. The data presented support further clinical investigation in well-powered studies. Clinical trial registration: ISRCTN 10011715., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)- Published
- 2021
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16. Assessment of Risks Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Experimental Human Infection Studies.
- Author
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Kuiper VP, Rosendaal FR, Kamerling IMC, Visser LG, and Roestenberg M
- Subjects
- Disease Outbreaks, Humans, COVID-19, SARS-CoV-2
- Abstract
Controlled human infection (CHI) models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been proposed as a tool to accelerate the development of vaccines and drugs. Such models carry inherent risks. Participants may develop severe disease or complications after deliberate infection. Prolonged isolation may negatively impact their well-being. Through secondary infection of study personnel or participant household contacts, the experimental virus strain may cause a community outbreak. We identified risks associated with such a SARS-CoV-2 CHI model and assessed their likelihood and impact and propose strategies that mitigate these risks. In this report, we show that risks can be minimized with proper risk mitigation strategies; the residual risk, however, should be weighed carefully against the scientific and social values of such a CHI model., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)
- Published
- 2021
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17. How to expedite early-phase SARS-CoV-2 vaccine trials in pandemic setting-A practical perspective.
- Author
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van der Plas JL, Roestenberg M, Cohen AF, and Kamerling IMC
- Subjects
- Humans, COVID-19 prevention & control, COVID-19 Vaccines, Clinical Trials as Topic organization & administration, Pandemics
- Published
- 2021
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18. A novel sustained-release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers.
- Author
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Berends CL, Pagan L, van Esdonk MJ, Klarenbeek NB, Bergmann KR, Moerland M, van der Wel V, de Visser SJ, Büller H, de Loos F, de Vries WS, Waals H, de Leede LGJ, Burggraaf J, and Kamerling IMC
- Subjects
- Adult, Area Under Curve, Cross-Over Studies, Cysteamine administration & dosage, Cysteamine adverse effects, Cystine Depleting Agents administration & dosage, Cystine Depleting Agents adverse effects, Delayed-Action Preparations administration & dosage, Delayed-Action Preparations adverse effects, Delayed-Action Preparations pharmacokinetics, Healthy Volunteers, Humans, Male, Netherlands, Young Adult, Cysteamine pharmacokinetics, Cystine Depleting Agents pharmacokinetics, Cystinosis drug therapy
- Abstract
The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers. This was a randomized, investigator-blinded, three-way cross-over study to compare single doses (600 mg) of PO-001 with Cystagon
® (immediate-release) and Procysbi® (delayed-release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM® . Pharmacokinetics showed clear sustained-release characteristics of PO-001 over time with a lower Cmax and longer Tmax compared to Cystagon® and Procysbi® . All treatment-emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon® intake. Population PK simulations showed a favourable PK profile based on Cmax and Ctrough concentrations at steady state. In conclusion, a single dose of 600 mg PO-001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained-release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained-release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18)., (© 2021 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2021
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19. Pharmacokinetics of fosfomycin in patients with prophylactic treatment for recurrent Escherichia coli urinary tract infection.
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Kuiper SG, Dijkmans AC, Wilms EB, Kamerling IMC, Burggraaf J, Stevens J, and van Nieuwkoop C
- Subjects
- Anti-Bacterial Agents therapeutic use, Chromatography, Liquid, Escherichia coli, Humans, Prospective Studies, Quality of Life, Tandem Mass Spectrometry, Fosfomycin, Urinary Tract Infections drug therapy, Urinary Tract Infections prevention & control
- Abstract
Objectives: To evaluate the pharmacokinetics and clinical effectiveness of IV and oral fosfomycin treatment in patients with recurrent urinary tract infection (rUTI) with Escherichia coli., Patients and Methods: Patients with rUTI treated with 3 g of oral fosfomycin every 72 h for at least 14 days were included in a prospective open-label single-centre study. Serum samples were taken after oral and IV administration of fosfomycin. Urine was collected for 24 h on 3 consecutive days. Fosfomycin concentrations in serum and urine were analysed using validated LC-MS/MS. Pharmacokinetics were evaluated using a population model. EudraCT number 2018-000616-25., Results: Twelve patients were included, of whom nine were also administered IV fosfomycin. Data were best described by a two-compartment model with linear elimination and a transit-absorption compartment. Median values for absolute bioavailability and serum half-life were 18% and 2.13 h, respectively. Geometric mean urine concentrations on Days 1, 2 and 3 were above an MIC of 8 mg/L after both oral and IV administration. Quality of life reported on a scale of 1-10 increased from 5.1 to 7.4 (P = 0.001). The average score of UTI symptoms decreased after fosfomycin dosing (by 3.1 points, 95% CI = -0.7 to 7.0, P = 0.10)., Conclusions: Oral fosfomycin at 3 g every 72 h provides plasma and urine concentrations of fosfomycin above the MIC for E. coli. This pharmacokinetic model can be used to develop optimal dosing regimens of fosfomycin in patients with UTI., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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20. The effect of food and formulation on the population pharmacokinetics of cholesteryl ester transferase protein inhibitor DRL-17822 in healthy male volunteers.
- Author
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Goulooze SC, Kruithof AC, Alikunju S, Gautam A, Burggraaf J, Kamerling IMC, and Stevens J
- Subjects
- Administration, Oral, Biological Availability, Cross-Over Studies, Food-Drug Interactions, Healthy Volunteers, Humans, Male, Quinolines, Tetrazoles, Transferases, Cholesterol Esters, Pharmaceutical Preparations
- Abstract
We aimed to characterise the population pharmacokinetics of cholesteryl ester transferase protein inhibitor DRL-17822 in healthy males and explore the effect of food and formulation on the oral absorption of DRL-17822 in 4 phase I studies. DRL-17822 was dosed orally (2-1000 mg) in 2 different drug formulations (nanocrystal formulation and amorphous solid dispersion formulation) after either an overnight fast, or a low-fat, continental or high-fat breakfast. A 2-compartment model with 6 transit absorption compartments best characterised the data. Additionally, a strong interaction of food and formulation on bioavailability was observed and parsimoniously characterised in the model by binning combinations of food state and formulation with similar bio-availabilities. The final model adequately characterised the pharmacokinetic data of DRL-17822 in healthy males including the complex interaction of food and drug formulation. The amorphous solid dispersion formulation has a lower food effect on bioavailability compared with the nanocrystal formulation., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
- Published
- 2020
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21. The Optimal Imaging Window for Dysplastic Colorectal Polyp Detection Using c-Met-Targeted Fluorescence Molecular Endoscopy.
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de Jongh SJ, Vrouwe JPM, Voskuil FJ, Schmidt I, Westerhof J, Koornstra JJ, de Kam ML, Karrenbeld A, Hardwick JCH, Robinson DJ, Burggraaf J, Kamerling IMC, and Nagengast WB
- Subjects
- Aged, Colonic Polyps pathology, Colorectal Neoplasms pathology, Female, HT29 Cells, Humans, Male, Middle Aged, Adenoma diagnostic imaging, Colonic Polyps diagnostic imaging, Colonoscopy methods, Colorectal Neoplasms diagnostic imaging, Proto-Oncogene Proteins c-met metabolism, Spectrometry, Fluorescence methods
- Abstract
Fluorescence molecular endoscopy (FME) is an emerging technique that has the potential to improve the 22% colorectal polyp detection miss-rate. We determined the optimal dose-to-imaging interval and safety of FME using EMI-137, a c-Met-targeted fluorescent peptide, in a population at high risk for colorectal cancer. Methods: We performed in vivo FME and quantification of fluorescence by multidiameter single-fiber reflectance/single-fiber fluorescence spectroscopy in 15 patients with a dysplastic colorectal adenoma. EMI-137 was intravenously administered (0.13 mg/kg) at a 1-, 2- or 3-h dose-to-imaging interval ( n = 3 patients per cohort). Two cohorts were expanded to 6 patients on the basis of target-to-background ratios. Fluorescence was correlated to histopathology and c-Met expression. EMI-137 binding specificity was assessed by fluorescence microscopy and in vitro experiments. Results: FME using EMI-137 appeared to be safe and well tolerated. All dose-to-imaging intervals showed significantly higher fluorescence in the colorectal lesions than in surrounding tissue, with a target-to-background ratio of 1.53, 1.66, and 1.74 for the 1-, 2-, and 3-h cohorts, respectively, and a mean intrinsic fluorescence of 0.035 vs. 0.023 mm
-1 ( P < 0.0003), 0.034 vs. 0.021 mm-1 ( P < 0.0001), and 0.033 vs. 0.019 mm-1 ( P < 0.0001), respectively. Fluorescence correlated with histopathology on a macroscopic and microscopic level, with significant c-Met overexpression in dysplastic mucosa. In vitro, a dose-dependent specific binding was confirmed. Conclusion: FME using EMI-137 appeared to be safe and feasible within a 1- to 3-h dose-to-imaging interval. No clinically significant differences were observed among the cohorts, although a 1-h dose-to-imaging interval was preferred from a clinical perspective. Future studies will investigate EMI-137 for improved colorectal polyp detection during screening colonoscopies., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2020
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22. First-in-human administration of a live-attenuated RSV vaccine lacking the G-protein assessing safety, tolerability, shedding and immunogenicity: a randomized controlled trial.
- Author
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Verdijk P, van der Plas JL, van Brummelen EMJ, Jeeninga RE, de Haan CAM, Roestenberg M, Burggraaf J, and Kamerling IMC
- Subjects
- Adult, Aged, Animals, Antibodies, Neutralizing, Antibodies, Viral, Child, Child, Preschool, GTP-Binding Proteins, Humans, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Vaccines adverse effects, Respiratory Syncytial Virus, Human
- Abstract
Background: Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in early infancy and in elderly. A pediatric vaccine against RSV would not only prevent morbidity and mortality amongst infants and young children but could also reduce transmission to elderly. The RSVΔG vaccine consists of a live-attenuated RSV that lacks the G attachment protein. RSVΔG is severely impaired in binding to host cells and exhibits reduced infectivity in preclinical studies. Intranasal immunization of cotton rats with RSVΔG vaccine protected against replication of wildtype RSV, without inducing enhanced disease., Methods: We performed a first-in-human trial with primary objective to evaluate safety and shedding of RSVΔG (6.5 log
10 CCID50 ) after intranasal administration. Healthy adults aged between 18 and 50, with RSV neutralizing serum titers below 9.6 log2 , received a single dose of either vaccine or placebo (n = 48, ratio 3:1). In addition to safety and tolerability, nasal viral load, and systemic and humoral immune responses were assessed at selected time points until 4 weeks after immunization., Results: Intranasal administration of RSVΔG was well tolerated with no findings of clinical concern. No infectious virus was detected in nasal wash samples. Similar to other live-attenuated RSV vaccines, neutralizing antibody response following inoculation was limited in seropositive adults., Conclusions: A single dose of 6.5 log10 CCID50 of RSVΔG was safe and well-tolerated in seropositive healthy adults. RSVΔG was sufficiently attenuated but there were no signs of induction of antibodies. Safety and immunogenicity can now be explored in children and eventually in seronegative infants. Clinical trial register: NTR7173/EudraCT number 2016-002437-30., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)- Published
- 2020
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23. Prevalent levels of RSV serum neutralizing antibodies in healthy adults outside the RSV-season.
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Van Der Plas JL, Verdijk P, Van Brummelen EMJ, Jeeninga RE, Roestenberg M, Burggraaf J, and Kamerling IMC
- Subjects
- Adult, Antibodies, Neutralizing, Antibodies, Viral, Humans, Seasons, Respiratory Syncytial Virus Infections epidemiology, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Virus, Human
- Abstract
One of the main challenges in early clinical research with respiratory syncytial virus (RSV) live-attenuated vaccines (LAVs) is to assess immunogenicity in healthy adults. Healthy adults will have preexisting levels of serum neutralizing antibodies that could prematurely neutralize the LAV and underestimate the potential effect of the vaccine on the immune system. Data on prevalence and distribution of virus neutralizing titers (VNTs) in healthy adults is limited and there is no absolute threshold for protection against RSV-infection that can serve as an eligibility criterion in early phase trials. We assessed the RSV-specific serum VNT in healthy adults outside the Dutch RSV-Season in two clinical studies performed in 2017 (exploratory study, n = 100) and 2018 (first-in-human LAV-study, n = 190) using the same neutralizing assay. Our findings show that the prevalence and distribution of serum VNT was overall consistent in the two clinical studies. Log
2 VNTs were normally distributed, distributions of VNTs were similar and there was no statistical difference in mean log2 VNT for both studies ( p = .3). Serum VNTs were comparable during the 6 months of screening in the FIH LAV-study. Our findings will help to determine a cutoff serum VNT to be used as an eligibility criterion in future early phase clinical trials.- Published
- 2020
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24. Effect of Food on the Pharmacokinetics of 2 Formulations of DRL-17822, a Novel Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Males.
- Author
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Kruithof AC, Kumar R, Stevens J, de Kam ML, Gautam A, Alikunju S, Padhi BK, Kulkarni S, Raghuvanshi RS, Gandhi R, Burggraaf J, and Kamerling IMC
- Subjects
- Administration, Oral, Adolescent, Adult, Area Under Curve, Cholesterol, HDL blood, Cholesterol, LDL blood, Cross-Over Studies, Dietary Fats administration & dosage, Dietary Fats adverse effects, Drug Compounding, Healthy Volunteers, Humans, Male, Middle Aged, Quinolines administration & dosage, Quinolines blood, Tetrazoles administration & dosage, Tetrazoles blood, Triglycerides blood, Young Adult, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Food-Drug Interactions, Quinolines pharmacokinetics, Tetrazoles pharmacokinetics
- Abstract
DRL-17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20-fold of maximum concentration and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, following a high-fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL-17822 in a 2-part randomized, open-label, 4-way crossover study involving healthy adult males 18-45 years of age. In both parts of the study, 12 subjects received both formulations of DRL-17822 in both the fasted and fed states; a low-fat breakfast was provided in the first part and a high-fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL-17822 exposure in the fasted state, including increased maximum concentration, area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, and area under plasma concentration-time curve from time zero to infinity. Following a high-fat breakfast, DRL-17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high-density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL-17822 on high-density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL-17822 has a favorable exposure profile and therefore a more predictable food effect profile., (© 2019, The American College of Clinical Pharmacology.)
- Published
- 2019
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25. The simplified oral flucloxacillin absorption test: an accurate method to identify patients with inadequate oral flucloxacillin absorption.
- Author
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Dijkmans AC, Kweekel DM, Balmforth C, van Esdonk MJ, van Dissel JT, Burggraaf J, and Kamerling IMC
- Subjects
- Administration, Oral, Adult, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents pharmacokinetics, Chromatography, Liquid methods, Dose-Response Relationship, Drug, Female, Humans, Infusions, Intravenous, Male, Microbial Sensitivity Tests methods, Reproducibility of Results, Staphylococcus aureus drug effects, Staphylococcus aureus isolation & purification, Drug Monitoring methods, Floxacillin administration & dosage, Floxacillin pharmacokinetics, Gastrointestinal Absorption, Staphylococcal Infections diagnosis, Staphylococcal Infections drug therapy
- Abstract
Background: The preferred treatment for severe methicillin-sensitive Staphylococcus aureus infections is flucloxacillin, a small-spectrum antibiotic administered intravenously (IV) and orally. However, clinicians switch to the less preferred broad-spectrum antibiotics because of the variable absorption after oral administration of flucloxacillin. A classical oral absorption test (OAT) requires overnight fasting and interruption of IV therapy, and is laborious. In the current study, we investigated whether a simplified OAT can be utilized in a clinical setting to guide antibiotic treatment in patients with severe S. aureus infections. For this, OAT IV therapy is continued and oral dosing is performed after a one-hour fast and implemented after a small study., Methods: In 196 patients receiving IV flucloxacillin by continuous infusion, a classical OAT (test A) or simplified version of the OAT (test B) was performed. In both tests, 1 g oral flucloxacillin was given and serum samples were taken prior to intake and at one and two hours after administration. Flucloxacillin concentrations were determined by high-performance liquid chromatography. Adequate absorption was defined as an increase of flucloxacillin concentration of at least 10 mg/l after one or two hours compared to baseline., Results: In a sample of 196 patients (85 F/111 M), test A was performed in 28 patients, and test B in 168 patients. Age, gender, and baseline values of creatinine and albumin were similar in both groups. The maximal increase of flucloxacillin absorption was highly variable between patients. In 26 (13%) of the 196 patients, the flucloxacillin increase did not reach the value of 10 mg/l. The median (interquartile range, IQR) maximal increase of flucloxacillin absorption was 22.0 (15-31.25) mg/l for test A and 21.5 (13-32.25) mg/l for test B. There was no significant difference in maximal increase of flucloxacillin absorption between test A and B (p = 0.74), nor between males and females (p = 0.95). Age, creatinine, and albumin were not correlated with flucloxacillin levels., Conclusions: The simplified version of the OAT is useful to identify patients with adequate oral flucloxacillin absorption, and to ensure the effective continuation of an oral small-spectrum treatment.
- Published
- 2019
26. The Oral Pheneticillin Absorption Test: An Accurate Method to Identify Patients with Inadequate Oral Pheneticillin Absorption.
- Author
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Dijkmans AC, Kweekel DM, van Dissel JT, van Esdonk MJ, Kamerling IMC, and Burggraaf J
- Abstract
Severe streptococcal infections are commonly treated with intravenous followed by oral penicillin (pheneticillin) therapy. However, switching from iv to oral therapy is complicated by the variability in oral pheneticillin absorption. We employed an Oral Absorption Test (OAT) for pheneticillin to identify patients in whom oral pheneticillin absorption is poor. Out of 84 patients 30 patients (36%) were identified as insufficient absorbers. Treatment failure due to pheneticillin malabsorption can be avoided by performing an OAT, and these patients should be treated by another antibiotic, which is known to be absorbed well.
- Published
- 2019
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27. Corrigendum: Controlled Human Infections As a Tool to Reduce Uncertainty in Clinical Vaccine Development.
- Author
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Roestenberg M, Kamerling IMC, and de Visser SJ
- Abstract
[This corrects the article DOI: 10.3389/fmed.2018.00297.].
- Published
- 2019
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28. Colistin methanesulfonate infusion solutions are stable over time and suitable for home administration.
- Author
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Post TE, Kamerling IMC, van Rossen RCJM, Burggraaf J, Stevens J, Dijkmans AC, Heijerman HGM, Touw DJ, van Velzen AJ, and Wilms EB
- Abstract
The stability of colistin methanesulfonate (CMS) was determined in quadruplicate in elastomeric home infusion pumps containing 1, 2 or 3 MU CMS and in infusion bags with 2 MU CMS all in 100 mL normal saline. Infusions were stored at room temperature (20°C-24°C) with or without exposure to natural light or refrigerated (4°C-8°C) and protected from light up to 2 weeks. In the initial solution of 2 MU CMS in 100 mL saline sampled immediately after reconstitution and dilution, 1.5% of CMS was hydrolysed to colistin. When stored at room temperature and exposed to natural light, colistin concentration in elastomeric infusion pumps increased to 2.6% in 8 days and to 2.1% when stored at 4°C. CMS stability increases at lower temperatures and higher concentrations. Based on the current data, chemical stability of CMS infusion solution is sufficient for a shelf life of 7 days refrigerated plus 1 day at room temperature., Competing Interests: Competing interests: None declared.
- Published
- 2018
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29. Controlled Human Infections As a Tool to Reduce Uncertainty in Clinical Vaccine Development.
- Author
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Roestenberg M, Kamerling IMC, and de Visser SJ
- Abstract
Vaccines can be extremely cost-effective public health measures. Unfortunately the research and development (R&D) of novel vaccines is suffering from rising costs and declining success rates. Because many vaccines target low- and middle income markets (LMIC), output needs to be maintained at a constrained budget. In addition, scientific neglect and political uncertainty around reimbursement decisions make it an unattractive arena for private investors. The vaccine development pipeline for LMIC thus is in need for a different, sustainable, and cost-effective development model. In conventional vaccine development, objectives for every clinical development phase have been predefined. However, given the scarcity of resources, the most efficient clinical development path should identify vaccine candidates with the highest potential impact as soon as possible. We argue for a custom-made question-based development path based on the scientific questions, success probabilities and investments required. One question can be addressed by several studies and one study can provide partial answers to multiple questions. An example of a question-based approach is the implementation of a controlled human malaria infection model (CHMI). Malaria vaccine R&D faces major scientific challenges and has limited resources. Therefore, early preliminary efficacy data needs to be obtained in order to reallocate resources as efficiently as possible and reduce clinical development costs. To meet this demand, novel malaria vaccines are tested for efficacy in so-called CHMI trials in which small groups of healthy volunteers are vaccinated and subsequently infected with malaria. Early evaluation studies of critical questions, such as CHMI, are highly rewarding, since they prevent expenditures on projects that are unlikely to succeed. Each set of estimated probabilities and costs (combined with market value) will have its own optimal priority sequence of questions to address. Algorithms can be designed to determine the optimal order in which questions should be addressed. Experimental infections of healthy volunteers is an example of how a question-based approach to vaccine development can be implemented and has the potential to change the arena of clinical vaccine development.
- Published
- 2018
- Full Text
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30. Fosfomycin as a potential therapy for the treatment of systemic infections: a population pharmacokinetic model to simulate multiple dosing regimens.
- Author
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Ortiz Zacarías NV, Dijkmans AC, Burggraaf J, Mouton JW, Wilms EB, van Nieuwkoop C, Touw DJ, Kamerling IMC, and Stevens J
- Subjects
- Administration, Oral, Anti-Bacterial Agents therapeutic use, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Resistance, Multiple, Bacterial drug effects, Escherichia coli physiology, Feasibility Studies, Fosfomycin therapeutic use, Humans, Microbial Sensitivity Tests, Sepsis microbiology, Treatment Outcome, Anti-Bacterial Agents pharmacology, Escherichia coli drug effects, Fosfomycin pharmacology, Models, Biological, Sepsis drug therapy
- Abstract
Fosfomycin has emerged as a potential therapy for multidrug-resistant bacterial infections. In most European countries, the oral formulation is only approved as a 3 g single dose for treatment of uncomplicated cystitis. However, for the treatment of complicated systemic infections, this dose regimen is unlikely to reach efficacious serum and tissue concentrations. This study aims to investigate different fosfomycin-dosing regimens to evaluate its rationale for treatment of systemic infections. Serum concentration-time profiles of fosfomycin were simulated using a population pharmacokinetic model based on published pharmacokinetic parameter values, their uncertainty, inter-individual variability and covariates. The model was validated on published data and used to simulate a wide range of dosing regimens for oral and intravenous administration of fosfomycin. Finally, based on the minimum inhibitory concentration for E. coli, surrogate pharmacodynamic indices were calculated for each dosing regimen. This is the first population pharmacokinetic model to describe the oral pharmacokinetics of fosfomycin using data from different literature sources. The model and surrogate pharmacodynamic indices provide quantitative evidence that a dosing regimen of 6-12 g per day divided in 3 doses is required to obtain efficacious exposure and may serve as a first step in the treatment of systemic multi-drug-resistant bacterial infections., (© 2018 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2018
- Full Text
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31. Fosfomycin: Pharmacological, Clinical and Future Perspectives.
- Author
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Dijkmans AC, Zacarías NVO, Burggraaf J, Mouton JW, Wilms EB, van Nieuwkoop C, Touw DJ, Stevens J, and Kamerling IMC
- Abstract
Fosfomycin is a bactericidal, low-molecular weight, broad-spectrum antibiotic, with putative activity against several bacteria, including multidrug-resistant Gram-negative bacteria, by irreversibly inhibiting an early stage in cell wall synthesis. Evidence suggests that fosfomycin has a synergistic effect when used in combination with other antimicrobial agents that act via a different mechanism of action, thereby allowing for reduced dosages and lower toxicity. Fosfomycin does not bind to plasma proteins and is cleared via the kidneys. Due to its extensive tissue penetration, fosfomycin may be indicated for infections of the CNS, soft tissues, bone, lungs, and abscesses. The oral bioavailability of fosfomycin tromethamine is <50%; therefore, oral administration of fosfomycin tromethamine is approved only as a 3-gram one-time dose for treating urinary tract infections. However, based on published PK parameters, PK/PD simulations have been performed for several multiple-dose regimens, which might lead to the future use of fosfomycin for treating complicated infections with multidrug-resistant bacteria. Because essential pharmacological information and knowledge regarding mechanisms of resistance are currently limited and/or controversial, further studies are urgently needed, and fosfomycin monotherapy should be avoided., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
- Full Text
- View/download PDF
32. [Fosfomycin, an old antibiotic with new possibilities].
- Author
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Dijkmans AC, Kuiper SG, Burggraaf J, Mouton JW, Wilms EB, Touw DJ, Stevens J, van Nieuwkoop C, and Kamerling IMC
- Subjects
- Bacteria, Humans, Infections microbiology, Netherlands, Anti-Bacterial Agents therapeutic use, Drug Resistance, Multiple, Fosfomycin therapeutic use, Infections drug therapy
- Abstract
- Fosfomycin is a broad-spectrum antibiotic agent used orally for uncomplicated cystitis. The intravenous form of administration has recently been authorised in the Netherlands.- Thanks to its broad spectrum and extensive tissue penetration, fosfomycin offers possibilities for the treatment of infections in different organs.- Infections with multidrug-resistant bacteria pose a significant threat to public health. Many of these multidrug-resistant bacteria are sensitive to fosfomycin, which means fosfomycin may be an option for the treatment of infections with multidrug-resistant bacteria. - There is a lack of knowledge about the pharmacological properties of fosfomycin to establish a good dosing schedule. Knowledge is also lacking about the safety of fosfomycin and the extent of its tolerability in the treatment of different infections. - More research is needed before fosfomycin can be used in the battle against multidrug-resistant bacteria.
- Published
- 2017
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