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Article ; Online: Denosumab in Giant Cell Rich Tumors of Bone: An Open-Label Multicenter Phase II Study.

Lipplaa, Astrid / Schreuder, Willem H / Pichardo, Sarina E C / Gelderblom, Hans

2023 Volume 28, Issue 11, Page(s) 1005–e1104

Abstract: Background: Since giant cell tumors of bone (GCTB) and other giant cell rich tumors of bone (GCRTB) share the histological presence of osteoclastic giant cells and expression of RANK/RANKL, we hypothesized that GCRTB will respond similarly to denosumab ... ...

Abstract	Background: Since giant cell tumors of bone (GCTB) and other giant cell rich tumors of bone (GCRTB) share the histological presence of osteoclastic giant cells and expression of RANK/RANKL, we hypothesized that GCRTB will respond similarly to denosumab as GCTB. The primary objective of this study was to determine the efficacy of denosumab in patients with GCRTB that have recurred or require morbid surgery. Methods: In this open-label, multicenter, phase II trial, patients with GCRTB were included (June 2018-March 2020). Recruitment was stopped because of low accrual. Patients received denosumab (120 mg) subcutaneously (SC) on day 1 of every 4-week cycle with a loading dose of 120 mg SC on days 8 and 15. Results: Three patients were enrolled. One withdrew consent before start of study. The remaining patients had central giant cell granuloma of the jawbone (CGCG). Median treatment duration was 15 cycles (range 12-18). In both subjects, improvement in ossification of lesions was seen. Median follow-up was 28.5 months (range 20-37). One patient developed a recurrence for which surgery was performed. Conclusion: Due to critical emerging real-world data of denosumab in GCRTBs, the study was prematurely stopped and not supportive of use of denosumab for this indication. (ClinicalTrials.gov Identifier: NCT03605199).
MeSH term(s)	Humans ; Denosumab ; Bone Density Conservation Agents/therapeutic use ; Bone Neoplasms/drug therapy ; Giant Cell Tumor of Bone/drug therapy ; Giant Cells/pathology
Chemical Substances	Denosumab (4EQZ6YO2HI) ; Bone Density Conservation Agents
Language	English
Publishing date	2023-07-10
Publishing country	England
Document type	Clinical Trial, Phase II ; Multicenter Study ; Journal Article
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1093/oncolo/oyad196
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Zs.A 4845: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A novel colony-stimulating factor 1 (CSF1) translocation involving human endogenous retroviral element in a tenosynovial giant cell tumor.

Lipplaa, Astrid / Meijer, Debora / van de Sande, Michiel A J / Gelderblom, Hans / Bovée, Judith V M G / Mei, Hailiang / Szuhai, Karoly

Genes, chromosomes & cancer

2023 Volume 62, Issue 4, Page(s) 223–230

Abstract: Tenosynovial giant cell tumors (TSGCTs) are rare tumors arising in tendons or the synoviae of joints and bursae. The localized type is benign while the diffuse type shows expansive growth leading to greater morbidity and is therefore considered locally ... ...

Abstract	Tenosynovial giant cell tumors (TSGCTs) are rare tumors arising in tendons or the synoviae of joints and bursae. The localized type is benign while the diffuse type shows expansive growth leading to greater morbidity and is therefore considered locally aggressive. Typical recurrent chromosomal aberrations are found in the majority of TSCGT and the CSF1 gene is frequently involved. In this article, we describe a newly identified gene fusion mediated by an inversion in a case of diffuse TSGCT. Multicolor-fluorescence in situ hybridization (FISH) molecular karyotyping identified a pericentric inversion of chromosome 1 in 7 out of 17 analyzed cells 46,XX,inv(1)(p13.3q24.3) [7]/46,XX [10], and with interphase FISH the involvement the CSF1 locus was detected. After performing transcriptome sequencing analysis for fusion detection, only one out of five fusion gene algorithms detected a fusion involving the CSF1 gene product. The resulting chimera fuses a sequence from a human endogenous retrovirus (HERV) gene to CSF1 Exon 6 on chromosome 1, abrogating the regulatory element of the 3' untranslated region of the CSF1 gene. This new translocation involving Exon 6 of the CSF1 gene fused to 1q24.1, supports the hypothesis that a mutated CSF1 protein is likely to play a vital role in the pathogenesis of TSGCT. The role of the HERV partner identified as a translocation partner, however, remains unclear. Our data add to the complexity of involved translocation partners in TSGCT and point to the potential difficulty of identifying fusion partners in tumor diagnostics using transcriptome sequencing when HERV or other repeat elements are involved.
MeSH term(s)	Humans ; Macrophage Colony-Stimulating Factor/genetics ; Macrophage Colony-Stimulating Factor/metabolism ; Endogenous Retroviruses/metabolism ; In Situ Hybridization, Fluorescence ; Giant Cell Tumor of Tendon Sheath/genetics ; Giant Cell Tumor of Tendon Sheath/metabolism ; Translocation, Genetic
Chemical Substances	Macrophage Colony-Stimulating Factor (81627-83-0)
Language	English
Publishing date	2023-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	1018988-9
ISSN	1098-2264 ; 1045-2257
ISSN (online)	1098-2264
ISSN	1045-2257
DOI	10.1002/gcc.23116
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Zs.A 2966: Show issues

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Article ; Online: Challenges of denosumab in giant cell tumor of bone, and other giant cell-rich tumors of bone.

Lipplaa, Astrid / Dijkstra, Sander / Gelderblom, Hans

Current opinion in oncology

2019 Volume 31, Issue 4, Page(s) 329–335

Abstract: Purpose of review: Giant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like giant cells and neoplastic spindle-shaped cells. Denosumab ...

Abstract	Purpose of review: Giant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like giant cells and neoplastic spindle-shaped cells. Denosumab was approved by FDA in 2013 and by EMA in 2014 to treat adults and skeletally mature adolescents with unresectable GCTB or when resection is likely to result in severe morbidity. However, there is much discussion regarding the optimal applied treatment strategy. Recent findings: Neoadjuvant treatment of GCTB with denosumab can effectively downstage tumors to facilitate less morbid surgery or completely avoid the need for resection, but there is concern about local recurrence postsurgery. Definitive treatment of unresectable GTCB improves symptoms and halts tumor progression. The optimal treatment duration is unclear and long-term treatment is associated with adverse events like osteonecrosis of the jaw (ONJ) and atypical femoral fractures. Denosumab maintenance dose interval is currently being investigated. Summary: For the related but heterogenous group of giant cell rich tumors of bone, like aneurysmal bone cysts (ABC) and central giant cell granuloma (CGCG), denosumab is a new treatment modality under investigation. Given the effectiveness in GCTB, this could be a promising treatment option for selected patients with advanced disease.
MeSH term(s)	Bone Density Conservation Agents/administration & dosage ; Bone Neoplasms/drug therapy ; Bone Neoplasms/pathology ; Bone Neoplasms/surgery ; Chemotherapy, Adjuvant ; Denosumab/administration & dosage ; Giant Cell Tumor of Bone/drug therapy ; Giant Cell Tumor of Bone/pathology ; Giant Cell Tumor of Bone/surgery ; Humans ; Neoadjuvant Therapy ; Neoplasm Staging ; Randomized Controlled Trials as Topic
Chemical Substances	Bone Density Conservation Agents ; Denosumab (4EQZ6YO2HI)
Language	English
Publishing date	2019-03-15
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1049384-0
ISSN	1531-703X ; 1040-8746
ISSN (online)	1531-703X
ISSN	1040-8746
DOI	10.1097/CCO.0000000000000529
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Zs.A 3046: Show issues

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Article ; Online: Updated concepts in treatment of giant cell tumor of bone.

van der Heijden, Lizz / Lipplaa, Astrid / van Langevelde, Kirsten / Bovée, Judith V M G / van de Sande, Michiel A J / Gelderblom, Hans

Current opinion in oncology

2022 Volume 34, Issue 4, Page(s) 371–378

Abstract: Purpose of review: Giant cell tumors of bone (GCTB) are intermediate, locally aggressive primary bone tumors. For conventional GCTB, surgery remains treatment of choice. For advanced GCTB, a more important role came into play for systemic therapy ... ...

Abstract	Purpose of review: Giant cell tumors of bone (GCTB) are intermediate, locally aggressive primary bone tumors. For conventional GCTB, surgery remains treatment of choice. For advanced GCTB, a more important role came into play for systemic therapy including denosumab and bisphosphonates over the last decade. Recent findings: In diagnostics, focus has been on H3F3A (G34) driver mutations present in GCTB. The most frequent mutation (G34W) can be detected using immunohistochemistry and is highly specific in differentiating GCTB from other giant cell containing tumors. PD-L1 expression can be used as biological marker to predict higher recurrence risks in GCTB patients.The use of bisphosphonate-loaded bone cement is under investigation in a randomized controlled trial. A new technique consisting of percutaneous microwave ablation and bisphosphonate-loaded polymethylmethacrylate cementoplasty was proposed for unresectable (pelvic) GCTB.Increased experience with use of denosumab raised concern on elevated recurrence rates. However, conclusions of meta-analyses should be interpreted with risk of indication bias in mind. Several small studies are published with short-course denosumab (varying from 3 to 6 doses). One small trial directly compared denosumab and zoledronic acid, with no statistical differences in radiological and clinical outcome, and nonsignificantly higher recurrence rate after denosumab. As bisphosphonates directly target neoplastic stromal cells in GCTB, larger directly comparative trials are still warranted. Summary: Neoadjuvant denosumab is highly effective for advanced GCTB, and a short-course is advised to facilitate surgery, whereas increased recurrence rates remain of concern. Randomized controlled trials are conducted on bisphosphonate-loaded bone cement and on optimal dose and duration of neoadjuvant denosumab. PD-L1 could be a potential new therapy target in GCTB.
MeSH term(s)	B7-H1 Antigen ; Bone Cements/therapeutic use ; Bone Density Conservation Agents/therapeutic use ; Bone Neoplasms/drug therapy ; Bone Neoplasms/genetics ; Denosumab/therapeutic use ; Giant Cell Tumor of Bone/drug therapy ; Giant Cell Tumor of Bone/genetics ; Giant Cell Tumor of Bone/surgery ; Humans ; Randomized Controlled Trials as Topic ; Zoledronic Acid/therapeutic use
Chemical Substances	B7-H1 Antigen ; Bone Cements ; Bone Density Conservation Agents ; Denosumab (4EQZ6YO2HI) ; Zoledronic Acid (6XC1PAD3KF)
Language	English
Publishing date	2022-07-14
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1049384-0
ISSN	1531-703X ; 1040-8746
ISSN (online)	1531-703X
ISSN	1040-8746
DOI	10.1097/CCO.0000000000000852
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Article: Efficacy of pazopanib and sunitinib in advanced axial chordoma: a single reference centre case series.

Lipplaa, Astrid / Dijkstra, Sander / Gelderblom, Hans

Clinical sarcoma research

2016 Volume 6, Page(s) 19

Abstract: Background: Chordomas are rare malignant tumours of the axial skeleton and skull base supposed to arise from cellular remnants of the notochord. These tumours have the potential to metastasize (30-40 %), usually in the later course of the disease. ... ...

Abstract	Background: Chordomas are rare malignant tumours of the axial skeleton and skull base supposed to arise from cellular remnants of the notochord. These tumours have the potential to metastasize (30-40 %), usually in the later course of the disease. However, the greatest morbidity is usually a result of loco-regional recurrence with infiltration and destruction of surrounding bone and soft tissue. Patients with unresectable or metastatic chordoma are faced with a poor prognosis since cytotoxic chemotherapy or other systemic therapies have not proven their efficacy yet. However, several molecularly targeted drugs have been proposed as potentially beneficial, including tyrosine kinase inhibitors (TKIs) directed at vascular endothelial growth factor receptor (VEGFR), like pazopanib and sunitinib. Case presentation: Five patients with unresectable or metastatic chordoma were treated with VEGFR inhibitors pazopanib or sunitinib in the Leiden University Medical Centre (LUMC) between 2008 and 2015. Two out of four patients treated with pazopanib derived clinical benefit and disease remained stable for respectively 14 and 15 months. The one patient treated with sunitinib achieved a partial response according to RECIST 1.1 which lasted for a total of 27 months. No serious adverse events were observed. Conclusion: These results on the use of pazopanib and sunitinib in chordoma are promising, with an objective response on sunitinib and a median progression free interval of 8.5 months (range 3-15 months), comparable to that of imatinib, in the pazopanib subgroup. However further research is needed to assess the definite role of VEGFR inhibitors in chordoma.
Language	English
Publishing date	2016-11-01
Publishing country	England
Document type	Case Reports
ZDB-ID	2623217-0
ISSN	2045-3329
ISSN	2045-3329
DOI	10.1186/s13569-016-0059-x
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Article ; Online: Adjuvant Zoledronic Acid in High-Risk Giant Cell Tumor of Bone: A Multicenter Randomized Phase II Trial.

Lipplaa, Astrid / Kroep, Judith R / van der Heijden, Lizz / Jutte, Paul C / Hogendoorn, Pancras C W / Dijkstra, Sander / Gelderblom, Hans

The oncologist

2019 Volume 24, Issue 7, Page(s) 889–e421

Abstract: Lessons learned: Adjuvant treatment with zoledronic acid did not decrease the recurrence rate of giant cell tumor of bone (GCTB) in this study. The efficacy could not be determined because of the small sample size.GCTB recurrences, even in the denosumab ...

Abstract	Lessons learned: Adjuvant treatment with zoledronic acid did not decrease the recurrence rate of giant cell tumor of bone (GCTB) in this study. The efficacy could not be determined because of the small sample size.GCTB recurrences, even in the denosumab era, are still an issue; therefore, a randomized study exploring the efficacy of zoledronic acid in the adjuvant setting in GCTB is still valid. Background: Bisphosphonates are assumed to inhibit giant cell tumor of bone (GCTB)-associated osteoclast activity and have an apoptotic effect on the neoplastic mononuclear cell population. The primary objective of this study was to determine the 2-year recurrence rate of high-risk GCTB after adjuvant zoledronic acid versus standard care. Methods: In this multicenter randomized open-label phase II trial, patients with high-risk GCTB were included (December 2008 to October 2013). Recruitment was stopped because of low accrual after the introduction of denosumab. In the intervention group, patients received adjuvant zoledronic acid (4 mg) intravenously at 1, 2, 3, 6, 9, and 12 months after surgery. Results: Fourteen patients were included (intervention Conclusion: Adjuvant treatment with zoledronic acid did not decrease the recurrence rate of GCTB in this study. The efficacy could not be determined because of the small sample size. Because recurrences, even in the denosumab era, are still an issue, a randomized study exploring the efficacy of zoledronic acid in the adjuvant setting in GCTB is still valid.
MeSH term(s)	Adult ; Aged ; Bone Density Conservation Agents/therapeutic use ; Bone Neoplasms/drug therapy ; Bone Neoplasms/pathology ; Case-Control Studies ; Female ; Follow-Up Studies ; Giant Cell Tumor of Bone/drug therapy ; Giant Cell Tumor of Bone/pathology ; Humans ; Incidence ; Male ; Middle Aged ; Neoplasm Recurrence, Local/diagnosis ; Neoplasm Recurrence, Local/epidemiology ; Netherlands/epidemiology ; Prognosis ; Risk Factors ; Survival Rate ; Young Adult ; Zoledronic Acid/therapeutic use
Chemical Substances	Bone Density Conservation Agents ; Zoledronic Acid (6XC1PAD3KF)
Language	English
Publishing date	2019-04-30
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1634/theoncologist.2019-0280
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Zs.A 4845: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: RANKL inhibition for giant cell lesions of the jaw: A retrospective cohort analysis.

Schreuder, Willem H / Lipplaa, Astrid / Cleven, Arjen H G / van den Berg, Henk / Bisschop, Peter H / de Jongh, Renate T / Witjes, Max J H / Kessler, Peter A W H / Merkx, Matthias A W / Edelenbos, Esther / Klop, Cornelis / Schreurs, Ruud / Westermann, Anneke M / Tromp, Jacqueline M / Levenga, Henriette / Gelderblom, Hans / de Lange, Jan

European journal of cancer (Oxford, England : 1990)

2022 Volume 175, Page(s) 263–273

Abstract: Background: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL ... ...

Abstract	Background: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ). Methods: A retrospective cohort study was conducted compromising patients treated with a 1-year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety. Results: Twenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0-62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8-43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0-50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity. Conclusion: High-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ.
MeSH term(s)	Bone Density Conservation Agents/adverse effects ; Bone Neoplasms/drug therapy ; Cohort Studies ; Denosumab/adverse effects ; Female ; Giant Cell Tumor of Bone/diagnostic imaging ; Giant Cell Tumor of Bone/drug therapy ; Giant Cells/metabolism ; Giant Cells/pathology ; Humans ; Male ; Neoplasm Recurrence, Local/drug therapy ; Retrospective Studies
Chemical Substances	Bone Density Conservation Agents ; Denosumab (4EQZ6YO2HI)
Language	English
Publishing date	2022-09-26
Publishing country	England
Document type	Journal Article
ZDB-ID	82061-1
ISSN	1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
ISSN (online)	1879-0852
ISSN	0277-5379 ; 0959-8049 ; 0964-1947
DOI	10.1016/j.ejca.2022.08.011
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Zs.A 456: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 583: Show issues

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Article ; Online: 25-hydroxyvitamin D serum levels in patients with high risk resected melanoma treated in an adjuvant bevacizumab trial.

Lipplaa, Astrid / Fernandes, Ricardo / Marshall, Andrea / Lorigan, Paul / Dunn, Janet / Myers, Kevin A / Barker, Emily / Newton-Bishop, Julia / Middleton, Mark R / Corrie, Pippa G

British journal of cancer

2018 Volume 119, Issue 7, Page(s) 793–800

Abstract: Background: Studies evaluating a relationship of vitamin D in patients with primary melanoma have consistently identified an inverse correlation with Breslow thickness, but an inconsistent impact on survival. Vitamin D in later stages of melanoma has ... ...

Abstract	Background: Studies evaluating a relationship of vitamin D in patients with primary melanoma have consistently identified an inverse correlation with Breslow thickness, but an inconsistent impact on survival. Vitamin D in later stages of melanoma has been less studied. Methods: Vitamin D was measured in serum from 341 patients with resected stage IIB-IIIC melanoma recruited to the AVAST-M adjuvant melanoma randomised trial, collected prior to randomisation, then at 3 and 12 months. Vitamin D levels were compared with patient demographics, known melanoma prognostic factors, disease-free interval (DFI) and overall survival (OS). Results: A total of 73% patients had stage III melanoma, 32% were enroled (and therefore tested) >1 year after primary melanoma diagnosis. Median pre-randomisation vitamin D level was 56.5 (range 12.6-189.0 nmol/L). Vitamin D levels did not significantly vary over 12 months (p = 0.24). Individual pre-randomisation vitamin D levels did not differ significantly for Breslow thickness, tumour ulceration, or disease stage. Neither did pre-randomisation vitamin D predict for DFI (HR = 0.98 per 10 nmol/L increase; 95% confidence interval (CI) 0.93-1.04, p = 0.59) or OS (HR = 0.96 per 10 nmol/L increase, 95% CI 0.90-1.03, p = 0.31). For stage II patients, DFI improved with higher pre-randomisation vitamin D levels for those on bevacizumab (HR = 0.74 per 10 nmol nmol/L increase; 95% CI 0.56-0.97), but not for the observation arm (HR = 1.07 per 10 nmol/L increase; 95% CI 0.85-1.34). Conclusions: In this stage II/III melanoma cohort, vitamin D did not correlate with known prognostic markers, nor predict for DFI or OS, but there was some evidence of benefit for patients with stage II disease treated with bevacizumab.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents, Immunological/administration & dosage ; Antineoplastic Agents, Immunological/therapeutic use ; Bevacizumab/administration & dosage ; Bevacizumab/therapeutic use ; Chemotherapy, Adjuvant ; Female ; Humans ; Male ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Melanoma/surgery ; Middle Aged ; Neoplasm Staging ; Survival Analysis ; Treatment Outcome ; United Kingdom ; Vitamin D/analogs & derivatives ; Vitamin D/blood ; Young Adult
Chemical Substances	Antineoplastic Agents, Immunological ; Vitamin D (1406-16-2) ; Bevacizumab (2S9ZZM9Q9V) ; 25-hydroxyvitamin D (A288AR3C9H)
Language	English
Publishing date	2018-07-23
Publishing country	England
Document type	Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-018-0179-6
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Article ; Online: Novel Δ(9) -tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects.

Klumpers, Linda E / Beumer, Tim L / van Hasselt, Johan G C / Lipplaa, Astrid / Karger, Lennard B / Kleinloog, H Daniël / Freijer, Jan I / de Kam, Marieke L / van Gerven, Joop M A

British journal of clinical pharmacology

2012 Volume 74, Issue 1, Page(s) 42–53

Abstract: What is already known about this subject: • Cannabis based medicines are registered as a treatment for various indications, such as pain and spasms in multiple sclerosis (MS) patients, and anorexia and nausea in patients with HIV or receiving cancer ... ...

Abstract	What is already known about this subject: • Cannabis based medicines are registered as a treatment for various indications, such as pain and spasms in multiple sclerosis (MS) patients, and anorexia and nausea in patients with HIV or receiving cancer treatment. • the pharmacokinetics of the various administration routes of cannabis and cannabis based medicines are variable and dosing is hard to regulate. What this study adds: • Namisol is a new tablet containing pure THC (>98%) that has a beneficial pharmacokinetic profile after oral administration. • Namisol gives a quick onset of pharmacodynamic effects in healthy volunteers, which implies a rapid initiation of therapeutic effects in patients. Aims: Among the main disadvantages of currently available Δ(9) -tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®. Methods: This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed. Results: Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t(1/2) was 72-80 min, t(max) was 39-56 min and C(max) 2.92-4.69 ng ml(-1) . THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (-2.7 mm, 95% CI -4.5, -0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min(-1) , 95% CI 2.7, 6.5). Namisol® was well tolerated. Conclusions: Oral Namisol® showed promising PK and PD characteristics. Variability and t(max) of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.
MeSH term(s)	Adolescent ; Adult ; Analgesics, Non-Narcotic/pharmacokinetics ; Analgesics, Non-Narcotic/pharmacology ; Central Nervous System/drug effects ; Cross-Over Studies ; Dose-Response Relationship, Drug ; Double-Blind Method ; Dronabinol/analogs & derivatives ; Dronabinol/pharmacokinetics ; Dronabinol/pharmacology ; Female ; Heart Rate/drug effects ; Humans ; Male ; Pain/drug therapy ; Pain Measurement ; Postural Balance/drug effects ; Young Adult
Chemical Substances	Analgesics, Non-Narcotic ; Dronabinol (7J8897W37S)
Language	English
Publishing date	2012-06-22
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/j.1365-2125.2012.04164.x
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