Abstract
Purpose
To assess the pharmacokinetics, pharmacodynamics and tolerability of different doses of octreotide and pasireotide (subcutaneous [sc] and long-acting release [LAR]) when co-administered in healthy volunteers.
Methods
This was an exploratory, Phase I, single-centre study. Healthy adults were enrolled in a staggered approach into seven cohorts to receive octreotide and pasireotide (sc and LAR formulations), alone or in combination. Plasma drug concentrations, growth hormone (GH), insulin-like growth factor I (IGF-I), and plasma glucose were assessed at baseline, immediately after sc treatment, and 21 and 28 days after LAR treatment.
Results
Of 88 enrolled subjects, 52 and 82 participated in sc and LAR dosing phases, respectively. There were no relevant pharmacokinetic interactions between octreotide and pasireotide. In combination, pasireotide sc (150 µg) and octreotide sc (100/300 µg) resulted in numerically greater reductions in insulin levels and a higher incidence of AEs than either single agent; the rapid (within 1 h) increase in plasma glucose after pasireotide was delayed with combination treatment. Octreotide sc and pasireotide sc, alone or in combination, reduced IGF-I levels and led to undetectable GH levels in most subjects. During the LAR phase, addition of a low dose of pasireotide (5 mg) to a standard dose of octreotide (20 mg) resulted in an ~2-fold reduction in median IGF-I versus octreotide 20 mg 21 days post-dose; this effect was numerically greater than seen for pasireotide 20 mg alone. Peak plasma glucose was substantially lower after LAR than sc dosing. Interestingly, glucose levels were also numerically lower in the pasireotide 5 mg plus octreotide 20 mg group than for 20 mg of octreotide or pasireotide alone. AEs were less frequent after LAR than sc dosing.
Conclusions
Combined low doses of pasireotide LAR (5 mg) and octreotide LAR (10–30 mg) provided greater suppression of IGF-I than either single agent and did not increase blood glucose or incidence of AEs versus either agent alone.
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Data availability
Novartis is committed to sharing with qualified external researchers access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. This trial data availability is in accordance with the criteria and process described on www.clinicalstudydatarequest.com.
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Acknowledgements
Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Robert Jenn Ph.D., Mudskipper Business Ltd, for medical writing assistance with this paper. We also thank the site investigators, study coordinators and subjects who participated in the study.
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This study was sponsored by Novartis Pharma AG.
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L.T. is a former employee of Novartis. A.B. is an employee of Parexel International GmbH; Parexel International GmbH was paid by Novartis Pharma AG for assistance in conducting the study. G.H., K.T.H., S.C., C.D., M.P., E.D., G.G. and H.A.S. are employees of Novartis. A.M.P. is a former employee of Novartis and a current employee of Recordati.
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The protocol and all amendments were reviewed and approved by the Berlin State Ethics Committee (Turmstraße 21, Haus A, Berlin 10559, Germany). The study was conducted according to the ICH E6 Guideline for Good Clinical Practice and the ethical principles of the Declaration of Helsinki.
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Tauchmanova, L., Breitschaft, A., Holder, G. et al. Combination of pasireotide and octreotide: effects on GH and IGF-I secretion and glucose metabolism in healthy volunteers. Endocrine 75, 537–548 (2022). https://doi.org/10.1007/s12020-021-02908-6
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DOI: https://doi.org/10.1007/s12020-021-02908-6