Quantifying the growth hormone lowering effect of BIM23B065 after a GH stimulation test
Michiel J. van Esdonk (1,2), J. Stevens (1,3), M. Dehez (4), L. Pons (4), F.E. Stuurman (1), W. de Boon (1), P.H. van der Graaf (2,5), I. Paty (4), J. Burggraaf (1,2)
(1) Centre for Human Drug Research, Leiden, The Netherlands. (2) Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. (3) Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands. (4) Ipsen Innovation, Les Ulis, France. (5) Certara QSP (current affiliation), Canterbury, UK.
Objectives: To establish the pharmacokinetic-pharmacodynamic relationship of a novel somatostatin-dopamine chimeric compound (BIM23B065) on a growth hormone (GH) stimulation test.
Methods: A phase I, double-blind, randomized, placebo-controlled study was conducted in 63 healthy male volunteers. The study was performed in two parts; a single ascending dose with 5 cohorts and a 13 day multiple ascending dose with 3 cohorts (1.2 mg q.d., 0.8 mg b.i.d. and 1.0 mg b.i.d. administered subcutaneously). A 6 day up-titration period was included for the 3 cohorts of the multiple ascending dose study to counteract the dopaminergic effect of BIM23B065. Each cohort consisted of 8 planned subjects of which 2 received placebo. GH stimulation tests using growth hormone releasing hormone (GHRH) (1μg/kg bolus injection) were conducted on two occasions during the multiple ascending dose study (24 subjects in total).
Results: Population PK/PD analysis was performed on a total of 276 plasma GH concentrations using NONMEM 7.3 [1]. The structural model contained three key elements: 1) a previously developed PK model of BIM23B065, 2) the PK model of GHRH and 3) the GH release model. As GHRH PK was not obtained, GHRH concentrations over time were simulated using literature data [2]. The GH release model consisted of a turnover compartment (kin= 43.3 mU/L/h, kout= 0.279/h) from which GH was released in the central compartment. A zero-order release from the turnover compartment to the central compartment mimics the endogenous baseline secretion of GH. Stimulation of GH release was modeled as a first-order release from the turnover compartment following an Emax relationship (Emax = 1/h, EC50= 0.055 μg), driven by the amount of GHRH in the GHRH compartment.
Treatment with BIM23B065 was added as a covariate on the EC50 of GHRH to decrease the release of GH during the GH stimulation test. The addition of treatment with BIM23B065 as a covariate resulted in a significant increase (3000 fold) in the EC50 and drop in OFV. No changes in drug effect between the three different dosing regimens could be identified.
Conclusions: BIM23B065 significantly reduced the release of GH during a GH stimulation test which warrant investigation of the compound in patients with excessive growth hormone production.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ, and Bauer RJ (eds) NONMEM 7.3.0 Users Guides. (1989–2013). ICON Development Solutions, Hanover, MD.
[2] Ferring Pharmaceuticals Ltd, GHRH Ferring, Retrieved from https://www.medicines.org.uk/emc/medicine/664