Pharmacodynamic Modeling of the Effects of Lanreotide Autogel on Growth Hormone and Insulin‐Like Growth Factor 1

Abstract

Acromegaly arises from excessive levels of growth hormone (GH), many of whose effects are mediated by stimulation of secretion of insulin-like growth factor 1 (IGF-1). Synthetic somatostatin analogues inhibit GH secretion. The objective of the study was to develop a population pharmacodynamic model describing the relationship between serum concentrations of lanreotide (C(P)) and its GH and IGF-1 effects in patients with acromegaly receiving lanreotide Autogel (LA) at doses of 60, 90, or 120 mg by deep subcutaneous route every 28 days. Data were analyzed from 104 patients. The GH and IGF-1 profiles were fit simultaneously using the population approach with NONMEM. The GH vs C(P) and the IGF-1 vs GH relationships were described using inhibitory I(max) and E(max) models, respectively. Results indicated that lanreotide cannot abolish GH completely. C(P) levels of 3.4 ng/mL are required to achieve percentages of hormonal control (GH and IGF-1) of 21% and 36% in not treated and previously treated patients. If the focus is only GH, a C(P) of 3.4 ng/mL corresponds to 33% and 56% controlling rates. Simulations showed that there is a possible clinical benefit if the highest dose of 120 mg LA is administered to patients who are not well controlled by lower doses of LA.

How are growth hormone and insulin-like growth factor-1 reported as markers for drug effectiveness in clinical acromegaly research? A comprehensive methodologic review

“…Approximately 92% of the studies reported both the IGF-1 and the GH response in the population. One article was excluded from the summary tables due to the reporting of a population pharmacokinetic/pharmacodynamic (PK/PD) model instead of focusing on the biochemical control in the population, which will therefore be reported in the “ Pharmacokinetics ” section [ 20 ]. Only nine studies measured and reported the PK of the drug of interest (Table 4 ).…”

“…A total of 9 studies took samples for PK analysis of the drug of interest. The data were analyzed using a non-compartmental analysis in all but one article that applied a population PK/PD model [ 20 ]. Due to the wide range in the number of samples taken in each study, different ways of reporting were used.…”

“…In this review, nine studies (18% of total) were available that measured at least 1 PK sample. When these studies were explored, all except one study [ 20 ], performed a standard non-compartmental analysis. A non-compartment analysis will generally result in the reporting of summary statistics of the secondary PK parameters (C max , t max , area under the curve) [ 71 ].…”

“…The studies that measured the PK of the drug had the unique opportunity to investigate the concentration-effect relationship and explore possible covariates, variables that could explain the inter-individual variability in the PK, while studying a wide range of concentrations in a highly heterogeneous population. This approach was only undertaken by Garrido et al [ 20 ] in the development of a population pharmacodynamic model that included drug response on both the individual mean GH and IGF-1 levels, allowing a more evidence based approach in acromegaly treatment.…”

Quantification of the endogenous growth hormone and prolactin lowering effects of a somatostatin-dopamine chimera using population PK/PD modeling

“…To quantify the pharmacokinetic/pharmacodynamic (PK/PD) relationship on endogenous GH secretion, commonly the mean of multiple GH observations [7,8], the area under the GH-concentration-time curve [9], or a simplification of the circadian rhythm of GH was used [10]. However, these methods do not incorporate the high intraand inter-individual variability in pulsatility that is characteristic of endogenous GH profiles.…”