Endocrine Abstracts

Introduction: A recent 12-month randomized, double-blind study showed that pasireotide LAR was superior to octreotide LAR at providing biochemical control (GH and IGF1) in medically naïve patients with acromegaly. This analysis evaluates the PK/PD of pasireotide and octreotide in these patients.

Methods: Patients received pasireotide LAR 40 mg/28 day (n=176) or octreotide LAR 20 mg/28 day (n=182) for 12 m. The relationship between pasireotide/octreotide concentrations and efficacy (GH and IGF1) was analysed using a non-linear inhibitory E_max model and logistic regression models. Exposure and safety (FPG, ECG and liver function parameters) were also evaluated.

Results: Gender, baseline GGT levels and body weight are statistically significant PK covariates for pasireotide, with no clinically meaningful impact on PK exposure; findings were similar for octreotide except for body weight. E_max model parameters (Table) show that pasireotide exposure covers the estimated effective concentrations for suppression of GH and IGF1, and pasireotide achieves stronger suppression of IGF1 than octreotide. Octreotide would not achieve normalization of IGF1 even at higher doses. Logistic regression analysis indicated a 36.6% increase in odds of IGF1 normalization with a 50% increase in pasireotide exposure; the corresponding odds increase was only 26.1% for octreotide. The odds of hyperglycaemia occurring increased with pasireotide exposure but to a lesser extent than the odds of clinical response, supporting a positive benefit-to-risk ratio for pasireotide within the dose range tested. There was no clinically significant relationship between exposure to either drug and QTcF/QTcB or liver function parameters.

Conclusions: PK/PD results support the efficacy analyses; pasireotide LAR has a superior effect on suppressing IGF1 than octreotide LAR. Besides hyperglycaemia, no other safety parameters had relevant associations with pasireotide exposure.