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Endocrine Abstracts (2014) 35 P918 | DOI: 10.1530/endoabs.35.P918

ECE2014 Poster Presentations Pituitary Clinical (<emphasis role="italic">Generously supported by IPSEN</emphasis>) (108 abstracts)

Pharmacokinetic (PK) and pharmacodynamic (PD) analyses of pasireotide LAR and octreotide LAR: Randomized, double-blind Phase III study in patients with medically naive acromegaly

George Shen 1 , Christelle Darstein 2 , Karina Hermosillo Reséndiz 1 , Yanfeng Wang 1 & Ke Hu 1


1Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; 2Novartis Pharma AG, Basel, Switzerland.


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 Emax 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. Emax 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.

Table 1 Key model parameters estimated using the non-linear Emax model
GH (mean±S.E.M.)IGF1 (mean±S.E.M.)
EC50 ng/mlCeffective ng/mlMaximum suppressionEC50 ng/mlCeffective ng/mlMaximum suppression
Pasireotide LAR0.73±0.166.25±1.1285.31±1.67%1.84±0.2813.45±2.397358±1.86%
Octreotide UR0.13±0.021.94±0.5984.05±1.65%0.22±0.04NAdueto Insufficient suppression <1xULN57 59±2.15%
EC50: half the maximal effective concentration to induce a response on GH or IGF1. Ceffective: the estimated effective concentration for either treatment to suppress G H or IG F1.

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.

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