Sihang Liu (1), Can Hu (2), Jane Peters (3), Amanda Tsang (3), Serge Cremers (3), Robert Bies (1), Gabrielle Page-Wilson (3)
(1) School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA (2) SUNY Downstate College of Medicine, Brooklyn, NY, USA (3) College of Physicians and Surgeons, Columbia University, New York, NY, USA
Objectives: While ergoline dopamine agonists are standard therapies for the treatment of hyperprolactinemia and prolactinomas, in a subset of patients their use is limited by drug intolerance and resistance. This study aims to examine the acute effect of the non-ergot dopamine agonist ropinirole on prolactin levels in hyperprolactinemic subjects, in order to evaluate the drug’s pharmacokinetic and pharmacodynamic (PKPD) profile and to assess its therapeutic potential as a novel therapy for hyperprolactinemia and prolactinomas.
Methods: Five non-pregnant female subjects (21-77 years), with prolactinomas (n=4) or idiopathic hyperprolactinemia (n=1) and baseline prolactin levels 39-470 ng/mL, participated in an inpatient dose-response study. Subjects received up to 3 oral doses of ropinirole (0.5, 1.0, and 2.0mg), each on a separate occasion, and frequent blood samples were collected at baseline and during the 24-hour period following drug administration. The proposed population PK/PD model features a one-compartment model with linear absorption and elimination to describe ropinirole PK, and an indirect response (IDR) model (Type I) to capture the inhibition effect of ropinirole on prolactin secretion. The time-dependent receptor desensitization was incorporated into the subjects whose prolactin concentration reached nadir before the corresponding ropinirole concentration reached Cmax. The hill factor was added to capture the sigmoidicity exhibited in the data. A conventional 2-step approach was used in conducting the fitting. First, ropinirole concentrations were fit with the population PK model. The parameters to describe ropinirole PK include CL/F, Vc/F, Ka, and Tlag. Second, the empirical Bayes estimates of ropinirole PK parameters obtained in step 1 were fixed, and the predicted individual PK profiles were used as input functions in the PD model to drive the inhibition effect on prolactin secretion. The parameters to depict the ropinirole exposure-response (Kin, Baseline, IC50, Alpha, Gamma) were fit simultaneously, where Gamma is the hill factor to characterize the sigmoidicity in the data, and Alpha is the exponential slope of receptor desensitization.
All PK parameters and most PD parameters with between-subject variability (BSV) that were estimated were assumed to be log-normally distributed. Due to the limited identifiability provided by the data, Gamma was estimated as same value across subjects, and Imax was fixed to 1. The residual variability was estimated with the additive plus proportional error model in the PK part and with the proportional error model in the PD part.
Results: The population PK model reasonably described ropinirole plasma concentrations across all three dosing levels. All population means and variance parameters in the PK model were well estimated, where the relative standard errors of the estimates were moderate (<60%). The indirect response model (Type I) was used for the description of the exposure-response relationship between ropinirole and prolactin [1]. In 3 out of 5 subjects, a time-dependent desensitization term was multiplied by the Imax term in the model to account for this backward shift of peak drug effect from peak drug concentration [2]. The ratio of %Inhibition of prolactin secretion over ropinirole AUC in the desensitization group (1.5±0.6) was lower than that of the non-desensitization group (3.2±0.7). The sigmoidal Imax model for the inhibition of prolactin input rate (Kin) was superior to the basic Imax (>100 reduction in the objective function value, p<1.5E-23).
Conclusions: Utilizing a carefully collected high-density data set from a unique clinical cohort of hyperprolactinemic patients, this population PD model adequately describes the temporal relationship between ropinirole exposure and the inhibition of prolactin release. This model demonstrates that ropinirole significantly inhibits prolactin secretion in patients with hyperprolactinemia. Time-dependent D2 receptor desensitization was detected in 3 out of 5 subjects, indicating screening for desensitization during the initial treatment may be beneficial, as subjects with D2 receptor desensitization will need an increased dose to achieve the same degree of inhibition. Further studies investigating the long-term effect of ropinirole on prolactin levels are needed to establish ropinirole’s utility as a pharmacologic alternative for the treatment of prolactinomas and hyperprolactinemia.
References:
[1] Jusko, W. J. and Ko, H. C. (1994), Physiologic indirect response models characterize diverse types of pharmacodynamic effects. Clinical Pharmacology & Therapeutics, 56: 406–419.
[2] Sander, C., Hooker, J., Catana, C., Rosen, B. and Mandeville, J. (2015). Imaging Agonist-Induced D2/D3 Receptor Desensitization and Internalization In Vivo with PET/fMRI. Neuropsychopharmacology, 41(5), pp.1427-1436.
Reference: PAGE 27 (2018) Abstr 8527 [www.page-meeting.org/?abstract=8527]
Poster: Drug/Disease Modelling - Endocrine