Pharmacokinetics and pharmacodynamics of ropinirole in patients with prolactinomas

Abstract

Aims: Treatment of prolactinomas with ergoline dopamine agonists can be complicated by intolerance and resistance. This study investigated the pharmacokinetics and pharmacodynamics of the nonergot dopamine agonist ropinirole, to assess its therapeutic potential as a novel therapy for prolactinomas.

Methods: Five female subjects with prolactinomas participated in this dose-response study. Subjects received up to three doses of ropinirole (0.5, 1.0 and 2.0 mg), each on separate occasions. Frequent blood samples for prolactin and ropinirole were collected for 24 h following drug administration. Data were analysed using noncompartmental and compartmental pharmacokinetic-pharmacodynamic (PKPD) techniques.

Results: Seven 24-h curves revealed increased systemic drug exposure with increasing ropinirole doses. Ropinirole concentrations peaked at 4.4 ± 2.7 h and exhibited a half-life of 5.8 ± 1.7 h. A dose-dependent prolactin nadir occurred 4.4 ± 1.2 h after drug intake and prolactin concentrations transiently normalized in two of five subjects. PKPD modelling revealed that single-dose PK of ropinirole is dose-independent and can be described with a one-compartment model with linear absorption and elimination. An indirect response model successfully captures the inhibitory effect of ropinirole on prolactin secretion and incorporates time-dependent receptor desensitization for three of five subjects whose prolactin concentrations nadired before ropinirole reached Cmax .

Conclusions: This data-rich study has informed our understanding of the clinical pharmacokinetics and pharmacodynamics of ropinirole, which are successfully captured by the proposed semi-mechanistic PKPD model. This model can be used to further investigate the PKPD of ropinirole and may facilitate the identification of optimal dose regimens for the treatment of prolactinomas and the establishment of a new therapeutic option for patients impacted by this rare disease.

Keywords: modelling and simulation; pharmacokinetic-pharmacodynamic; pharmacometrics; ropinirole; therapeutics.

© 2018 The British Pharmacological Society.

Figures

Figure 1

(A) Individual plasma ropinirole concentration versus time profiles after the oral administration of single doses of ropinirole (0.5, 1.0 and 2.0 mg) in five hyperprolactinaemic patients. Symbols represent observations from individual patients and lines are individual predictions. (B) Time profiles of prolactin concentrations after oral administration of ropinirole at the indicated doses to hyperprolactinaemic patients. Solid lines indicate individual model predictions and empty circles are observed prolactin concentrations. Green dashed lines indicate the upper limit of normal for prolactin which is 25 ng ml–1

Figure 2

Pharmacokinetic–pharmacodynamic model diagram of ropinirole for the treatment of hyperprolactinaemia. The pharmacokinetics of ropinirole are characterized with a one compartment model with linear absorption and linear elimination. The concentration in the central compartment is used as the driving force for the inhibition of prolactin secretion. The indirect response model is used to capture the exposure response relationship. Xa is the dosing compartment (absorption compartment), Ka is the first order absorption rate constant, Tlag is the lag time for absorption, Cp is the concentration in the central compartment, Vc is the central compartment volume and CL is the clearance ropinirole (l h–1) from the central compartment. Prolactin is the concentration of prolactin in plasma. Imax is the maximum fractional ability of the ropinirole to inhibit prolactin production, which is defined as a function of desensitization slope α and time (t) in patients exhibiting time‐dependent dopamine receptor desensitization (n = 3). IC50 is the plasma concentration of ropinirole that results in 50% of the maximum inhibition. Kin and Kout are the zero‐order production rate and first order elimination rate of prolactin, respectively.

Figure 3

Simulations of ropinirole's drug effect under various conditions including after a single dose (top) and at steady state in nondesensitizing subjects after once and twice daily dosing (bottom)