Pharmacokinetics and pharmacodynamics of ropinirole in patients with prolactinomas

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. M...

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Published in:British journal of clinical pharmacology 2019-02, Vol.85 (2), p.366-376
Main Authors: Liu, Sihang, Hu, Can, Peters, Jane, Tsang, Amanda, Cremers, Serge, Bies, Robert, Page‐Wilson, Gabrielle
Format: Article
Language:English
Subjects:
Adult
Aged
Dopamine Agonists - pharmacology
Dopamine Agonists - therapeutic use
Dose-Response Relationship, Drug
Female
Half-Life
Humans
Indoles - pharmacology
Indoles - therapeutic use
Middle Aged
modelling and simulation
Models, Biological
Original
pharmacokinetic–pharmacodynamic
pharmacometrics
Pituitary Neoplasms - blood
Pituitary Neoplasms - drug therapy
Prolactin - blood
Prolactinoma - blood
Prolactinoma - drug therapy
ropinirole
therapeutics
Treatment Outcome
Young Adult
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Summary: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.
ISSN:0306-5251
1365-2125
DOI:10.1111/bcp.13802