Pharmacokinetics and pharmacodynamics of ropinirole in patients with prolactinomas.
modelling and simulation
pharmacokinetic-pharmacodynamic
pharmacometrics
ropinirole
therapeutics
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
18
04
2018
revised:
20
09
2018
accepted:
12
10
2018
pubmed:
27
10
2018
medline:
4
3
2020
entrez:
27
10
2018
Statut:
ppublish
Résumé
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. 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. 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 C 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.
Identifiants
pubmed: 30362146
doi: 10.1111/bcp.13802
pmc: PMC6339972
doi:
Substances chimiques
Dopamine Agonists
0
Indoles
0
ropinirole
030PYR8953
Prolactin
9002-62-4
Types de publication
Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
366-376Subventions
Organisme : NIDDK NIH HHS
ID : R21 DK112093
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1 RR024156
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000040
Pays : United States
Informations de copyright
© 2018 The British Pharmacological Society.
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