A dose rising study of the safety and effects on serum prolactin of SK&amp;F 101468, a novel dopamine D2‐receptor agonist.

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.

Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Pharmacokinetics and pharmacodynamics of ropinirole in patients with prolactinomas

Liu

Peters

et al. 2018

“…By comparison the mean maximum increase in prolactin following 400 mg of sulpiride was significantly higher than that produced by 10 mg DU 29894. The increase produced by 3 mg haloperidol was significantly less than that following 10 ported to the pituitary lactotrophs by the pituitary lime (h) portal system and inhibits prolactin release [19,20].…”

Section: Discussionmentioning

confidence: 99%

A comparison of the neuro‐endocrinological and temperature effects of DU 29894, flesinoxan, sulpiride and haloperidol in normal volunteers.

Koning

Vries

1995

1. Nineteen healthy male volunteers participated in a double-blind, six-way, crossover study. With a separation of 1 week between sessions, volunteers received randomly one oral dose of each of the following compounds: 3 or 10 mg of the dopamine (DA2) receptor antagonist and serotonin (5HT1A) agonist DU 29894, 1 mg flesinoxan, 400 mg sulpiride, 3 mg haloperidol or placebo. 2. To assess the dopamine (DA2) antagonistic activity of the different compounds, plasma levels of prolactin were assessed at pre-dose, 0.5, 1, 2, 3, 4, 6 and 24 h post-dose. To assess the serotonin (5HT1A) agonistic activity, plasma levels of ACTH, cortisol and growth hormone were assessed at the same time-points as well as body temperature; the latter was also assessed 8 h post-dose. Plasma levels of DU 29894 were assessed at pre-dose and 2, 3, 4 and 24 h post-dose. 3. Sulpiride, haloperidol and both doses of 3 mg and 10 mg DU 29894 produced statistically significant increases in prolactin levels. The increase produced by 3 mg was roughly equivalent to that produced by 3 mg haloperidol whereas the increase produced by 10 mg DU 29894 was significantly larger. 4. Only 10 mg DU 29894 and 1 mg flesinoxan produced statistically significant increases in ACTH, cortisol and growth hormone. All compounds either showed a significant attenuation of the normal day time increase of body temperature (3 mg DU 29894, haloperidol and sulpiride) or a true significant decrease in body temperature (10 mg DU 29894 and flesinoxan).(ABSTRACT TRUNCATED AT 250 WORDS)

“…Ropinirole, SK&F 101468, (4-[2-dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one, monochloride), is a novel non-phenolic indolone derivative which acts as a dopamine D2-receptor agonist (Gallagher et al, 1985). Previous studies in healthy subjects showed that single doses of ropinirole could cause nausea, orthostatic hypotension and prolactin inhibition (Acton & Broom, 1989;de Mey et al, 1990). Domperidone is a well established dopamine D2receptor antagonist practically devoid of central effects (Heykants et al, 1981;Kohli et al, 1983;Laduron & Leysen, 1979;Niemegeers et al, 1980).…”

Section: Introduction Methodsmentioning

confidence: 99%

Interactions between domperidone and ropinirole, a novel dopamine D2‐ receptor agonist.

Mey¹,

Enterling²,

Meineke³

et al. 1991

1. Ropinirole, SK&F 101468 has been characterized preclinically as a specific dopamine D2‐receptor agonist. Nine male healthy subjects were investigated for the effects on supine and erect heart rate and blood pressure, catecholamines and prolactin, of a single dose of 800 micrograms ropinirole preceded by a single dose of 20 mg domperidone or domperidone‐placebo, and those of a single dose of domperidone followed by ropinirole‐placebo. 2. Single doses of 800 micrograms ropinirole did not cause clinically significant changes in supine resting heart rate and blood pressure. However, they caused postural faintness on 3 min immobile upright standing on 10/26 occasions. 3. Pretreatment with 20 mg domperidone 1 h before administration of ropinirole prevented the postural symptoms in all but one subject. It did not alter ropinirole's plasma pharmacokinetics. 4. Ropinirole did not alter supine or standing catecholamine concentrations. 5. Domperidone increased the plasma concentrations of prolactin whereas ropinirole administered alone reduced them. A single dose of 800 micrograms ropinirole did not attenuate the prolactin increase induced by a single dose of 20 mg domperidone administered 1 h earlier.