Pharmacokinetic profile and endocrine effects of posatirelin treatment in healthy elderly subjects.
The pharmacokinetics and endocrine effects of a therapeutic dose (10 mg/day) of posatirelin (L-pyro-2-aminoadipyl-L-leucyl-L-prolinamide) were investigated in healthy elderly subjects. Posatirelin was given once daily by intramuscular injection for 7 days. Pharmacokinetic parameters were estimated using a model-independent approach. The plasma concentrations of free triiodotyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) and the circadian rhythms of prolactin and cortisol were considered as indicator variables of endocrine response to posatirelin administration. Posatirelin was well tolerated and no significant adverse effects were observed during the study. Peak plasma concentration (Cmax), time of peak plasma concentration (tmax), area under the plasma concentration-time curve from time zero to infinity (AUC0-infinity), elimination half-life (t1/2), and total clearance (CI/F) were measured after single-dose intramuscular injection (day 1) and after multiple-dose administration (day 7). There were no significant changes in these parameters after multiple-dose administration (day 7). Posatirelin induced a progressive reduction in basal TSH levels and maximum response. There were no significant changes during treatment in the time at which basal levels of FT3 and FT4 occurred, and these levels remained within the normal range throughout the study. The circadian rhythms of cortisol and prolactin were not influenced by posatirelin treatment. The pharmacokinetics of posatirelin were not time dependent, and the drug did not accumulate after multiple-dose administration. Short-term treatment with posatirelin did not induce clinically relevant endocrine consequences in healthy elderly subjects.
Dipartimento di Medicina Interna e Scienze Endocrine Metaboliche, Medical School, University of Perugia, Italy.
G
G
Reboldi
L
L
Parnetti
F
F
Santeusanio
L
L
Ambrosoli
B
B
Palumbo
A
A
Cherubini
R
R
Girardello
A
A
Poli
D T
DT
Lowenthal
U
U
Senin
D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D002491:Central Nervous System Agents / Q000493:pharmacokinetics*; D002940:Circadian Rhythm / Q000187:drug effects*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008657:Metabolic Clearance Rate; D011388:Prolactin / Q000097:blood; D013963:Thyroid Hormones / Q000097:blood*; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D002491:Central Nervous System Agents; D013963:Thyroid Hormones; D013973:Thyrotropin-Releasing Hormone; C055448:posatirelin; D011388:Prolactin; D006854:Hydrocortisone