A preclinical pharmacokinetic/pharmacodynamic approach to determine a dose of GnRH, for treatment of ovarian follicular cyst in cattle

• Published in: Journal of veterinary pharmacology and therapeutics 2004-12, Vol.27 (6), p.527-535
• Main Authors: MONNOYER, S., GUYONNET, J., TOUTAIN, P. L.
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; Cattle; Cattle Diseases - drug therapy; Cattle Diseases - pathology; Female; Gonadotropin-Releasing Hormone - administration & dosage; Gonadotropin-Releasing Hormone - pharmacokinetics; Gonadotropin-Releasing Hormone - pharmacology; Gonadotropin-Releasing Hormone - therapeutic use; Life Sciences; Luteinizing Hormone - blood; Luteinizing Hormone - drug effects; Ovarian Cysts - drug therapy; Ovarian Cysts - veterinary; Pituitary Gland - drug effects; Pituitary Gland - metabolism
• ISSN: 0140-7783; 1365-2885
• DOI: 10.1111/j.1365-2885.2004.00615.x

The objective of this study was to explore the value of a preclinical PK/PD approach to determine a gonadotropin‐releasing hormone (GnRH) dose in cows using the pituitary LH response as a surrogate endpoint. Using an indirect effect model with stimulation of the LH entry rate, the in vivo basic pharmacodynamic parameters of GnRH were determined. The EC50 of GnRH was 51 ± 16 pg/mL, the EC50 being the GnRH plasma concentration able to produce 50% of the maximum possible stimulation (Smax) of the hypophysis (Smax = 48 ± 13). From individual PK/PD parameters, the ED50 of GnRH, i.e. the estimated dose of GnRH required to determine half the maximum possible stimulating effect on LH release, was calculated to 62 μg/h per cow. Using the PK/PD model, the GnRH dose required to achieve a selected breakpoint value of 5 ng/mL for maximum LH concentration (surrogate value for LH concentration predicting clinical efficacy for cystic conditions), was 52 ± 18 μg and for a standard GnRH dose of 100 μg, the mean maximum plasma LH concentration predicted by the model was 7.22 ± 0.98 ng/mL.