A preclinical pharmacokinetic/pharmacodynamic approach to determine a dose of GnRH, for treatment of ovarian follicular cyst in cattle.
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 EC(50) of GnRH was 51 +/- 16 pg/mL, the EC(50) being the GnRH plasma concentration able to produce 50% of the maximum possible stimulation (S(max)) of the hypophysis (S(max) = 48 +/- 13). From individual PK/PD parameters, the ED(50) 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 microg/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 microg and for a standard GnRH dose of 100 microg, the mean maximum plasma LH concentration predicted by the model was 7.22 +/- 0.98 ng/mL.
Monnoyer
S
S
CEVA Santé Animale, Preclinical Department, Z.I. La Ballastière, Libourne cedex, France.
Guyonnet
J
J
Toutain
P L
PL
D000818:Animals; D019540:Area Under Curve; D002417:Cattle; D002418:Cattle Diseases / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D007986:Luteinizing Hormone / Q000097:blood / Q000187:drug effects; D010048:Ovarian Cysts / Q000188:drug therapy / Q000662:veterinary*; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*
D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone