Pharmacokinetic Characteristics of the Gonadotropin-Releasing Hormone Analog D-Ser(TBU)-⁶EA-¹⁰Luteinizing Hormone-Releasing Hormone (Buserelin) after Subcutaneous and Intranasal Administration in Children with Central Precocious Puberty

Abstract

A double antibody RIA was developed for the measurement of the long-acting GnRH agonist D-Ser(TBU)6EA10GnRH (buserelin). The antibody, raised in rabbits against a buserelin-hemocyanin conjugate, reacted with the intact molecule and also molecular fragments containing the C6-9 tetrapeptide sequence and permitted the measurement of buserelin activity in serum and urine. Natural GnRH, LH, and FSH did not cross-react in this assay system. The assay was applied to samples obtained from children receiving buserelin for the management of central precocious puberty either by once daily injection of 30 micrograms/kg or by nasal spray (in; 200 micrograms every 8 h). Urine and serum samples, chromatographed on Sephadex G-25, contained immunoreactive material corresponding closely in molecular size to [125I]buserelin. In unextracted serum samples taken at intervals after sc therapy in 11 girls, the peak immunoreactive buserelin levels of 52.2 +/- 14.8 ng/ml (mean +/- SEM) occurred at 30 min. The half-time of elimination was 74.9 +/- 36.9 min. Approximately 30% of the dose was detected in urine collected for 3 h after injection. Similar data were obtained in 3 normal adults given 10 micrograms/kg buserelin, iv. By contrast, after the administration of 200 micrograms buserelin by metered nasal spray, the mean peak serum concentration in 10 girls was 100-fold less (0.65 +/- 0.14 ng/ml), although the halftime of elimination was almost identical. Only 0.73% of the nasal dose was excreted by 3 h. Calculated relative bioavailability data indicated maximal nasal absorption of 6%. However, absorption after nasal administration varied greatly, and in 2 children, serum and urinary concentrations of buserelin after supervised administration were negligible. We conclude that in buserelin therapy, in the dose used in this study, does not represent optimal treatment for the initial management of patients with precocious puberty. The success of in therapy in sustaining initial effects of buserelin given by sc administration presumably reflects changes in receptor sensitivity induced by sc treatment.

Treatment of central precocious puberty with an intranasal analogue of GnRH (Buserelin)

“…These clinical observations emphasize the role of the dosage of the agonist using the intranasal route, in agreement with the experimental doseresponse studies in rats and dogs [19,34] and in adult man [37]. The poor intranasal absorption (less than 5%) of GnRH [5] and its agonist, Buserelin [20,30] probably accounts for the particular importance of the dosage using the intranasal route. Although serum Buserelin concentrations achieved after intranasal administration are several times lower than after subcutaneous injection of a similar dose [20,30], we found that a daily intranasal dose of 1200 gg Buserelin, not associated with cyproterone, could be effective in initiating the inhibition of pituitary-gonadal function.…”

“…The poor intranasal absorption (less than 5%) of GnRH [5] and its agonist, Buserelin [20,30] probably accounts for the particular importance of the dosage using the intranasal route. Although serum Buserelin concentrations achieved after intranasal administration are several times lower than after subcutaneous injection of a similar dose [20,30], we found that a daily intranasal dose of 1200 gg Buserelin, not associated with cyproterone, could be effective in initiating the inhibition of pituitary-gonadal function. During long-term administration of GnRH agonists, gonadotropin responses to a single injection of GnRH [4,26,28,32,38,39] or to pulsatile administration of GnRH [14] as well as spontaneous pulsatile LH secretion [28,38,39] are abolished.…”

Gonadotropin-Releasing Hormone and Its Physiological and Pathophysiological Roles in Relation to the Structure and Function of the Gastrointestinal Tract

“…Antibody development does not appear to be obligatory after GnRH treatment, but it does appear to occur more frequently in patients who develop complications in relation to the treatment [48,49]. Although no specific pathophysiological mechanisms have been confirmed, polymorphisms of the LH receptor gene and concomitant endometriosis have been suggested as triggering factors for developing gastrointestinal dysmotility in response to GnRH analogs [46].…”

Treatment of central precocious puberty

“…In some publications with relatively large numbers of treated patients, FH is only reported for those children in which FH was attained at the time of publication. The figures are often promising but the bias towards less serious cases must be suspected as those with a very early CPP were probably not yet at their FH [32,63,64].…”