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Ajay Madan,
Zhihong O'Brien,
Jianyun Wen,
Chris O'Brien,
Robert H Farber,
Graham Beaton,
Paul Crowe,
Berend Oosterhuis,
R Colin Garner,
Graham Lappin, Haig P Bozigian
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ABSTRACT: To evaluate the pharmacokinetics (PK) of five H(1) receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg).
Five H(1) receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy.
The median clearance (CL), apparent volume of distribution (V(d)) and apparent terminal elimination half-life (t(1/2)) of diphenhydramine after an i.v. microdose were 24.7 l h(-1), 302 l and 9.3 h, and the oral C(max) and AUC(0-infinity) were 0.195 ng ml(-1) and 1.52 ng h ml(-1), respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2.
Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.
British Journal of Clinical Pharmacology 04/2009; 67(3):288-98. · 2.96 Impact Factor
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Ajay Madan,
Zhihong O'Brien,
Jianyun Wen,
Chris O'Brien,
Robert H. Farber,
Graham Beaton,
Paul Crowe,
Berend Oosterhuis,
R. Colin Garner,
Graham Lappin, Haig P. Bozigian
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ABSTRACT: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Human microdosing studies with novel drug candidates offer an opportunity to evaluate their pharmacokinetic (PK) behaviour early in drug development and before committing to the expense of clinical Phase I-enabling activities.• Such studies assume linearity of exposure with dose all the way down to a subtherapeutic dose.• Previous studies have reported partial success in the use of this technique for assessing human PK of marketed drugs.WHAT THIS STUDY ADDS• The present study describes the application of the microdosing concept in early drug development for an H1 antagonist programme where having good estimates of human PK and information about the shape of the concentration–time curve was critical for compound selection.• Microdosing data were generated for four novel compounds and one reference compound, and the data were used for advancing the compound with the most favourable PK properties.• To our knowledge, this is the first example of the use microdosing technique for compound selection.AIMS To evaluate the pharmacokinetics (PK) of five H1 receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg).METHODS Five H1 receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy.RESULTS The median clearance (CL), apparent volume of distribution (Vd) and apparent terminal elimination half-life (t1/2) of diphenhydramine after an i.v. microdose were 24.7 l h−1, 302 l and 9.3 h, and the oral Cmax and AUC0–∞ were 0.195 ng ml−1 and 1.52 ng h ml−1, respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2.CONCLUSIONS Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.
British Journal of Clinical Pharmacology 03/2009; 67(3):288 - 298. · 2.96 Impact Factor
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ABSTRACT: Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist.
Our objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single-dose and 7-d elagolix administration to healthy premenopausal women.
This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation.
Fifty-five healthy, regularly cycling premenopausal women participated.
Subjects were administered a single oral dose of 25-400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg once daily or 100 mg twice daily for 7 d. Treatment was initiated on d 7 (+/-1) after onset of menses.
Safety, tolerability, pharmacokinetics, and serum LH, FSH, and estradiol concentrations were assessed.
Elagolix was well tolerated and rapidly bioavailable after oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 h in subjects receiving at least 50 mg/d. Daily (50-200 mg) or twice-daily (100 mg) administration for 7 d maintained low estradiol levels (17 +/- 3 to 68 +/- 46 pg/ml) in most subjects during late follicular phase. Effects of the compound were rapidly reversed after discontinuation.
Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.
Journal of Clinical Endocrinology & Metabolism 12/2008; 94(2):545-51. · 6.50 Impact Factor
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R Scott Struthers,
Qui Xie,
Susan K Sullivan,
Greg J Reinhart,
Trudy A Kohout,
Yun-Fei Zhu,
Chen Chen,
Xin-Jun Liu,
Nicholas Ling,
Weidong Yang,
Richard A Maki,
Anne K Bonneville,
Ta-Kung Chen, Haig P Bozigian
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ABSTRACT: Suppression of the hypothalamic-pituitary-gonadal axis by peptides that act at the GnRH receptor has found widespread use in clinical practice for the management of sex-steroid-dependent diseases (such as prostate cancer and endometriosis) and reproductive disorders. Efforts to develop orally available GnRH receptor antagonists have led to the discovery of a novel, potent nonpeptide antagonist, NBI-42902, that suppresses serum LH concentrations in postmenopausal women after oral administration. Here we report the in vitro and in vivo pharmacological characterization of this compound. NBI-42902 is a potent inhibitor of peptide radioligand binding to the human GnRH receptor (K(i) = 0.56 nm). Tritiated NBI-42902 binds with high affinity (K(d) = 0.19 nm) to a single class of binding sites and can be displaced by a range of peptide and nonpeptide GnRH receptor ligands. In vitro experiments demonstrate that NBI-42902 is a potent functional, competitive antagonist of GnRH stimulated IP accumulation, Ca(2+) flux, and ERK1/2 activation. It did not stimulate histamine release from rat peritoneal mast cells. Finally, it is effective in lowering serum LH in castrated male macaques after oral administration. Overall, these data provide a benchmark of pharmacological characteristics required for a nonpeptide GnRH antagonist to effectively suppress gonadotropins in humans and suggest that NBI-42902 may have clinical utility as an oral agent for suppression of the hypothalamic-pituitary-gonadal axis.
Endocrinology 03/2007; 148(2):857-67. · 4.46 Impact Factor
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ABSTRACT: Parenteral administration of peptide GnRH analogs is widely used in clinical practice for the suppression of pituitary gonadotropins. NBI-42902 is an orally available, high-affinity nonpeptide antagonist of the human GnRH receptor.
The objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropin secretion of NBI-42902 in postmenopausal women.
This was a phase I, double-blind, placebo-controlled, single-dose study with sequential dose escalation.
Fifty-six healthy, postmenopausal women were included. FSH levels were greater than 40 IU/liter, and body mass index was within 20% of ideal values for all subjects.
Subjects were administered 5, 10, 25, 50, 75, 100, 150, or 200 mg NBI-42902 as an oral solution.
Safety, tolerability, and serum LH and FSH concentrations were evaluated.
NBI-42902 was well tolerated. Serum LH concentrations rapidly declined, and dose-dependent suppression was observed. Maximal change from baseline LH concentrations ranged from -19 +/- 5% in the 5-mg group to -55 +/- 2% in the 150-mg group. Suppression of FSH was less pronounced (-15 to -22% of baseline). NBI-42902 was rapidly absorbed after oral administration with a terminal elimination half-life ranging from 2.7 +/- 0.3 to 4.8 +/- 0.8 h. A clear relationship between plasma NBI-42902 concentrations and LH suppression was evident.
Dose-dependent LH suppression was achieved by oral administration of a nonpeptide GnRH antagonist suggesting that compounds such as NBI-42902 may enable adjustable gonadotropin suppression as part of novel treatment strategies for benign gynecological conditions.
Journal of Clinical Endocrinology & Metabolism 11/2006; 91(10):3903-7. · 6.50 Impact Factor
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ABSTRACT: Indiplon (NBI 34060; N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-alpha]pyrimidin-7-yl]phenyl]acetamide), a novel pyrazolopyrimidine and high-affinity allosteric potentiator of GABA(A) receptor function, was profiled for its effects in rodents after oral administration. In mice, indiplon inhibited locomotor activity (ED(50) = 2.7 mg/kg p.o.) at doses lower than the nonbenzodiazepine hypnotics zolpidem (ED(50) = 6.1 mg/kg p.o.) and zaleplon (ED(50) = 24.6 mg/kg p.o.), a sedative effect that was reversed by the benzodiazepine site antagonist flumazenil. Indiplon inhibited retention in the mouse passive avoidance paradigm over a dose range and with a temporal profile that coincided with its sedative activity. Indiplon, zolpidem, and zaleplon were equally effective in inhibiting locomotor activity in the rat and produced dose-related deficits on the rotarod. In a rat vigilance paradigm, indiplon, zolpidem, and zaleplon produced performance deficits over a dose range consistent with their sedative effects, although indiplon alone showed no significant increase in response latency. Indiplon produced a small deficit in the delayed nonmatch to sample paradigm at a dose where sedative effects became apparent. Indiplon was active in the rat Vogel test of anxiety, but it showed only a sedative profile in the mouse open field test. The pharmacokinetic profile of indiplon in both rat and mouse was consistent with its pharmacodynamic properties and indicated a rapid T(max), short t(1/2), and excellent blood-brain barrier penetration. Therefore, indiplon has the in vivo profile of an efficacious sedative-hypnotic, in agreement with its in vitro receptor pharmacology as a high-affinity allosteric potentiator of GABA(A) receptor function, with selectivity for alpha1 subunit-containing GABA(A) receptors.
Journal of Pharmacology and Experimental Therapeutics 12/2004; 311(2):547-59. · 3.83 Impact Factor
