safety, tolerance, and pharmacodynamics of ci-1007, a new dopamine ...

SAFETY, TOLERANCE, AND PHARMACODYNAMICS OF CI-1007, A NEW DOPAMINE AUTORECEPTOR AGONIST, IN HEALTHY SUBJECTS M.A. Eldon, Ph.D., B.A. Underwood, B.S., E.L. Posvar, M.D.,M.P.H., R. Feng, Ph.D., D.S. Wright, Ph.D., and A.J. Sedman, M.D. Ph.D.

Parke-Davis Pharmaceutical Research, Div. of Warner-Lambert Co., Ann Arbor, MI 48105

CH2

•

CO2H C

H

C H

CI-1007 inhibits the firing of central dopaminergic neurons and reduces the synthesis and release of dopamine in dopamine-containing nerve terminals through activation of presynaptic dopamine autoreceptors in the brain. Because CI-1007 has lower intrinsic agonist activity than dopamine, it also acts as a weak antagonist of postsynaptic dopamine D2 and D3 receptors. Oral CI-1007 demonstrated effects indicative of antipsychotic efficacy in rats, and monkeys, and appears to have reduced liability for extrapyramidal side effects and tardive dyskinesia. In the conditioned (Sidman) avoidance test in monkeys, CI-1007 had oral ED50 and ED100 values of 0.6 and 1.2 mg/kg that were associated with mean plasma Cmax values of 8 and 34 ng/mL, respectively 1 . Co-incubation of CI-1007 with chemical inhibitors of cytochrome P450 isoenzymes in human liver microsomal preparations suggests that P450 2D6 plays a significant role in the metabolism of CI-1007. Other centrally active dopamine autoreceptor agonists (preclamol, pramipexole) suppress prolactin secretion and stimulate growth hormone (GH) release. In contrast classic dopamine antagonist antipsychotic drugs (haloperidol, perphenazine) cause hyperprolactinemia and associated untoward effects (gynecomastia, menstrual irregularities, infertility), but do not significantly effect GH. In this study, plasma prolactin and GH concentrations were monitored as potential indicators of central dopaminergic effect, as well as for the potential of CI-1007 to cause hyperprolactinemia. METHODS Randomized, double-blind, placebo-controlled, oral, rising single-dose, safety, tolerance, pharmacokinetic, and pharmacodynamic study • Healthy male and female volunteers with P450 2D6 extensive metabolizer genotype • Doses from 0.5 to 250 mg planned, plus placebo (two-way crossover) • Four subjects per dose level • Objectives: − Determine safety and tolerance − Assess single dose pharmacokinetics − Assess changes in serum prolactin and growth hormone as possible markers of pharmacologic effect RESULTS AND DISCUSSION

Pharmacokinetics CI-1007 was rapidly absorbed, with maximal plasma concentrations occurring 1 to 3 hours postdose in most subjects. Mean plasma concentrations of CI-1007 and PD 147693, an active monohydroxy metabolite occurring in plasma, increased approximately proportionally with CI-1007 dose, although concentrations of both were very low or not detectable following administration of the 0.5 and 1 mg doses. Substantial variability in plasma concentrations of CI-1007 and PD 147693 between subjects was evident at each dose level. Apparent elimination half-life values for CI1007 ranged from approximately 3 to 10 hours, with a trend towards slightly larger values at higher doses.

The reversal of suppression of prolactin secretion in 3 of 4 subjects receiving 15 mg of CI-1007 may reflect responses to stress 4 as these subjects experienced adverse events of moderate to severe intensity lasting several hours. Alternatively, the reversal could reflect a transition from dopamine agonism to dopamine antagonism specifically at receptors on the lactotropes, as these subjects demonstrated relatively high plasma CI1007 concentrations. No evidence of reversal of GH stimulation was seen in these or any of the other subjects, suggesting that CI-1007 acted solely as a dopamine agonist at D2 receptors in the hypothalamus that are involved in tonic control of GH secretion. No evidence of postsynaptic dopamine antagonism (EPS, tardive dyskinesia, hyperactivity) was observed at any dose level, consistent with receptor binding studies which show that CI-1007 has greater affinity for presynaptic dopamine receptors as compared with postsynaptic receptors. 5,6

Mitchelson F, Drugs 1992; 43:295-315 Lokhandwala MF, et al; J Auton Pharmac 1982; 3:189-215. Felig P, et al; Endocrinology and metabolism, 2nd ed., McGraw Hill, 1987, p 272 5 Pugsley TA, et al; J Pharmacol Exp Ther 1995; 274(2):898-911 6 Meltzer LT, et al; J Pharmacol Exp Ther 1995; 274(2):912-20 2 3 4

1

Feng MR, Pharm Res 1997; 14(3):329-336

Presented at the 98th Annual Mtg. of the Amer. Society for Clinical Pharmacology and Therapeutics, San Diego, CA

Serum Prolactin Conc. (ng/mL) 25

Mean CI-1007 Mean Placebo


20

12

15

2.5 mg 2

8 10

1

4

5

0

0

0

6 5 3

16

25

Individual Subjects Mean


5 mg


20

12

15

2

8 10

1

4

0

5

0

6 5 3

0

16


25


15

2

8

10 mg

10 1

4

5

0

0

0

6 5 3

16

25




20

12

15 mg


20

12

15

2

8 10

1

Pharmacodynamics Beginning at the 1 mg dose level, plasma GH increased markedly to 10 to 50 ng/mL above placebo baseline (essentially zero GH concentration) in 18 of 20 subjects. Maximal GH concentrations occurred 2 to 4 hours postdose, increased with increasing CI-1007 dose (Figure 1), and were linearly related to CI-1007 Cmax (Figure 2). At doses of 2.5 to 10 mg, plasma prolactin decreased 20 to 80% from placebo baseline in 7 of 12 subjects, whereas prolactin increased slightly in 3 of 4 subjects receiving 15 mg (Figure 1) and did not change from baseline in the remaining subjects. Maximal suppression of prolactin secretion occurred about 4 hours postdose, increased with increasing CI-1007 dose, and was related to CI-1007 Cmax values according to an inhibitory Emax model (Figure 2). These findings are consistent with the preclinical pharmacologic profile of CI-1007 and with those of other dopamine autoreceptor agonists. The duration of pharmacodynamic effect was relatively brief; GH and prolactin returned to baseline values within 6 to 8 hours after dosing at all dose levels.

Serum GH Conc. (ng/mL) 16


4

0

5

0 0

6

12

18

24

0 0

6

12

18

24

0

6

12

18

24

Time After Dosing (hr) Figure 1. CI-1007, prolactin and GH concentration-time profiles in subjects receiving single oral CI-1007 doses ≥ 2.5 mg, or placebo. Mean prolactin profiles for doses of 2.5, 5, and 10 mg are from subjects demonstrating reduction in prolactin after drug treatment; profiles for doses of 15 mg show response from all 4 subjects. Mean GH profiles are from all 4 subjects within each dose level. 0

50 40 30 20 10 O b served Pred icted (Linear M od el)

0 0

1

2

3

4

5

Prolactin R esp ond ers Pred icted E=Im ax*C m ax IC 50+C m ax

-1 0 -2 0 from Placebo (%)

HO2C N

Nausea and vomiting and orthostatic hypotension, commonly associated with administration of dopamine agonists such as bromocriptine or pergolide, arise from direct dopamine D2 receptor stimulation of the chemoreceptor trigger zone 2 and both central and peripheral dopamine receptors within the cardiovascular system 3 , respectively. The occurrence of these adverse events following administration of CI1007, although undesirable during chronic therapy, confirms in part its preclinical pharmacologic profile as a centrally active dopamine receptor agonist.

Plasma CI-1007 Conc. (ng/mL) 6 5 3

Maximum Prolactin Change

INTRODUCTION CI-1007 (maleate salt), a partial dopamine D2 and D3 receptor agonist, has a novel chemical structure for an antipsychotic agent and is not a member of any other drug class:

Clinical Twenty-four healthy subjects 19 to 37 years old participated in the study. Doses of 0.5, 1, 2.5, and 5 mg were extremely well tolerated, with only 2 reports of mild adverse events that were considered not be related to drug. However, adverse events increased at the 10 mg dose level and became dose limiting at 15 mg. At the 10 mg dose level, 3 of 4 subjects reported mild to moderate nausea and 2 subsequently had emesis of moderate intensity. At the 15 mg dose level, 3 of 4 subjects also reported mild to moderate nausea and 2 subsequently had emesis of moderate intensity. In addition, 2 subjects displayed marked orthostatic hypotension (standing BP as low as 60/30) which lasted 8 hours in 1 case. Accordingly, the study was terminated. There were no significant changes observed on physical examination, electrocardiograms, or clinical laboratory measurements. No extrapyramidal signs were observed.

Serum GH Cmax (ng/mL)

ABSTRACT CI-1007 is a new partial dopamine D2 and D3 receptor agonist being developed for the treatment of schizophrenia. In a randomized, double-blind, dose-escalation trial, groups of 4 healthy subjects were scheduled to received a single oral dose of 0.5 to 250 mg CI1007 and placebo. Doses from 0.5 to 5 mg were extremely well tolerated, but adverse events increased at the 10 mg dose level and were limiting at 15 mg. Three of 4 subjects were nauseated and 2 vomited at doses of 10 and 15 mg, and 2 of 4 developed marked orthostatic hypotension at 15 mg. Beginning at the 1 mg dose, serum growth hormone (GH) increased markedly to 10 to 50 ng/mL above baseline in 18 of 20 subjects. Maximal GH concentrations occurred 2 to 4 hours postdose, increased with increasing CI-1007 dose, and were linearly related to CI-1007 Cmax. At doses of 2.5 to 10 mg, serum prolactin decreased 20 to 80% from placebo baseline in 7 of 12 subjects, whereas prolactin increased slightly in 3 of 4 subjects receiving 15 mg. Maximal reductions in prolactin occurred about 4 hours postdose, decreased with increasing CI1007 dose, and were related to CI-1007 Cmax values according to an inhibitory Emax model. These findings are consistent with the pharmacologic profiles of CI-1007 and other dopamine autoreceptor agonists, and indicate central dopamine agonist activity at doses less than those which were poorly tolerated.

-3 0 -4 0 -5 0 -6 0 -7 0 -8 0 -9 0

6

P la s m a C I-1 0 0 7 C m a x (ng /m L )

0

1

2

3

4

5

6

P la s m a C I-1 0 0 7 C m a x (ng /m L )

Figure 2. Relationships between maximal response in pharmacodynamic parameters for GH and prolactin and maximal plasma CI-1007 concentration

CONCLUSIONS • Single CI-1007 doses up to 5 mg were well tolerated; 15 mg is the maximum tolerated single dose in healthy subjects • Adverse events that limited further dose escalation included nausea, vomiting, and orthostatic hypotension • CI-1007 stimulated secretion of GH and suppressed secretion of prolactin in dose- and concentration-dependent manners − Central dopamine receptor agonist activity was observed following administration of well tolerated doses − Significant elevations in plasma prolactin concentrations were not observed • The pharmacodynamic and adverse event profiles of CI-1007 in humans are consistent with preclinical data that demonstrate it is a centrally active dopamine receptor agonist.

Reference: Clin Pharm Ther 1997;61(2):176