I. De Lepeleire

Suppression of Niacin-induced Vasodilation with an Antagonist to Prostaglandin D2 Receptor Subtype 1

Niacin (nicotinic acid) reduces cardiovascular events in patients with dyslipidemia. However, symptoms associated with niacin-induced vasodilation (e.g., flushing) have limited its use. Laropiprant is a selective antagonist of the prostaglandin D(2) receptor subtype 1 (DP1), which may mediate niacin-induced vasodilation. The aim of this proof-of-concept study was to evaluate the effects of laropiprant (vs placebo) on niacin-induced cutaneous vasodilation. Coadministration of laropiprant 30, 100, and 300 mg with extended-release (ER) niacin significantly lowered flushing symptom scores (by approximately 50% or more) and also significantly reduced malar skin blood flow measured by laser Doppler perfusion imaging. Laropiprant was effective after multiple doses in reducing symptoms of flushing and attenuating the increased malar skin blood flow induced by ER niacin. In conclusion, the DP1 receptor antagonist laropiprant was effective in suppressing both subjective and objective manifestations of niacin-induced vasodilation.Niacin (nicotinic acid) reduces cardiovascular events in patients with dyslipidemia. However, symptoms associated with niacin‐induced vasodilation (e.g., flushing) have limited its use. Laropiprant is a selective antagonist of the prostaglandin D2 receptor subtype 1 (DP1), which may mediate niacin‐induced vasodilation. The aim of this proof‐of‐concept study was to evaluate the effects of laropiprant (vs placebo) on niacin‐induced cutaneous vasodilation. Coadministration of laropiprant 30, 100, and 300 mg with extended‐release (ER) niacin significantly lowered flushing symptom scores (by approximately 50% or more) and also significantly reduced malar skin blood flow measured by laser Doppler perfusion imaging. Laropiprant was effective after multiple doses in reducing symptoms of flushing and attenuating the increased malar skin blood flow induced by ER niacin. In conclusion, the DP1 receptor antagonist laropiprant was effective in suppressing both subjective and objective manifestations of niacin‐induced vasodilation.

Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans.

AbstractObjective: Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (VioxxTM), characterized in vitro as a COX-2 inhibitor. Methods: Four panels of healthy men (n=8 per panel) were administered rofecoxib (n=6) (25, 100, 250, 375 mg) or placebo (n=2) once daily on day 1 and days 3–14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose. Results: Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on day 14 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient. Conclusion: The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.

Pharmacokinetics, Pharmacodynamics, and Safety of a Prostaglandin D2 Receptor Antagonist

Laropiprant is a selective antagonist of the prostaglandin D2 (PGD2) receptor subtype 1 (DP1). Three double‐blind, randomized, placebo‐controlled studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of laropiprant in healthy male volunteers. Single doses up to 900 mg and multiple doses up to 450 mg were generally well tolerated. Laropiprant exhibited dose‐proportional pharmacokinetics. Oral absorption is rapid (Tmax=0.8–2.0 h) and the terminal half‐life is approximately 12–18 h. The pharmacokinetics of laropiprant was not affected by food. Single doses of 6 mg and higher were effective in suppressing PGD2‐induced cyclic AMP accumulation in platelets, demonstrating laropiprant target engagement with DP1. Laropiprant has detectable off‐target antagonist effects at the thromboxane A2 receptor but no clinically significant effect on collagen‐induced platelet aggregation or bleeding times with multiple doses up to 200 mg.

MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans.

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABAA receptors with comparable high affinity (0.21–0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABAA receptors, measured using an in vivo [3H]flumazenil binding assay, with an Occ50 of 2.2 mg/kg p.o. and a corresponding plasma EC50 of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a Cmax plasma concentration of 28 ng/mL, which, based on the rodent plasma EC50 for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [11C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABAA receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35–65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.

Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist.

In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABAA receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABAA subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABAA receptors as measured using an in vivo [3H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [11C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABAA receptor population for avoiding sedation in man.

Calcitonin Gene-Related Peptide8-37 Antagonizes Capsaicin-Induced Vasodilation in the Skin: Evaluation of a Human in Vivo Pharmacodynamic Model

The purpose of this study was to identify the mediators involved in capsaicin-induced vasodilation in the human skin and to evaluate a pharmacodynamic model for the early clinical evaluation of calcitonin gene-related peptide (CGRP) receptor antagonists. Dermal blood flow (DBF) response of the forearm skin to topically applied capsaicin was measured using laser Doppler perfusion imaging in 22 subjects. The effect of intra-arterially administered CGRP8-37 (1200 ng · min–1 · dl–1 forearm), indomethacin (5 μg · min–1 · dl–1 forearm), and NG-monomethyl-l-arginine (l-NMMA; 0.2 mg · min–1 dl–1 forearm), and orally administered aprepitant (375 mg) on capsaicin-induced dermal vasodilation was assessed. Furthermore, the diurnal variation of the DBF response to capsaicin was studied. CGRP8-37 inhibited the capsaicin-induced DBF increase: 217(145, 290)% in infused versus 370 (254, 486)% in the noninfused arm [mean (95% CI); p = 0.004]. In contrast, indomethacin, l-NMMA, aprepitant, and the time of assessment did not affect the DBF response to capsaicin. Thus, capsaicin-induced vasodilation in the human forearm skin is largely mediated by CGRP, but not by vasodilating prostaglandins, nitric oxide, or substance P. The response to capsaicin does not display a circadian rhythm. A pharmacodynamic model is proposed to evaluate CGRP receptor antagonists in humans in vivo.

Equivalent Dynamic Human Brain NK1-Receptor Occupancy Following Single-Dose i.v. Fosaprepitant vs. Oral Aprepitant as Assessed by PET Imaging

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single‐dose i.v. infusion of 150‐mg fosaprepitant and single‐dose oral administration of 165‐mg aprepitant, using serial [18F]MK‐0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (Tmax; ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41–75%, respectively. After aprepitant, NK1R occupancy rates at these time points (Tmax ~4 h) were ≥99, ≥99, ≥97, and 37–76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects.

Bronchodilator properties of an inhaled leukotriene D4 antagonist (verlukast—MK-0679) in asthmatic patients

The safety, tolerability and bronchodilator properties of inhaled verlukast (MK-0679), a new potent and selective LTD4-receptor antagonist, were studied in 12 asthmatic subjects with more than 15% increase in FEV1 after salbutamol inhalation. On three separate study days the patients inhaled placebo, verlukast 2 mg and verlukast 8 mg from a metered dose inhaler according to a randomized, double-blind, cross-over allocation schedule. Pulmonary function and tolerability were assessed regularly and after 8 h a second dose of test drug was inhaled. Thirty minutes later a beta 2-agonist dose-response curve was performed by inhaling salbutamol in cumulative doses of 200, 400 and 800 micrograms. Verlukast (8 mg) caused significant improvement in mean FEV1 from 1.5 through 8 h after inhalation as compared to placebo (P less than 0.05). The maximum change in FEV1 occurred at 2 h after inhalation with mean percent increases above baseline of 3.5, 7.7, and 9.2% after placebo, verlukast 2 mg and 8 mg, respectively. The bronchodilator response to inhaled salbutamol was significantly larger after verlukast 8 mg than after placebo pretreatment (P less than 0.05), whereas verlukast 2 mg afforded no additive bronchodilator effect. We conclude that inhalation of the LTD4-antagonist verlukast induces modest but significant bronchodilatation and may be beneficial in the treatment of asthma.

Effects of enteric-coated, low-dose aspirin on parameters of platelet function

Background : Aspirin is widely used as an anti‐thrombotic drug; however, it has been suggested that enteric‐coated formulations of aspirin may be less bioavailable and less effective as anti‐thrombotic agents.

PET imaging in healthy subjects and migraineurs suggests CGRP receptor antagonists do not have to act centrally to achieve clinical efficacy.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator and sensory neuropeptide implicated in the pathophysiology of migraine headache. CGRP receptor (CGRP-R) antagonists, including telcagepant, have shown clinical efficacy in treating migraine. CGRP-Rs are expressed in the CNS, particularly in the brainstem and cerebellum as well as in the periphery on vascular smooth muscle cells. To investigate whether central CGRP-Rs were likely to be involved in the anti-migraine effects of CGRP-R antagonists we examined central CGRP-R occupancy (CGRP RO) at an efficacious dose of telcagepant in healthy volunteers and in migraineurs during ictal and interictal periods using the novel PET tracer [11C]MK-4232. CGRP RO was evaluated in healthy subjects (n=3) at the lowest clinically efficacious dose (140 mg, PO) of telcagepant ~2h after dosing, coinciding with the time point of efficacy evaluation in clinical migraine studies. PET imaging showed only low CGRP RO (4% - 10%) which is within test-retest variability, suggesting that central activity is not a pre-requisite for anti-migraine efficacy of CGRP-R antagonists. A supratherapeutic telcagepant dose (1120 mg, PO) produced only moderate (43-58%, n=4) CGRP RO at ~Tmax (3h after administration). Subsequently, the possibility that brain penetration of telcagepant, a P-gp brain efflux pump substrate, may be increased in migraine patients or during migraine by blood brain barrier opening, was investigated by PET studies in the ictal and interictal periods in migraineurs (n=3) ~2 h after telcagepant dosing (140 mg, PO). Comparison of [11C]MK-4232 PET study results from ictal and interictal periods in migraineurs to healthy volunteers, suggests similar low RO and no significant differences between states. In conclusion, PET studies with the CGRP-R PET tracer [11C]MK-4232 after therapeutic doses of telcagepant in healthy volunteers and migraineurs suggest that central antagonism of CGRP-R is not necessary for therapeutic efficacy in migraine pain relief and that migraine pain is therefore at least in part peripheral in origin.