Tae H. Han

Single- and Multiple-Dose Pharmacokinetics and Tolerability of Telcagepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, in Adults

Telcagepant is a novel, orally active, and selective calcitonin gene‐related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half‐life was approximately 6 hours. A greater than dose‐proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice‐daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.

Lack of effect of aprepitant or its prodrug fosaprepitant on QTc intervals in healthy subjects.

BACKGROUND: A single 115-mg dose of fosaprepitant, the IV prodrug of the NK1 receptor antagonist aprepitant, is bioequivalent to a 125-mg dose of oral aprepitant. Thus far, fosaprepitant/aprepitant has not shown a meaningful effect on QTc intervals; in this study, we sought to confirm these findings. METHODS: This double-blind, active-controlled, randomized, three-treatment, three-period, crossover study in healthy young subjects evaluated the effect of a 200-mg dose of fosaprepitant on QTc prolongation. In each period, subjects received 400 mg moxifloxacin per os, 200 mg fosaprepitant IV, or placebo in randomized sequence. The effect of fosaprepitant on QTc interval was assessed by 12-lead electrocardiograms (ECGs). The baseline value for QTc interval for each subject during each period was defined as the average of five replicate baseline QTc intervals extracted from predose ECGs. ECGs were performed at predose, 2, 5, 10, 15, 20, 30, 45 min; and 1, 1.5, 2, 3, 4, 6, and 8 h postinfusion. Values for individual QTc change from baseline were evaluated in a repeated-measures mixed model appropriate for a crossover design. A two-sided 90% confidence interval (CI) for the true difference in QTc interval change from baseline at each timepoint was calculated for fosaprepitant versus placebo and for moxifloxacin versus placebo. RESULTS: After fosaprepitant 200-mg administration, the mean (95% CI) QTc interval change from baseline at Tmax was −1.45 (−4.67 to 1.77) ms, and the placebo-corrected mean (90% CI) QTc interval change from baseline was −1.37 (−4.78 to 2.05) ms. Neither was statistically significant at &agr; = 0.05. After 400 mg moxifloxacin administration, the mean (95% CI) QTc interval change from baseline at 2 h was 9.71 (6.49–12.93) ms, and the placebo-corrected mean (90% CI) QTc interval change from baseline at moxifloxacin Tmax was 10.50 (7.09–13.92) ms. Both were statistically significant at &agr; = 0.05. The maximum aprepitant concentration after fosaprepitant 200 mg administration was 6300 ng/mL (approximately twofold, fourfold, and ninefold higher than that observed historically with fosaprepitant 115 mg [3095 ng/mL], aprepitant 125 mg [1600 ng/mL], and aprepitant 40 mg [675 ng/mL]). CONCLUSIONS: In subjects receiving fosaprepitant 200 mg, no clinically meaningful increases in QTc were seen at any timepoint, whereas after moxifloxacin 400 mg, increases were observed at the approximate Tmax of moxifloxacin and additional timepoints. The lack of QTc increase at this high dose of fosaprepitant and resulting aprepitant plasma exposures support the expectation that clinical doses of fosaprepitant or aprepitant will not be associated with significant QTc prolongation.

Lack of hemodynamic interaction between CGRP-receptor antagonist telcagepant (MK-0974) and sumatriptan: results from a randomized study in patients with migraine.

Objective The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period. Methods A double-blind, placebo-controlled, four-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at seven post-dose timepoints over a period of six hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times. Results The mean difference in time-weighted (0–2.5 h) MAP (90% confidence interval) was 1.2 mmHg (−0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0–6h and Cmax of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels. Conclusion Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect.

Characterizing the PK/PD relationship for inhibition of capsaicin‐induced dermal vasodilatation by MK‐3207, an oral calcitonin gene related peptide receptor antagonist

AIMS Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy. METHODS An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure-response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose-response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated. RESULTS The results suggested that a 20 mg dose of MK-3207 (EC50 of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose-response would be reached around 40-100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial. CONCLUSIONS The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose-response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.

The Dose Proportionality of Telcagepant after Administration of Single Oral and Intravenous Doses in Healthy Adult Subjects

Introduction Telcagepant (MK-0974) is a novel, orally active and selective CGRP receptor antagonist being investigated for acute treatment of migraine. Early clinical data suggested greater than dose proportional increases in exposure following oral administration. The aim of the present studies was to definitively characterize the oral and IV dose proportionality of telcagepant. Methods Healthy adult subjects were enrolled in two separate open-label randomized dose proportionality studies: 1) single oral dose crossover from 50 to 600 mg (N = 19); 2) single IV dose parallel group from 5 to 250 mg (N = 10 per dose). Blood samples were collected at time points from 0 to 48 hours postdose. Results Telcagepant was rapidly absorbed with a Tmax of approximately 1 to 2 hours after oral administration. The terminal half-life was approximately 8 to 9 hours after IV dosing and approximately 4 to 7 hours after oral dosing. Oral administration of telcagepant resulted in greater than dose proportional increases in exposure, while IV administration resulted in approximately dose proportional increases in exposure. Conclusions Telcagepant was generally well tolerated. Oral telcagepant exhibits non-linear pharmacokinetics.