Pharmacoscintigraphic comparison of HMR 1031, a VLA-4 antagonist, in healthy volunteers following delivery via a nebulizer and a dry powder inhaler.
A pharmacoscintigraphic study was conducted to compare the dose deposition of HMR 1031 from the existing nebulizer formulation and the new Ultrahaler device to help determine the doses for future phase 2 trials. This was a single-dose, open-label, randomized, two-way crossover study in which HMR 1031 (3 mg) was delivered by the Ultrahaler and the Pari LC Star nebulizer to 12 healthy male subjects. For both treatments, the formulations were radiolabeled with technetium-99m pertechnetate such that a maximum of 10 MBq was delivered on each study day. Scintigraphic images were acquired immediately after dosing to estimate the percentage of the dose delivered to the lungs and oropharynx. Serial plasma samples were collected up to 12 hours post-dose on each occasion and analyzed for HMR 1031 by a LC/MS/MS method with a lower limit of quantitation of 10 pg/mL (0.01 ng/mL). Pharmacokinetic parameters were calculated for HMR 1031 using noncompartmental methods. No serious adverse events were reported. The systemic absorption of HMR 1031 following inhalation administration was relatively rapid, with median T(max) values of 0.5 hours and 1.0 hours post-dose after administration via Ultrahaler and nebulizer, respectively. The mean plasma AUC(0-12) (Ultrahaler, 15.8 ng*h/mL; nebulizer, 11.1 ng*h/mL) and C(max) (Ultrahaler, 4.96 ng/mL; nebulizer, 2.28 ng/mL) values were approximately 42% and 118% higher for the Ultrahaler compared with the nebulizer. The mean terminal half-life of HMR 1031 was similar after administration from both devices (2.91 and 3.18 hours). Based on the scintigraphic data, the lung deposition of HMR 1031 after administration by Ultrahaler (24.6% of the administered dose) was approximately 37% higher compared with the lung deposition from the nebulizer (18.0% of the administered dose). This observation was in agreement with the relative difference in the plasma AUC values achieved after administration of the two formulations. The in vivo results based on the scintigraphic data were also comparable with those from in vitro studies for the Ultrahaler. Based on the ratio of the dose delivered by both the formulations, the required doses for the future Ultrahaler formulation can be predicted.
Aventis Pharmaceuticals, Bridgewater, New Jersey 08807-0800, USA. shashank.rohatagi@aventis.com
Shashank
S
Rohatagi
Sunny
S
Chapel
Stephane
S
Kirkesseli
Stephen
S
Newman
Jie
J
Zhang
Dominique
D
Paccaly
Linda
L
Randall
H
H
Wray
Sheree
S
Wellington
Bharti
B
Shah
Bradford K
BK
Jensen
D000280:Administration, Inhalation; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D011422:Propionates / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D013667:Technetium; D014018:Tissue Distribution
C483465:(3S)-3-(((2S)-2-(4,4-dimethyl-3-(4-((((2-methylphenyl)amino)carbonyl)amino)benzyl)-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoyl)amino)-3-phenylpropanoic acid; D018927:Anti-Asthmatic Agents; D007093:Imidazoles; D011422:Propionates; D013667:Technetium