title: Estimating mass balance for inhaled drugs in humans: an example with a VLA-4 antagonist, IVL745.
abstract: IVL745 is an inhaled VLA-4 antagonist developed for the treatment of asthma. Following inhalation (Inh), a fraction of the drug is deposited in the oropharynx, and the rest is deposited in the lungs. For inhaled drugs, it is technically and ethically difficult to formulate and administer radiolabeled drugs. Hence, if the drug is metabolically stable in the lungs, mass balance and metabolism of inhaled drugs, such as IVL745, can be determined by administering radiolabeled intravenous (IV) and oral drugs and by comparing with the data following Inh administration. The study was a three-period crossover design in 6 healthy subjects to evaluate the absorption, distribution, metabolism, and elimination following IV and oral administration of (14)C-IVL745 (4 mg/50 microCi) and inhaled (10-mg) dose. Serial sampling of blood and excreta was performed maximally up to 168 hours postdose. Plasma IVL745 concentrations were determined using a liquid chromatography tandem mass spectrometry (LC/MS/MS) method with a minimum quantifiable limit of 10 pg/mL. Overall, the drug was safe and well tolerated. The recovery of the radioactive dose varied from 94.8% to 117% for both IV and oral administration. Following IV administration, 90.2% of the radioactive dose was recovered in the feces, suggesting extensive biliary excretion of the drug. After oral administration, 99.7% of the radioactivity was recovered in the feces, and no radioactivity was detected in plasma, suggesting lack of absorption of the drug. Negligible (14)C-radioactivity concentrations were observed in the red blood cell fractions. The mean t(1/2) values were 1.6, 1.5, and 4.4 hours following IV, oral, and Inh administration, respectively. The oral bioavailability of IVL745 was low (< 2%), and the inhaled bioavailability was 26%. The volume of distribution at steady state (V(ss)) was low (19.0 L). The predicted blood clearance of IVL745 was 86 L/h, which was comparable to the commonly used liver blood flow value of 90 L/h. Only a minor fraction of the dose was excreted in the urine with low to moderate renal clearance. The parent drug accounted for 77% to 89% of the dosed radioactivity in excreta. Two major metabolites observed in excreta were mono-o-desmethyl IVL745 and di-o-desmethyl IVL745. The data showed that the drug had negligible oral bioavailability, low oral absorption, 26% inhaled bioavailability, low extent of metabolism, high biliary excretion, and low renal clearance. This knowledge may aid in the prediction of potentially relevant drug-drug interactions and dosing adjustments in high-risk populations for IVL745.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Building M-309, Mail Stop 303B, Route 202-206, Aventis Pharmaceuticals, Bridgewater, NJ 08807-0800, USA.
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: Bharti
authors.initials: B
authors.lastname: Shah
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhaopie
authors.initials: Z
authors.lastname: Zeng
authors.forename: Stephane
authors.initials: S
authors.lastname: Kirkesseli
authors.forename: Bradford K
authors.initials: BK
authors.lastname: Jensen
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000328:Adult; D001555:Benzene Derivatives; D001682:Biological Availability; D018592:Cross-Over Studies; D006207:Half-Life; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D010671:Phenylurea Compounds; D011422:Propionates / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: C487626:3-(N-(3,4-dimethoxybenzyl)-2-(2-(3-methoxy-4-(3-o-tolylureido)phenyl)acetylamino)acetamido)propanoic acid; D001555:Benzene Derivatives; D039041:Integrin alpha4beta1; D010671:Phenylurea Compounds; D011422:Propionates