Contribution of metabolites to P450 inhibition-based drug-drug interactions: scholarship from the drug metabolism leadership group of the innovation and quality consortium metabolite group.

Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ≥ 25% of the parent and ≥ 10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is low. Only metabolites from 5 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R(met) strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic.

Exploring the feasibility of using the DBS technique for metabolite radioprofiling.

BACKGROUND: The dried blood spots (DBS) technique has been actively evaluated as plasma replacement for monitoring drug exposure to support drug development in preclinical/clinical pharmacokinetic and toxicokinetic studies. Plasma samples from some of these studies are typically used for metabolite profiling and identification and for determination of disproportionate metabolites between safety species and humans to address metabolites in safety testing issues. The objectives of this study were to explore the feasibility of using the DBS technique for a metabolism study and to compare metabolite radioprofiles between DBS, plasma and whole blood samples. RESULTS: The radioactivity extraction recovery in DBS samples was similar or better than that in plasma or whole blood. The metabolite radioprofiles in AUC pooled DBS samples using FTA(®) and FTA(®) Elute cards were comparable to those in AUC pooled plasma and whole blood. CONCLUSION: It is feasible to use DBS as an alternative matrix to plasma for in vivo metabolite radioprofiling studies for SA-1.

Estimating mass balance for inhaled drugs in humans: an example with a VLA-4 antagonist, IVL745.

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.