No abstract

(2017) Clinical disposition, metabolism and invitro drug-drug interaction properties of omadacycline, Xenobiotica, 47:8, 682-696, DOI: 10.1080/00498254.2016 Omadacycline was a substrate of P-glycoprotein, but not of the other transporters. 3. Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300 mg oral dose of [ 14 C]-omadacycline (36.6 mCi). Absorption was rapid with peak radioactivity ($610 ngEq/mL) between 1-4 h in plasma or blood. The AUC last of plasma radioactivity (only quantifiable to 8 h due to low radioactivity) was 3096 ngEq h/mL and apparent terminal half-life was 11.1 h. Unchanged omadacycline reached peak plasma concentrations ($563 ng/mL) between 1-4 h. Apparent plasma half-life was 17.6 h with biphasic elimination. Plasma exposure (AUC inf ) averaged 9418 ng h/mL, with high clearance (CL/F, 32.8 L/h) and volume of distribution (Vz/F 828 L). No plasma metabolites were observed. 4. Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.

Omadacycline is a first-in-class aminomethylcycline antibiotic with microbiological activity against Gram-positive and Gram-negative aerobes and anaerobes and atypical bacteria that is being developed for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). The bioavailability of a phase 3 tablet formulation relative to that obtained via intravenous (i.v.) administration (and of other oral formulations relative to that of the phase 3 tablet) was investigated in an open-label, randomized, four-period, crossover study with healthy subjects age 18 to 50 years. Subjects received omadacycline at 100 mg i.v., 300 mg orally as two different tablet formulations with different dissolution profiles, and 300 mg as an oral solution. Plasma omadacycline concentrations were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Twenty of 24 subjects completed all treatment periods. The two tablet formulations produced equivalent total exposures. The phase 3 tablet produced an exposure equivalent to that of the 100-mg i.v. dose, with a geometric mean ratio (90% confidence intervals [CI]) for area under the concentration-time curve from 0 h to infinity [AUC∞]) of 1.00 (0.93, 1.07). The absolute bioavailability of the tablets was approximately 34.5%. Intersubject variability was consistent among the oral formulations (∼20 to 25%). Single oral and i.v. doses of omadacycline were well tolerated; three subjects experienced mild adverse events (dizziness, nausea, and vomiting) that resolved without intervention. A 300-mg dose of the tablet formulation of omadacycline intended for use in phase 3 studies produced a total exposure equivalent to that of a 100-mg i.v. dose.

Urinary excretion of 6 beta-hydroxycortisol may be useful as a screening tool in early-phase development to assess the potential for an investigational drug to induce CYP3A.

Extrapolation can be used to address challenges in pediatric drug development. This review describes how these challenges could be addressed by further evolution of quantitative frameworks (i.e., model-based/informed drug discovery and development) and regulatory science in support of pediatric drug development. Included are examples of diseases/indications where extrapolation has been used in different ways as a basis for identifying gaps in the framework and opportunities for continued advancement of pediatric drug development.

This open-label, randomized, crossover study was conducted to demonstrate bioequivalence for telithromycin administered as crushed or whole tablets. Single 800-mg telithromycin doses (2x400-mg tablets) were administered as crushed tablets mixed in 240 mL nutritional supplement drink followed by 120 mL water or as whole tablets swallowed with 240 mL water. Plasma telithromycin concentrations were measured by liquid chromatography/mass spectrometry; pharmacokinetic parameters were determined using noncompartmental methods. Average bioequivalence criteria were applied. Thirty-two subjects received telithromycin by both methods. The 90% confidence intervals for the geometric mean ratios of maximum plasma concentration and area under the plasma concentration-time curve to 24 hours were within the 0.80 to 1.25 range. Median tmax was 3.00 hours for both treatments. Both methods of administration were well tolerated. Crushing telithromycin tablets and administering them with a nutritional supplement drink is bioequivalent to ingesting whole tablets and could be a viable method of administration for patients unable to swallow tablets whole.

Leflunomide is a pyrimidine synthesis inhibitor used in the treatment of rheumatoid arthritis. Data from two clinical studies were used to establish a population pharmacokinetic (PPK) model for the active metabolite (M1) of leflunomide in patients with juvenile rheumatoid arthritis (JRA) and determine appropriate pediatric doses. Seventy-three subjects 3-17 years of age provided 674 M1 concentrations. The PPK model was derived from nonlinear mixed-effects modeling and qualified by cross-study evaluation and predictive check. A one-compartment model with first-order input described M1 PPK well. Body weight (WT) correlated weakly with oral clearance (CL/F = 0.020.[WT/40](0.430)) and strongly with volume of distribution (V/F = 5.8.[WT/40](0.769)). Steady-state concentrations (C(ss)) of M1 in JRA were compared for a variety of leflunomide dose regimens using Monte-Carlo simulation. To achieve comparable C(ss) values in pediatric patients with JRA to that in adult patients, doses of leflunomide should be adjusted modestly: 10 mg/d for 10-20 kg, 15 mg/d for 20-40 kg, and 20 mg/d for > 40 kg.

No abstract