Clinical Population Pharmacokinetics/Pharmacodynamics Protocol of Alkaloids from Leaf of Alstonia scholaris on Acute Bronchitis Patients
Abstract Background Acute tracheobronchitis is the acute tracheobronchial mucosal inflammation caused by biological, physical, chemical stimulation, and accompanied by symptoms of cough and expectoration. The capsule of alkaloids from leaf of Alstonia scholaris (CALAS), an effective part riches in alkaloids, has the antiviral, antibacterial, anti-inflammatory, expectorant, anti-tussive, anti-asthmatic, immunoregulation effects. However, whether the clinical indexes could be improved by the same ingredients and pathways after oral administration, and the changes in the relationship between ingredients and pharmacodynamics indexes, still need further clinical verification.Methods/design This is a prospectively planned, blinded, placebo-controlled, parallel-grouped clinical trial with aggregated population pharmacokinetics/pharmacodynamics (PPK/PD) data. 55 subjects will be randomly allocated into four arms, specifically, 10 of the 55 subjects were selected randomly for the placebo arm who will be orally administered with placebo (Tid), and 45 subjects were randomly assigned to CALAS treatment group (20 mg, 40 mg, 80 mg Tid, 15 subjects per group). The medication, cough and phlegm, body temperature of every subject should be recorded daily during treatment. Each subject will be collected 3-4 blood samples at the following points for PPK/PPD parameters analysis. Blood samples will be acquired pre-dose (0 h) and post-dose at 15 min, 40 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 30 h, 48 h after last dosing. All subjects will receive a laboratory examination and efficacy evaluation on day 8.Discussion A new integrating strategy to explore relationship among drug ingredients, action pathway and clinical efficacy will be established through this study. We aim to explore the mechanism of CALAS in treatment of acute bronchitis on the premise of definite active ingredients and reliable clinical efficacy. It is difficult to be accepted by patients since classical pharmacokinetics (PK) research adopts intensive sampling method, meanwhile, it cannot quantify the variability of PK parameters (Intra-individual variation, interindividual variation and weekly variation). Moreover, extrapolation and prediction of dosage regimen between different species and populations cannot be realized. Therefore, PPK/PPD method, usually taking advantage of sparse data (3-5 time points sampling per patient), which be selected to find out the measurable factors of pathology and physiology that lead to the change of dose-concentration, and guide reasonable dose adjustment to achieve the optimal clinical effects.