Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose.

BACKGROUND: Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure. OBJECTIVES: To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial. METHODS: The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis. RESULTS: A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min. CONCLUSIONS: The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily.

Capillary microsampling of 25 µl blood for the determination of toxicokinetic parameters in regulatory studies in animals.

BACKGROUND: Capillary microsampling (CMS) is a new technique for simplified collection, handling and analysis of small, exact volumes of liquid matrices. CMS was compared with conventional large volume sampling, in toxicology studies in rat and dog. RESULTS: Bioanalytical validation data were well within acceptance limits. Toxicokinetic (TK) parameters from microsampling were in agreement with data from conventional volume sampling. Clinical pathology parameters in rats measured 2 days after repeated microsampling were not affected when compared with rats not sampled. CONCLUSION: The fast collection and simple handling of small, exact volumes of liquid blood makes the CMS technique generic and flexible, as well as easily implemented and automated. Presented data support that TK measurements can be performed in main study rats, instead of dosing additional satellite animals only for TK sampling, giving both a higher scientific value and a substantial reduction of animal numbers in preclinical development.