Lanopepden mesylate

Directly testing proposed clinical dosing regimens in nonclinical studies can reduce the risk during the development of novel antibacterial agents. Optimal dosing regimens can be identified in animal models by testing recreated human pharmacokinetic profiles. An example of this approach using continuous intravenous infusions of GSK1322322 in immunocompetent rats to evaluate recreated human exposures from phase I trials in pneumonia models with Streptococcus pneumoniae and Haemophilus influenzae and an abscess model with Staphylococcus aureus is presented. GSK1322322 was administered via continuous intravenous infusion to recreate 1,000- or 1,500-mg oral doses every 12 h in humans. Significant reductions ( P ≤ 0.05 for all comparisons) in bacterial numbers compared with those for the baseline controls were observed for S. pneumoniae and H. influenzae (mean log 10 reductions, 1.6 to ≥2.7 and 1.8 to 3.3 CFU/lungs, respectively) with the recreated 1,000-mg oral dose. This profile was also efficacious against S. aureus (mean log 10 reduction, 1.9 to 2.4 CFU/abscess). There was a nonsignificant trend for improved efficacy against S. aureus with the 1,500-mg oral dose (mean log 10 reduction, 2.4 to 3.1 CFU/abscess). These results demonstrate that the human oral 1,000- or 1,500-mg exposure profiles of GSK1322322 recreated in rats were effective against representative community-associated pathogens and supported selection of the 1,500-mg oral dose given every 12 h for a phase II clinical skin infection study. Furthermore, this work exemplifies how the testing of recreated human pharmacokinetic profiles can be incorporated into the development process and serve as an aid for selecting optimal dosing regimens prior to conducting large-scale clinical studies.

Acid-reducing agents (ARAs) may affect drug exposure for orally-administered drugs exhibiting pH-dependent solubility. The aim of this research was to investigate factors predicting the effect of ARAs on drug exposure. Dose (mg)/250 mL/solubility at neutral pH and ratio of solubility at acidic pH to that at neutral pH were investigated as potential factors.

Drug-drug interaction (DDI) study results with ARAs were selected based on PubMed search from 2007 to 2016 and novel drug approvals at the US Food and Drug Administration (FDA) from 2014 to 2016. For the selected drugs, solubility data at acidic and neutral pH were obtained from publications, FDA and European Medicines Agency (EMA) review report, and Japanese interview form.

32 DDI study results with ARAs from 27 drugs having solubility data were obtained. The effect of ARAs on the C_max or AUC ratio% (with/without ARAs) decreased with the increasing values of both factors, but the ratio of solubility showed higher values of squared correlation coefficient R2 (0.75 - 0.78) than the dose (mg)/250 mL/solubility at neutral pH (0.48 - 0.59).

Ratio of solubility at acidic pH to that at neutral pH was a good predictor to estimate the effect of ARAs on drug exposure. Prediction of the effect of ARAs on drug exposure using solubility data would help to consider the necessity and timing for conducting a dedicated DDI study with ARAs and contribute to efficient drug development.
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