Backgrounds: Polymyxin B， which is a last line antibiotic for multi-drug resistant gram-negative bacteria, has been reported to induce skin hyperpigmentation in patients during treatments. 8~15% or more cases were reported hyperpigmentation, especially in head and neck, seriously influencing the compliance of patients. To investigate the mechanism of hyperpigmentation is beneficial for intervention strategy and improve compliance. Methods: The melanoma cells, SK-MEL-2 cells were employed in the present study to verify whether polymyxin B treatment could directly induce hyperpigmentation. Melanin contents were measured by hot alkali lysis method and tyrosinase were quantified by dopaquinone oxidation method. The real-time quantitative PCR was applied to measure the mRNA levels of melanogenesis-related genes to investigate the possible signaling pathway involved in the polymyxin B induced hyperpigmentation. Results: The melanin content and tyrosinase activity were up-regulated after 5 μg/mL polymyxin B treatment in SK-MEL-2 cells at 48 hr. and 72 hr. The mRNA levels of melanogenesis-related genes were up-regulated, including PI3K, Akt, GSK-3β, CREB, MITF in the polymyxin B treatment group compared with control group at 48 hr. (p<0.001). Conclusions: In the present study, for the first time to reveal that polymyxin B induced hyperpigmentation involved the signaling pathway of PI3K/AKT/GSK-3β and the up-regulation of CREB and MITF subsequently, then induced the activity of tyrosinase and melanin content in melanoma cells.

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis. Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 48 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation. Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC ≤ 0.5 mg/L. Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

Pharmacometrics is an emerging science that interprets drug, disease and trial information in a mathematical fashion to inform and facilitate efficient drug development and/or regulatory decisions. Pharmacometric study is increasingly adopted in the regulatory review of new antimicrobial agents. We summarized and reviewed the 31 antimicrobial agents approved by the US Food and Drug Administration (FDA) and the 26 antimicrobial agents approved by European Medicines Agency (EMA) from January 2001 to May 2019. Regulatory concerns in pharmacometric review of antimicrobial agents were expounded with examples, including modeling and simulation methods, effects of internal/external factors on PK parameters, safety and efficacy evaluation in terms of exposure-response analysis, refinement of the wording of product labeling and package leaflet, and possible post-marketing clinical trial. Ongoing communication among regulators, academia, and industry regarding pharmacometrics is encouraged to streamline and facilitate the development of new antimicrobial agents. The industry can maximize its benefit in drug development through continued pharmacometric education/training.