Safety and pharmacokinetics of dicloxacillin in healthy Chinese volunteers following single and multiple oral doses

Abstract

BackgroundDicloxacillin, a semisynthetic isoxazolyl penicillin antibiotic, has antimicrobial activity against a wide variety of gram-positive bacteria including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumonia, Streptococcus epidermidis, Streptococcus viridans, Streptococcus agalactiae, and Neisseria meningitidis. The objective of this study was to evaluate the safety and pharmacokinetic profile of dicloxacillin after single and multiple oral dose in healthy Chinese volunteers.MethodsA single-center, open-label, randomized, two-phase study was conducted in 16 subjects. In the single-dose phase, subjects were randomly assigned to receive single doses of 0.25, 0.5, 1.0, and 2.0 g of dicloxacillin sodium capsule in a 4-way crossover design with a 5-day washout period between administrations. In the multiple-dose phase, subjects were assigned to receive 0.25 or 0.5 g every 6 hours for 3 days in a 2-way crossover design. Plasma and urine pharmacokinetic samples were assayed by a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated and analyzed statistically. Safety assessments were conducted throughout the study.ResultsFollowing a single oral dose of 0.25–2.0 g dicloxacillin sodium, the maximum plasma drug concentration (Cmax) and the corresponding values for the area under the concentration– time curve from 0 to 10 hours (AUC0–10 h) increased in a dose-proportional manner. The mean elimination half-life (t1/2) was in the range of 1.38–1.71 hours. Dicloxacillin was excreted in its unchanged form via the kidney, with no tendency of accumulation, and varied from 38.65% to 50.10%. No appreciable accumulation of drug occurred with multiple oral doses of dicloxacillin. No serious adverse events were reported. Adverse events were generally mild.ConclusionDicloxacillin was safe and well tolerated in the volunteers and displayed linear increases in the Cmax and AUC0–10 h values.

Determining optimal dosing regimen of oral administration of dicloxacillin using Monte Carlo simulation

“…Previous studies have proved that it showed time-dependent bactericidal activity and could be well tolerated in patients and volunteers 12,17. Several studies on PK properties of dicloxacillin revealed that it can be rapidly absorbed after oral administration, with the higher serum concentration, absolute bioavailability, and cumulative urinary excretion compared with other isoxazole penicillins, such as oxacillin and cloxacillin 18,19.…”

“…Previous publication trial of dicloxacillin in healthy Chinese volunteers provides reference PK parameters for our Monte Carlo simulation 12. They found that C max and AUC 0–∞ were approximately four times and five times higher in healthy Chinese subjects compared with Western population 12,20.…”

“…They found that C max and AUC 0–∞ were approximately four times and five times higher in healthy Chinese subjects compared with Western population 12,20. Part of that is due to lower body weight of Asian population, resulting in greater dicloxacillin exposure.…”

“…In the present study, we simulated different dosing interval PK/PDs on the basis of a previous PK trial 12. % T > MIC of 40% has been identified as the target for near-maximal bacterial killing 9.…”

“…The clinical probability of success for different dosing regimens of antibiotics can be predicted by Monte Carlo simulation 10,11. Dicloxacillin is not marketed in Mainland China; however, the safety and PK data for a generic formulation of dicloxacillin sodium in healthy Chinese volunteers have been published in 2015 12. Therefore, the primary objective of this study was to combine the results of PK with antibacterial activity to explore reasonable dosage regimens of dicloxacillin by using Monte Carlo simulation.…”