The restricted distribution of baclofen in the brain ISF may be ascribed to the efficient efflux from the brain through the BBB which is regulated possibly by a probenecid-sensitive organic anion transport system.
PurposeGarenoxacin, a novel des-F(6)-quinolone, possesses potent antibacterial activity against infectious pathogens in the respiratory tract. Population pharmacokinetic/pharmacodynamic (PK/PD) modeling and Monte Carlo simulations were used to optimize garenoxacin dosage regimens.MethodsAt the end of phase II stage, the clinical dose of garenoxacin was predicted to be 400 mg once daily by the interim PK/PD analysis using phase I and phase II clinical data. The criteria used to determine an optimal dose were (1) the target attainment of the area under the unbound concentration–time curve divided by the minimum inhibitory concentration (fAUC0−24/MIC ratio) and (2) the maintenance of a trough concentration above the mutant prevention concentration. In a confirmatory phase III study, garenoxacin was administered 400 mg once daily to 136 patients infected with mild or moderate chronic respiratory diseases.ResultsLogistic regression analysis showed that fAUC0−24/MIC ratio was a significant variable that predicted clinical response (p = 0.0164). Of all subjects, 92.4% reached the target value of fAUC0−24/MIC ratio > 30 h, and the clinical efficacy rate of this population was 91.8%. On the other hand, there was no significant relationship between exposure values (AUC0−24 and maximum concentration) and the incidence of adverse events by the Mann–Whitney test.ConclusionsThe antimicrobial efficacy of the actual phase III study was consistent with the expectation from the Monte Carlo PD simulation. We were able to show that the optimal garenoxacin dosage regimens were successfully determined using prospective population PK/PD analysis and clinical trial simulations.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-011-1095-3) contains supplementary material, which is available to authorized users.
This study sought to investigate whether dosing frequency (the number of doses per day) affects the antimicrobial efficacy and safety of ampicillin/sulbactam (ABPC/SBT) in Japanese elderly pneumonia patients treated with ABPC/SBT at 6 g/day. This was a retrospective observational study that included hospitalized elderly patients (aged ≥75 years, 10 ml/min ≤CLcr <50 ml/min) who received 3 g every 12 h (BID; n = 61) or 1.5 g every 6 h (QID; n = 45) for the treatment of pneumonia. The primary endpoint was clinical response, assessed by measuring body temperature, white blood cell count, and C‐reactive protein levels. Pharmacokinetic and pharmacodynamic simulations were conducted in silico to rationalize the clinical findings. The clinical response rates (extremely effective and effective) in the BID and QID groups were 36.1% and 55.6%, respectively ( p = .0459). QID tended to be more effective in patients with gram‐negative rods detected ( p = .0563). According to the simulated minimum plasma ABPC concentrations at steady state for BID and QID were 2.5 and 7.3 μg/ml, respectively ( p < .0001). Based on the simulated time above minimum inhibitory concentration (MIC), pharmacological (not clinical) efficacy was predicted to be higher with QID. Both groups had similar safety profiles. The main adverse event in both groups was liver damage. The present retrospective survey demonstrated that ABPC/SBT treatment for elderly patients with pneumonia and renal dysfunction was more effective with QID than with BID. Therefore, the QID regimen is worthy of consideration to improve the clinical outcomes of ABPC/SBT therapy in the present patient population.
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