Meropenem-RPX7009 Concentrations in Plasma,Epithelial Lining Fluid,and Alveolar Macrophages of Healthy Adult Subjects

The steady-state concentrations of meropenem and the β-lactamase inhibitor RPX7009 in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ± the standard deviations of meropenem and RPX7009 determined from serial plasma concentrations were as follows: C_max = 58.2 ± 10.8 and 59.0 ± 8.4 μg/ml, V_ss = 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, and t_1/2 = 1.03 ± 0.15 and 1.27 ± 0.21 h, respectively. The intrapulmonary penetrations of meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC_0–8) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 μg/ml. The results from the present study lend support to exploring a fixed combination of meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by meropenem-resistant Gram-negative pathogens susceptible to the combination of meropenem-RPX7009.     

Penetration of GSK1322322 into Epithelial Lining Fluid and Alveolar Macrophages as Determined by Bronchoalveolar Lavage

GSK1322322 is a potent peptide deformylase inhibitor with in vitro and in vivo activity against multidrug-resistant skin and respiratory pathogens. This report provides plasma and intrapulmonary pharmacokinetics, safety, and tolerability of GSK1322322 after repeat (twice daily intravenous dosing for 4 days) dosing at 1,500 mg. Plasma samples were collected over the last 12-hour dosing interval of repeat dosing following the day 4 morning dose (the last dose). Bronchoalveolar lavage samples were collected once in each subject, either before or at 2 or 6 h after the last intravenous dose. Plasma area under the concentration-time curve (AUC_0–τ) was 66.7 μg · h/ml, and maximum concentration of drug in serum (C_max) was 25.4 μg/ml following repeat doses of intravenous GSK1322322. The time course of epithelial lining fluid (ELF) and alveolar macrophages (AM) mirrored the plasma concentration-time profile. The AUC_0–τ for ELF and AM were 78.9 μg · h/ml and 169 μg · h/ml, respectively. The AUC_0–τ ratios of ELF and AM to total plasma were 1.2 and 2.5, respectively. These ratios increased to 3.5 and 7.4, respectively, when unbound plasma was considered. These results are supportive of GSK1322322 as a potential antimicrobial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under registration number {"type":"clinical-trial","attrs":{"text":"NCT01610388","term_id":"NCT01610388"}}NCT01610388.)     

Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole at Steady State in Healthy Subjects

We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole (POS) in a prospective, open-label study. Twenty-five healthy adults received 14 doses of POS oral suspension (400 mg twice daily) with a high-fat meal over 8 days. Pulmonary epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage, and blood samples were collected during the 24 h after the last dose. POS concentrations were determined using liquid chromatography with tandem mass spectrometry parameters. The maximum concentrations (C_max) (mean ± standard deviation) in plasma, ELF, and ACs were 2.08 ± 0.93, 1.86 ± 1.30, and 87.7 ± 65.0 μg/ml. The POS concentrations in plasma, ELF, and ACs did not decrease significantly, indicating slow elimination after multiple dosing. The mean concentrations of POS in plasma, ELF, and ACs were above the MIC₉₀ (0.5 μg/ml) for Aspergillus spp. over the 12-h dosing interval and for 24 h following the last dose. Area under the curve from 0 to 12 h (AUC_0-12) ratios for ELF/plasma and AC/plasma were 0.84 and 33. AUC_0-24/MIC₉₀ ratios in plasma, ELF, and AC were 87.6, 73.2, and 2,860. Nine (36%) of 25 subjects had treatment-related adverse events during the course of the study, which were all mild or moderate. We conclude that a dose of 400 mg twice daily resulted in sustained plasma, ELF, and AC concentrations above the MIC₉₀ for Aspergillus spp. during the dosing interval. The intrapulmonary PK/PD of POS are favorable for treatment or prevention of aspergillosis, and oral POS was well tolerated in healthy adults.     

Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi

Limited data address the impact of HIV coinfection on the pharmacokinetics (PK) of antituberculosis drugs in sub-Saharan Africa. A total of 47 Malawian adults underwent rich pharmacokinetic sampling at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 h postdose. Of the subjects, 51% were male, their mean age was 34 years, and 65% were HIV-positive with a mean CD4 count of 268 cells/μl. Antituberculosis drugs were administered as fixed-dose combinations (150 mg rifampin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol) according to recommended weight bands. Plasma drug concentrations were determined by high-performance liquid chromatography (rifampin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analyzed by noncompartmental methods and analysis of variance of log-transformed summary parameters. The pharmacokinetic parameters were as follows (median [interquartile range]): for rifampin, maximum concentration of drug in plasma (C_max) of 4.129 μg/ml (2.474 to 5.596 μg/ml), area under the curve from 0 to 24 h (AUC_0–∞) of 21.32 μg/ml · h (13.57 to 28.60 μg/ml · h), and half-life of 2.45 h (1.86 to 3.08 h); for isoniazid, C_max of 3.97 μg/ml (2.979 to 4.544 μg/ml), AUC_0–24 of 22.5 (14.75 to 34.59 μg/ml · h), and half-life of 3.93 h (3.18 to 4.73 h); for pyrazinamide, C_max of 34.21 μg/ml (30.00 to 41.60 μg/ml), AUC_0–24 of 386.6 μg/ml · h (320.0 to 463.7 μg/ml · h), and half-life of 6.821 h (5.71 to 8.042 h); and for ethambutol, C_max of 2.278 μg/ml (1.694 to 3.098 μg/ml), AUC_0–24 of 20.41 μg/ml · h (16.18 to 26.27 μg/ml · h), and half-life of 7.507 (6.517 to 8.696 h). The isoniazid PK data analysis suggested that around two-thirds of the participants were slow acetylators. Dose, weight, and weight-adjusted dose were not significant predictors of PK exposure, probably due to weight-banded dosing. In this first pharmacokinetic study of antituberculosis drugs in Malawian adults, measures of pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the C_max and AUC_0–24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half-life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further.     

Bronchopulmonary Disposition of Intravenous Voriconazole and Anidulafungin Given in Combination to Healthy Adults

Voriconazole and anidulafungin in combination are being investigated for use for the treatment of pulmonary aspergillosis. We determined the pulmonary disposition of these agents. Twenty healthy participants received intravenous voriconazole (at 6 mg/kg of body weight every 12 h [q12h] on day 1 and then at 4 mg/kg q12h) and anidulafungin (200 mg on day 1 and then 100 mg every 24 h) for 3 days. Five participants each were randomized for collection of bronchoalveolar lavage samples at times of 4, 8, 12, and 24 h. Drug penetration was determined by the ratio of the total drug area under the concentration-time curve during the dosing interval (AUC_0-τ) for epithelial lining fluid (ELF) and alveolar macrophages (AM) to the total drug AUC_0-τ in plasma. The mean (standard deviation) half-life and AUC_0-τ were 6.9 (2.1) h and 39.5 (19.8) μg·h/ml, respectively, for voriconazole and 20.8 (3.1) h and 101 (21.8) μg·h/ml, respectively, for anidulafungin. The AUC_0-τ values for ELF and AM were 282 and 178 μg·h/ml, respectively, for voriconazole, and 21.9 and 1,430 μg·h/ml, respectively, for anidulafungin. This resulted in penetration ratios into ELF and AM of 7.1 and 4.5, respectively, for voriconazole and 0.22 and 14.2, respectively, for anidulafungin. The mean total concentrations of both drugs in ELF and AM at 4, 8, 12, and 24 h remained above the MIC₉₀/90% minimum effective concentration for most Aspergillus species. In healthy adult volunteers, voriconazole achieved high levels of exposure in both ELF and AM, while anidulafungin predominantly concentrated in AM.Over the last few decades, the incidence of infections caused by Aspergillus spp. has steadily increased (17, 27). This increase parallels the rise in the numbers of immunocompromised patients who have been seen. Given the vulnerability of this patient population, Aspergillus infections cause a considerable number of deaths. The reported mortality rate for pulmonary aspergillosis, the most common presentation, ranges from 60 to 86% (9, 17).Recent clinical practice guidelines recommend the use of voriconazole as the first-line therapy for patients with pulmonary aspergillosis (29). This recommendation stems from the predictable in vitro activity of voriconazole, coupled with its proven clinical efficacy in a randomized control trial (12, 18). The same guidelines note the potential utility of monotherapy or combination therapy with antifungal agents of different classes in patients whose infections are refractory to primary treatment. Secondary to their potent in vitro activity, unique mechanism of action, and favorable side effect profile, the echinocandin class of antifungals has become a popular option for combination therapy with voriconazole or polyenes. While at present caspofungin is the only echinocandin approved for use for the treatment of invasive aspergillosis (29), clinical trials with anidulafungin plus voriconazole are currently under way (see http://clinicaltrials.gov/).Given that pulmonary aspergillosis is the most common presentation of invasive Aspergillus infections, it is important to understand the bronchopulmonary disposition of these agents. While a previously conducted pilot study shed at least some light on the penetration of voriconazole (5), no data exist for anidulafungin or a combination of anidulafungin and voriconazole. The purpose of this study was to characterize the pulmonary disposition of intravenous (i.v.) voriconazole and anidulafungin when they were given in combination to healthy adult volunteers.     

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 2. Cerebrospinal Fluid Concentration Measurements in Patients with External Ventricular Drain

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC_0–τ ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC_0–τ ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF.     

Pharmacokinetics and Safety of Ofloxacin in Children with Drug-Resistant Tuberculosis

Ofloxacin is widely used for the treatment of multidrug-resistant tuberculosis (MDR-TB). Data on its pharmacokinetics and safety in children are limited. It is not known whether the current internationally recommended pediatric dosage of 15 to 20 mg/kg of body weight achieves exposures reached in adults with tuberculosis after a standard 800-mg dose (adult median area under the concentration-time curve from 0 to 24 h [AUC_0–24], 103 μg · h/ml). We assessed the pharmacokinetics and safety of ofloxacin in children <15 years old routinely receiving ofloxacin for MDR-TB treatment or preventive therapy. Plasma samples were collected predose and at 1, 2, 4, 8, and either 6 or 11 h after a 20-mg/kg dose. Pharmacokinetic parameters were calculated using noncompartmental analysis. Children with MDR-TB disease underwent long-term safety monitoring. Of 85 children (median age, 3.4 years), 11 (13%) were HIV infected, and of 79 children with evaluable data, 14 (18%) were underweight. The ofloxacin mean (range) maximum concentration (C_max), AUC_0–8, and half-life were 8.97 μg/ml (2.47 to 14.4), 44.2 μg · h/ml (12.1 to 75.8), and 3.49 h (1.89 to 6.95), respectively. The mean AUC_0–24, estimated in 72 participants, was 66.7 μg · h/ml (range, 18.8 to 120.7). In multivariable analysis, AUC_0–24 was increased by 1.46 μg · h/ml for each 1-kg increase in body weight (95% confidence interval [CI], 0.44 to 2.47; P = 0.006); no other assessed variable contributed to the model. No grade 3 or 4 events at least possibly attributed to ofloxacin were observed. Ofloxacin was safe and well tolerated in children with MDR-TB, but exposures were well below reported adult values, suggesting that dosage modification may be required to optimize MDR-TB treatment regimens in children.     

Daptomycin Pharmacokinetics in Adult Oncology Patients with Neutropenic Fever

Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means ± standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (C_max) was 49.04 ± 12.42 μg/ml (range, 21.54 to 75.20 μg/ml), the 24-h plasma concentration was 6.48 ± 5.31 μg/ml (range, 1.48 to 29.26 μg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 ± 523.53 μg·h/ml (range, 164.64 to 3155.11 μg·h/ml), the volume of distribution at steady state was 0.18 ± 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 ± 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 ± 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 ± 20.66 h (range, 7.00 to 121.73 h), and the median time to C_max was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 ± 0.02. All patients achieved C_max/MIC and AUC from time zero to 24 h (AUC_0-24)/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a C_max/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC_0-24/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.     

Pharmacokinetics of Hydroxymethylnitrofurazone,a Promising New Prodrug for Chagas' Disease Treatment

Hydroxymethylnitrofurazone (NFOH) is a trypanocidal prodrug of nitrofurazone (NF), devoid of mutagenic toxicity. The purpose of this work was to study the chemical conversion of NFOH into NF in sodium acetate buffer (pH 1.2 and 7.4) and in human plasma and to determine preclinical pharmacokinetic parameters in rats. At pH 1.2, the NFOH was totally transformed into NF, the parent drug, after 48 h, while at pH 7.4, after the same period, the hydrolysis rate was 20%. In human plasma, 50% of NFOH was hydrolyzed after 24 h. In the investigation of kinetic disposition, the concentration of drug in serum versus time curve was used to calculate the pharmacokinetic parameters after a single-dose regimen. NFOH showed a time to maximum concentration of drug in serum (T_max) as 1 h, suggesting faster absorption than NF (4 h). The most important results observed were the volume of distribution (V) of NFOH through the tissues, which showed a rate that is 20-fold higher (337.5 liters/kg of body weight) than that of NF (17.64 liters/kg), and the concentration of NF obtained by in vivo metabolism of NFOH, which was about four times lower (maximum concentration of drug in serum [C_max] = 0.83 μg/ml; area under the concentration-time curve from 0 to 12 h [AUC_0–12] = 5.683 μg/ml · h) than observed for administered NF (C_max = 2.78 μg/ml; AUC_0–12 = 54.49 μg/ml · h). These findings can explain the superior activity and lower toxicity of the prodrug NFOH in relation to its parent drug and confirm NFOH as a promising anti-Chagas'' disease drug candidate.     

Intracellular time course, pharmacokinetics, and biodistribution of isoniazid and rifabutin following pulmonary delivery of inhalable microparticles to mice

Intracellular concentrations of isoniazid and rifabutin resulting from administration of inhalable microparticles of these drugs to phorbol-differentiated THP-1 cells and the pharmacokinetics and biodistribution of these drugs upon inhalation of microparticles or intravenous administration of free drugs to mice were investigated. In cultured cells, both microparticles and dissolved drugs established peak concentrations of isoniazid (~1.4 and 1.1 μg/10⁶ cells) and rifabutin (~2 μg/ml and ~1.4 μg/10⁶ cells) within 10 min. Microparticles maintained the intracellular concentration of isoniazid for 24 h and rifabutin for 96 h, whereas dissolved drugs did not. The following pharmacokinetic parameters were calculated using WinNonlin from samples obtained after inhalation using an in-house apparatus (figures in parentheses refer to parameters obtained after intravenous administration of an equivalent amount, i.e., 100 μg of either drug, to parallel groups): isoniazid, serum half-life (t_1/2) = 18.63 ± 5.89 h (3.91 ± 1.06 h), maximum concentration in serum (C_max) = 2.37 ± 0.23 μg·ml⁻¹ (3.24 ± 0.57 μg·ml⁻¹), area under the concentration-time curve from 0 to 24 h (AUC_0-24) = 55.34 ± 13.72 μg/ml⁻¹ h⁻¹ (16.64 ± 1.80 μg/ml⁻¹ h⁻¹), and clearance (CL) = 63.90 ± 13.32 ml·h⁻¹ (4.43 ± 1.85 ml·h⁻¹); rifabutin, t_1/2 = 119.49 ± 29.62 h (20.18 ± 4.02 h), C_max = 1.59 ± 0.01 μg·ml⁻¹ (3.47 ± 0.33 μg·ml⁻¹), AUC_0-96 = 109.35 ± 14.78 μg/ml⁻¹ h⁻¹ (90.82 ± 7.46 μg/ml⁻¹ h⁻¹), and CL = 11.68 ± 7.00 ml·h⁻¹ (1.03 ± 0.11 ml·h⁻¹). Drug targeting to the lungs in general and alveolar macrophages in particular was observed. It was concluded that inhaled microparticles can reduce dose frequency and improve the pharmacologic index of the drug combination.     

Repeated-Dose Pharmacokinetics of an Oral Solution of Itraconazole in Infants and Children

The safety, tolerability, and pharmacokinetics of an oral solution of itraconazole and its active metabolite hydroxyitraconazole were investigated in an open multicenter study of 26 infants and children aged 6 months to 12 years with documented mucosal fungal infections or at risk for the development of invasive fungal disease. The most frequent underlying illness was acute lymphoblastic leukemia, except in the patients aged 6 months to 2 years, of whom six were liver transplant recipients. The patients were treated with itraconazole at a dosage of 5 mg/kg of body weight once daily for 2 weeks. Blood samples were taken after the first dose, during treatment, and up to 8 days after the last itraconazole dose. On day 1, the mean peak concentrations in plasma after the first and last doses (C_max) and areas under the concentration-time curve from 0 to 24 h (AUC_0–24) for itraconazole and hydroxyitraconazole were lower in the children aged 6 months to 2 years than in children aged 2 to 12 years but were comparable on day 14. The mean AUC_0–24-based accumulation factors of itraconazole and hydroxyitraconazole from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, respectively. After 14 days of treatment, C_max, AUC_0–24, and the half-life, respectively, were (mean ± standard deviation) 571 ± 416 ng/ml, 6,930 ± 5,830 ng · h/ml, and 47 ± 55 h in the children aged 6 months to 2 years; 534 ± 431 ng/ml, 7,330 ± 5,420 ng · h/ml, and 30.6 ± 25.3 h in the children aged 2 to 5 years; and 631 ± 358 ng/ml, 8,770 ± 5,050 ng · h/ml, and 28.3 ± 9.6 h in the children aged 5 to 12 years. There was a tendency to have more frequent low minimum concentrations of the drugs in plasma for both itraconazole and hydroxyitraconazole for the children aged 6 months to 2 years. The oral bioavailability of the solubilizer hydroxypropyl-β-cyclodextrin was less than 1% in the majority of the patients. In conclusion, an itraconazole oral solution given at 5 mg/kg/day provides potentially therapeutic concentrations in plasma, which are, however, substantially lower than those attained in adult cancer patients, and is well tolerated and safe in infants and children.     

Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (C_max) values were generally attained within 2 h postdose. The mean values of C_max and area under the concentration-time curve from 0 to 24 h (AUC_0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean C_max and AUC_0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These C_max and AUC_0–24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (V_ss/F), half-life (t_1/2), and renal clearance (CL_R) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, V_ss/F, t_1/2, and CL_R following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.     

Pharmacokinetics and pharmacodynamics profiles of enteric‐coated mycophenolate sodium in female patients with difficult‐to‐treat lupus nephritis

Relapsed or resistant lupus nephritis (LN) is considered a difficult‐to‐treat type of LN, and enteric‐coated mycophenolate sodium (EC‐MPS) has been used in this condition. Therapeutic drug monitoring using the area under the plasma mycophenolic acid concentration from 0 to 12 h postdose (MPA‐AUC_0–12h) ≥45 μg.h/ml is a useful approach to achieve the highest efficiency. This study assessed EC‐MPS’s pharmacokinetic (PK) and pharmacodynamic (PD) profiles and investigated an optimal level of the single time point of plasma MPA concentration. Nineteen biopsy‐proven patients with class III/IV LN received 1440 mg/day of EC‐MPS for 24 weeks. PK (maximum plasma MPA concentration [C _max], time to C _max, and MPA‐AUC_0–12h) and PD (activity of inosine‐5′‐monophosphate dehydrogenase [IMPDH]) parameters were measured at weeks 2, 8, 16, and 24. We found that IMPDH activity decreased from baseline by 31–42% within 2–4 h after dosing, coinciding with the increased plasma MPA concentration. MPA‐AUC_0–12h ≥45 μg.h/ml was best predicted by a single time point MPA concentration at C0.5, C2, C3, C4, and C8 (r ² = 0.516, 0.514, 0.540, 0.611, and 0.719, respectively), independent of dose, albumin, urine protein/creatinine ratio, and urinalysis. The MPA‐C0.5 cutoff of 2.03 g/ml yielded the highest overall sensitivity of 85% and specificity of 88.2% in predicting MPA‐AUC_0–12h ≥45 μg.h/ml. A single timepoint of plasma MPA‐C0.5 ≥2.03 μg/ml may help guide EC‐MPS adjustment to achieve adequate drug exposure. Further study of EC‐MPS used to validate this cutoff is warranted.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Therapeutic drug monitoring (TDM) is crucial in lupus nephritis (LN) treated with mycophenolic acid (MPA), especially mycophenolate mofetil. The area under the plasma concentration‐time curve of MPA from time 0 to 12 h (MPA‐AUC_0–12h) ≥ 45 μg.h/ml or a single plasma MPA concentration (C0 or C1) are used as tools to enhance the highest treatment efficacy. In addition, enteric‐coated mycophenolate sodium (EC‐MPS) was also used to treat relapsed or resistant LN. However, little is known regarding the TDM of EC‐MPS. WHAT QUESTION DID THIS STUDY ADDRESS? This study assessed EC‐MPS’s pharmacokinetics (PKs) and pharmacodynamics (PDs) in adult patients with relapsed or resistant LN and investigated a surrogate single timepoint of plasma MPA concentration with optimum plasma level cutoff as an alternative for MPA‐AUC. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study provided EC‐MPS’s PK and PD profiles and suggested a surrogate single timepoint of plasma MPA concentration with optimum plasma level cutoff as potential alternatives for MPA‐AUC_0–12 ≥45 μg.h/ml to be applied in TDM. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study supports the role of TDM in relapsed or resistant LN treated with EC‐MPS. In addition, a single timepoint of plasma MPA concentration at C0.5 with the proposed cutoff at ≥2.03 μg/ml is a TDM tool that can be easily applied in clinical practice. However, a more significant number of study patients is required.     

Ceftolozane-Tazobactam Pharmacokinetics in a Critically Ill Patient on Continuous Venovenous Hemofiltration

Extended-infusion ceftolozane-tazobactam treatment at 1.5 g every 8 h was used to treat multidrug-resistant Pseudomonas aeruginosa in a critically ill patient on continuous venovenous hemofiltration. Serum drug concentrations were measured at 1, 4, 5, 6, and 8 h after the start of infusion. Prefilter levels of ceftolozane produced a maximum concentration of drug (C_max) of 38.57 μg/ml, concentration at the end of the dosing interval (C_min) of 31.63 μg/ml, time to C_max (T_max) of 4 h, area under the concentration-time curve from 0 to 8 h (AUC_0–8) of 284.38 μg · h/ml, and a half-life (t_1/2) of 30.7 h. The concentrations were eight times the susceptibility breakpoint for the entire dosing interval.     

Safety,Tolerability, and Pharmacokinetics of Intravenous Nemonoxacin in Healthy Chinese Volunteers

Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and erythromycin-resistant S. pneumoniae. This first-in-human study was aimed at assessing the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin in healthy Chinese volunteers. The study comprised a randomized, double-blind, placebo-controlled, dose escalating safety and tolerability study in 92 subjects and a randomized, single-dose, open-label, 3-period Latin-square crossover pharmacokinetic study in 12 subjects. The study revealed that nemonoxacin infusion was well tolerated up to the maximum dose of 1,250 mg, and the acceptable infusion rates ranged from 0.42 to 5.56 mg/min. Drug-related adverse events (AEs) were mild, transient, and confined to local irritation at the injection site. The pharmacokinetic study revealed that after the administration of 250, 500, and 750 mg of intravenous nemonoxacin, the maximum plasma drug concentration (C_max) values were 4.826 μg/ml, 7.152 μg/ml, and 11.029 μg/ml, respectively. The corresponding values for the area under the concentration-time curve from 0 to 72 hours (AUC_{0–72 h}) were 17.05 μg · h/ml, 39.30 μg · h/ml, and 61.98 μg · h/ml. The mean elimination half-life (t_1/2) was 11 h, and the mean cumulative drug excretion rate within 72 h ranged from 64.93% to 77.17%. Volunteers treated with 250 to 750 mg nemonoxacin exhibited a linear dose-response relationship between the AUC_{0–72 h} and AUC_0–∞. These findings provide further support for the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01944774","term_id":"NCT01944774"}}NCT01944774.)     

Tissue Pharmacokinetics of Cefazolin in Patients with Lower Limb Infections

Cefazolin, a first-generation cephalosporin with activity against methicillin-susceptible Staphylococcus aureus and streptococci, is often used to treat lower limb infections caused by these pathogens. Antimicrobial penetration is often limited in these patients due to compromised vasculature. Therefore, we sought to evaluate the exposure profile of cefazolin in serum and tissue in patients with lower limb infections. An in vivo microdialysis catheter was inserted into the tissue near the margin of the wound and constantly perfused with lactated Ringer''s solution. Steady-state serum and tissue samples were simultaneously collected over a dosing interval. Serum protein binding was also assessed. Serum concentrations were analyzed by noncompartmental analysis. Tissue concentrations were corrected for percent in vivo recovery by using the retrodialysis technique. Seven patients with a mean weight of 95.45 ± 18.51 kg and a mean age of 54 ± 19 years were enrolled. Six patients received 1 g every 8 h, and one patient received 2 g every 24 h due to acute kidney injury. The free area under the curve from 0 to 8 h (fAUC_0–8) values for serum and wound were 48.0 ± 18.66 and 56.35 ± 41.17 μg · h/ml, respectively, for the patients receiving 1 g every 8 h. The fAUC_0–24 values for serum and wound were 1,326.1 and 253.9 μg · h/ml, respectively, for the single patient receiving 2 g every 24 h. The mean tissue penetration ratio (tissue/serum fAUC ratio) was 1.06. These data suggest that the amount of time that free-drug concentrations remain above the MIC (fT>MIC) for cefazolin in wound tissue is adequate to treat patients with lower limb infections.     

Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 1. Ciprofloxacin,Moxifloxacin, and Grepafloxacin

The aim of this study was to evaluate the biopharmaceutical characteristics of three fluoroquinolones (FQs), ciprofloxacin (CIP), moxifloxacin (MXF), and grepafloxacin (GRX), after delivery via a nebulized aerosol to rats. Bronchoalveolar lavages (BAL) were conducted 0.5, 2, 4, and 6 h after FQ intravenous administration and nebulized aerosol delivery to estimate epithelial lining fluid (ELF) drug concentrations. Plasma drug concentrations were also measured, and profiles of drug concentrations versus time after intravenous administration and nebulized aerosol delivery were virtually superimposable, attesting for rapid and complete systemic absorption of FQs. ELF drug concentrations were systematically higher than corresponding plasma drug concentrations, whatever the route of administration, and average ELF-to-unbound plasma drug concentration ratios post-distribution equilibrium did not change significantly between the ways of administration and were equal: 4.0 ± 5.3 for CIP, 12.6 ± 7.3 for MXF, and 19.1 ± 10.5 for GRX (means ± standard deviations). The impact of macrophage lysis on estimated ELF drug concentrations was significant for GRX but reduced for MXF and CIP; therefore, simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was only performed for the latter two drugs. The model was characterized by a fixed volume of ELF (V_ELF), passive diffusion clearance (Q_ELF), and active efflux clearance (CL_out) between plasma and ELF, indicating active efflux transport systems. In conclusion, this study demonstrates that ELF drug concentrations of these three FQs are several times higher than plasma drug concentrations, probably due to the presence of efflux transporters at the pulmonary barrier level, but no biopharmaceutical advantage of FQ nebulization was observed compared with intravenous administration.     

Synthesis,solid state self-assembly driven by antiparallel π⋯π stacking and {⋯H–C–C–F}2 dimer synthons,and in vitro acetyl cholinesterase inhibition activity of phenoxy pendant isatins

A series of novel phenoxy pendant isatins PI1–12 have been synthesized in excellent yields by a simple nucleophilic substitution reaction involving isatins and 1-(2-bromoethoxy)-4-substituted benzenes, and characterized by their FT-IR, ¹H NMR, ¹³C NMR and GC-MS data, and in the case of PI4 by its single crystal X-ray analysis. The solid-state structure of PI4 showed an intriguing and unique 1D-supramolecular chain-based self-assembled structure, the driving force of which is mainly the strong antiparallel π⋯π stacking and {⋯H–C–C–F}₂ dimer synthons. This compound not only highlights the potential of the isatin moiety in forming strong antiparallel π⋯π stacking interactions but also provides a platform to have considerable insight into the nature, strength and directionality of much debated π–π and C–H⋯F–C interactions. The in vitro biological studies revealed that three phenoxy pendant isatins PI1, PI2 and PI4 are highly potent inhibitors of acetylcholinesterase enzyme with IC₅₀ values of 0.52 ± 0.073 μg ml⁻¹, 0.72 ± 0.012 μg ml⁻¹ and 0.68 ± 0.011 μg ml⁻¹, respectively, showing comparable activity to the standard drug, donepezil (IC₅₀ = 0.73 ± 0.015 μg ml⁻¹). A simple and efficient synthesis of phenoxy pendant isatins PI1–12 from inexpensive and commercially available starting materials, and their high potential of acetyl cholinesterase inhibition provide an attractive opportunity to find more effective medication for Alzheimer''s disease (AD).

The phenoxy pendant isatins were observed to be highly potent inhibitors of acetylcholinesterase. In addition, the solid-state structure of a phenoxy pendant isatin showed an intriguing 1D-supramolecular self-assembled structure.     

Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 2. Colistin

The purpose of this study was to investigate the pharmacokinetic properties of colistin following intrapulmonary administration of colistin sulfate in rats. Colistin was infused or delivered in nebulized form at a dose of 0.35 mg/kg of body weight in rats, and plasma drug concentrations were measured for 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2, and 4 h after intravenous (i.v.) administration and administration via nebulized drug to estimate epithelial lining fluid (ELF) drug concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h postdosing) were almost identical after i.v. infusion and nebulized drug inhalation. ELF drug concentrations were undetectable in BAL samples after i.v. administration, but they were about 1,800 times higher than unbound plasma drug levels at 2 h and 4 h after administration of the nebulized drug. Simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was performed with a model characterized by a fixed physiological volume of ELF (V_ELF), a passive diffusion clearance (Q_ELF) between plasma and ELF, and a nonlinear influx transfer from ELF to the central compartment, which was assessed by reducing the nebulized dose of colistin by 10-fold (0.035 mg kg⁻¹). The k_m was estimated to be 133 μg ml⁻¹, and the V_{max, in}-to-K_m ratio was equal to 2.5 × 10⁻³ liter h⁻¹ kg⁻¹, which was 37 times higher than the Q_ELF (6.7 × 10⁻⁵ liter h⁻¹ kg⁻¹). This study showed that with the higher ELF drug concentrations after administration via nebulized aerosol than after intravenous administration, for antibiotics with low permeability such as colistin, nebulization offers a real potential over intravenous administration for the treatment of pulmonary infections.     

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 1. Microdialysis Assessment of Brain Extracellular Fluid Concentrations in Patients with Acute Brain Injury

The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC_0–τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml⁻¹. This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution.