Intrapulmonary pharmacokinetics and pharmacodynamics of itraconazole and 14-hydroxyitraconazole at steady state

We determined the steady-state intrapulmonary pharmacokinetic and pharmacodynamic parameters of orally administered itraconazole (ITRA), 200 mg every 12 h (twice a day [b.i.d.]), on an empty stomach, for a total of 10 doses, in 26 healthy volunteers. Five subgroups each underwent standardized bronchoscopy and bronchoalveolar lavage (BAL) at 4, 8, 12, 16, and 24 h after administration of the last dose. ITRA and its main metabolite, 14-hydroxyitraconazole (OH-IT), were measured in plasma, BAL fluid, and alveolar cells (AC) using high-pressure liquid chromatography. Half-life and area under the concentration-time curves (AUC) in plasma, epithelial lining fluid (ELF), and AC were derived using noncompartmental analysis. ITRA and OH-IT maximum concentrations of drug (C(max)) (mean +/- standard deviation) in plasma, ELF, and AC were 2.1 +/- 0.8 and 3.3 +/- 1.0, 0.5 +/- 0.7 and 1.0 +/- 0.9, and 5.5 +/- 2.9 and 6.6 +/- 3.1 microg/ml, respectively. The ITRA and OH-IT AUC for plasma, ELF, and AC were 34.4 and 60.2, 7.4 and 18.9, and 101 and 134 microg. hr/ml. The ratio of the C(max) and the MIC at which 90% of the isolates were inhibited (MIC(90)), the AUC/MIC(90) ratio, and the percent dosing interval above MIC(90) for ITRA and OH-IT concentrations in AC were 1.1 and 3.2, 51 and 67, and 100 and 100%, respectively. Plasma, ELF, and AC concentrations of ITRA and OH-IT declined monoexponentially with half-lives of 23.1 and 37.2, 33.2 and 48.3, and 15.7 and 45.6 h, respectively. An oral dosing regimen of ITRA at 200 mg b.i.d. results in concentrations of ITRA and OH-ITRA in AC that are significantly greater than those in plasma or ELF and intrapulmonary pharmacodynamics that are favorable for the treatment of fungal respiratory infection.     

Steady-state plasma and intrapulmonary pharmacokinetics and pharmacodynamics of cethromycin

The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods. C(max)/90% minimum inhibitory concentration (MIC(90)) ratios, area under the concentration-time curve (AUC)/MIC(90) ratios, intrapulmonary drug exposure ratios, and percent time above MIC(90) during the dosing interval (%T > MIC(90)) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, the C(max) (mean +/- standard deviations), AUC(0-24), and half-life for plasma were 0.181 +/- 0.084 microg/ml, 0.902 +/- 0.469 microg. h/ml, and 4.85 +/- 1.10 h, respectively; for ELF the values were 0.9 +/- 0.2 microg/ml, 11.4 microg. h/ml, and 6.43 h, respectively; for AC the values were 12.7 +/- 6.4 microg/ml, 160.8 microg. h/ml, and 10.0 h, respectively. In the 300-mg-dose group, the C(max) (mean +/- standard deviations), AUC(0-24), and half-life for plasma were 0.500 +/- 0.168 microg/ml, 3.067 +/- 1.205 microg. h/ml, and 4.94 +/- 0.66 h, respectively; for ELF the values were 2.7 +/- 2.0 microg/ml, 24.15 microg. h/ml, and 5.26 h, respectively; for AC the values were 55.4 +/- 38.7 microg/ml, 636.2 microg. h/ml, and 11.6 h, respectively. We concluded that the C(max)/MIC(90) ratios, AUC/MIC(90) ratios, %T > MIC(90) values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.     

Pharmacokinetics and pharmacodynamics of two multiple-dose piperacillin-tazobactam regimens.

The pharmacokinetics and pharmacodynamics of two multiple-dose regimens of piperacillin-tazobactam (3.375 g every 6 h and 4.5 g every 8 h) were evaluated at steady state for 12 healthy adult volunteers. Inhibitory and bactericidal activities for the two regimens were determined with five American Type Culture Collection (ATCC) organisms (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Bacteroides fragilis). The percentage of time that plasma concentrations remained above the MIC (T > MIC) for each organism and dosage regimen was calculated. Areas under the inhibitory (AUIC0-24) and bactericidal activity (AUBC0-24) curves were calculated with the trapezoidal rule by using the reciprocal of the inhibitory and bactericidal titers determined for each dosage regimen. In order to assess the validity of predicted measures of bactericidal (AUC0-24/MBC) and inhibitory (AUC0-24/MIC) activity to determine bacteriological response to beta-lactam antimicrobial agents, AUC0-24/MBC and AUC0-24/MIC values were compared with measured AUBC0-24 and AUIC0-24 values. Total body clearance values were equivalent for piperacillin (183.96 +/- 22.66 versus 181.72 +/- 19.54 ml/min/1.73 m2, P > 0.05) and tazobactam (184.71 +/- 19.89 versus 184.87 +/- 18.35 ml/min/1.73 m2, P > 0.05) following the administration of the 3.375-g-every-6-h and 4.5-g-every-8-h dosages, respectively. Comparison of area under the plasma concentration-time curve (AUC0-24) for piperacillin (967.74 +/- 135.56 microg x h/ml versus 978.88 +/- 140.96 microg x h/ml) and tazobactam (120.14 +/- 15.78 microg x h/ml versus 120.01 +/- 16.22 microg x h/ml) revealed no significant differences (P > 0.05) between the 3.375-g-every-6-h and 4.5-g-every-8-h regimens, respectively. Both regimens provided T > MIC values of > 60% for all organisms tested. Measured values of bactericidal (AUBC) and inhibitory (AUIC) activity were significantly different (P < 0.05) from predicted values (AUC0-24/MBC and AUC0-24/MIC) for all organisms studied with the exception of the bactericidal activity for P. aeruginosa and S. aureus. Additionally, ATCC organisms possessing the same MICs and MBCs exhibited great differences in measured AUBC0-24 and AUIC0-24 values. Reasons for this difference may be inherent differences in organism specific susceptibility.     

In vitro and in vivo activities of posaconazole against Coccidioides immitis

Posaconazole (SCH 56592) was tested against 25 strains of Coccidioides immitis to determine their in vitro susceptibilities. The geometric mean 48-h MIC of posaconazole (POSA) was 0.5 microg/ml, the MIC range was 0.25 to 1 microg/ml, and the MIC at which 50% of the isolates tested are inhibited (MIC50) and the MIC90 were 0.5 and 1 microg/ml, respectively. The geometric mean 48-h MIC of itraconazole (ITRA) was 0.23 microg/ml, the MIC range was 0.125 to 0.5 microg/ml, and the MIC50 and MIC90 were both 0.25 microg/ml. Two strains of C. immitis were selected for in vivo studies on the basis of the POSA 48-h MICs for the isolates. POSA orally administered at 0.01, 0.1, 0.5, 1, 5, and 10 mg/kg of body weight/day was compared with ITRA administered at 10 and 30 mg/kg three times a day. The spleens and livers of mice that died or survived to day 50 were removed to measure the fungal burdens. Mice had >or=90% survival when they were treated with >or=0.5 mg of POSA per kg or 30 mg of ITRA per kg. Cultures of whole spleens and livers from mice treated with 10 mg of POSA per kg showed >or=70% sterilization. No sterilization of whole spleens and livers from mice treated with ITRA was seen. POSA displayed potent in vivo activity against the two strains of C. immitis tested.     

Intracellular pharmacokinetics of once versus twice daily zidovudine and lamivudine in adolescents

Zidovudine (ZDV) and lamivudine (3TC) metabolism to triphosphates (TP) is necessary for antiviral activity. The aims of this study were to compare ZDV-TP and 3TC-TP concentrations in adolescents receiving twice daily (BID) and once daily (QD) regimens and to determine the metabolite concentrations of ZDV and 3TC during chronic therapy on a QD regimen. Human immunodeficiency virus-infected patients (12 to 24 years) taking ZDV (600 mg/day) and 3TC (300 mg/day) as part of a highly active antiretroviral therapy regimen received QD and BID regimens of ZDV and 3TC for 7 to 14 days in a crossover design. Serial blood samples were obtained over 24 h on the QD regimen. Intracellular mono-, di-, and triphosphates for ZDV and 3TC were measured. The median ratio of BID/QD for ZDV-TP predose concentrations was 1.28 (95% confidence interval [CI] = 1.00 to 2.45) and for 3TC-TP was 1.12 (95% CI = 0.81 to 1.96). The typical population estimated half-lives (+/- the standard error of the mean) were 9.1 +/- 0.859 h for ZDV-TP and 17.7 +/- 2.8 h for 3TC-TP. Most patients had detectable levels of the TP of ZDV (24 of 27) and 3TC (24 of 25) 24 h after dosing, and half-lives on a QD regimen were similar to previously reported values when the drugs were given BID. Lower, but not significantly different, concentrations of ZDV-TP were demonstrated in the QD regimen compared to the BID regimen (P = 0.056). Although findings were similar between the BID and QD groups, the lower concentrations of ZDV and the number of patients below the level of detection after 24 h suggests that ZDV should continue to be administered BID.     

Pharmacodynamic activity of telithromycin at simulated clinically achievable free-drug concentrations in serum and epithelial lining fluid against efflux (mefE)-producing macrolide-resistant Streptococcus pneumoniae for which telithromycin MICs vary

The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity at simulated clinically achievable free-drug concentrations in serum (S) and epithelial lining fluid (ELF) against efflux (mefE)-producing macrolide-resistant Streptococcus pneumoniae. Two macrolide-susceptible (PCR negative for both mefE and ermB) and 11 efflux-producing macrolide-resistant [PCR-positive for mefE and negative for ermB) S. pneumoniae strains with various telithromycin MICs (0.015 to 1 microg/ml) were tested. The steady-state pharmacokinetics of telithromycin were modeled, simulating a dosage of 800 mg orally once daily administered at time 0 and at 24 h (free-drug maximum concentration [C(max)] in serum, 0.7 microg/ml; half-life [t(1/2)], 10 h; free-drug C(max) in ELF, 6.0 microg/ml; t(1/2), 10 h). Starting inocula were 10(6) CFU/ml in Mueller-Hinton Broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24, and 48 h assessed the extent of bacterial killing (decrease in log(10) CFU/ml versus initial inoculum). Free-telithromycin concentrations in serum achieved in the model were C(max) 0.9 +/- 0.08 microg/ml, area under the curve to MIC (AUC(0-24 h)) 6.4 +/- 1.5 microg . h/ml, and t(1/2) of 10.6 +/- 0.6 h. Telithromycin-free ELF concentrations achieved in the model were C(max) 6.6 +/- 0.8 microg/ml, AUC(0-24 h) 45.5 +/- 5.5 microg . h/ml, and t(1/2) of 10.5 +/- 1.7 h. Free-telithromycin S and ELF concentrations rapidly eradicated efflux-producing macrolide-resistant S. pneumoniae with telithromycin MICs up to and including 0.25 microg/ml and 1 microg/ml, respectively. Free-telithromycin S and ELF concentrations simulating C(max)/MIC > or = 3.5 and AUC(0-24 h)/MIC > or = 25 completely eradicated (> or =4 log(10) killing) macrolide-resistant S. pneumoniae at 24 and 48 h. Free-telithromycin concentrations in serum simulating C(max)/MIC > or = 1.8 and AUC(0-24 h)/MIC > or = 12.5 were bacteriostatic (0.1 to 0.2 log(10) killing) against macrolide-resistant S. pneumoniae at 24 and 48 h. In conclusion, free-telithromycin concentrations in serum and ELF simulating C(max)/MIC > or = 3.5 and AUC(0-24 h)/MIC > or = 25 completely eradicated (> or =4 log(10) killing) macrolide-resistant S. pneumoniae at 24 and 48 h.     

Pharmacokinetics of Enrofloxacin and Danofloxacin in Plasma, Inflammatory Exudate, and Bronchial Secretions of Calves following Subcutaneous Administration

Enrofloxacin (2.5 mg/kg of body weight) and danofloxacin (1.25 mg/kg) were administered subcutaneously to ruminating calves (n = 8) fitted with subcutaneous tissue cages. Concentrations of enrofloxacin, its metabolite ciprofloxacin, and danofloxacin in blood (plasma), tissue cage exudate (following intracaveal injection of 0.3 ml of 1% [vol/wt] carrageenan), and bronchial secretions were measured by high-performance liquid chromatography (HPLC) and microbiological assay (enrofloxacin plus ciprofloxacin and danofloxacin). Mean maximum concentrations (C(max)) +/- standard deviations of enrofloxacin (0.24 +/- 0.08 microg/ml), ciprofloxacin (0.11 +/- 0.03 [total, 0.34 +/- 0.10] microg/ml), and danofloxacin (0.23 +/- 0.05 microg/ml) were detected in the plasma of calves by HPLC. The C(max) were 0.49 +/- 0.17 microg/ml (enrofloxacin equivalents) and 0.24 +/- 0.03 microg/ml (danofloxacin) when they were measured by microbiological assay. Mean C(max) in exudate (HPLC) were 0.18 +/- 0.07 microg/ml (enrofloxacin), 0.10 +/- 0.04 microg/ml (ciprofloxacin), 0.27 +/- 0.09 microg/ml (enrofloxacin plus ciprofloxacin), and 0.19 +/- 0.05 microg/ml (danofloxacin), and concentrations in exudate exceeded those in plasma from 8 h (enrofloxacin and ciprofloxacin) or 6 h (danofloxacin) after drug administration. The C(max) were 0.34 +/- 0.09 microg/ml (enrofloxacin equivalents) and 0.22 +/- 0.04 microg/ml (danofloxacin) in exudate when they were measured by the microbiological assay. The maximum mean concentration achieved in bronchial secretions (HPLC) were 0.07 +/- 0.04 microg/ml (enrofloxacin), 0.04 +/- 0.07 microg/ml (ciprofloxacin), 0.10 +/- 0. 05 microg/ml (enrofloxacin plus ciprofloxacin), and 0.12 +/- 0.09 microg/ml (danofloxacin). The maximum mean concentration in bronchial secretions from a limited number of animals from which samples were available for microbiological assay were 0.27 +/- 0.11 microg/ml (n = 4 [enrofloxacin equivalents]) and 0.14 +/- 0.02 microg/ml (n = 3 [danofloxacin]). With predictive models of efficacy (C(max)/MIC and area under the concentration-time curve/MIC ratios in plasma) for Pasteurella multocida (MIC of enrofloxacin, 0.06 microg/ml [24]; MIC of danofloxacin, 0.06 microg/ml [6]), enrofloxacin produced scores of 8.17 and 52.00, respectively, compared to those of danofloxacin, which were 4.02 and 23.05, respectively. With the dosing rates recommended in some markets by manufacturers, enrofloxacin and danofloxacin achieved concentrations above the MICs for important pathogenic organisms in plasma, tissue cage exudate, and bronchial secretion. Since fluoroquinolones display concentration-dependent activities, C(max)/MIC ratios may be critical to efficacy. In the United States enrofloxacin is currently the only fluoroquinolone licensed for food animals and dosages for acute respiratory disease are 2.5 to 5 mg/kg for 3 days or 7.5 to 12. 5 mg/kg once. The higher dosages on a single occasion are likely to confer C(max)/MIC ratios that are associated with greater clinical efficacy.     

Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366): reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling

The compartmental pharmacokinetics of anidulafungin (VER-002; formerly LY303366) in plasma were characterized with normal rabbits, and the relationships between drug concentrations and antifungal efficacy were assessed in clinically applicable infection models in persistently neutropenic animals. At intravenous dosages ranging from 0.1 to 20 mg/kg of body weight, anidulafungin demonstrated linear plasma pharmacokinetics that fitted best to a three-compartment open pharmacokinetic model. Following administration over 7 days, the mean (+/- standard error of the mean) peak plasma concentration (C(max)) increased from 0.46 +/- 0.02 microg/ml at 0.1 mg/kg to 63.02 +/- 2.93 microg/ml at 20 mg/kg, and the mean area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) rose from 0.71 +/- 0.04 to 208.80 +/- 24.21 microg. h/ml. The mean apparent volume of distribution at steady state (V(ss)) ranged from 0.953 +/- 0.05 to 1.636 +/- 0.22 liter/kg (nonsignificant [NS]), and clearance ranged from 0.107 +/- 0.01 to 0.149 +/- 0.00 liter/kg/h (NS). Except for a significant prolongation of the terminal half-life and a trend toward an increased V(ss) at the higher end of the dosage range after multiple doses, no significant differences in pharmacokinetic parameters were noted in comparison to single-dose administration. Concentrations in tissue at trough after multiple dosing (0.1 to 10 mg/kg/day) were highest in lung and liver (0.85 +/- 0.16 to 32.64 +/- 2.03 and 0.32 +/- 0.05 to 43.76 +/- 1.62 microg/g, respectively), followed by spleen and kidney (0.24 +/- 0.65 to 21.74 +/- 1.86 and <0.20 to 16.92 +/- 0.56, respectively). Measurable concentrations in brain tissue were found at dosages of > or =0.5 mg/kg (0.24 +/- 0.02 to 3.90 +/- 0.25). Implementation of optimal plasma sampling in persistently neutropenic rabbit infection models of disseminated candidiasis and pulmonary aspergillosis based on the Bayesian approach and model parameters from normal animals as priors revealed a significantly slower clearance (P < 0.05 for all dosage groups) with a trend toward higher AUC(0-24) values, higher plasma concentrations at the end of the dosing interval, and a smaller volume of distribution (P < 0.05 to 0.193 for the various comparisons among dosage groups). Pharmacodynamic modeling using the residual fungal tissue burden in the main target sites as the primary endpoint and C(max), AUC(0-24), time during the dosing interval of 24 h with plasma drug concentration equaling or exceeding the MIC or the minimum fungicidal concentration for the isolate, and tissue concentrations as pharmacodynamic parameters showed predictable pharmacokinetic-pharmacodynamic relationships in experimental disseminated candidiasis that fitted well with an inhibitory sigmoid maximum effect pharmacodynamic model (r(2), 0.492 to 0.819). However, no concentration-effect relationships were observed in experimental pulmonary aspergillosis using the residual fungal burden in lung tissue and survival as parameters of antifungal efficacy. Implementation of optimal plasma sampling in discriminative animal models of invasive fungal infections and pharmacodynamic modeling is a novel approach that holds promise of improving and accelerating our understanding of the action of antifungal compounds in vivo.     

Simulated comparison of the pharmacodynamics of ciprofloxacin and levofloxacin against Pseudomonas aeruginosa using pharmacokinetic data from healthy volunteers and 2002 minimum inhibitory concentration data

BACKGROUND: Until the 2002 approval of levofloxacin 750 mg QD, ciprofloxacin was the fluoroquinolone of choice against Pseudomonas aeruginosa infections. OBJECTIVE: This study evaluated the AUC:MIC ratios for ciprofloxacin 400 mg BID and TID and levofloxacin 750 mg QD, all administered intravenously, against P. aeruginosa using a Monte Carlo simulation. METHODS: Pharmacokinetic data for ciprofloxacin and levofloxacin and 2002 MIC distributions against P. aeruginosa were obtained from studies in healthy volunteers published in the peer-reviewed literature. Pharmacokinetic studies of each agent were identified by separate MEDLINE searches combining the MeSH heading pharmacokinetics with the generic name of the antimicrobial. Only human studies published in English between 1990 and 2001 were included. Included studies also had to meet 3 minimum criteria: evaluation of clinically relevant dosing regimens, use of rigorous study methods, and provision of mean (SD) values for the pharmacokinetic parameters of interest. When multiple studies met these criteria, a single study was selected for each antimicrobial regimen. Pharmacodynamic analysis was performed using a Monte Carlo simulation of 10,000 patients by integrating the pharmacokinetic parameters, their variability, and 2002 MIC distributions for each antimicrobial regimen. The probability of target attainment was determined for each regimen for an AUC:MIC ratio from 0 to 300. A > or =90% probability of target attainment was considered satisfactory. RESULTS: For ciprofloxacin 400 mg TID and levofloxacin 750 mg QD, the AUC:MIC ratio at the corresponding 2002 Clinical Laboratory Standards Institute break points of 1 and 2 microg/mL were 33 and 34, respectively. The probabilities of target attainment for a free AUC:MIC ratio >90 (equivalent to a total AUC:MIC ratio > or =125) were 47% for ciprofloxacin 400 mg BID, 54% for ciprofloxacin 400 mg TID, and 48% for levofloxacin 750 mg QD. CONCLUSION: When pharmacokinetic data from healthy volunteers and 2002 MIC data were used, none of the simulated fluoroquinolone regimens achieved a high likelihood of target attainment against P. aeruginosa.     

Efficacy of PLD-118, a novel inhibitor of candida isoleucyl-tRNA synthetase, against experimental oropharyngeal and esophageal candidiasis caused by fluconazole-resistant C. albicans

PLD-118, formerly BAY 10-8888, is a synthetic antifungal derivative of the naturally occurring beta-amino acid cispentacin. We studied the activity of PLD-118 in escalating dosages against experimental oropharyngeal and esophageal candidiasis (OPEC) caused by fluconazole (FLC)-resistant Candida albicans in immunocompromised rabbits. Infection was established by fluconazole-resistant (MIC > 64 microg/ml) clinical isolates from patients with refractory esophageal candidiasis. Antifungal therapy was administered for 7 days. Study groups consisted of untreated controls; animals receiving PLD-118 at 4, 10, 25, or 50 mg/kg of body weight/day via intravenous (i.v.) twice daily (BID) injections; animals receiving FLC at 2 mg/kg/day via i.v. BID injections; and animals receiving desoxycholate amphotericin B (DAMB) i.v. at 0.5 mg/kg/day. PLD-118- and DAMB-treated animals showed a significant dosage-dependent clearance of C. albicans from the tongue, oropharynx, and esophagus in comparison to untreated controls (P 相似文献   

A comparison of dynamic characteristics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans using time-kill methodology

This study evaluated the in vitro pharmacodynamics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans. MICs were determined for three clinical isolates according to NCCLS guidelines (M27). Time-kill studies were performed using antifungal concentrations of 0.25-32 x MIC and inocula of 10(3) and 10(5) CFU/ml. At predetermined time points over 72 hours, samples of each inoculum/drug combination were withdrawn and plated using a spiral plater. Colony counts were determined after incubation at 35 degrees C for 48 hours. Area under the kill curves (AUKCs) were plotted versus the AUC/MIC ratios. Inoculum effect was evaluated by calculating an estimated AUKC for the low inoculum then comparing it to the measured low inoculum using the unpaired Student's t-test. The MICs of fluconazole and itraconazole for isolate 97-1199, 97-1061, and 97-585 were 2, 4, 32 microg/ml and 0.03, 0.06, 0. 5 microg/ml, respectively. For amphotericin B, the MIC was 0. 25 microg/ml for each isolate. The triazoles demonstrated fungistatic activity against each isolate at both inocula with the exception of itraconazole against C. neoformans 97-585. Maximal suppression was noted at concentrations 8-16 x MIC correlating with an AUC/MIC of 192 for both inocula. Conversely, amphotericin B was fungicidal and displayed concentration-dependent activity against each isolate at both inocula. Maximal killing was observed at concentrations >4 x MIC for the low inoculum and >8 x MIC for the high inoculum for each isolate. No statistically significant differences were detected between the measured and estimated AUKCs for each antifungal agent. In conclusion, our results suggest that the triazoles were most effective against C. neoformans when concentrations were maintained at 8-16 x MIC. Amphotericin B, on the other hand, was concentration-dependent; thus, greater activity was exerted at higher concentrations.     

Comparative pharmacokinetic and pharmacodynamic profile of piperacillin/tazobactam 3.375G Q4H and 4.5G Q6H

When piperacillin/tazobactam has been used to treat hospitalized patients with serious infections, including nosocomial pneumonia caused by Pseudomonas aeruginosa, it has usually been dosed at 3.375 g q4h to provide serum concentrations above commonly encountered organisms' MICs (T > MIC) for at least 40-50% of the dosing interval. Pharmacodynamic principles suggest that a similar efficacy can be realized with extended dosing intervals when a larger dose (e.g. 4.5 g q6h) is administered, which was the objective of this study. Twelve healthy volunteers, 29.4 +/- 8.9 years of age, were enrolled in this multiple-dose, open-labeled, randomized, two-period crossover study. Blood samples were collected after the third dose and concentrations of piperacillin/tazobactam were determined with a validated HPLC method. Pharmacokinetic profiles were determined by noncompartment analysis. T > MIC of piperacillin was calculated for a range of MIC values. Piperacillin/tazobactam was well tolerated in 11 subjects who completed both regimens. The C(max), T(1/2), K, and AUC of P were significantly different according to a paired t test (p < 0.05) between two study regimens. Significant differences (p < 0.05) in tazobactam regimens were noted for C(max), and AUC. The piperacillin/tazobactam regimen of 4.5 g q6h achieved a 44% T > MIC for MIC values of < or = 16 microg/ml, while the 3.375-gram q4h regimen achieved 42% T > MIC, for MIC values of < or = 32 microg/ml. Dosage regimens for treating serious infections can be extended safely and effectively to 4.5 g q6h and obtain at least 40-50% T > MIC in the coverage of pathogens implicated with serious infections, including P. aeruginosa.     

Pharmacokinetic interaction between fosamprenavir-ritonavir and rifabutin in healthy subjects

Rifabutin (RFB) is administered for treatment of tuberculosis and Mycobacterium avium complex infection, including use for patients coinfected with human immunodeficiency virus (HIV). Increased systemic exposure to RFB and its equipotent active metabolite, 25-O-desacetyl-RFB (dAc-RFB), has been reported during concomitant administration of CYP3A4 inhibitors, including ritonavir (RTV), lopinavir, and amprenavir (APV); therefore, a reduction in the RFB dosage is recommended when it is coadministered with these protease inhibitors. Fosamprenavir (FPV), the phosphate ester prodrug of the HIV type 1 protease inhibitor APV, is administered either with or without RTV. A randomized, open-label, two-period, two-sequence, balanced, crossover drug interaction study was conducted with 22 healthy adult subjects to compare steady-state plasma RFB pharmacokinetic parameters during concomitant administration of FPV-RTV (700/100 mg twice a day [BID]) with a 75%-reduced RFB dose (150 mg every other day [QOD]) to the standard RFB regimen (300 mg once per day [QD]) by geometric least-squares mean ratios. Relative to results with RFB (300 mg QD), coadministration of dose-adjusted RFB with FPV-RTV resulted in an unchanged RFB area under the concentration-time curve for 0 to 48 h (AUC(0-48)) and a 14% decrease in the maximum concentration of drug in plasma (C(max)), whereas the AUC(0-48) and C(max) of dAc-RFB were increased by 11- and 6-fold, respectively, resulting in a 64% increase in the total antimycobacterial AUC(0-48). Relative to historical controls, the plasma APV AUC from 0 h to the end of the dosing interval (AUC(0-tau)) and C(max) were increased approximately 35%, and the concentration at the end of the dosing interval at steady state was unchanged following coadministration of RFB with FPV-RTV. The safety profile of the combination of RFB and FPV-RTV was consistent with previously described events with RFB or FPV-RTV alone. Based on the results of this study, a reduction in the RFB dose by > or =75% (to 150 mg QOD or three times per week) is recommended when it is coadministered with FPV-RTV (700/100 mg BID).     

Oral solid gentamicin preparation using emulsifier and adsorbent.

Oral gentamicin (GM) therapy has been challenged by formulating GM in oral solid preparation. GM was dispersed with a surfactant used for the self-microemulsifying drug delivery system (SMEDDS), PEG-8 caprylic/capric glycerides (Labrasol), and the mixture was solidified with several kinds of adsorbents. The used adsorbents were microporous calcium silicate (Florite RE), magnesium alminometa silicate (Neusilin US2), and silicon dioxide (Sylysia 320). In vitro release study showed that the percentage released of GM from each preparation per 2 h was 99.8+/-0.06% for Florite RE 10 mg, 96.7+/-1.16% for Florite RE 20 mg, 98.3+/-0.32% for Neusilin US2, and 94.4+/-0.23% for Sylysia 320. The T50% values were 0.35+/-0.05 h for Florite RE 10 mg, 0.34+/-0.03 h for Florite RE 20 mg, 0.26+/-0.03 h for Neusilin US2, and 0.15+/-0.01 h for Sylysia 320. The in vivo rat absorption study showed that Florite RE 10 mg preparation had the highest C(max) (2.14+/-0.67 microg/ml) and AUC (4.74+/-1.21 microg h/ml). Other preparations had C(max) and AUC of 0.69+/-0.10 microg/ml and 1.56+/-0.43 microg h/ml for Florite RE 20 mg, 1.07+/-0.31 microg/ml and 1.80+/-0.33 microg h/ml for Neusilin US2, and 0.99+/-0.21 microg/ml and 1.77+/-0.50 micorg h/ml for Sylysia 320, respectively. The bioavailability (BA) of GM from the microporous calcium silicate preparation, Florite RE 10 mg, was 14.1% in rats, derived by comparing the AUC obtained after intravenous injection of GM, 1.0 mg/kg, to another group of rats. The microporous calcium silicate preparation using Florite RE 10 mg was evaluated in dogs after oral administration in an enteric capsule, Eudragit S100 (50 mg/dog). High plasma GM levels were obtained (i.e., the C(max) was 1.26+/-0.20 microg/ml and the AUC was 2.59+/-0.33 microg h/ml). These results suggest that an adsorbent system is useful as an oral solid delivery system of poorly absorbable drugs such as GM.     

Safety, tolerance, and pharmacokinetics of amphotericin B lipid complex in children with hepatosplenic candidiasis.

The safety, tolerance, and pharmacokinetics of amphotericin B lipid complex (ABLC) were studied in a cohort of pediatric cancer patients. Six children with hepatosplenic candidiasis (HSC) received 2.5 mg of ABLC/kg of body weight/day for 6 weeks for a total dosage of 105 mg/kg. Mean serum creatinine (0.85 +/- 0.12 mg/dl at baseline) was stable at the end of therapy at 0.85 +/- 0.18 mg/dl and at 1-month follow-up at 0.72 +/- 0.12 mg/dl. There was no increase in hepatic transaminases. Mean plasma concentrations over the dosing interval (C(ave)) and area under the curve from 0 to 24 h (AUC(0-24h)) increased between the first and seventh doses but were similar between doses 7 and 42, suggesting that steady state was achieved by day 7 of therapy. Following the final (42nd) dose of ABLC, mean AUC(0-24h) was 11.9 +/- 2.6 microg h/ml, C(ave) was 0.50 +/- 0.11 microg/ml, maximum concentration of the drug in whole blood was 1.69 +/- 0.75 microg/ml, and clearance was 3.64 +/- 0.78 ml/min/kg. Response of hepatic and splenic lesions was monitored by serial computerized tomographic and magnetic resonance imaging scans. The five evaluable patients responded to ABLC with complete or partial resolution of physical findings and of lesions of HSC. During the course of ABLC infusions and follow-up, there was no progression of HSC, breakthrough fungemia, or posttherapy recurrence. Hepatic lesions continued to resolve after the completion of administration of ABLC. Thus, ABLC administered in multiple doses to children was safe, was characterized by a steady state attainable within 1 week of therapy, and was effective in treatment of HSC.     

Pharmacokinetics and virological efficacy after switch to once-daily lopinavir-ritonavir in treatment-experienced HIV-1-infected children

Lopinavir-ritonavir (LPV/r) is a protease inhibitor that is used twice daily (BID) in the treatment of HIV infection in children. In the context of a single-center observational study, a switch to a once-a-day (QD) LPV/r regimen was proposed for considerations of convenience and to support adherence. The aims of this study were to compare the pharmacokinetics, viral loads, percentages of CD4(+) T cells, and lipid profiles after switching from a twice-daily to a once-daily regimen of LPV/r in experienced children. For this purpose, LPV concentrations, viral loads, CD4(+) T cells, and biochemistry data were measured in routine therapeutic drug monitoring procedures in 45 children and adolescents. Thirty-six children were switched to the QD regimen. Nine children on the BID or QD regimen were added for pharmacokinetic-study purposes only. The QD trough concentrations (C(trough)) of lopinavir in plasma were significantly lower than those observed with the BID regimen (P < 0.0001), but the 24-h exposure levels were not significantly lower with the QD than with the BID regimen (P = 0.09). Among 34 evaluable patients who switched from the BID to the QD regimen, the virological efficacy of LPV/r appeared to differ (P < 0.001), with 74% and 57% of viral loads, respectively, being <50 copies/ml (mean follow-up times, 33 and 20 months). Among 22 patients with stable virological control before the switch, 12 experienced either failure or blip (one observation of detectable viral load between two observations of undetectable viral load) after the switch. The change from the BID to the QD regimen did not result in significant differences in CD4(+) T cell percentages or total cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels. The switch from the BID to the QD LPV/r regimen led to equivalent exposure and lower C(trough) values and resulted in lower levels of virological control in these antiretroviral-experienced children.     

Intrapulmonary distribution of intravenous telavancin in healthy subjects and effect of pulmonary surfactant on in vitro activities of telavancin and other antibiotics

Steady-state concentrations of telavancin, a novel, bactericidal lipoglycopeptide, were determined in the plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AMs) of 20 healthy subjects. Telavancin at 10 mg of drug/kg of body weight/day was administered as a 1-h intravenous infusion on three successive days, with bronchoalveolar lavage performed on five subjects, each at 4, 8, 12, and 24 h after the last dose. Plasma samples were collected before the first and third infusions and at 1, 2, 3, 4, 8, 12, and 24 h after the third infusion. The plasma telavancin concentration-time profile was as reported previously. Telavancin (mean +/- standard deviation) penetrated well into ELF (3.73 +/- 1.28 microg/ml at 8 h and 0.89 +/- 1.03 microg/ml at 24 h) and extensively into AMs (19.0 +/- 16.8 microg/ml at 8 h, 45.0 +/- 22.4 microg/ml at 12 h, and 42.0 +/- 31.4 microg/ml at 24 h). Mean concentrations in AMs and plasma at 12 h were 45.0 microg/ml and 22.9 microg/ml (mean AM/plasma ratio, 1.93), respectively, and at 24 h were 42.0 microg/ml and 7.28 microg/ml (mean AM/plasma ratio, 6.67), respectively. Over the entire dosing interval, telavancin was present in ELF and AMs at concentrations up to 8-fold and 85-fold, respectively, above its MIC 90 for methicillin-resistant Staphylococcus aureus (0.5 microg/ml). Pulmonary surfactant did not affect telavancin's in vitro antibacterial activity. Telavancin was well tolerated. These results support the proposal for further clinical evaluation of telavancin for treating gram-positive respiratory infections.     

Pharmacokinetics of sparfloxacin and interaction with cisapride and sucralfate.

In an open, randomized, triple crossover study, the effects of cisapride and sucralfate on the pharmacokinetics of sparfloxacin were assessed. Fifteen healthy volunteers received 400 mg of sparfloxacin as a single oral dose on day 0. In a random order, concomitant doses of 10 mg of cisapride three times daily from day -2 to day 2 and 1 g of sucralfate four times daily from day -2 to day 0 were administered. Sparfloxacin concentrations were measured by bioassay and high-performance liquid chromatography. Pharmacokinetic parameters for sparfloxacin alone were as follows (mean +/- standard deviation): maximum concentration of drug in serum (C(max)), 1.27 +/- 0.39 microg/ml; time to C(max) (T(max)), 4.1 +/- 1.9 h; area under the concentration-time curve (AUC), 35.0 +/- 9.7 microg x h/ml; mean residence time, 28.5 +/- 5.7 h; half-life (t1/2), 20 +/- 4 h; urinary recovery (UR x f), 11.0% +/- 2.7%; and metabolite-sparfloxacin ratio in urine, 2.6. For the cisapride group there was a significant decrease in the sparfloxacin T(max) (1.9 +/- 2.1 h) and a significant increase in C(max) (1.74 +/- 0.73 microg/ml). The QTc interval for patients receiving sparfloxacin and cisapride was prolonged by 7.7% compared to the QTc interval during medication-free periods. Significant differences in the values for the group receiving sucralfate compared to the values for the group receiving sparfloxacin alone were found: C(max), 0.77 +/- 0.31 microg/ml; AUC, 18.6 +/- 5.8 microg x h/ml; t1/2, 26 +/- 10 h; and UR x f, 5.8 +/- 1.8%. Concomitant adminstration of cisapride accelerates the absorption and increases the peak concentration of sparfloxacin without having a significant effect on the extent of bioavailability. Coadministration of sucralfate leads to a 44% decrease in the bioavailability of sparfloxacin.     

Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naive HIV-infected patients

QDMRK was a phase III clinical trial of raltegravir given once daily (QD) (800-mg dose) versus twice daily (BID) (400 mg per dose), each in combination with once-daily coformulated tenofovir-emtricitabine, in treatment-naive HIV-infected patients. Pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analyses were conducted using a 2-step approach: individual non-model-based PK parameters from observed sparse concentration data were determined, followed by statistical analysis of potential relationships between PK and efficacy response parameters after 48 weeks of treatment. Sparse PK sampling was performed for all patients (QD, n = 380; BID, n = 384); selected sites performed an intensive PK evaluation at week 4 (QD, n = 22; BID, n = 20). In the intensive PK subgroup, daily exposures (area under the concentration-time curve from 0 to 24 h [AUC(0-24)]) were similar between the two regimens, but patients on 800 mg QD experienced ~4-fold-higher maximum drug concentration in plasma (C(max)) values and ~6-fold-lower trough drug concentration (C(trough)) values than those on 400 mg BID. Geometric mean (GM) C(trough) values were similarly lower in the sparse PK analysis. With BID dosing, there was no indication of any significant PK/PD association over the range of tested PK parameters. With QD dosing, C(trough) values correlated with the likelihood of virologic response. Failure to achieve an HIV RNA level of <50 copies/ml appeared predominantly at high baseline HIV RNA levels in both treatment arms and was associated with lower values of GM C(trough) in the 800-mg-QD arm, though other possible drivers of efficacy, such as time above a threshold concentration, could not be evaluated due to the sparse sampling scheme. Together, these findings emphasize the importance of the shape of the plasma concentration-versus-time curve for long-term efficacy.