Pharmacokinetics, safety, and tolerability of ascending single intravenous doses of oritavancin administered to healthy human subjects

Oritavancin (LY333328 diphosphate) is a novel glycopeptide antimicrobial agent with potent microbiological activity in vitro against Gram-positive bacteria. A single-dose, open-label, noncontrolled, dose-escalation study in 11 healthy human subjects was carried out to evaluate the safety and pharmacokinetics of oritavancin. One subject at each dose level received a single intravenous dose of 0.02, 0.03, 0.05, 0.08, 0.125, 0.20, and 0.325 mg/kg infused over 1 hour and four subjects each received a single-dose of 0.5 mg/kg. Safety and tolerability were evaluated by monitoring adverse events and laboratory parameters. Oritavancin pharmacokinetics were assessed by blood, urine, and fecal sampling. The plasma concentrations of oritavancin after the end of infusion followed a multiexponential decline over a 2-week period. Median (range) C(max) for the 0.5 mg/kg dose group was 6.5 (4.7-7.6) microg/mL. In every subject, plasma concentrations declined to < or =10% of the C(max) within 24 hours. Following a short, constant-rate infusion, the pharmacokinetics of oritavancin were linear across a total dose range from 3.66-44.6 mg. Renal clearance was approximately 0.457 mL/min. The mean (range) plasma terminal half-life of oritavancin was 195.4 (135.8-273.8) hours across all dose levels from 0.05-0.5 mg/kg. Less than 5% and 1% of administered drug were recovered in the urine and feces, respectively, after 7 days. This first time in man evaluation of oritavancin revealed that single doses of oritavancin of up to and including 0.5 mg/kg were safe and well tolerated. Although no clinically relevant changes in renal, hepatic and hematologic indices from baseline were observed, five subjects did manifest asymptomatic and transient elevations of hepatic transaminase concentrations. Because this study was not placebo-controlled and enrolled a small number of subjects, the safety and pharmacokinetic profiles of oritavancin need to be confirmed in additional studies.     

Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its major metabolites in squirrel monkeys at plasma concentrations of MDMA that develop after typical psychoactive doses

At certain doses, the psychoactive drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") destroys brain serotonin axon terminals. By causing increases in plasma MDMA concentrations that exceed those predicted by the increase in dose, nonlinear pharmacokinetics has the potential to narrow the range between safe and neurotoxic doses of MDMA. The present study sought to determine whether the pharmacokinetics of MDMA in nonhuman primates are nonlinear and, if they are, to identify plasma concentrations of MDMA at which nonlinear accumulation of MDMA occurs. Four different oral doses of MDMA were tested in the same six squirrel monkeys in random order. At each dose, pharmacokinetic parameters for MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 3,4-methylenedioxyamphetamine were determined. Doses were selected to be equivalent to 0.4, 0.8, 1.6, and 2.8 mg/kg doses in humans. The maximal concentration (C(max)) and area under the curve (AUC) of MDMA increased nonlinearly with dose, whereas the C(max) and AUC of the metabolites HHMA and HMMA remained relatively constant. Nonlinear MDMA pharmacokinetics occurred at plasma MDMA concentrations of 100 to 300 ng/ml and above. The half-life (T(1/2)) of MDMA and its metabolites also increased with dose. These results firmly establish nonlinear pharmacokinetics for MDMA in squirrel monkeys and indicate that nonlinear MDMA accumulation occurs at plasma MDMA concentrations that develop in humans taking typical doses. By raising MDMA concentrations and prolonging its action, nonlinear pharmacokinetics and T(1/2) prolongation, respectively, may influence the likelihood and severity of MDMA toxicities (including brain serotonin neurotoxicity).     

The effect of pharmacokinetics on the bactericidal activity of ciprofloxacin and sparfloxacin against Streptococcus pneumoniae and the emergence of resistance.

The pharmacokinetics of ciprofloxacin and sparfloxacin were simulated in vitro and the effects of pharmacodynamic parameters on bactericidal activity and the emergence of quinolone resistance were examined for Streptococcus pneumoniae. Simulated serum concentrations of ciprofloxacin 500 mg bd were more rapidly bactericidal than sparfloxacin 200 mg bd, despite lower values for the key pharmacodynamic parameters (AUC/MIC and C(max)/MIC). This was possibly related to the slower oral absorption of sparfloxacin, which delayed achievement of the MIC compared with ciprofloxacin. In addition, sparfloxacin was shown to have similar bactericidal activity to ciprofloxacin when tested at the same concentrations, despite its four-fold better potency in MIC terms. The emergence of resistance following exposure to ciprofloxacin appeared to be dependent on the C(max)/MIC ratio and the AUC above the MIC, but not the AUC/MIC ratio. Resistance (at least four-fold increase in MIC) developed when the C(max)/MIC ratio was less than four or the AUC above the MIC was less than 10, and the resulting cultures regrew fully. In contrast, pneumococci with a two- to four-fold increase in sparfloxacin MIC were selected in the presence of serum concentrations of sparfloxacin despite a C(max)/MIC ratio higher than 12, but these isolates remained clinically susceptible by breakpoint MIC and their growth was inhibited by repeated dosage of sparfloxacin. Nevertheless, the selection of pneumococci with reduced susceptibility, and the possibility of further mutation to highly resistant strains supports the use of quinolones that rapidly eradicate pneumococci at conventional doses and achieve concentrations, in both serum and tissues, which exceed at least 4 x MIC.     

Pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin in patients with major thermal injuries

Adequate penetration of antibiotics into burn tissue and maintenance of effective serum levels are essential for the treatment of patients sustaining major thermal injuries. The pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin were determined in 12 critically ill patients with burn injuries. Mean age for the 12 patients was 45 +/- 17 (range 25-82 years), total body surface area burned (TBSAB) = 38 +/- 15% and Acute Physiology and Chronic Health Evaluation (APACHE) II score = 8 +/- 6. Patients received recommended doses of ciprofloxacin, 400 mg q12h iv, for three doses beginning 72 h post-burn. Serum concentrations were measured at t = 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 4.0 and 12.0 h after the first and third doses. Burn eschar biopsies were obtained after the third ciprofloxacin dose. Three of these 12 patients (25%) manifested later signs of clinical sepsis (TBSAB = 61 +/- 6% and APACHE II score = 11 +/- 3) and underwent a second infusion of three doses of intravenous ciprofloxacin, blood sampling and eschar biopsy. Serum and eschar concentrations were determined by high performance liquid chromatography. Serum ciprofloxacin concentrations were comparable to those of normal volunteers (C(max) = 4.0 +/- 1 mg/L and AUC = 11.4 +/- 2 mg.h/L) during the immediate post-burn period after dose 1 (C(max1) = 4.8 +/- 3 mg/L and AUC(0-12) = 12.5 +/- 7 mg. h/L) and dose 3 (C(max3) = 4.9 +/- 2 mg/L and AUC(24-36) = 17.5 +/- 11 mg.h/L). Mean burn eschar concentration during the 72 h post-burn was significantly lower than that found during clinical sepsis (18 +/- 17 compared with 41.3 +/- 54 microg/g; P < 0.05 by t test). Similar serum concentrations were achieved in patients with clinical sepsis (C(max1) = 4.2 +/- 0.2 mg/L and AUC(0-12) = 15.0 +/- 3 mg. h/L; C(max3) = 5.0 +/- 1 mg/L and AUC(24-36) = 22.8 +/- 9 mg.h/L). A positive correlation between burn eschar concentrations and C(max) (r = 0.71, r(2) = 0.51, P = 0.01) was found by linear regression analysis. A C(max)/MIC ratio > 10 (MIC = 0.5 mg/L) and an AUC/MIC ratio > 100 SIT(-1).h (serum inhibitory titre) (MIC = 0.125 mg/L) were achieved. High burn eschar concentrations and serum levels, similar to those found in normal volunteers, can be achieved after intravenous ciprofloxacin infusion in critically ill burns patients.     

Pharmacokinetics and pharmacodynamics of TMC207 and its N-desmethyl metabolite in a murine model of tuberculosis

TMC207 is a first-in-class diarylquinoline with a new mode of action against mycobacteria targeting the ATP synthase. It is metabolized to an active derivative, N-desmethyl TMC207, and both compounds are eliminated with long terminal half-lives (50 to 60 h in mice) reflecting slow release from tissues such as lung and spleen. In vitro, TMC207 is 5-fold more potent against Mycobacterium tuberculosis than N-desmethyl TMC207, and the effects of the two compounds are additive. The pharmacokinetic and pharmacodynamic (PK-PD) response was investigated in the murine model of tuberculosis (TB) infection following oral administration of different doses of TMC207 or N-desmethyl TMC207 at 5 days per week for 4 weeks starting the day after intravenous infection with M. tuberculosis and following administration of different doses of TMC207 at various dosing frequencies for 6 weeks starting 2 weeks after infection. Upon administration of N-desmethyl TMC207, maximum plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to 168 h postdose (AUC(168h)), and minimum plasma concentration (C(min)) were approximately dose proportional between 8 and 64 mg/kg, and the lung CFU counts were strongly correlated with these pharmacokinetic parameters using an inhibitory sigmoid maximum effect (E(max)) model. Administration of the highest dose (64 mg/kg) produced a 4.0-log(10) reduction of the bacillary load at an average exposure (average concentration [C(avg)] or AUC(168h) divided by 168) of 2.7 μg/ml. Upon administration of the highest dose of TMC207 (50 mg/kg) 5 days per week for 4 weeks, the total reduction of the bacillary load was 4.7 log(10). TMC207 was estimated to contribute to a 1.8-log(10) reduction and its corresponding exposure (C(avg)) was 0.5 μg/ml. Optimal bactericidal activity with N-desmethyl TMC207 was reached at a high exposure compared to that achieved in humans, suggesting a minor contribution of the metabolite to the overall bactericidal activity in TB-infected patients treated with TMC207. Following administration of TMC207 at a total weekly dose of 15, 30, or 60 mg/kg fractionated for either 5 days per week, twice weekly, or once weekly, the bactericidal activity was correlated to the total weekly dose and was not influenced by the frequency of administration. Exposures (AUC(168h)) to TMC207 and N-desmethyl TMC207 mirrored this dose response, indicating that the bactericidal activity of TMC207 is concentration dependent and that AUC is the main PK-PD driver on which dose optimization should be based for dosing frequencies up to once weekly. The PK-PD profile supports intermittent administration of TMC207, in agreement with its slow release from tissues.     

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.     

PA-824 exhibits time-dependent activity in a murine model of tuberculosis

PA-824 is one of two nitroimidazoles in phase II clinical trials to treat tuberculosis. In mice, it has dose-dependent early bactericidal and sterilizing activity. In humans with tuberculosis, PA-824 demonstrated early bactericidal activity (EBA) at doses ranging from 200 to 1,200 mg per day, but no dose-response effect was observed. To better understand the relationship between drug exposure and effect, we performed a dose fractionation study in mice. Dose-ranging pharmacokinetic data were used to simulate drug exposure profiles. Beginning 2 weeks after aerosol infection with Mycobacterium tuberculosis, total PA-824 doses from 144 to 4,608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days. Lung CFU counts after treatment were strongly correlated with the free drug T(>MIC) (R(2) = 0.87) and correlated with the free drug AUC/MIC (R(2) = 0.60), but not with the free drug C(max)/MIC (R(2) = 0.17), where T(>MIC) is the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions and AUC is the area under the concentration-time curve. When the data set was limited to regimens with dosing intervals of ≤72 h, both the T(>MIC) and the AUC/MIC values fit the data well. Free drug T(>MIC) of 22, 48, and 77% were associated with bacteriostasis, a 1-log kill, and a 1.59-log kill (or 80% of the maximum observed effect), respectively. Human pharmacodynamic simulations based on phase I data predict 200 mg/day produces free drug T(>MIC) values near the target for maximal observed bactericidal effect. The results support the recently demonstrated an EBA of 200 mg/day and the lack of a dose-response between 200 and 1,200 mg/day. T(>MIC), in conjunction with AUC/MIC, is the parameter on which dose optimization of PA-824 should be based.     

Pharmacokinetics of telbivudine following oral administration of escalating single and multiple doses in patients with chronic hepatitis B virus infection: pharmacodynamic implications

The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times T(max) to the maximum plasma concentration (C(max)) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum C(max)s and the areas under the plasma concentration-time curve from time zero to time t (AUC(0-t)s) increased proportionally with dose. At steady-state, the values of C(max) and AUC(0-t) were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for C(max) and from 1.40 to 1.70 for AUC(0-t). While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state C(max) and AUC(0-t). In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.     

Pharmacodynamic activity of telithromycin against macrolide-susceptible and macrolide-resistant Streptococcus pneumoniae simulating clinically achievable free serum and epithelial lining fluid concentrations

BACKGROUND: The association between macrolide resistance mechanisms and ketolide bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity against macrolide-susceptible and macrolide-resistant S. pneumoniae simulating clinically achievable free serum and epithelial lining fluid (ELF) concentrations. MATERIALS AND METHODS: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Telithromycin was modelled simulating a dosage of 800 mg by mouth once daily [free serum: maximum concentration (C(max)) 0.7 mg/L, t(1/2) 10 h; and free ELF: C(max) 6.0 mg/L, t(1/2) 10 h]. Starting inocula were 1 x 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). RESULTS: Telithromycin free serum concentrations achieved in the model were: C(max) 0.9+/-0.08 mg/L, AUC(0-24) 6.4+/-1.5 mg.h/L and t(1/2) of 10.6+/-1.6 h. Telithromycin free ELF concentrations achieved in the model were: C(max) 6.6+/-0.8 mg/L, AUC(0-24) 45.5+/-5.5 mg.h/L and t(1/2) of 10.5+/-1.7 h. At 2 h, free serum telithromycin concentrations achieved a 1.0-1.9 log(10) reduction in inoculum compared with a 3.0-3.3 log(10) reduction with free ELF versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Free telithromycin serum and ELF concentrations simulating C(max)/MIC > or =14.1 and area under the curve to MIC (AUC(0-24)/MIC) > or =100 [time above the MIC (t > MIC) of 100%], were bactericidal (> or =3 log(10) killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae. CONCLUSION: Telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving C(max)/MIC > or =14.1 and AUC(0-24)/MIC > or =100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.     

Pharmacodynamics of TD-1792, a novel glycopeptide-cephalosporin heterodimer antibiotic used against Gram-positive bacteria, in a neutropenic murine thigh model

TD-1792 is a novel glycopeptide-cephalosporin heterodimer investigational antibiotic that displays potent bactericidal effects against clinically relevant Gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of TD-1792 in the neutropenic murine thigh infection animal model. TD-1792, dosed subcutaneously (SC), produced dose-dependent reduction in the thigh bacterial burden of several organisms, including methicillin-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis (MSSA, MRSA, MSSE, MRSE, respectively), penicillin-susceptible strains of Streptococcus pneumoniae (PSSP), Streptococcus pyogenes, and vancomycin-intermediate-susceptible Staphylococcus aureus (VISA). In single-dose efficacy studies, the 1-log(10) CFU kill effective dose (ED(1-log kill)) estimates for TD-1792 ranged from 0.049 to 2.55 mg/kg of body weight administered SC, and the bacterial burden was reduced by up to 3 log(10) CFU/g from pretreatment values. Against S. aureus ATCC 33591 (MRSA), the total 24-h log(10) stasis dose (ED(stasis)) and ED(1-logkill) doses for TD-1792 were 0.53 and 1.11 mg/kg/24 h, respectively, compared to 23.4 and 54.6 mg/kg/24 h for vancomycin, indicating that TD-1762 is 44- to 49-fold more potent than vancomycin. PK-PD analysis of data from single-dose and dose-fractionation studies for MRSA (ATCC 33591) demonstrated that the total-drug 24-h area under the concentration-time curve-to-MIC ratio (AUC/MIC ratio) was the best predictor of efficacy (r(2) = 0.826) compared to total-drug maximum plasma concentration of drug-to-MIC ratio (Cmax/MIC ratio; r(2) = 0.715) and percent time that the total-drug plasma drug concentration remains above the MIC (%Time>MIC; r(2) = 0.749). The magnitudes of the total-drug AUC/MIC ratios associated with net bacterial stasis, a 1-log(10) CFU reduction from baseline and near maximal effect, were 21.1, 37.2, and 51.8, respectively. PK-PD targets based on such data represent useful inputs for analyses to support dose selection decisions for clinical studies of patients.     

Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects

Endoxifen is an active metabolite of tamoxifen, a drug used in the treatment of breast cancer. In order to be clinically effective, tamoxifen must be converted to endoxifen by cytochrome P450 2D6 (CYP2D6). A study involving single escalating oral doses was conducted in humans to evaluate the safety, tolerability, and pharmacokinetics (PK) of endoxifen. This is the first study demonstrating that single oral doses of endoxifen are safe and well tolerated and have sufficient bioavailability to reach systemically effective levels in human subjects. Furthermore, it was found that endoxifen is rapidly absorbed and systemically available and that it displays dose proportionality in peak drug concentrations in plasma (C(max)) and area under the concentration-time curve extrapolated from 0 to ∞ (AUC(0-∞)) over the dose range 0.5-4.0 mg.     

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.     

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.     

Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and paclitaxel

OBJECTIVES: The data reported are from a trial designed to determine, in patients with advanced cancer, the maximum tolerated dose and pharmacokinetics of calcitriol when administered with paclitaxel, an agent whose antitumor activity in in vitro and in vivo studies has been shown to be enhanced by calcitriol. An additional goal was to evaluate the relationship between calcitriol dose and hypercalcemia. METHODS: Calcitriol was given orally for 3 consecutive days each week, and paclitaxel (80 mg/m(2)) was given intravenously weekly. Thirty-six patients were treated in cohorts composed of 3 to 9 patients, at escalating dose levels of calcitriol. The starting dose of calcitriol was 4 microg for 3 consecutive days each week, and the maximum dose administered was 38 microg for 3 consecutive days each week. The preparation of calcitriol used in this trial was a commercially available caplet (0.5 microg per caplet). Serum calcitriol concentrations were measured by radioimmunoassay. Detailed assessments of calcitriol pharmacokinetics were performed in 26 patients. RESULTS: There was substantial interpatient variation in peak serum calcitriol concentrations (C(max)), time to reach C(max), and area under the concentration versus time curve (AUC). Serum calcitriol AUC was not proportional to calcitriol dose (P =.0014). AUC for the 24-hour period after calcitriol administration [AUC (0-24)] at 38 microg was only 4 times that at 4 microg, instead of the 9.5-fold increase expected for a proportional relationship. Calcitriol plasma concentrations of 600 to 1440 pg/mL were achieved. No dose-limiting toxicity occurred in this trial. CONCLUSIONS: Despite variability in absorption, very high doses of calcitriol can be safely administered with paclitaxel. The high calcitriol serum concentrations achieved in this study approach those that, both in vitro and in vivo, potentiate the cytotoxicity of taxanes and platinum analogs.     

Evaluation of daptomycin activity against Staphylococcus aureus in an in vitro pharmacodynamic model under normal and simulated impaired renal function

OBJECTIVES: Daptomycin is a lipopeptide antimicrobial that is primarily excreted by the kidney. We examined daptomycin bactericidal activity in an in vitro pharmacodynamic model (IVPM) under normal and simulated impaired renal function against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). METHODS: Two clinical strains MSSA-1199 and MRSA-494 were used in an IVPM. MICs and MBCs were determined according to CLSI. Daptomycin free concentrations were simulated that corresponded to dose regimens of 4, 6 and 8 mg/kg every 24 h at 8 h t(1/2) (Scheme I) and every 48 h at 30 h t(1/2) (Scheme II). In addition, we simulated daptomycin free concentrations corresponding to fractional dose regimens of 2, 3 and 4 mg/kg every 24 h at 30 h t(1/2) (Scheme III). The targeted C(max free)/MIC for 2, 3, 4, 6 and 8 mg/kg against MSSA-1199 ranged from 5.2 to 21.2. The targeted C(max free)/MIC for 2, 3, 4, 6 and 8 mg/kg against MRSA-494 ranged from 10.4 to 42.2. The targeted AUC(free)/MIC for Schemes I, II and III against MSSA-1199 ranged from 94 to 392. The targeted AUC(free)/MIC for Schemes I, II and III against MRSA-494 ranged from 188 to 581. Bactericidal activity and the potential for resistance were determined over 96 h. All models were completed in triplicate. RESULTS: Daptomycin MICs (MBCs) for MSSA-1199 and MRSA-494 were 0.5 (1.0) mg/L and 0.25 (0.25) mg/L, respectively. Daptomycin 6 and 8 mg/kg at both 8 and 30 h t(1/2) achieved 99.9% kill as early as 1 h. Daptomycin 4 mg/kg achieved 99.9% kill as early as 1 h when given at 8 and 30 h t(1/2) but was not maintained to an endpoint of 96 h (P > 0.05). CONCLUSIONS: Overall, there was no difference in kill noted for daptomycin regimens at 4, 6 and 8 mg/kg every 24 h at 8 h t(1/2) versus every 48 h at 30 h t(1/2). Fractional doses of daptomycin at 30 h t(1/2) were inferior to daptomycin regimens of 4, 6 and 8 mg/kg administered every 48 h (P = 0.03).     

In vitro pharmacodynamic evaluation of the mutant selection window hypothesis using four fluoroquinolones against Staphylococcus aureus

To study the hypothesis of the mutant selection window (MSW) in a pharmacodynamic context, the susceptibility of a clinical isolate of methicillin-resistant Staphylococcus aureus exposed to moxifloxacin (MOX), gatifloxacin (GAT), levofloxacin (LEV), and ciprofloxacin (CIP) was tested daily by using an in vitro dynamic model that simulates human pharmacokinetics. A series of monoexponential pharmacokinetic profiles that mimic once-daily administration of MOX (half-life, 12 h), GAT (half-life, 7 h), and LEV (half-life, 6.8 h) and twice-daily administration of CIP (half-life, 4 h) provided peak concentrations (C(max)) that either equaled the MIC, fell between the MIC and the mutant prevention concentration (MPC) (i.e., within or "inside" the MSW), or exceeded the MPC. The respective ratios of the area under the curve (AUC) over a 24-h dosing interval (AUC(24)) to the MIC varied from 13 to 244 h, and the starting inoculum was 10(8) CFU/ml (6 x 10(9) CFU per 60-ml central compartment). With all four quinolones, the greatest increases in MIC were observed at those AUC(24)/MIC values (from 24 to 62 h) that corresponded to quinolone concentrations within the MSW over most of the dosing interval (>20%). Less-pronounced increases in MIC were associated with the smallest simulated AUC(24)/MIC values (15 to 16 h) of GAT and CIP, whose C(max) exceeded the MICs. No such increases were observed with the smallest AUC(24)/MIC values (13 to 17 h) of MOX and LEV, whose C(max) were close to the MICs. Also, less pronounced but significant increases in MIC occurred at AUC(24)/MIC values (107 to 123 h) that correspond to quinolone concentrations partly overlapping the MIC-to-MPC range. With all four drugs, no change in MIC was seen at the highest AUC(24)/MIC values (201 to 244 h), where quinolone concentrations exceeded the MPC over most of the dosing interval. These "protective" AUC(24)/MIC ratios correspond to 66% of the usual clinical dose of MOX (400 mg), 190% of a 400-mg dose of GAT, 220% of a 500-mg dose of LEV, and 420% of two 500-mg doses of CIP. Thus, MOX may protect against resistance development at subtherapeutic doses, whereas GAT, LEV, and CIP provide similar effects only at doses that exceed their usual clinical doses. These data support the concept that resistant mutants are selectively enriched when antibiotic concentrations fall inside the MSW and suggest that in vitro dynamic models can be used to predict the relative abilities of quinolones to prevent mutant selection.     

Comparative distribution of azithromycin in lung tissue of patients given oral daily doses of 500 and 1000 mg

OBJECTIVES: The administration of antibacterial agents should be optimized on the basis of their distribution to enhance drug exposure and obtain bacterial eradication. This study examines the pharmacokinetics of azithromycin in plasma, lung tissue and bronchial washing in patients after oral administration of 500 mg versus 1000 mg once daily for 3 days. PATIENTS AND METHODS: Samples of plasma, lung tissue and bronchial washing were obtained from a cohort of 48 patients during open-chest surgery for lung resection up to 204 h after the last drug dose, and assayed for antibiotic concentrations. RESULTS: Azithromycin was widely distributed within the lower respiratory tract and sustained levels of the drug were detectable at the last sampling time in lung tissue. Doubling the dose of the antibiotic resulted in a proportional increase in lung area under the curve (AUC, 1245.4 versus 2514.2 h x mg/kg) and peak tissue concentration (Cmax, 8.93 +/- 2.05 versus 18.6 +/- 2.20 mg/kg). The pharmacodynamic parameter AUC/MIC for susceptible and intermediate strains of Streptococcus pneumoniae (MICs 0.5 and 2 mg/L, respectively) increased after administration of the 1000 mg schedule compared with 500 mg (AUC/MIC0.5 2414 versus 1144 and AUC/MIC2 2112 versus 814.1 h x mg/kg, respectively) in pulmonary tissue. CONCLUSIONS: Lung exposure to azithromycin is increased proportionally by doubling the dose, which results in a predictable pharmacokinetic behaviour of the drug in the lower respiratory tract.     

Pharmacodynamics of gemifloxacin against Streptococcus pneumoniae in an in vitro pharmacokinetic model of infection

The pharmacodynamics of gemifloxacin against Streptococcus pneumoniae were investigated in a dilutional pharmacodynamic model of infection. Dose fractionation was used to simulate concentrations of gemifloxacin in human serum associated with 640 mg every 48 h (one dose), 320 mg every 24 h (two doses), and 160 mg every 12 h (four doses). Five strains of S. pneumoniae for which MICs were 0.016, 0.06, 0.1, 0.16, and 0.24 mg/liter were used to assess the antibacterial effect of gemifloxacin. An inoculum of 10(7) to 10(8) CFU/ml was used, and each experiment was performed at least in triplicate. The pharmacodynamic parameters (area under the concentration-time curve [AUC]/MIC, maximum concentration of drug in serum [C(max)]/MIC, and the time that the serum drug concentration remains higher than the MIC [T > MIC]) were related to antibacterial effect as measured by the area under the bacterial-kill curve from 0 to 48 h (AUBKC(48)) using an inhibitory sigmoid E(max) model. Weighted least-squares regression was used to predict the effect of the pharmacodynamic parameters on AUBKC(48), and Cox proportional-hazards regression was used to predict the effect of the three pharmacodynamic parameters on the time needed to kill 99.9% of the starting inoculum (T99.9). There was a clear relationship between strain susceptibility and clearance from the model. The simulations (160 mg every 12 h) were associated with slower initial clearance than were the other simulations; in contrast, bacterial regrowth occurred with the 640-mg simulation when MICs were > or =0.1 mg/liter. The percentage coefficient of variance was 19% for AUBKC(48), and the inhibitory sigmoid E(max) model best fit the relationship between AUBKC(48) and AUC/MIC. C(max)/MIC and T > MIC fit less well. The maximum response occurred at an AUC/MIC of >300 to 400. In weighted least-squares regression analysis, there was no evidence that C(max)/MIC was predictive of AUBKC(48), but both AUC/MIC and T > MIC were. A repeat analysis using only data for which the T > MIC was >75% and for which hence regrowth was minimized indicated that AUC/MIC alone was predictive of AUBKC(48). Initial univariate analysis indicated that all three pharmacodynamic parameters were predictive of T99.9, but in the multivariate model only C(max)/MIC reached significance. These data indicate that gemifloxacin is an effective antipneumococcal agent and that AUC/MIC is the best predictor of antibacterial effect as measured by AUBKC(48). However, C(max)/MIC is the best predictor of speed of kill, as measured by T99.9. T > MIC also has a role in determining AUBKC(48), especially when the dose spacing is considerable. Once-daily dosing seems most suitable for gemifloxacin.     

Pharmacokinetics and safety of ascending single doses of DZ-2640, a new oral carbapenem antibiotic, administered to healthy Japanese subjects

DZ-2640 is the ester-type oral carbapenem prodrug of an active parent compound, DU-6681. The pharmacokinetics and safety of DU-6681 were investigated in six studies after oral administration of a single dose of DZ-2640 to healthy male Japanese volunteers at doses of 25, 50, 100, 200, and 400 mg (as the equivalents of DU-6681) in the fasted state. The same volunteers received the drug at a dose of 100 mg in the fasted and fed states to examine the effect of food intake on the bioavailability of DZ-2640. The concentrations of DU-6681 in plasma and urine were determined by a validated high-performance liquid chromatography method and a bioassay. A good correlation between both methods was seen, indicating an absence of major active metabolites. The mean maximum concentrations of DU-6681 in plasma (C(max)) ranged from 0.263 microgram/ml (25-mg dose) to 2.489 microgram/ml (400-mg dose) and were reached within 1.5 h following drug administration. After reaching the C(max), plasma DU-6681 concentrations declined in a monophasic manner, with a half-life of 0.47 to 0.89 h. The area under the concentration-time curve (AUC) and C(max) increased almost linearly with the dose up to the 200-mg dose. The AUC and C(max) increased less than proportionally after administration of the 400-mg dose, suggesting a reduction in drug absorption. The plasma protein binding of DU-6681 was in the range of 23.3 to 25.6%. The cumulative urinary recoveries (0 to 24 h) were in the range of 31.9 to 44.9%. The AUC was slightly but statistically significantly reduced by food intake. However, the C(max), half-life, and recovery in urine were not affected by food intake. The renal clearance (402 to 510 ml/min) was much greater than the mean glomerular filtration rate (ca. 120 ml/min), which indicated active tubular secretion of the drug. A mild transient and moderate diarrhea was observed in two of six volunteers in the study with a single dose of 25 mg. Mild soft stools were observed in two of six volunteers who received a 400-mg dose of the drug.     

Pharmacokinetics-pharmacodynamics of a sordarin derivative (GM 237354) in a murine model of lethal candidiasis

Sordarins are a new class of antifungal agents which selectively inhibit fungal protein synthesis (FPS) by impairing the function of elongation factor 2. The present study investigates possible correlations between sordarin pharmacokinetic (PK) properties and therapeutic efficacy, based on a murine model of invasive systemic candidiasis, and provides a rationale for dose selection in the first study of efficacy in humans. A significant correlation between PK parameters and the in vivo activity of GM 237354, taken as a representative FPS inhibitor, was demonstrated in a murine model of lethal systemic candidiasis. Area under the concentration-time curve (AUC) and maximum concentration of drug in serum (C(max)) over 24 h were determined after a single GM 237354 subcutaneous (s.c.) dose (50 mg/kg of body weight) in healthy animals (no significant PK changes with infection were observed for other sordarin derivatives). These results have been used to simulate PK profiles obtained after several doses and/or schedules in animal therapy. A PK-pharmacodynamic (PD) parameter such as the time that serum drug concentrations remain above the MIC (t > MIC) was also determined. Treatment efficacies were evaluated in terms of the area under the survival time curve (AUSTC), using Kaplan-Meier survival analysis and in terms of kidney fungal burden (log CFU/gram) after s.c. doses of 2.5, 5, 10, 20, and 40 mg/kg every 4, 8, or 12 h (corresponding to total daily doses of 5 to 240 mg/kg). The results show all treatments to significantly prolong survival versus that of infected and nontreated controls (P < 0.05). Relationships between simulated PK and PK-PD parameters and efficacy were explored. A good correlation independent of the dosing interval was observed with AUC (but not C(max) or t > MIC) and both AUSTC and kidney burden. Following repeated dosing every 8 h, AUC(50) (AUC at which 50% of the maximum therapeutic efficacy is obtained) was estimated as 21.7 and 37.1 microg. h/ml (total concentrations) for AUSTC and kidney burden using a sigmoid E(max) and an inhibitory sigmoid E(max) PK-PD model, respectively. For an efficacy target of 90% survival, AUC was predicted as 67 microg. h/ml. We conclude that the PK-PD approach is useful for evaluating relationships between PK parameters and efficacy in antifungal research. Moreover, the results obtained with this approach could be successfully applied to clinical studies.