Stability, efficacy, and safety of continuously infused sucrose-formulated recombinant factor VIII (rFVIII-FS) during surgery in patients with severe haemophilia.

Bolus injection (BI) of sucrose-formulated recombinant factor VIII (rFVIII-FS) is an approved treatment for haemophilia patients undergoing major surgery. Continuous infusion (CI) during surgery has potential benefits by providing steady administration of replacement factor to the patient, avoiding high peaks and low troughs. We tested the stability of rFVIII-FS under CI conditions and conducted a single-centre, open-label, phase III study to evaluate the efficacy and safety of CI using rFVIII-FS in haemophilia A patients undergoing surgery. Patients received bolus rFVIII-FS to achieve >or=80% FVIII levels 30-60 min presurgery, followed by CI of rFVIII-FS at a rate calculated to maintain haemostatic factor levels until days 8-10 post surgery. The rate of infusion was adjusted according to daily calculations derived from the actual clearance. The stability of rFVIII-FS was found to be appropriate for CI for 7 days under the same conditions as clinical settings. Fourteen patients (mean age 37.8 years) receiving on-demand FVIII treatment without a history of inhibitors underwent 15 surgical procedures including joint replacements, synovectomies, multiple tooth extractions, and cholecystectomy. Bleeding was similar to that observed in non-haemophilia patients undergoing similar operations in the same department. Haemostasis during surgery was considered by the attending surgeons as 'excellent' or 'good' in all cases; study investigators rated all 15 cases as 'excellent' overall. There were no adverse events, including inhibitor formation, related to rFVIII-FS. rFVIII-FS was found to be suitable for use in CI in haemophilia A patients undergoing major surgery.

Determination of the concentration of ciprofloxacin in prostate tissue following administration of a single, 1000 mg, extended-release dose.

OBJECTIVE: Infection is a potential complication of transrectal needle biopsy of the prostate (TRNBP), and antibiotic prophylaxis with a fluoroquinolone is commonly used. The objective of this study was to demonstrate penetration of ciprofloxacin into prostate tissue after administration of a ciprofloxacin 1000 mg extended-release formulation prior to TRNBP. SUBJECTS AND METHODS: The study enrolled 13 men aged 45-78 years scheduled for TRNBP. They received a single, 1000 mg, extended-release tablet of ciprofloxacin at about 3 hours or at about 1 hour prior to the scheduled biopsy time. Blood and urine samples were taken just prior to the biopsy procedure, and prostate tissue samples after all needle biopsy specimens required for diagnostic purposes had been obtained, for determination of ciprofloxacin concentrations. Population data from a previous crossover study of 25 healthy male volunteers was used to model the prostate tissue concentrations for extended-release ciprofloxacin up to 24 hours after administration. These data were used to predict the normal range data for the current study. RESULTS: The mean sampling time in the 1-hour group was 1.47 hours (range, 1.25-1.75 hours) and in the 3-hour group was 3.27 hours (range, 3.03-3.42 hours) after ciprofloxacin dosing. The mean concentrations of ciprofloxacin at 1 hour and 3 hours were 4.75 +/- 1.33 microg/g and 4.29 +/- 1.61 microg/g in prostate tissue, 2.11 +/- 1.00 mg/L and 3.08 +/- 1.44 mg/L in serum, and 126.2 +/- 141.7 mg/L and 803.3 +/- 596.3 mg/L in urine. The mean prostate : serum ciprofloxacin concentration ratio was 1.9 : 1 for the 1-hour group and 1.6 : 1 for the 3-hour group. The measured concentrations of ciprofloxacin in prostate tissue fell within the range modelled from the pharmacokinetic data from the 25 healthy, male subjects. No drug-related adverse events were reported. CONCLUSIONS: Extended-release ciprofloxacin is well tolerated and penetrates effectively into prostate tissue. Tissue levels of ciprofloxacin are similar whether the extended-release ciprofloxacin is administered 1 hour or 3 hours before TRNBP, indicating that tissue levels are maintained for several hours after administration. PK modelling as used in this trial is suitable to prospectively outline clinical designs. Further investigation of single-dose, extended-release ciprofloxacin as prophylaxis for TRNBP is warranted.

Safety and pharmacokinetics of a recombinant factor VIII with pegylated liposomes in severe hemophilia A.

BACKGROUND: BAY 79-4980 is a sucrose-formulated recombinant factor VIII (rFVIII-FS) combined with pegylated liposomes to prolong activity. OBJECTIVES: To investigate the safety, tolerability, bioavailability, pharmacokinetics and pharmacodynamics of a single administration of BAY 79-4980 compared with standard rFVIII-FS in patients with severe hemophilia A. METHODS: This randomized, double-blind study consisted of two crossover substudies comparing two doses of liposomal rFVIII-FS with standard rFVIII-FS. Males (12-60 years) with severe hemophilia A received a single infusion of standard rFVIII-FS (35 IU kg(-1)) followed by a single infusion of BAY 79-4980 (13 or 22 mg kg(-1) pegylated liposomes) or vice versa, with 12 observation days and a 2-day washout period between treatments. RESULTS: Twenty-six subjects were enrolled at two centers. No serious adverse events were reported. Transient increases in complement C3a, but not CH50, were seen in subjects receiving both the low- and high-liposome-dose BAY 79-4980. Mild transient elevations of total and low-density lipoprotein cholesterol were observed. There were no clinically significant differences in clotting or laboratory parameters or in pharmacokinetic behavior between BAY 79-4980 and standard rFVIII-FS. The number of subjects with spontaneous bleeds on days 1-14 postinfusion was low, and group comparisons were inconclusive. CONCLUSIONS: Single-dose administration of BAY 79-4980 is well tolerated in patients with severe hemophilia A. Plasma pharmacokinetics of FVIII cannot explain the extended protection from bleeding observed previously with BAY 79-4980. Further studies of efficacy and long-term safety of chronic administration are planned.

The influence of continuous venovenous haemodialysis on the pharmacokinetics of multiple oral moxifloxacin administration to patients with severe renal dysfunction.

AIM: We investigated single dose and steady-state pharmacokinetics of moxifloxacin in eight venovenous haemodialysis patients. METHODS: Plasma, dialysate and urine pharmacokinetic parameters for moxifloxacin and its main metabolites were calculated after single and multiple (7 days) dosing with 400 mg day(-1). RESULTS: Moxifloxacin pharmacokinetics after a single dose and at steady state (multidose day 7) were comparable in patients with impaired renal function and healthy subjects (geometric mean/%CV AUC mg l(-1) h single dose 37.0/24.3 in haemodialysis patients vs. 29.8/22.6 in healthy subjects, 95% CI for ratio of haemodialysis patients to healthy subjects 99.34%, 154.60%; steady state 40.4/29.1 haemodialysis patients vs. 33.9/20.1 in healthy subjects, 95% CI for ratio of haemodialysis patients to healthy subjects 90/39%, 156.93%). In haemodialysis patients plasma concentrations of moxifloxacin at steady-state were elevated compared with those after a single 400 mg dose (AUC mg l(-1) h, geometric mean/%CV, 40.4/29.1) compared with 37.0/24.3; 95% CI for ratio of steady-state to single dose 87.29%, 136.52%, as were concentrations of metabolite M1 3.21/34.6 compared with 2.02/45.3, 95% CI for ratio of steady state to single dose 14.21%, 175.07%. Haemodialysis cleared about 9% of the dose as unchanged moxifloxacin. CONCLUSIONS: No dose adjustments are required for venovenous haemodialysis patients on oral moxifloxacin therapy.

Pharmacokinetics and peritoneal penetration of moxifloxacin in peritonitis.

OBJECTIVES: To investigate the penetration of moxifloxacin into peritoneal exudate in patients with complicated intra-abdominal infections (cIAIs). PATIENTS AND METHODS: Patients (n = 10) with evidence of peritonitis who required surgery with drainage of the abdominal cavity received a single intravenous infusion of moxifloxacin, 400 mg, over 1 h. Plasma and peritoneal exudate samples were obtained over 24 h, and moxifloxacin concentrations were measured by HPLC with fluorescence detection. RESULTS: Plasma moxifloxacin concentrations decreased from a geometric mean of 3.61 mg/L at 1 h to 0.36 mg/L at 24 h. Concentrations in peritoneal exudate were highest 2 h after the start of the infusion, reaching a geometric mean of 3.32 mg/L, and declined to a geometric mean of 0.69 mg/L at 24 h. The exudate/plasma concentration ratio rose from 1.45 at 2 h to 1.91 at 24 h; the 95% confidence intervals for the ratio excluded unity at all time points, suggesting that moxifloxacin penetrates and accumulates in peritoneal exudate. The area under the concentration-time curve (AUC) tended to be greater in exudate; the time to peak concentrations (T(max)) was longer in exudate than in plasma, as were half-life and mean residence time (MRT). CONCLUSIONS: Following intravenous administration, moxifloxacin penetrated peritoneal exudate in patients with peritonitis, achieving and maintaining concentrations that exceed the MICs for pathogens commonly isolated in cIAIs. These findings support the clinical use of moxifloxacin as treatment for cIAIs.

Influence of activated charcoal on the pharmacokinetics of moxifloxacin following intravenous and oral administration of a 400 mg single dose to healthy males.

AIMS: To evaluate the extent to which enterohepatic recycling circulation contributes to moxifloxacin bioavailability in healthy, males by administration of activated charcoal and to evaluate the efficacy of activated charcoal administration in decreasing systemic concentrations of moxifloxacin in the event of overdose. METHODS: Nine healthy males, mean age 34 years (range 23-45 years) participated in a single centre, randomized, nonplacebo-controlled, three way crossover study. The pharmacokinetics of moxifloxacin in plasma and urine were determined for up to 96 h following a 400 mg single dose randomly administered on three separate occasions with a minimum washout phase of 1 week. Treatment A was 400 mg moxifloxacin IV as a 1 h infusion, treatment B was 400 mg moxifloxacin IV as a 1 h infusion with oral activated charcoal (5 g directly before the start of the infusion, 5 g immediately after the end of the infusion, and 10 g at 2, 4 and 8 h after the start of the infusion), treatment C was 400 mg oral moxifloxacin with activated charcoal (10 g 15 min before and at 2, 4 and 8 h after drug administration). The subjects underwent a series of clinical and laboratory tests. RESULTS: Single 400 mg doses of moxifloxacin (PO and/or IV) were safe and well tolerated. The bioavailability of moxifloxacin was significantly decreased when given with charcoal (AUC = 35.5 (IV reference) vs 5.40 (PO) vs 28.5 (IV) mg l(-1) h). Concurrently peak concentrations were lowered C(max) = 3.38 (IV reference) vs 0.62(PO) vs 2.97 (IV) mg l(-1)) by approximately 85% (P < 0.05) following oral administration and by 20% after IV treatment (P < 0.05). Bioavailability amounted to 15.4% (95% confidence interval 9.6, 25.0%) for treatment B while it was 80.4% (95% confidence interval 76.3.6, 84.6%) for treatment C. Terminal half-lives were not affected. The kinetics of urinary excretion corroborated these findings. CONCLUSIONS: The results of this study show that moxifloxacin undergoes pronounced enteric recycling after systemic uptake. In addition, these findings confirm that activated charcoal may be useful in treating moxifloxacin overdose by preventing its absorption.

Pharmacodynamics of moxifloxacin and levofloxacin simulating human serum and lung concentrations.

Fluoroquinolones are known to penetrate well into the infectious foci such as lung mucosa, epithelial lining fluid and alveolar macrophages achieving higher target site concentrations than the corresponding serum levels. In order to integrate the in vitro antibacterial activity and pharmacokinetics of moxifloxacin and levofloxacin, their bactericidal efficacy was assessed by simulating human serum and lung tissue concentrations using Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae as indicator organisms. The bacteria were exposed to fluctuating moxifloxacin and levofloxacin concentrations simulating the drug levels in serum, lung mucosa, epithelial lining fluid and alveolar macrophages. The following parameters were deduced from the kill curves: area under the bactericidal kill curve normalized to the initial inoculum (AUBKC norm), the time needed to reduce the inoculum by 3 log(10) titers, and the initial bactericidal activity. In general, all these three parameters were for all the bacterial isolates having been exposed to moxifloxacin concentration dependent. In contrast, beyond a levofloxacin concentration of optimal bactericidal effect, higher drug concentrations did not further augment the bactericidal activity of levofloxacin. These data demonstrate that not all fluoroquinolones share the same pharmacodynamic targets needed to maximize their antibacterial effect.

Pharmacokinetic/pharmacodynamic (PK/PD) evaluation of a once-daily treatment using ciprofloxacin in an extended-release dosage form.

OBJECTIVE: To evaluate the suitability of a once-a-day dosing regimen of ciprofloxacin using a new extended-release dosage form based on PK/PD principles. METHODS: Ciprofloxacin's serum concentrations were measured after administration of 500 mg immediate-release twice-daily, and 1,000 mg extended-release once-daily to 19 healthy volunteers. Pharmacokinetic parameters were determined using non-compartmental and compartmental data analysis. Measured serum concentration profiles were linked to ciprofloxacin's effect against Escherichia coli (MIC 0.013 mg/l) from in vitro kill curve studies where the pharmacokinetics of ciprofloxacin were simulated and change in number of bacteria (CFU/ml) versus time was monitored. Resulting parameters were used to compare expected kill curves for the two dosing regimens based on measured ciprofloxacin concentrations. RESULTS: Fitting the data using an appropriate PK/PD model resulted in a set of mean pharmacodynamic parameters (bacterial growth rate constant, k0, maximum kill rate constant, Kmax, and EC50). The model included a novel term to account for a change in kill rate after approximately 4 h when Kmax decreased in concentration-dependent matter. The model allowed excellent curve fits of all ciprofloxacin concentrations investigated. Comparison of expected kill curves with the immediate-release versus extended-release treatments showed similar outcome. Both treatments resulted in a decrease in CFU/ml > 5 log units over 24 h. CONCLUSION: Results indicate that once-a-day dosing of equal total daily doses with the new and more compliance-friendly extended-release dosing form will be therapeutically equivalent to once-a-day dosing with traditional immediate-release dosage forms for treatment of infections with this microorganism.

The integrated use of pharmacokinetic and pharmacodynamic models for the definition of breakpoints.

For fluoroquinolones AUC/MIC ratios are known to correlate with clinical outcomes for patients suffering from respiratory tract infections (RTI) and complicated skin and skin structure infections (cSSSI). This paper describes the results of a population PK/PD analysis followed by Monte Carlo simulations to estimate clinical outcome and the microbiological breakpoints for a 400 mg once-daily moxifloxacin (MFX) treatment schedule. Based on PK data from 416 subjects, a non-compartmental population PK model was developed first to describe the expected exposure (AUC) distribution in humans. Height and gender were the main population covariates with moderate influence on PK variability. Albumin, bilirubin, and creatinine clearance (as derived from serum creatinine according to Cockroft and Gault) had a mild effect on AUC. Residual unexplained variability of AUC was low (13.1%). To describe the PD function the MIC distribution pattern of more than 3,000 isolates of S. pneumoniae as the representative pathogen for RTI (MIC90, range: 0.125; 0.006-4 mg/l) was built into the population PK/PD model for RTI, while 126 isolates of methicillin-susceptible Staphylococcus aureus strains (MIC90, range: 0.125; 0.03-4 mg/l) were the basis for the PD function in cSSSI. Simulations for 20,000 (RTI) and 4,000 (cSSSI) subjects were performed to evaluate the AUC/MIC characteristics for moxifloxacin for these two diseases. Overall, a target hit rate was THR = 99% for RTI, while it amounted to THR = 97.5% for cSSSI when applying a threshold of AUIC > 30 [h] as the PK/PD surrogate parameter which is predictive for a positive clinical outcome. A target hit rate of THR = 93.6 % (RTI) and 97.3% (cSSSI), respectively, was predicted when assuming that an AUIC of > 125 [h] is indicative of clinical success (as shown for ciprofloxacin and severe RTIs due to gram-negative infections). In clinical trials with patients receiving 400 mg moxifloxacin once daily for the treatment of community-acquired pneumonia (CAP) success rate was approximately 93.5%. From the simulations performed for RTI an analysis of the overall likelihood of therapeutic failure broken down according to MICs suggests that the risk of a negative clinical outcome at a MIC = 1 mg/l is approximately 0.25% (for MIC = 2 mg/l: predicted likelihood approximately 0.5%) assuming that a cutoff of AUIC = 30 [h] is applicable. Likewise, for cSSSI the probability to fail is predicted as 1.6% at a MIC = 2 mg/l (no strains with MICs between 0.5 and 1 mg/l available from the clinical isolates). These findings are in line with the breakpoint definition of the former National Committee for Clinical Laboratory Standards (NCCLS) for MFX (=1 mg/L to differentiate between susceptible and intermediately susceptible microorganisms; = 2 mg/l to separate intermediate from resistant pathogens). The results of the investigation indicate that the noncompartmental PK/PD model for MFX is suitable to predict clinical outcomes in CAP and cSSSI caused by gram-positive aerobe pathogens. They confirmed that a 400 mg once-daily dosing regimen is suitable to treat these diseases successfully. They are in agreement with the microbiological breakpoints determined by independent methods by the Clinical and Laboratory Standards Institute (CLSI) (former NCCLS).

Pharmacokinetics of moxifloxacin are not influenced by a 7-day pretreatment with 200 mg oral itraconazole given once a day in healthy subjects.

AIM: The primary objective of this interaction study was to confirm preclinical data suggesting that moxifloxacin is not metabolized by CYP 450 isozymes. Itraconazole, a strong CYP 3A4 inhibitor, was used as comedication. METHODS: Twelve healthy male subjects were enrolled in this randomized study using 400 mg of oral moxifloxacin (MXF) administered alone and on the 7th day of a 9-day treatment regimen with itraconazole (ITR) 200 mg p.o., o.d. In addition to the assessment of safety and tolerability, non-compartmental pharmacokinetics of moxifloxacin, itraconazole and their respective metabolites were analyzed using plasma concentrations obtained using HPLC. RESULTS: All treatment regimens were safe and well-tolerated. No interaction with itraconazole was observed for moxifloxacin (relative bioavailability: 111.6% (90% CI 106.5 to 117.0%), C(max) ratio: 103.7% (84.8-126.9%) and its sulfometabolite (Ml) (AUC ratio: 107.7% (95.6, 121.4%), C(max) ratio: 105.8% (89.9-124.5%)). There was a 30% decrease in AUC with M2 moxifloxacin metabolite (glucuronide) accompanied by an approximately 54% increase in renal excretion, which may be due to changes in phase 2 metabolism and/or transport mechanisms altered by itraconazole. Exposure (AUC) to itraconazole and its hydroxymetabolite were marginally altered by moxifloxacin (AUC +5% for itraconazole and -5% for hydroxy-itraconazole (OH-ITR)) indicating the absence of a clinically relevant influence of moxifloxacin on itraconazole. Mean peak concentrations in plasma (C(max)) were reduced for ITR and OH-ITR by approximately 14% and 18%, respectively, when administered concomitantly with moxifloxacin. This was attributed to the sensitivity of itraconazole absorption to changes in gastric physiology (pH, gastric transit, administration after fasting) and was deemed as clinically irrelevant. CONCLUSION: Results of this study indicate that moxifloxacin is not a substrate for CYP 450 3A4 isozymes confirming previous preclinical in vitro data. Moxifloxacin can therefore be safely coadministered with CYP 3A4 inhibitors without the need for dose adjustment. No clinically relevant changes in the pharmacokinetics of itraconazole were observed during the study.

A prospective, multicentre study of moxifloxacin concentrations in the sinus mucosa tissue of patients undergoing elective surgery of the sinus.

A pharmacokinetic study was carried out to determine moxifloxacin concentrations in sinus tissue, after oral moxifloxacin 400 mg once daily for 5 days to patients with chronic sinusitis, undergoing elective sinus surgery. Patients were randomly allocated to one of seven treatment groups, in which tissues were sampled 2, 3, 4, 6, 12, 24 or 36 h post-dose. A control group with non-infected nasal polyps was also included. Forty-eight patients (13 female, 35 male, mean age 47.1 years) were allocated to one of each active treatment group (n = 42) or to the control group (n = 6). Tissue and plasma samples were taken simultaneously and stored frozen until assayed by HPLC. Thirty-nine patients were fully valid for pharmacokinetic analysis. The geometric mean moxifloxacin plasma concentration increased from 2.32 mg/L at 2 h to a maximum of 3.37 mg/L at 4 h post-dose, decreasing to 0.37 mg/L at 36 h post-dose. The moxifloxacin concentration in sinus mucosa was consistently greater than that in plasma being 4.56-5.73 mg/kg from 2 to 6 h and 2.81-1.25 mg/kg from 12 to 36 h post-dose. The elimination rates in plasma and sinus tissues were similar. The tissue/plasma ratio was c. 200% between 2 and 6 h, and up to 328.9% at 36 h. Results were similar whatever the site of tissue sampling (maxillary sinus, anterior ethmoid sinus or nasal polyps). Tissue levels exceeded the MIC(90) of all pathogens commonly causing acute sinusitis (e.g. 5-30 x MIC for Streptococcus pneumoniae: 0.25 mg/L). These results sup-port the use of moxifloxacin 400 mg once daily as a regimen for the treatment of sinus infections.

Ciprofloxacin pharmacokinetic profiles in paediatric sepsis: how much ciprofloxacin is enough?

OBJECTIVE: To determine the pharmacokinetic profile of ciprofloxacin 20 mg/kg per day (10 mg/kg administered intravenously 12 hourly) in paediatric patients with severe sepsis. DESIGN: Open and prospective. SETTING: Tertiary referral multi-disciplinary ICU. PATIENTS: Twenty patients (two groups - group A: 3 months-1 year; group B 1-5 years). INTERVENTIONS: Timed blood samples were taken for pharmacokinetics after the first dose (D(0)), as well as day 2 (D(2)) and then between days 6-8. MEASUREMENTS AND RESULTS: Ciprofloxacin serum levels were measured by high performance liquid chromatography. Demographic and clinical data and all adverse events were noted. Standard pharmacokinetic variables were calculated by non-compartmental methods. Peak concentrations (C(max)) for group A were D(0) 6.1+/-1.2 mg/l, D(2) 9.0+/-1.8 mg/l and D(7) 5.8+/-1.3 mg/l and, for group B, 7.4+/-1.3 mg/l, 7.8+/-1.6 mg/l and 6.4+/-1.3 mg/l, respectively, for the study periods. Concentration 12 h after the start of infusion (C(min)) for all periods were 0.2 mg/l or less. Areas under the curve (AUC, 12 h) were group A: 15.6+/-1.3, 19.2+/-1.63 and 14.1+/-1.4 mg/h per l, and group B: 15.9+/-1.3, 18.0+/-1.7 and 13.2+/-1.26 mg/h per l. One patient presenting with seizures, initially controlled, had another convulsion and a further patient developed seizures whilst on ciprofloxacin. C(max) in these patients were higher than the average C(max). The convulsions of both patients were easily controlled. No other drug-related serious adverse events occurred. No arthropathy was noted. Three patients died of their underlying disease. CONCLUSIONS: There was no accumulation of drug even after 7 days of administration. Our C(max) and AUC were lower than that achieved in a similar adult pharmacokinetic study. To achieve end points of area under the inhibitory curve (AUIC) of 100-150 mg/h per l, 10 mg/kg ciprofloxacin eight hourly would be required for some resistant ICU organisms.

Pharmacokinetics of moxifloxacin, a novel 8-methoxy-quinolone, in patients with renal dysfunction.

AIMS: To evaluate the influence of impaired renal function on the plasma and urinary pharmacokinetics of moxifloxacin, a novel 8-methoxy-quinolone antibacterial drug. METHODS: Twenty male and 12 female subjects (8 healthy subjects, 24 patients with impaired renal function), 18--75 years of age were investigated in parallel fashion with four groups stratified according to creatinine clearance (CLCR; n=8 for each group). The pharmacokinetics of moxifloxacin and the metabolites M1 (sulphonate metabolite) and M2 (glucuronide) in plasma and urine were determined repeatedly up to 96 h after single oral doses of 400 mg. Patients were monitored intensively with regard to clinical and laboratory safety and tolerability. RESULTS: Single doses of 400 mg moxifloxacin were safe and well tolerated. The urinary excretion of moxifloxacin (Aeur, P: 0.0002) and renal clearance (CLR, P<0.0001) were reduced with decreasing CLCR, mean Cmax was slightly reduced (Cmax-ratio 85.0%, 90% CI 67.9, 106.4% severe renal impairment vs healthy subjects) but the AUC was unchanged even in severe renal impairment (AUC-ratio 101.3%, 90% CI 79.7, 128.6%). The mean AUC of the N-sulphonate M1 was slightly increased (by about 53% for the most severe disease) by impaired renal function, but there was no significant correlation between individual AUC and CLCR, whilst Aeur and CLR were significantly correlated with CLCR. In contrast, for the acylglucuronide M2, Aeur (P: 0.0026), CLR (P<0.0001) and AUC (P: 0.0011) were directly correlated with CLCR. CONCLUSIONS: Renal dysfunction had little effect on the plasma pharmacokinetics of either moxifloxacin or metabolite M1, although their renal clearance and urinary excretion were reduced. In contrast renal dysfunction did result in changes in the plasma pharmacokinetics of metabolite M2, causing greater and longer exposure. However the extent of these changes is unlikely to be of clinical relevance.

Angioplasty increases target site concentrations of ciprofloxacin in patients with peripheral arterial occlusive disease.

OBJECTIVE: Patients with peripheral arterial occlusive disease are prone to soft tissue infections and frequently require antibiotics. To date, however, it is not known whether improvement of arterial blood flow by angioplasty of stenosis increases antibiotic concentrations in ischemic lesions. PATIENTS AND METHODS: All patients were scheduled to undergo elective percutaneous transluminal angioplasty (n = 10). Following a single, 400-mg dose of ciprofloxacin, drug concentrations in plasma, ischemic and healthy soft tissue; arterial peak systolic velocity; and ankle-brachial pressure index were assessed before and after angioplasty. Unbound ciprofloxacin concentrations were measured at the site of infection with use of in vivo microdialysis. RESULTS: Angioplasty increased peak systolic velocity and ankle-brachial pressure index compared with baseline (P <.002). Before angioplasty area under concentration-time curve (AUC(0-300)) values for ciprofloxacin were lower in ischemic tissue than in healthy tissue, with median values of 7.1 mg.h/L (range, 3.5-13.0) and 11.3 mg.h/L (range, 3.4-19.0), respectively (P =.03). After angioplasty AUC(0-300) values were identical in ischemic and healthy adipose tissue; median AUC(0-300) values were 8.0 mg.h/L (range, 4.0-20.7) and 8.5 mg.h/L (range, 4.4-22.9), respectively (P =.7). A combined in vivo pharmacokinetic/in vitro pharmacodynamic simulation based on tissue concentration data indicates that this difference in pharmacokinetics is also reflected in antimicrobial effect. CONCLUSION: Antibiotic concentrations are reduced significantly in ischemic lesions compared to those of healthy adipose tissue in patients with peripheral arterial occlusive disease. From the present data it might be speculated that improvement of arterial blood flow at the affected extremity is associated with increased cure rates of soft tissue infections in these patients.

Pharmacokinetics, safety and tolerability of moxifloxacin, a novel 8-methoxyfluoroquinolone, after repeated oral administration.

OBJECTIVE: To investigate the pharmacokinetics, safety and tolerability of moxifloxacin after single and repeated doses. DESIGN AND SETTING: This series comprised 3 separate placebo-controlled studies, 2 studies with a randomised crossover design (up to 400 mg/day) and 1 study with a group comparison design (600mg once daily). PATIENTS AND PARTICIPANTS: Healthy male volunteers were included in these studies. METHODS: Participants received 5-day treatment courses of moxifloxacin 100mg (n = 8) or 200mg (n = 8) twice daily or 400mg once daily (n = 7), or a 10-day treatment course of moxifloxacin 600mg once daily (n = 7). Pharmacokinetics were characterised after the first dose (24-hour profile) and the last dose (96-hour profile), with additional trough and peak measurements during the courses. RESULTS: All treatments were well tolerated. No clinically relevant changes in the standard laboratory tests, vital signs or ECG were observed. Minimum plasma concentrations required to inhibit 90% of susceptible micro-organisms (e.g. 0.125 mg/L for Streptococcus pneumoniae) were attained rapidly and exceeded until the end of treatment. Repeated doses of 100 and 200mg twice daily and 400mg once daily resulted in stable trough and peak concentrations within 3 days of the first dose. The concentrations at steady state were moderately higher (approximately 30% for 400mg once daily) than after the first dose. Steady-state peak concentrations were between 0.9 mg/L (100mg twice daily) and 5.7 mg/L (600mg once daily). The terminal elimination half-life was 14 to 15 hours, supporting once daily administration of the drug. Accumulation ratios ranged between 87% for the lowest dosage and 111% after repeated doses of 600mg once daily, indicating the absence of clinically relevant accumulation due to non-linear pharmacokinetics. Across the studies, the average exposure after single and repeated doses was proportional to the dose administered. CONCLUSIONS: These studies indicate that, based on the safety profile and the pharmacokinetic behaviour of moxifloxacin, a dosage regimen of 400mg given once daily should be effective and well tolerated for the treatment of various infections.

Effects of dairy products on the oral bioavailability of moxifloxacin, a novel 8-methoxyfluoroquinolone, in healthy volunteers.

OBJECTIVE: To investigate the effect of concomitant administration of dairy products on the pharmacokinetics and tolerability of moxifloxacin. DESIGN: This was a single-centre, randomised, controlled, nonblinded, 2-way crossover study in healthy volunteers. PARTICIPANTS: 12 healthy men (aged 25 to 46 years) were enrolled in the study. METHODS: The plasma and urinary pharmacokinetics of moxifloxacin were investigated after single doses of moxifloxacin 400mg administered orally either under fasting conditions or immediately after 250g of yoghurt that was to be consumed within 15 minutes. There was a 1-week interval between the study periods. RESULTS: Administration of moxifloxacin after yoghurt had no effect on the extent of absorption, as estimated by the area under the plasma concentration-time curve from zero to infinity [AUCinfinty; geometric means 31.8 versus 33.9 mg/L x h after test and reference, respectively; estimated true treatment ratio 94%, 90% confidence interval (CI) 90 to 98%]. The rate of absorption was slightly decreased, with a slight reduction in maximum plasma concentration (Cmax; geometric means 2.44 versus 2.87 mg/L; estimated true treatment ratio 85%, 90% CI 74 to 98%) and a prolonged time to reach Cmax (tmax; median 2.75 versus 0.88 hours). The treatments were well tolerated in these healthy individuals. CONCLUSIONS: The effects of yoghurt on the pharmacokinetics of moxitloxacin are considered not clinically relevant. Hence, no special recommendations for administration are required when moxifloxacin is given together with dairy products.

Effect of calcium supplements on the oral bioavailability of moxifloxacin in healthy male volunteers.

OBJECTIVE: To investigate the effect of concomitant calcium administration on the pharmacokinetics and tolerability of moxifloxacin. DESIGN: This was a nonblinded, randomised, single dose, crossover study in healthy male volunteers. PARTICIPANTS: 12 healthy male Caucasians (age 24 to 45 years) were enrolled in the study. METHODS: In each of the 2 study periods, each volunteer received a single oral morning dose of moxifloxacin 400mg after an overnight fast. In 1 of the study periods, Ca2+ 500mg (Calcium-Sandoz Forte) was administered immediately before, and 12 and 24 hours after, moxifloxacin (total of 3 doses of Ca2+). The 2 study periods were separated by a washout period of at least 2 weeks. RESULTS: Moxifloxacin was well tolerated throughout the study. There was no difference in the area under the plasma concentration-time curve from zero to infinity [AUCinfinity; geometric mean (SD)] of moxifloxacin [32.2 (1.24) vs 33.0 (1.26) mg/L x h, with vs without Ca2+]. Maximum plasma concentration (Cmax) [2.29 (1.27) vs 2.71 (1.33) mg/L, with vs without Ca2+] slightly decreased by approximately 16% and the time to Cmax [median (range)] tended to be slightly prolonged [2.5 (0.8 to 3) vs 0.9 (0.5 to 2.5) hours, with vs without Ca2+]. CONCLUSIONS: The extent of absorption of moxifloxacin is not affected by concomitant Ca2+ intake, whereas the rate of absorption is slightly reduced, an effect not considered to be of clinical relevance. Hence, moxifloxacin may be administered together with Ca2+ without dosage adjustments or special recommendations.

Evaluation of the influence of antacids and H2 antagonists on the absorption of moxifloxacin after oral administration of a 400mg dose to healthy volunteers.

OBJECTIVE: To determine the effect of concomitant administration of the antacid Maalox 70 or the histamine H2 receptor antagonist ranitidine on the bioavailability of moxifloxacin. DESIGN: These were nonblinded, randomised, crossover studies performed in healthy volunteers. PARTICIPANTS: 24 healthy males aged 22 to 39 years (study 1; n = 12) and 24 to 43 years (study 2; n = 12) were included in these studies. METHODS: In study 1, 12 participants received ranitidine 150mg twice daily during a 3-day pretreatment phase and 1 tablet of ranitidine together with a single 400mg dose of moxifloxacin on the profile day. In study 2, 12 participants received a single 400mg dose of moxifloxacin alone (treatment A), simultaneously with Maalox 70 10ml (treatment B), or with Maalox 70 10ml given 4 hours before (treatment C) or 2 hours after (treatment D) the fluoroquinolone. In treatments B, C and D, administration of the antacid (10ml, 1 hour after each meal) was continued for 2 days. Plasma and urine samples were obtained for determination of the pharmacokinetic parameters of moxifloxacin. RESULTS: Coadministration of moxifloxacin with ranitidine showed lack of interaction for area under the plasma concentration-time curve extrapolated to infinity (AUCinfinity) [35.5 versus 34.3 mg/L x h with versus without ranitidine; relative bioavailability 103%, 90% confidence interval (CI) 97.7 to 109.3%] and maximum plasma concentration (Cmax) [2.98 versus 2.76 mg/L with versus without ranitidine; ratio 107.9%, 90% CI 90.5 to 128.6%]. When moxifloxacin was given simultaneously with Maalox 70, AUCinfinity ( 14.7 mg/L x h) and Cmax (1.00 mg/L) were reduced by approximately 60%. When the antacid was given 4 hours before or 2 hours after the fluoroquinolone, AUCinfinity values (28.0 and 26.7 versus 34.3 mg/L x h) were moderately reduced (by <27%), terminal elimination half-life values declined by approximately 24% (9.4 and 9.3 versus 12.3 hours) compared with moxifloxacin alone and Cmax values were almost unchanged (2.55 and 2.38 versus 2.57 mg/L). The mean bioavailabilities corrected for the elimination rate constants (lambdaz) were 101% (antacid given 4 hours before moxifloxacin) and 98% (antacid given 2 hours after moxifloxacin), indicating that Maalox 70 may interfere with the gastrointestinal recirculation of moxifloxacin. CONCLUSIONS: The bioavailability of moxifloxacin is not affected by concurrent administration of ranitidine. Absorption of moxifloxacin is impaired by concomitant administration of aluminium- and magnesium-containing antacids and administration of these agents should be staggered. An interval of 2 hours before or 4 hours after taking the antacid ensures that the effect of the interaction is not clinically relevant.

Effects of sucralfate on the oral bioavailability of moxifloxacin, a novel 8-methoxyfluoroquinolone, in healthy volunteers.

OBJECTIVE: To investigate the effect of concomitant Al3+ (sucralfate) administration on the pharmacokinetics and tolerability of moxifloxacin. DESIGN: This was a single-centre, randomised, nonblinded, 2-way crossover study in healthy volunteers. PARTICIPANTS: 12 healthy men (age 21 to 41 years) were enrolled in the study. METHODS: The plasma and urinary pharmacokinetics of moxifloxacin were characterised up to 72 hours after single doses of moxifloxacin 400mg administered orally either alone or together with 190mg of Al3+ (Sucralfat-Ratiopharm 1000) given immediately before and at 5, 10, 15 and 24 hours after the dose of moxifloxacin. There was a 2-week washout phase between the treatments. RESULTS: The treatments were well tolerated. The concomitant administration of Al3+ reduced the bioavailability of moxifloxacin [geometric mean area under the concentration-time curve from zero to infinity (AUCinfinity) 12.9 versus 32.2 mg/L x h; relative bioavailability 40%, 90% confidence interval (CI) 33 to 49%] and slowed down the absorption rate [median time to maximum concentration (tmax) 3.5 versus 1.0 hours], with a reduction of the maximum plasma concentration (Cmax) fgeometric mean Cmax0.82 versus 2.83 mg/L; estimated true ratio of Cmax 29%, 90% CI 20 to 42%]. CONCLUSIONS: Concomitant ingestion with sucralfate and/or oral Al3+-containing antacids significantly reduces the bioavailability of moxifloxacin. This is compatible with reduced solubilisation as a consequence of a chelation reaction with polyvalent cations, a common finding for quinolones. Therefore, staggered administration of moxifloxacin and Al3+-containing or related cationic interactants should be considered to avoid a loss of therapeutic efficacy due to subtherapeutic plasma concentrations of the quinolone.

Effects of iron supplements on the oral bioavailability of moxifloxacin, a novel 8-methoxyfluoroquinolone, in humans.

OBJECTIVE: To investigate the effect of concomitant iron administration on the pharmacokinetics and tolerability of moxifloxacin. DESIGN: This was a single-centre, nonblinded, randomised, 2-way crossover study in healthy male volunteers. PARTICIPANTS: 12 healthy males (age 19 to 41 years) were enrolled in the study. METHODS: The plasma and urinary pharmacokinetics of moxifloxacin were investigated after single oral doses of moxifloxacin 400mg given either alone or together with ferrous sulfate (Eryfer 100 equivalent to 100mg of Fe2+) administered concomitantly and again after 24 hours. There was a 1-week washout phase between the treatments. The plasma and urinary pharmacokinetics of moxifloxacin were characterised over the 72 hours after drug administration. RESULTS: The treatments were well tolerated. The concomitant administration of Eryfer reduced the bioavailability of moxifloxacin [geometric mean area under the plasma concentration-time curve 20.7 versus 34.0 mg/L x h; relative bioavailability 61%, 90% confidence interval (CI) 54 to 69%] and slowed down the absorption rate (median time to maximum concentration 2.79 versus 1.0 hours), with a reduction in the mean maximum concentration (Cmax) [geometric mean Cmax 1.17 and 2.86 mg/L; estimated true ratio of Cmax 41%, 90% CI 34 to 49%]. CONCLUSIONS: Concomitant ingestion of iron supplements significantly reduces the bioavailability of moxifloxacin. This is compatible with a reduction in solubilisation due to chelation with polyvalent cations, a common finding for quinolones. Because of the long half-life of moxifloxacin, staggered administration of moxifloxacin and potential cationic interactants should be considered to avoid a loss of therapeutic efficacy caused by subtherapeutic plasma concentrations of the quinolone.