First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.

AIMS: Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. METHODS: This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. RESULTS: In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l-1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l-1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. CONCLUSIONS: Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.

Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans.

Rivaroxaban is a novel, oral, direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders. The objective of this study was to investigate the in vivo metabolism and excretion of rivaroxaban in rats, dogs, and humans. Single doses of [(14)C]rivaroxaban (3 and 1 mg/kg) were administered to rats (orally/intravenously) and dogs (orally), respectively. A single oral dose of [(14)C]rivaroxaban (10 mg) was administered to healthy human males (n = 4). Plasma and excreta were collected and profiled for radioactivity. Recovery of total radioactivity was high and > or = 92% in all species. Unchanged rivaroxaban was the major compound in plasma at all time points investigated, across all species. No major or pharmacologically active circulating metabolites were detected. Rivaroxaban and its metabolites were rapidly excreted; urinary excretion of radioactivity was 25 and 52%, and fecal excretion was 67 and 43% of the dose in rats and dogs, respectively. In humans, 66% of the dose was excreted renally (36% unchanged drug) and 28% in the feces. Radioactivity profiles in excreta were similar across species. Three metabolic pathways were identified: oxidative degradation of the morpholinone moiety (major pathway) and hydrolysis of the central amide bond and of the lactam amide bond in the morpholinone ring (minor pathways). M-1, the main metabolite in excreta of all species, was eliminated via both renal and fecal/biliary routes. In total, 82 to 89% of the dose administered was assigned to unchanged rivaroxaban and its metabolites in the excreta of rats, dogs, and humans.

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.

Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor xa inhibitor--in healthy subjects.

OBJECTIVE: Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor being developed for the prevention and treatment of thromboembolic disorders. This analysis aimed to define population models for the pharmacokinetics (PK) and pharmacodynamics (PD) ofrivaroxaban in healthy males. METHODS: Non-linear, mixed-effect modeling was used to analyze rivaroxaban plasma concentration and PD data (FXa activity and clotting tests) from subjects in a phase I, multiple-ascending-dose study. Subjects received 5 mg rivaroxaban once, twice or three times daily, or 10, 20 or 30 mg rivaroxaban twice daily. RESULTS: The population PK of rivaroxaban were well described by an oral, two-compartment model with first-order absorption and elimination from the central compartment. Population mean estimates for apparent oral clearance and volume of distribution for the central compartment were 9.2 1/h and 55 1, respectively, with moderate inter-individual variability (17.4% and 30.7%, respectively). Total volume of distribution for rivaroxaban at steady state was approximately 70 1. Residual (unexplained) variability was 25%. FXa activity correlated with rivaroxaban plasma concentrations following an inhibitory Emax model; prothrombin time (PT) and rivaroxaban plasma concentrations correlated with a linear model, with a slope of 4.6 s/(100 microg/1). Inter-individual variability was low for the correlation with PT. The models derived were used to define sampling windows for population PK/PD modeling in Phase II studies. CONCLUSIONS: This analysis confirms that rivaroxaban has predictable, dose-proportional PK and PD. The linear correlation between rivaroxaban plasma concentrations and PT suggests that this test might be useful to assess rivaroxaban exposure in patients, if required.

Rivaroxaban. A novel, oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders.

Rivaroxaban (Xarelto) is a novel, oral, direct Factor Xa (FXa) inhibitor in late-stage development for the prevention and treatment of thromboembolic disorders. Rivaroxaban inhibits clot-associated and free FXa activity, and prothrombinase activity, and reduces thrombin generation. In animal models, rivaroxaban prevented venous and arterial thrombosis, and was effective at treating venous thrombosis. Rivaroxaban has high oral bioavailability, a rapid onset of action and predictable pharmacokinetics. In phase II studies, rivaroxaban was effective and well tolerated for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery, and for the treatment of deep vein thrombosis. In a phase III study, rivaroxaban demonstrated significantly superior efficacy to enoxaparin for thromboprophylaxis after total knee arthroplasty, with similar low bleeding. Rivaroxaban is also being assessed for the treatment and secondary prevention of VTE, prevention of stroke in patients with atrial fibrillation and secondary prevention in patients with acute coronary syndrome. Rivaroxaban is a promising alternative to current pharmacological agents for thromboembolic disorders.

Dissociation between the pharmacokinetics and pharmacodynamics of once-daily rivaroxaban and twice-daily apixaban: a randomized crossover study.

Essentials In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time. SUMMARY: Background The anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. Objectives To compare directly the steady-state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non-valvular atrial fibrillation. Methods Twenty-four healthy Caucasian male volunteers were included in this open-label, two-period crossover, phase 1 study (EudraCT number: 2015-002612-32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. Results Overall exposure was similar for both drugs: the geometric mean area under the plasma concentration-time curve for the 0-24-h interval was 1830 µg h L-1 for rivaroxaban and 1860 µg h L-1 for apixaban. Rivaroxaban was associated with greater inhibition of endogenous thrombin potential (geometric mean area under the curve relative to baseline during the 0-24-h interval: 15.5 h versus 17.5 h) and a more pronounced maximal prolongation relative to baseline of prothrombin time (PT) (1.66-fold versus 1.14-fold) and activated partial thromboplastin time (APTT) (1.43-fold versus 1.16-fold) at steady state than apixaban. Conclusions Despite similar exposure to both drugs, rivaroxaban 20 mg once daily was associated with greater and more sustained inhibition of thrombin generation than apixaban 5 mg twice daily. Sensitive PT and APTT assays can be used to estimate the anticoagulant effects of rivaroxaban.

Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects.

BACKGROUND: Moxifloxacin is a new fluoroquinolone. In vitro studies have suggested that it could prolong ventricular repolarization. The main objective of this study was to measure the actual effect of single oral doses of moxifloxacin on QT interval duration in healthy volunteers. METHODS: Nine men and 9 women participated in a double-blind, randomized, placebo-controlled, crossover study. Each participant received single oral doses (400 mg and 800 mg) of moxifloxacin or placebo. At the time of expected moxifloxacin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test. QT interval and the corresponding RR interval value were measured within a wide range of RR intervals in each subject. RESULTS: ANOVA showed that both moxifloxacin doses increased mean QT intervals compared with placebo. The mean QT interval duration at RR = 1000 ms was 379 +/- 24 ms during placebo, 394 +/- 33 ms during moxifloxacin 400 mg (P < .05), and 396 +/- 28 ms during moxifloxacin 800 mg (P < .05). Moxifloxacin-induced QT interval prolongation remained significant at all tested heart rates. The increase in QT interval duration relative to placebo remained between 2.3% +/- 2.8% and 4.5% + 3.8% across the range of RR intervals tested. CONCLUSION: Moxifloxacin prolongs QT interval duration. The amplitude of this effect is small, and the risk of moxifloxacin-induced torsades de pointes is expected to be minimal when the drug is administered at the recommended dose of 400 mg/d. However, moxifloxacin should not be used in patients with predisposing factors of torsades de pointes such as electrolyte disturbances and bradycardia or during coadministration of proarrhythmic drugs.

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.

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.

Lack of pharmacokinetic interaction between moxifloxacin, a novel 8-methoxyfluoroquinolone, and theophylline.

OBJECTIVE: To investigate the plasma and urinary pharmacokinetics, safety and tolerability of theophylline and moxifloxacin after single and repeated doses of either compound administered alone or concomitantly with the other. DESIGN: This was a randomised, multiple-dose, period-balanced, 3-way crossover study in healthy volunteers. PARTICIPANTS: 12 nonsmoking healthy volunteers, 21 to 30 years of age were included in this study. METHODS: The investigational medications, all given orally, were as follows: treatment A, moxifloxacin 200mg alone; treatment B, theophylline 400mg alone; treatment C, theophylline 400mg plus moxifloxacin 200mg. Each drug or combination was given twice daily on days 2 to 4 of the 5-day study period and as single morning doses on days 1 and 5. The study periods were separated by 1-week washout intervals. The plasma and urinary pharmacokinetics of moxifloxacin and theophylline were characterised after the first (morning of day 1) and eighth (morning of day 5) doses. RESULTS: At steady state, the plasma pharmacokinetics of theophylline for treatments B and C proved equivalent in terms of maximum concentration (Css(max)) and bodyweight- and dose-normalised Css(max) lestimated true ratio 96%, 90% confidence interval (CI) 87 to 105%] and also in terms of area under the concentration-time curve from 0 to 12 hours (AUCss(tau)) and normalised AUCss(tau) (ratio 95%, 90% CI 85 to 107%); the median times to Cmax(tmax) were also similar (5.0 and 6.0 hours for treatments B and C, respectively). The plasma pharmacokinetics of moxifloxacin for treatments A and C were equivalent with respect to Css(max) (estimated true ratio 109%, 90% CI 97 to 123%) and AUCss(tau) (ratio 104%, 90% CI 100 to 108%); the median tmax values were also similar (0.5 and 1.0 hour for treatments A and C, respectively). The treatments were well tolerated. CONCLUSIONS: Moxifloxacin - in contrast to some older quinolones - does not interact pharmacokinetically with theophylline, confirming preclinical results on the absence of cytochrome P450-mediated metabolism.

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.

Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers.

BACKGROUND: Four-factor prothrombin complex concentrates (PCCs), which contain factor II, FVII, FIX, and FX, have shown the potential to reverse the anticoagulant effect of rivaroxaban in healthy volunteers. The purpose of this study was to determine whether a three-factor PCC, which contains little FVII, has a similar effect. METHODS AND RESULTS: We performed an open-label, single-center, parallel-group study comparing the effect of a three-factor PCC (Profilnine SD) with that of a four-factor PCC (Beriplex P/N) on the pharmacodynamics of rivaroxaban in 35 healthy volunteers. After receiving 4 days of rivaroxaban 20 mg twice daily to obtain supratherapeutic steady-state concentrations, volunteers were randomized to receive a single 50 IU kg(-1) bolus dose of four-factor PCC, three-factor PCC or saline 4 h after the morning dose of rivaroxaban on day 5, and the effects of these interventions on prothrombin time and thrombin generation were determined. Within 30 min, four-factor PCC reduced mean prothrombin time by 2.5-3.5 s, whereas three-factor PCC produced only a 0.6-1.0-s reduction. In contrast, three-factor PCC reversed rivaroxaban-induced changes in thrombin generation more than four-factor PCC. CONCLUSIONS: This study demonstrates the potential of both three-factor and four-factor PCCs to at least partially reverse the anticoagulant effects of rivaroxaban in healthy adults. The discrepant effects of the PCC preparations may reflect differences in the procoagulant components present in each.

Absence of clinically relevant interactions between rivaroxaban--an oral, direct Factor Xa inhibitor--and digoxin or atorvastatin in healthy subjects.

OBJECTIVE: To investigate potential interactions between rivaroxaban, an oral direct Factor Xa inhibitor approved for the management of thromboembolic disorders, and digoxin or atorvastatin. METHODS: Two randomized, phase 1 clinical trials were undertaken in healthy men to assess pharmacokinetic and pharmacodynamic interactions between rivaroxaban and digoxin or atorvastatin, and the safety of these drug combinations. RESULTS: Steady-state rivaroxaban did not affect the pharmacokinetic profile of steady-state digoxin (n = 17). Digoxin did not significantly influence the pharmacokinetic profile of single-dose rivaroxaban and had minimal effects on rivaroxaban-induced inhibition of Factor Xa activity and prolongation of clotting time. Similarly, steady-state atorvastatin did not affect the pharmacokinetic profile or the pharmacodynamics of rivaroxaban and vice versa (n = 19). All drugs (alone or in combination) were well tolerated. CONCLUSIONS: There were no clinically relevant pharmacokinetic or pharmacodynamic interactions between rivaroxaban and digoxin, or between rivaroxaban and atorvastatin, suggesting that rivaroxaban can be coadministered with either drug. This study also confirmed that rivaroxaban does not interact with substrates for permeability (P)-glycoprotein alone (digoxin) or P-glycoprotein and cytochrome P(450) (CYP)3A4 (atorvastatin).

The in vitro anticoagulant effect of rivaroxaban in children.

INTRODUCTION: Current anticoagulation therapy in children is less than ideal, requiring regular venous monitoring and dosing adjustments. Limitations associated with conventional anticoagulants have prompted the development of novel drugs that specifically target key proteins in the coagulation system. Rivaroxaban is the first oral, direct Factor Xa inhibitor available for the prevention of venous thromboembolism in adults. Its predictable pharmacokinetic profile, high oral bioavailability and once-daily dosing make rivaroxaban an optimal anticoagulant that warrants investigation in children. The aim of this study was to investigate the age-related anticoagulant effect of rivaroxaban in vitro. MATERIALS AND METHODS: Age-specific plasma pools were created (i.e. 28 days-23 months, 2-6, 7-11, 12-16 years and adults) and spiked with increasing concentrations of rivaroxaban (0-500 ng/ml). Commercially available PT, APTT and anti-Factor Xa assays, as well as sub-sampling thrombin generation assays, were used to measure rivaroxaban effect. RESULTS: The results of this study indicate that there are no significant differences in rivaroxaban effect across the age groups in vitro. CONCLUSION: In vivo studies are required to confirm the consistency of dose-response across the paediatric age groups.

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.

Profile of moxifloxacin drug interactions.

We report a brief description of the interaction profile of moxifloxacin. After oral administration, the absorption of moxifloxacin was unaffected by ranitidine or by food consumption. Drugs containing multivalent cations (e.g., Mg(++), Al(+++), and Fe(++), but not Ca(++)) impaired absorption. No clinically relevant effect of moxifloxacin was seen on the pharmacokinetics of digoxin under combination steady state conditions. Also, moxifloxacin did not affect the pharmacokinetics of theophylline or vice versa. This result, plus further data proving lack of interaction with glyburide, warfarin, and oral contraceptives, confirms the absence of metabolic interactions involving the cytochrome P-450 system, as previously reported. Concomitant administration of probenecid did not affect the elimination of moxifloxacin. Moxifloxacin thus has a unique drug interaction profile that is advantageous for its safe use.

Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration in man.

The pharmacokinetics of moxifloxacin and its metabolites M1 (sulpho-compound) and M2 (acyl-glucuronide) were characterized in 12 healthy male volunteers in an open, randomized, crossover study. After an overnight fast the volunteers were given a single 400 mg dosage of moxifloxacin either as a tablet or a 1 h infusion with a washout phase of at least 1 week between the two treatments. Multiple plasma, faeces and urine samples were collected for the analysis of moxifloxacin and metabolites using validated HPLC with fluorescence detection. The AUC for both formulations was comparable with bioequivalence criteria fulfilled, with Cmax after oral treatment approximately 31% lower. Following oral administration, absorption was fast with low to medium variability (mean dissolution and absorption time 2.4 h). The absolute bioavailability was 86%. The excretion of moxifloxacin and its metabolites was quantified in a subset of eight subjects. More than 96% of the dose was recovered from urine and faeces after oral dosing, and >98% following i.v. administration of the drug. M1, which is strongly bound to plasma proteins (90%), was mainly eliminated into faeces (approximately 37-38% of the administered dose) and to a minor extent into urine (2.5% of the administered dose) by active tubular secretion. M2 (only 5% bound to plasma protein) was only found in urine, where it amounted to approximately 14% of the dose. Plasma concentrations of the metabolites were much lower than those of the parent compound. Moxifloxacin was well tolerated with few adverse events and no clinically relevant changes in laboratory values.

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.

Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects.

The pharmacokinetics of moxifloxacin were investigated in six studies after oral administration of 50, 100, 200, 400, 600, and 800 mg. Eight healthy male volunteers were included in each study. With doses of up to 200 mg the study was performed as a double-blind, randomized group comparison (n = 6 verum and n = 2 matched placebo); with the higher doses the study was conducted with a double-blind, randomized, crossover design. Safety and tolerability were assessed by evaluation of vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, results of urinalysis, and adverse events. The drug was well tolerated. The concentrations of moxifloxacin in plasma, urine, and saliva were determined by a validated high-pressure liquid chromatography assay with fluorescence detection. In addition, plasma and urine samples were analyzed by a bioassay. A good correlation between both methods was seen, indicating an absence of major active metabolites. The mean maximum concentrations of moxifloxacin in plasma (Cmax) ranged from 0.29 mg/liter (50-mg dose) to 4.73 mg/liter (800-mg dose) and were reached 0.5 to 4 h following drug administration. After reaching the Cmax, plasma moxifloxacin concentrations declined in a biphasic manner. Within 4 to 5 h they fell to about 30 to 55% of the Cmax, and thereafter a terminal half-life of 11 to 14 h accounted for the major part of the area under the concentration-time curve (AUC). During the absorption phase concentrations in saliva were even higher than those in plasma, whereas in the terminal phase a constant ratio of the concentration in saliva/concentration in plasma of between 0.5 and 1 was observed, indicating a correlation between unbound concentrations in plasma and levels in saliva (protein binding level, approximately 48%). AUC and Cmax increased proportionally to the dose over the whole range of doses investigated. Urinary excretion amounted to approximately 20% of the dose. Data on renal clearance (40 to 51 ml/min/1.73 m2) indicated partial tubular reabsorption of the drug. The pharmacokinetic parameters derived from compartmental and noncompartmental analyses were in good agreement. The kinetics could be described best by fitting the data to a two-compartment body model.