BAY 94-9027, a PEGylated recombinant factor VIII, exhibits a prolonged half-life and higher area under the curve in patients with severe haemophilia A: Comprehensive pharmacokinetic assessment from clinical studies.

INTRODUCTION: Recombinant factor VIII (rFVIII) products with extended half-lives, such as BAY 94-9027, can potentially maintain higher FVIII levels for longer periods of time, thus providing improved bleeding protection vs standard-acting FVIII products. AIM: To characterize the pharmacokinetic (PK) profile of BAY 94-9027 from phase 1, phase 2/3 (PROTECT VIII) and phase 3 (PROTECT VIII Kids) clinical trials in adults, adolescents and children with severe haemophilia A METHODS: Patients with severe haemophilia A (FVIII <1%) with >50 FVIII exposure days (EDs) and no history of inhibitors were included in the phase 1 (18-65 years, ≥150 EDs), PROTECT VIII (12-65 years, ≥150 EDs) and PROTECT VIII Kids (<12 years, >50 EDs) trials. PK parameters were assessed following a 25-IU/kg or 60-IU/kg BAY 94-9027 dose in the phase 1 study after the first and repeated infusion, in PROTECT VIII after the first and repeated 60-IU/kg infusion and in PROTECT VIII Kids after a single 60-IU/kg infusion. The chromogenic assay was used to assess FVIII activity. RESULTS: Compared with sucrose-formulated rFVIII, BAY 94-9027 had reduced clearance that resulted in a ~1.4-fold increase in half-life and dose-normalized area under the curve (AUC). The BAY 94-9027 PK profile was comparable after single- and repeated-dose administrations. Dose-proportional increases were observed between 25- and 60-IU/kg administrations. BAY 94-9027 PK characteristics were age dependent, consistent with other FVIII products. CONCLUSIONS: BAY 94-9027 shows an extended half-life and increased AUC vs standard-acting FVIII products. These PK characteristics will result in higher FVIII levels for longer duration.

Pharmacokinetic properties of BAY 81-8973, a full-length recombinant factor VIII.

INTRODUCTION: BAY 81-8973 is a full-length recombinant factor VIII (FVIII) with the same primary amino acid sequence as sucrose-formulated recombinant FVIII (rFVIII-FS) but is produced with advanced manufacturing technologies. AIM: To analyse the pharmacokinetics (PK) of BAY 81-8973 after single and multiple dosing across different age and ethnic groups in the LEOPOLD clinical trial programme. METHODS: The LEOPOLD trials enrolled patients with severe haemophilia A aged 12-65 years (LEOPOLD I and II) or ≤12 years (LEOPOLD Kids) with ≥150 (LEOPOLD I and II) or ≥50 (LEOPOLD Kids) exposure days to any FVIII product and no history of FVIII inhibitors. PK were assessed using chromogenic and one-stage assays (only chromogenic assay for LEOPOLD Kids) after a single 50-IU kg(-1) dose of BAY 81-8973 and, in a subset of patients in LEOPOLD I, after repeated dosing. Pharmacokinetic analyses were also performed based on age (18 to 65, 12 to <18, 6 to <12 and <6 years) and ethnicity (Asian and non-Asian). RESULTS: Pharmacokinetic assessments in the LEOPOLD I trial showed non-inferiority of BAY 81-8973 vs. rFVIII-FS. The PK of BAY 81-8973 were comparable after single and multiple dosing. Age-based analysis in the three trials showed that plasma concentrations were slightly lower for children, but similar for adolescents compared with adults. Pharmacokinetic results were similar in the different ethnic groups. CONCLUSIONS: Results of the LEOPOLD trials show that the BAY 81-8973 pharmacokinetic profile is non-inferior to rFVIII-FS. Similar BAY 81-8973 pharmacokinetic values were observed following single and repeated dosing and across ethnic groups.

Correlation between endogenous VWF:Ag and PK parameters and bleeding frequency in severe haemophilia A subjects during three-times-weekly prophylaxis with rFVIII-FS.

Patients with severe haemophilia A experience frequent and spontaneous bleeding, causing debilitating damage to joints and decreasing quality of life. Prophylaxis with factor VIII (FVIII) reduces joint damage if initiated early. Circulating FVIII levels may be influenced by endogenous von Willebrand factor (VWF), a chaperone protein that binds and stabilizes FVIII. The aim of this study was to determine whether endogenous VWF antigen (VWF:Ag) levels are correlated with FVIII pharmacokinetic (PK) parameters and clinical outcomes in patients with severe haemophilia A. Previously treated, non-inhibitor patients in a multinational, randomized, double-blind, Ph II study received prophylaxis with once-weekly BAY 79-4980 (35 IU kg(-1)) or thrice-weekly recombinant sucrose-formulated FVIII (rFVIII-FS; 25 IU kg(-1)). PK parameters were evaluated at weeks 1 and 26. The number of bleeds per patient during the study was captured as part of the core efficacy endpoint. Spearman rank correlations assessed relationships of VWF:Ag levels with patient age, PK and annualized bleeding rate. Of 131 study patients (aged 13-64 years; BAY 79-4980, n = 63; rFVIII-FS, n = 68), 27 (21%; n = 15 and 12 respectively) were evaluable for PK assessment. Baseline VWF:Ag levels correlated with patient age (P < 0.0001). There was no significant difference in PK results between treatments; thus, PK parameters and VWF levels of all patients were analysed together. AUC(norm) and T1/2 significantly increased with increased VWF:Ag (P < 0.001); clearance significantly decreased with increased VWF:Ag (P = 0.002). Annualized bleeding rate in patients treated with 3× per week rFVIII-FS significantly correlated with VWF:Ag and age (P = 0.038 and 0.021 respectively). PK parameters as well as the clinical outcome significantly correlated with endogenous VWF:Ag. The improved clinical outcome in subjects with high VWF:Ag levels may be explained by VWF:Ag influence on FVIII PK.

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.

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.

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.

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.

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.