In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites.

BACKGROUND: Nifurtimox is an effective treatment for patients with Chagas disease, but knowledge of its biotransformation and excretion is limited. OBJECTIVE: This study aimed to better understand the fate of oral nifurtimox in vivo. METHODS: We investigated the exposure and excretion pathways of [14C]-labeled nifurtimox and its metabolites in rats. We then quantified the prominent metabolites and nifurtimox in the urine and plasma of patients receiving nifurtimox using LC-HRMS with reference standards and quantified these compounds in rat plasma after a single, high dose of nifurtimox. We also investigated potential drug-drug interactions (DDIs) of these compounds in vitro. RESULTS: In rats, orally administered nifurtimox was rapidly absorbed (tmax 0.5 h) and eliminated (t½ 1.4 h). Metabolism of nifurtimox yielded six predominant metabolites (M-1 to M-6) in urine and plasma, and the dose was excreted equally via the renal and fecal routes with only traces of unchanged nifurtimox detectable due to its instability in excreta. In patients with Chagas disease, only M-6 and M-4 achieved relevant exposure levels, and the total amount of excreted metabolites in urine was higher in fed versus fasted patients, consistent with the higher systemic exposure. For nifurtimox, M-6, and M-4, no potential perpetrator pharmacokinetic DDIs with the main cytochrome P- 450 enzymes and drug transporters were identified in vitro. CONCLUSION: This contemporary analysis of the complex metabolite profile and associated exposures emerging after oral dosing of nifurtimox in rats and humans, together with the expected low risk for clinically relevant DDIs, expands the understanding of this important anti-trypanosomal drug.

Structural and Mechanistic Investigation of the Unusual Metabolism of Nifurtimox.

The oral antiparasitic drug nifurtimox has been used to treat Chagas disease for more than 50 years. Historical studies determined that very little nifurtimox is excreted unchanged, but contemporaneous preclinical studies of radiolabeled nifurtimox found almost all of the radiolabel was rapidly excreted, suggesting that metabolism is extensive. Attempts to study nifurtimox metabolism have had limited success, yet this knowledge is fundamental to characterizing the pharmacokinetics and pharmacodynamics of the drug. We conducted in vitro studies using hepatic and renal sources with 14C-labeled nifurtimox as substrate and obtained samples of urine, plasma, and feces from rats administered 2.5 mg/kg [14C]-nifurtimox, and samples of human urine and plasma from phase 1 clinical studies in which participants received a single dose of 120 mg nifurtimox. Analysis of metabolites was done by high-performance liquid chromatography (HPLC)-high-resolution mass spectrometry (HRMS) and HRMS/MS with offline liquid scintillation counting of radiolabeled samples. Surprisingly, only traces of a few metabolites were identified from in vitro incubations with hepatocytes and subcellular fractions, but more than 30 metabolites were identified in rat urine, mostly with atypical mass changes. We developed an HRMS scouting method for the analysis of human samples based on the sulfur atom in nifurtimox and the natural abundance of 34S, as well as a characteristic tandem mass spectrometry (MS/MS) fragmentation of nifurtimox and metabolites. Fragmentation patterns on HRMS/MS were used to propose structures for 18 metabolites (22 including stereoisomers), and based on these structures, the six most abundant products were synthesized and the structures of the synthetic forms were confirmed by HRMS and two-dimensional nuclear magnetic resonance (2D NMR). Overall, we determined that the metabolism of nifurtimox is almost certainly not mediated by typical hepatic and renal drug-metabolizing enzymes, and instead is rapidly metabolized mainly by reduction or nucleophilic attack, with some evidence of oxidation. Knowledge of the most abundant metabolites of nifurtimox affords the possibility of future studies to investigate levels of exposure and possible drug-drug interactions.

Nifurtimox for Treatment of Chagas Disease in Pediatric Patients: the Challenges of Applying Pharmacokinetic-Pharmacodynamic Principles to Dose Finding.

The antiparasitic drug nifurtimox was approved in the USA in 2020 for the treatment of patients with Chagas disease aged less than 18 years and weighing at least 2.5 kg, based on outcomes from the phase 3 CHICO study. Accordingly, pediatric patients with Chagas disease take nifurtimox thrice daily with food at one of two body weight-adjusted dose ranges. We investigated possible relationships between pharmacokinetic (PK) data, and pharmacodynamic efficacy and safety data collected in an analysis population of 111 participants in CHICO, using a published population PK model to estimate nifurtimox exposure at the patient level. Pediatric exposure to nifurtimox was benchmarked against levels of nifurtimox exposure known to be effective in adults with Chagas disease. Given the complex dosing regimen for nifurtimox, we also modeled nifurtimox exposure associated with simpler dosing strategies. We found no relationship between exposure to nifurtimox and efficacy measures (e.g., serological response to treatment), or between exposure and safety outcomes (including typical adverse events, e.g., headache, decreased appetite, nausea/vomiting). The analysis population appeared to represent the overall CHICO population based on the similarity of their baseline characteristics and the profiles of adverse events in the two groups. Modeled exposure based on the dosing regimen in CHICO was within the reference range derived from phase 1 data in adults. The relationship between nifurtimox exposure and cure is complex; a simplified pediatric dosing regimen is unlikely to be beneficial.

Population Pharmacokinetics of Nifurtimox in Adult and Pediatric Patients With Chagas Disease.

Nifurtimox (LAMPIT) has been used for decades for the treatment of Chagas disease, a chronic and potentially life-threatening disease caused by the parasite Trypanosoma cruzi. The pharmacokinetic (PK) information on nifurtimox in humans derived from controlled clinical studies is very limited. The objective was to investigate and compare the population PK of nifurtimox in adult and pediatric patients with Chagas disease to confirm the clinical dosing regimen in children, which was based on allometric approaches using the concept that a dose-equivalent exposure would reach equivalent antiparasitic efficacy as in adults. The resulting adult model adequately described the PK in adults. Significant predictors of the availability in PK were food intake, tablet formulation (fast- vs slow-dissolution tablet), study, and body weight. As the resulting adult model could not adequately predict the sparse sampled pediatric patient data, these data were analyzed separately to derive exposure estimates for comparison with adult exposure. In the population PK model for pediatric patients, significant covariates were body weight and age. As compared to adults, children aged >2 years were estimated to have 50.6% higher apparent clearance. No hints of dose nonlinearity were observed in a dose range of 30 to 240 mg single dose in adults and 15 to 300 mg 3 times daily (8-20 mg/kg) in children. Altogether, this study retroactively showed that the current mg/kg dosing regimen in children reached similar exposure as in adults receiving an 8 mg/kg total daily dose.

Clinical investigation of the biopharmaceutical characteristics of nifurtimox tablets - Implications for quality control and application.

Nifurtimox is approved in Chagas disease and has been used in endemic countries since the 1960s. Nifurtimox, available as a 120 mg tablet, is administered with food typically three times daily, and dose is adjusted for age and bodyweight. Accurately or reproducibly fragmenting the 120 mg tablet for dose adjustment in young children and those with low bodyweight is problematic. Based on the existing tablet formulation, new nifurtimox 30 mg and 120 mg tablets have been developed in a format that can be divided accurately into 15 mg and 60 mg fragments. In adults with chronic Chagas disease, we investigated whether nifurtimox bioavailability is affected by tablet dissolution rate, and whether different diets affect nifurtimox bioavailability. In an open-label, three-period cross-over study (n=36; ClinicalTrials.gov, NCT03350295), patients randomly received three 30 mg tablet formulations (slow, medium, or fast dissolution; a 4 × 30 mg dose of one formulation per period). In an open-label, four-period cross-over study (n=24; ClinicalTrials.gov, NCT03334838) patients randomly fasted or received one of three meal types (high-fat/high-calorie, low-fat, dairy-based) before ingesting nifurtimox (a 4 × 30 mg dose per period). Acceptance criteria for no difference between groups were 90% confidence intervals (CIs) of exposure ratios in the range 0.8-1.25. Nifurtimox bioavailability was unaffected by tablet dissolution kinetics. Ratios of area under the curve at final assessment (AUC(0-tlast) [90% CI]) were: fast/medium dissolution, 1.061 (0.990-1.137); slow/medium dissolution, 0.964 (0.900-1.033); fast/slow dissolution, 1.100 (1.027-1.179). Compared with a fasting state, nifurtimox bioavailability increased by 73% after a high-fat/high-calorie meal (AUC(0-tlast) ratio [90% CI], 1.732 [1.581-1.898]); smaller increases were seen with the other meal types (low-fat: 1.602 [1.462-1.755]; dairy-based: 1.340 [1.222-1.468]). Although type of diet can affect bioavailability, taking nifurtimox with food is most important.

Safety, tolerability and pharmacokinetics of emodepside, a potential novel treatment for onchocerciasis (river blindness), in healthy male subjects.

AIMS: Emodepside is an anthelmintic, originally developed for veterinary use. We investigated in healthy subjects the safety, and pharmacokinetics of a liquid service formulation (LSF) and immediate release (IR) tablet of emodepside in 2 randomised, parallel-group, placebo-controlled, Phase I studies. METHODS: Seventy-nine subjects in 10 cohorts in the single ascending dose study and 24 subjects in 3 ascending-dose cohorts in the multiple ascending dose study were enrolled. Emodepside as LSF was administered orally as single 1-40-mg doses and for 10 days as 5 or 10 mg once daily and 10-mg twice daily doses, respectively. Pharmacokinetics and safety were assessed up to 21 and 30 days, respectively. In addition, IR tablets containing 5 or 20 mg emodepside were tested in the single ascending dose study. RESULTS: Emodepside as LSF was rapidly absorbed under fasting conditions, with dose-proportional increase in plasma concentrations at doses from 1 to 40 mg. Terminal half-life was > 500 hours. In the fed state, emodepside was absorbed more slowly but overall plasma exposure was not significantly affected. Compared to the LSF, the rate and extent of absorption was significantly lower with the tablets. CONCLUSIONS: Overall, emodepside had acceptable safety and tolerability profiles, no major safety concerns, after single oral administration of 20 mg as LSF and after multiple oral administration over 10 days at 5 and 10 mg OD and at 10 mg twice daily. For further clinical trials, the development of a tablet formulation overcoming the limitations observed in the present study with the IR tablet formulation is considered.

Biopharmaceutical Characteristics of Nifurtimox Tablets for Age- and Body Weight-Adjusted Dosing in Patients With Chagas Disease.

Treatment of Chagas disease with nifurtimox requires age- and body weight-adjusted dosing, resulting in complex dosing instructions. Appropriate formulations are needed for precise and compliant dosing, especially in pediatric patients. We characterized the biopharmaceutical features of a standard nifurtimox 120-mg tablet and a 30-mg tablet developed to improve dose accuracy. Two open-label, randomized crossover studies were conducted in adult outpatients with Chagas disease. One study investigated whether 4 × 30-mg tablets and 1 × 120-mg tablet were bioequivalent and whether tablets can be administered as an aqueous slurry without affecting bioavailability. The second study investigated the effect of a high-calorie/high-fat diet versus fasting on the absorption of nifurtimox after a single 4 × 30-mg dose. Interventions were equivalent if the 90% confidence interval (CI) of their least-squares (LS) mean ratios for both AUC0-tlast and Cmax were in the range of 80%-125%. The 4 × 30-mg and 1 × 120-mg tablet doses were bioequivalent (AUC0-tlast : LS mean ratio, 104.7%; 90%CI, 99.1%-110.7%; Cmax : LS mean ratio, 101.7%; 90%CI, 89.4%-115.6%; n = 24). Exposure when giving the 4 × 30-mg dose as a slurry or as tablets was comparable, with an AUC0-tlast ratio of 93.2% (84.2%-103.1%; n = 12) and a slightly decreased Cmax ratio for the slurry of 76.5% (68.8%-85.1%). Food improved the bioavailability of nifurtimox substantially (AUC0-tlast ratiofed/fasted , 172%; 90%CI, 154%-192%; Cmax ratiofed/fasted , 168%; 90%CI, 150%-187%). The data indicate that the 30- and 120-mg tablets are suitable for dosing adult and pediatric patients accurately; nifurtimox should be administered under fed conditions.

Application of Physiologically-Based and Population Pharmacokinetic Modeling for Dose Finding and Confirmation During the Pediatric Development of Moxifloxacin.

Moxifloxacin is a widely used fluoroquinolone for the treatment of complicated intra-abdominal infections. We applied physiologically-based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) modeling to support dose selection in pediatric patients. We scaled an existing adult PBPK model to children based on prior physiological knowledge. The resulting model proposed an age-dependent dosing regimen that was tested in a phase I study. Refined doses were then tested in a phase III study. A popPK analysis of all clinical pediatric data confirmed the PBPK predictions, including the proposed dosing schedule in children, and supported pharmacokinetics-related safety/efficacy questions. The pediatric PBPK model adequately predicted the doses necessary to achieve antimicrobial efficacy while maintaining safety in the phase I and III pediatric studies. Altogether, this study retroactively demonstrated the robustness and utility of modeling to support dose finding and confirmation in pediatric drug development for moxifloxacin.

Ciprofloxacin Dry Powder for Inhalation: Inspiratory Flow in Patients with Non-cystic Fibrosis Bronchiectasis.

Background: As non-cystic fibrosis bronchiectasis (NCFB) progresses, patients suffer irreversible lung damage and deterioration in lung function. This study explored whether inhalational parameters (peak inspiratory flow [PIF, primary endpoint], inspiratory volume and time [secondary endpoints]) represent barriers to complete dosing in patients with poor lung function who are using Ciprofloxacin dry powder for inhalation (DPI) (a drug-device combination of the T-326 inhaler device and a Ciprofloxacin dry powder formulation). Methods: This open-label, multicenter study generated inspiratory flow rate data from patients with NCFB using the breath-actuated T-326 dry powder inhaler. These rates were compared against reference values to identify whether patients with all degrees of lung function impairment could generate sufficient flow rates to facilitate adequate drug delivery. Patients attended screening and a second visit 1 - 14 days later. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC, and inspiratory capacity were measured via spirometry at both visits. Forty-two patients were screened for inclusion; 33 met eligibility criteria and were stratified into one of three groups based on their FEV1% predicted value (group 1: 25% ≤ FEV1% predicted <45%; group 2: 45% ≤ FEV1% predicted <70%; group 3: FEV1% predicted ≥70%). Results: No significant between-group differences occurred in PIF (mean flow rates 68.21, 66.01, and 65.18 L/min in groups 1, 2, and 3, respectively). Individual minimum PIFs of 46.0-49.0 L/min were observed across groups. These results all exceeded the reference value (minimum PIF 45 L/min for Ciprofloxacin DPI) indicating that regardless of the level of airflow obstruction, patients were capable of achieving sufficient PIFs to aerosolize and inhale Ciprofloxacin dry powder with the T-326 inhaler. Conclusions: Our data indicate that T-326 is suitable for use in the drug-device combination Ciprofloxacin DPI to provide targeted pulmonary delivery in patients with NCFB, including those with significantly impaired lung function.

Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous Moxifloxacin in Pediatric Patients: Dose Optimization in a Phase 1 Study.

The pharmacokinetics, safety, and tolerability of a single dose of moxifloxacin were characterized in 31 pediatric patients already receiving antibiotics for a suspected or proven infection in an open-label phase 1 study. A dosing strategy for each age cohort (Cohort 1: ≥6 years to ≤14 years; Cohort 2: ≥2 years to <6 years; Cohort 3: >3 month to <2 years) was developed using physiology-based pharmacokinetic modeling combined with a stepwise dosing scheme to obtain a similar exposure to adults receiving 400 mg of moxifloxacin. Doses, adjusted to body weight and age, were gradually escalated from 5 mg/kg in Cohort 1 to 10 mg/kg in Cohort 3 based on interim analysis of the pharmacokinetic and safety data. Plasma and urine samples before and after the 60-minute infusion were collected for the analysis of moxifloxacin and its metabolites using a validated high-pressure liquid chromatography assay with tandem mass spectrometry. Moxifloxacin and metabolite concentrations in plasma were within the ranges observed in adults; however, clearance of all analytes was lower in pediatric patients compared with adults. Population pharmacokinetic analyses using the achieved exposure levels in the 3 age cohorts (with known body weight and clearance) predicted similar efficacy and safety profiles to adults. Moxifloxacin was well tolerated in all pediatric age cohorts. Adverse events related to moxifloxacin were mild or moderate in intensity and showed no correlation with increased weight-adjusted doses. Our findings guided the selection of age-appropriate clinical doses for a subsequent phase 3 clinical trial in pediatric patients with complicated intra-abdominal infections.

A Physiologically-Based Pharmacokinetic Model to Describe Ciprofloxacin Pharmacokinetics Over the Entire Span of Life.

BACKGROUND: Physiologically-based pharmacokinetic (PBPK) modeling has received growing interest as a useful tool for the assessment of drug pharmacokinetics by continuous knowledge integration. OBJECTIVE: The objective of this study was to build a ciprofloxacin PBPK model for intravenous and oral dosing based on a comprehensive literature review, and evaluate the predictive performance towards pediatric and geriatric patients. METHODS: The aim of this report was to establish confidence in simulations of the ciprofloxacin PBPK model along the development process to facilitate reliable predictions outside of the tested adult age range towards the extremes of ages. Therefore, mean data of 69 published clinical trials were identified and integrated into the model building, simulation and verification process. The predictive performance on both ends of the age scale was assessed using individual data of 258 subjects observed in own clinical trials. RESULTS: Ciprofloxacin model verification demonstrated no concentration-related bias and accurate simulations for the adult age range, with only 4.8% of the mean observed data points for intravenous administration and 12.1% for oral administration being outside the simulated twofold range. Predictions towards the extremes of ages for the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) over the entire span of life revealed a reliable estimation, with only two pediatric AUC observations outside the 90% prediction interval. CONCLUSION: Overall, this ciprofloxacin PBPK modeling approach demonstrated the predictive power of a thoroughly informed middle-out approach towards age groups of interest to potentially support the decision-making process.

Moxifloxacin in Pediatric Patients With Complicated Intra-abdominal Infections: Results of the MOXIPEDIA Randomized Controlled Study.

BACKGROUND: This study was designed to evaluate primarily the safety and also the efficacy of moxifloxacin (MXF) in children with complicated intra-abdominal infections (cIAIs). METHODS: In this multicenter, randomized, double-blind, controlled study, 451 pediatric patients aged 3 months to 17 years with cIAIs were treated with intravenous/oral MXF (N = 301) or comparator (COMP, intravenous ertapenem followed by oral amoxicillin/clavulanate; N = 150) for 5 to 14 days. Doses of MXF were selected based on the results of a Phase 1 study in pediatric patients (NCT01049022). The primary endpoint was safety, with particular focus on cardiac and musculoskeletal safety; clinical and bacteriologic efficacy at test of cure was also investigated. RESULTS: The proportion of patients with adverse events (AEs) was comparable between the 2 treatment arms (MXF: 58.1% and COMP: 54.7%). The incidence of drug-related AEs was higher in the MXF arm than in the COMP arm (14.3% and 6.7%, respectively). No cases of QTc interval prolongation-related morbidity or mortality were observed. The proportion of patients with musculoskeletal AEs was comparable between treatment arms; no drug-related events were reported. Clinical cure rates were 84.6% and 95.5% in the MXF and COMP arms, respectively, in patients with confirmed pathogen(s) at baseline. CONCLUSIONS: MXF treatment was well tolerated in children with cIAIs. However, a lower clinical cure rate was observed with MXF treatment compared with COMP. This study does not support a recommendation of MXF for children with cIAIs when alternative more efficacious antibiotics with better safety profile are available.

Ciprofloxacin Dry Powder for Inhalation in Patients with Non-Cystic Fibrosis Bronchiectasis or Chronic Obstructive Pulmonary Disease, and in Healthy Volunteers.

BACKGROUND: Ciprofloxacin dry powder for inhalation (Ciprofloxacin DPI) is in development as long-term intermittent therapy to reduce the frequency of acute exacerbations in non-cystic fibrosis bronchiectasis (NCFB) patients with respiratory bacterial pathogens. There is no approved therapy in this indication. Reliable, reproducible lung deposition is a prerequisite for inhaled drugs. METHODS: In this phase I study, six patients with NCFB, six with chronic obstructive pulmonary disease (COPD), and 12 healthy volunteers (HVs), received one dose of 99mTc-Ciprofloxacin DPI 32.5 mg to assess pulmonary drug deposition by quantitative scintigraphy. 81mKrypton ventilation scans were performed to map lung contours. Systemic exposure as mediated by absorption in the lung was measured using the charcoal block method. HVs ingested activated charcoal orally (20 g before and 2 × 10 g after inhalation) to block gastrointestinal absorption of drug swallowed during inhalation. Indirect determination of pulmonary drug deposition was based on plasma and urine pharmacokinetic (PK) data. RESULTS: Scintigraphic data revealed high, reproducible lung deposition in all participants (intrapulmonary deposition relative to nominal dose, mean [standard deviation; range]: NCFB, 53% [11%; 38%-64%]; COPD, 51% [10%; 34%-61%]; HVs, 51% [7%; 40%-64%] to 53% [8%; 44%-70%]). Similar ratios of central-to-peripheral airway deposition were seen across groups. Systemic exposure to ciprofloxacin was low. Relative bioavailability of Ciprofloxacin DPI was reduced by ∼60% after charcoal block, suggesting that systemic exposure was mainly caused by uptake via the lung. Lung deposition of 30% was estimated from PK data, but this may be an underestimation due to drug clearance from the lung and transintestinal secretion. Adverse events were no more frequent or severe in patients with lung diseases versus HVs, and no clinically relevant influence on vital signs or lung function was observed. CONCLUSION: This study supports the continued development of Ciprofloxacin DPI in NCFB patients with respiratory bacterial pathogens.

Safety and pharmacokinetics of ciprofloxacin dry powder for inhalation in cystic fibrosis: a phase I, randomized, single-dose, dose-escalation study.

BACKGROUND: Reliable, reproducible deposition to the lung is a major prerequisite for the clinical use of inhaled drugs. Ciprofloxacin dry powder for inhalation (ciprofloxacin DPI; Bayer HealthCare AG, Leverkusen, Germany) is an antibacterial therapy in development using Novartis' PulmoSphere™ technology (Novartis Pharma AG, Basel, Switzerland) for the targeted delivery of ciprofloxacin to the lung via a T-326 inhaler. METHODS: This randomized, single-blind, placebo-controlled, dose-escalation study investigated the safety, tolerability, and pharmacokinetics of single-dose ciprofloxacin DPI (32.5 mg [n=6] or 65 mg [n=6]) and matching placebo (n=4) in adult patients with cystic fibrosis and stable pulmonary status (forced expiratory volume in 1 sec ≥30%) who were colonized with Pseudomonas aeruginosa. RESULTS: Peak sputum concentrations of 34.9 mg/L (range 2.03-229) and 376 mg/L (8.95-1283) for ciprofloxacin 32.5 mg and 65 mg, respectively, indicated targeting of ciprofloxacin DPI to the lung. This contrasted with low systemic exposure (peak plasma concentrations: 0.0790 mg/L [32.5 mg] and 0.182 mg/L [65 mg]). Single-dose ciprofloxacin DPI 32.5 mg or 65 mg was well tolerated with similar incidences of adverse events across all groups. No deaths, discontinuations, treatment-related serious adverse events, or clinically relevant changes in laboratory parameters, vital signs, or lung function tests were reported. CONCLUSIONS: Lung targeting with high pulmonary concentrations of ciprofloxacin combined with low systemic exposure was confirmed. These results support further study of ciprofloxacin DPI as a potentially more convenient alternative to nebulized antibiotic solutions for managing chronic lung infections.

Tolerability and pharmacokinetic properties of ciprofloxacin dry powder for inhalation in patients with cystic fibrosis: a phase I, randomized, dose-escalation study.

BACKGROUND: Inhaled antibacterial agents are used to manage chronic pulmonary infections in cystic fibrosis (CF) and non-CF bronchiectasis. However, established nebulized preparations impose a substantial time burden on patients. A dry powder formulation of ciprofloxacin for inhalation (ciprofloxacin DPI) has been developed using PulmoSphere™ (Novartis, Pharma AG, Basel, Switzerland) technology (administered using a T-326 inhaler) to maximize antibacterial activity and convenience. OBJECTIVE: This study investigated the tolerability and pharmacokinetic properties of multiple-dose once-daily and twice-daily ciprofloxacin DPI in adults with CF. METHODS: A Phase I, randomized, single-blind, placebo-controlled, dose-escalation study in patients with CF (median age 29.0 years [19-40]), stable pulmonary status, and chronic Pseudomonas aeruginosa colonization. Sequential cohorts received ciprofloxacin DPI 32.5 mg qd (1 capsule for inhalation; n = 6), 65 mg qd (2 capsules for inhalation; n = 6), or 32.5 mg (n = 6) bid for 7 days. Each group was placebo controlled. RESULTS: Twenty-five patients were enrolled (12 men; median age, 29.0 years [range, 19-40 years]; 6, 6, 6, and 7 patients in the ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid and placebo groups, respectively). No serious treatment-emergent adverse events or clinically relevant changes in tolerability parameters, including lung function measurements, were reported. Twenty-one patients (ciprofloxacin, n = 17; placebo, n = 4) experienced 29 mild drug-related treatment-emergent adverse events, including bitter taste (ciprofloxacin, 17 patients; placebo, 2) and bronchospasm (ciprofloxacin, 3; placebo, 2). Ciprofloxacin DPI was absorbed rapidly after inhalation. Systemic exposure to ciprofloxacin was low and comparable between single and multiple dosing in all 3 dose groups, suggesting an absence of substantial drug accumulation. The geometric mean AUCs after the last dose were 0.383, 1.472, and 0.781 mg · h/L with ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. The range of geometric mean t(½) in plasma was 3.4 to 9.5 hours. Sputum concentrations of ciprofloxacin were high, with substantial variability. Geometric mean ciprofloxacin concentrations (%CV) in induced sputum were 57.7 (118.2), 177.5 (53.4), and 149.7 (249.7) mg/L 0.75 hours after the last dose of ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. CONCLUSIONS: Ciprofloxacin DPI was well tolerated, especially with respect to lung function, with minimal systemic exposure compared with data from previous studies of oral and intravenous administration, and with no apparent accumulation at steady state. Sputum ciprofloxacin concentrations above 100-times the minimum inhibitory concentration for P aeruginosa were detected. Ciprofloxacin DPI may be effectively delivered to the lungs at microbiologically active concentrations while minimizing the risk for systemic intolerabilities. Eudra clinical trial identifier: 2006-003690-26.

Inhalation of a dry powder ciprofloxacin formulation in healthy subjects: a phase I study.

BACKGROUND: Oral and intravenous formulations of ciprofloxacin have established efficacy and safety profiles in respiratory infections. A dry powder for inhalation (DPI) that uses Novartis' PulmoSphere™ technology has been developed to deliver high concentrations of ciprofloxacin to the lung with low systemic exposure using a portable and convenient passive dry powder inhaler (Novartis' T-326 inhaler). OBJECTIVES: The primary objective was to investigate the safety and tolerability of ciprofloxacin DPI in healthy male subjects, with a secondary objective to investigate the pharmacokinetics of ciprofloxacin after ciprofloxacin DPI administration. METHODS: This was a phase I, single-dose, single-site, randomized, single-blind, placebo-controlled, crossover study conducted in the hospital setting. Subjects were followed up for safety for approximately 2 weeks. Six healthy male subjects, aged 27-42 years with no history of pulmonary disease, repeated bronchitis or respiratory allergies were enrolled. In randomized order and separated by a 1-week washout period, subjects inhaled a single dose of ciprofloxacin DPI 32.5 mg or placebo from the T-326 inhaler. Primary safety parameters included vital signs, electrocardiogram, laboratory tests, adverse events and lung function (total specific resistance, thoracic gas volume and forced expiratory volume in 1 s). Plasma concentration-time data were used to calculate pharmacokinetic parameters. RESULTS: Ciprofloxacin DPI was well tolerated with no clinically relevant adverse effects on lung function. Estimates of lung deposition derived from physiology-based pharmacokinetic modelling suggest that approximately 40 % of the total dose of ciprofloxacin DPI reached the trachea/bronchi and alveolar space. Systemic ciprofloxacin was detected soon after inhalation [peak concentration in plasma (C(max)) 56.42 µg/L, median time to C max 0.625 h], but total systemic exposure was minimal (area under the plasma concentration-time curve 354.4 µg·h/L). Terminal elimination half-life (9.5 h), apparent total clearance from plasma after non-intravenous administration (91.7 L/h) and apparent volume of distribution (1,262 L) data suggest that elimination from the respiratory tract was prolonged. CONCLUSIONS: In healthy subjects, ciprofloxacin DPI was well tolerated, delivered ciprofloxacin to the lungs and resulted in minimal systemic exposure, allowing further investigation of its clinical use for the management of specific, chronic infections in pulmonary diseases.

Pharmacokinetics and tolerability of BAY41-6551 in subjects with chronic kidney disease.

UNLABELLED: Abstract Background: BAY41-6551, a drug-device combination in development for adjunctive treatment of Gram-negative pneumonia in mechanically ventilated patients, consists of amikacin formulated for inhalation coupled with the Pulmonary Drug Delivery System (PDDS) Clinical aerosol delivery platform. This study evaluated safety, tolerability, and pharmacokinetics (PK) of BAY41-6551 in subjects with chronic kidney disease (CKD). METHODS: Single doses of BAY41-6551 (400 mg amikacin) were administered using the PDDS Clinical handheld device to six subjects with mild-to-moderate (Group 1) and six subjects with severe renal impairment (Group 2). Seven subjects with end-stage renal disease (ESRD; Group 3) received single doses of BAY41-6551 on days 1 and 9, with hemodialysis (HD) scheduled 24 h postdose on day 1 and 3 h postdose on day 9. PK analysis was performed on serum, urine, and dialysate samples (Group 3). RESULTS: Individual serum amikacin concentrations in Groups 1 and 2 were below 6 mg/L at all times [mean maximum serum drug concentration (C(max)) 0.94 mg/L and 2.46 mg/L, respectively). In Group 3, serum amikacin concentrations decreased after each HD session, and amikacin area under the serum concentration-time curve from zero to 72 h (AUC(72)) and C(max) values were lower on day 9 than on day 1 (mean AUC(72) 71.5 mg · h/L vs. 151.5 mg · h/L; mean C(max) 2.09 mg/L vs. 6.16 mg/L). The amounts of amikacin removed by HD and the dialysate clearance rates were similar on days 1 and 9. No serious adverse events were reported. CONCLUSIONS: Single doses of BAY41-6551 were well tolerated in subjects with CKD. HD effectively removed amikacin from serum in subjects with ESRD, and the timing relative to BAY41-6551 administration was an important determinant of systemic amikacin exposure. Nevertheless, standard precautionary measures for intravenous amikacin should apply for patients receiving BAY41-6551, and dose adjustments and/or dialysis should be considered for subjects with severe renal impairment.

Pharmacokinetics and tolerability of amikacin administered as BAY41-6551 aerosol in mechanically ventilated patients with gram-negative pneumonia and acute renal failure.

BACKGROUND: BAY41-6551, a drug-device combination in development for adjunctive treatment of Gram-negative pneumonia in intubated and mechanically ventilated patients, consists of amikacin formulated for inhalation coupled with the Pulmonary Drug Delivery System (PDDS) Clinical aerosol delivery platform. Given the predominantly renal clearance of aminoglycosides, understanding systemic amikacin exposure and safety during administration of BAY41-6551 to patients with acute renal failure (ARF) is clinically important. METHODS: Seven mechanically ventilated patients with Gram-negative pneumonia and ARF receiving continuous veno-venous hemodiafiltration (CVVHDF) were treated with multiple administrations of BAY41-6551 400 mg amikacin twice daily using the PDDS Clinical on-ventilator device [in addition to standard intravenous (i.v.) antimicrobial therapy]. CVVHDF parameters were recorded and a PK analysis was performed using serum, urine, and bronchoalveolar lavage fluid samples. RESULTS: Maximum serum amikacin concentration [median 1.93 (range: 0.63-3.99) mg/L] and area under the concentration-time curve from zero to 12 h on day 3 [median 19.32 (range 6.32-36.87) mg · h/L] were elevated compared with mechanically ventilated patients with normal renal function; however, serum amikacin trough concentrations were within accepted safety limits. The median amikacin concentration in epithelial lining fluid [887 (range: 406-12,819) mg/L] was similar to that reported previously in mechanically ventilated patients with normal renal function. BAY41-6551 demonstrated acceptable safety and tolerability with most adverse events (AEs) as expected for the patient population. One serious AE of bronchospasm was attributed to the study medication; no reported AEs were related to the PDDS Clinical device. CONCLUSIONS: CVVHDF appears to provide adequate clearance of systemically absorbed amikacin in mechanically ventilated patients with ARF, suggesting that dose adjustments for BAY41-6551 are probably not necessary for this patient population. Nonetheless, the standard precautionary measures for critically ill patients receiving i.v. amikacin should be followed for patients with ARF who are treated with BAY41-6551.

Moxifloxacin does not alter ciclosporin pharmacokinetics in transplant patients: a multiple-dose, uncontrolled, single-centre study.

BACKGROUND: Moxifloxacin has a broad antibacterial spectrum and rapid bactericidal activity, and is thus a good option for the treatment of bacterial infections in patients who have undergone organ or bone marrow transplantation. Transplant patients also receive immunosuppressant therapy such as ciclosporin. OBJECTIVE: The primary objective of this study was to assess the steady-state pharmacokinetics of ciclosporin with and without concomitant treatment with moxifloxacin in transplant recipients. A secondary objective was to determine the safety and tolerability of the combined treatment. METHODS: Patients (n = 9) with stable graft function after bone marrow or renal transplantation and who were already receiving ciclosporin therapy were enrolled into the study. The patients were given ciclosporin (Sandimmun Optoral) capsules twice daily (total daily dosage 150-380 mg/day) throughout the study period. Moxifloxacin (Avolox) tablets 400 mg once daily were given on days 2-8 inclusive. The primary outcome measure was the change in ciclosporin pharmacokinetics on coadministration with moxifloxacin. Secondary outcomes were the steady-state pharmacokinetics of moxifloxacin and ciclosporin plus its metabolites in patients receiving moxifloxacin and ciclosporin concomitantly. Moxifloxacin pharmacokinetic parameters in the presence of ciclosporin were compared with previously published pharmacokinetic data for moxifloxacin in healthy individuals. RESULTS: No significant changes occurred in the concentration-time curves of ciclosporin and its metabolites following combination therapy with moxifloxacin. The geometric means of whole blood concentrations of ciclosporin and ciclosporin plus its metabolites on day 1 were similar to those on day 8 following combined administration of ciclosporin and moxifloxacin for 7 days. The ratio of combination treatment to monotherapy for ciclosporin was 1.01 (90% CI 0.91, 1.11) for the area under the blood concentration-time curve from time zero to 12 hours at steady state (AUC(12,ss)) and 0.96 (90% CI 0.88, 1.04) for the maximum steady-state blood drug concentration (C(max,ss)). For ciclosporin plus its metabolites the ratio was 1.07 (90% CI 0.99, 1.17) for AUC(12,ss) and 1.03 (90% CI 0.98, 1.09) for C(max,ss). The pharmacokinetic parameters for moxifloxacin were unaffected by the presence of ciclosporin. CONCLUSIONS: Concomitant administration of moxifloxacin does not alter the pharmacokinetic parameters of ciclosporin or ciclosporin plus its metabolites in immunosuppressed patients. Therefore, no dose adjustments or additional drug monitoring are required when ciclosporin is coadministered with moxifloxacin.