Pharmacokinetics of teduglutide in subjects with renal impairment.

PURPOSE: Teduglutide is a recombinant analogue of human glucagon-like peptide-2 that has recently been approved for the treatment of short bowel syndrome in adults. This study was designed to study the influence of renal function and age on teduglutide pharmacokinetics. METHODS: This was an open-label study with six parallel groups (6 subjects each). Three groups with renal impairment (moderate, severe and end-stage renal disease) were compared to healthy subjects with normal renal function, which were matched to the renal-impaired subjects with respect to demographics. At least two elderly subjects (≥65 years) were enrolled per group. A single dose of 10 mg teduglutide was subcutaneously administered to each subject. Teduglutide plasma concentrations were measured using a validated liquid chromatography method with tandem mass spectrometric detection, and the primary pharmacokinetic variables (AUCinf and Cmax) were calculated. RESULTS: Area under the concentration versus time curve extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of teduglutide in subjects with end-stage renal disease were approximately 2.59- and 2.08-fold higher, respectively, than those of healthy subjects. The AUCinf and Cmax were also slightly higher in subjects with moderate and severe renal impairment. Comparison of healthy subjects aged <65 years with healthy elderly subjects revealed very similar pharmacokinetics in both subgroups. CONCLUSIONS: In our study population, the primary pharmacokinetic parameters of teduglutide increased with increased severity of renal impairment. These results suggest that the daily dose of teduglutide should be reduced by 50 % in patients with moderate and severe renal impairment and end-stage disease. We found no effect of age on the pharmacokinetics of teduglutide in healthy subjects. The treatment was well tolerated, and there were no safety concerns.

An investigation of the pharmacokinetics, pharmacodynamics, safety, and tolerability of ciclesonide hydrofluoroalkane nasal aerosol in healthy subjects and subjects with perennial allergic rhinitis.

Ciclesonide hydrofluoroalkane nasal aerosol (CIC-HFA) is currently in development for treatment of allergic rhinitis. This Phase I study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of CIC-HFA in healthy subjects (N = 18) and subjects with perennial allergic rhinitis (PAR, N = 18) in a double-blind, placebo-controlled, 3-period crossover design following treatment with 282 µg or 148 µg CIC-HFA or placebo once-daily for 14 days. The concentrations of desisobutyryl-ciclesonide (des-CIC), the pharmacologically active metabolite of CIC were measured by a validated high performance liquid chromatography with tandem mass spectrometry. Maximum serum concentration (C(max)), area under the serum concentration time curve (AUC), time to maximum serum concentration (t(max)) and elimination half life (t(1/2)) where feasible, were calculated. Serum cortisol (AUC(0-24h)) and adverse events (AE) were also evaluated. The overall systemic exposure of des-CIC was low. The mean C(max) for des-CIC on Day 14 was 35.84 ng/L and 25.98 ng/L for the CIC-HFA 282 µg and CIC-HFA 148 µg treatment groups respectively. Mean AUC((0, last)) for des-CIC on Day 14 was 213 ng·h/L and 112.3 ng·h/L for CIC-HFA 282 µg and 148 µg respectively. Mean serum cortisol (AUC(0-24h)) was similar for CIC-HFA 282 µg (178 µg·h/dL), CIC-HFA 148 µg (169 µg·h/dL), and placebo (174 µg·h/dL) on Day 14. The overall incidence of AEs was low and headache and epistaxis were the most common individual AEs reported. In this study, systemic exposure of des-CIC was low and similar in healthy subjects and subjects with PAR with no evidence of clinically relevant accumulation over the 14 day treatment period in either treatment group. Both doses of CIC-HFA were well tolerated without significant effect on cortisol levels.

Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.

AIMS: To evaluate the effect of co-administration of rifampicin, an inducer of cytochrome P450 (CYP)3A4, on the pharmacokinetics of roflumilast and roflumilast N-oxide. Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor, being developed for the treatment of chronic obstructive pulmonary disease. Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. In vivo, roflumilast N-oxide contributes >90% to the total PDE4 inhibitory activity. METHODS: Sixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of roflumilast 500 microg on days 1 and 12 and repeated oral doses of rifampicin 600 mg once daily on days 5-15. Plasma concentrations of roflumilast and roflumilast N-oxide were measured for up to 96 h. Test/Reference ratios and 90% confidence intervals (CIs) of geometric means for AUC and C(max) of roflumilast and roflumilast N-oxide and for oral apparent clearance (CL/F) of roflumilast were estimated. RESULTS: During the steady-state of rifampicin, the AUC(0-infinity) of roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); C(max) by 68% (0.32; CI 0.26, 0.39); for roflumilast N-oxide, the AUC(0-infinity) decreased by 56% (0.44; CI 0.36, 0.55); C(max) increased by 30% (1.30; 1.15, 1.48); total PDE4 inhibitory activity decreased by 58% (0.42; 0.38, 0.48). CONCLUSIONS: Co-administration of rifampicin and roflumilast led to a reduction in total PDE4 inhibitory activity of roflumilast by about 58%. The use of potent cytochrome P450 inducers may reduce the therapeutic effect of roflumilast.

Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide.

Effects of single and multiple doses of oral ketoconazole on roflumilast and its active metabolite, roflumilast N-oxide, were investigated in healthy subjects. In study 1, subjects (n = 26) received oral roflumilast 500 microg once daily for 11 days and a concomitant 200-mg single dose of ketoconazole on day 11. In study 2, subjects (n = 16) received oral roflumilast 500 microg on days 1 and 11 and a repeated dose of ketoconazole 200 mg twice daily from days 8 to 20. Coadministration of single-dose ketoconazole with steady-state roflumilast increased the AUC of roflumilast by 34%; C(max) was unchanged. For roflumilast N-oxide, AUC and C(max) decreased by 12% and 20%, respectively. Repeated doses of ketoconazole increased the AUC and C(max) of roflumilast by 99% and 23%, respectively; for roflumilast N-oxide, AUC was unchanged, and C(max) decreased by 38%. No clinically relevant adverse events were observed. Coadministration of ketoconazole and roflumilast does not require dose adjustment of roflumilast.

Single-dose pharmacokinetics of roflumilast in children and adolescents.

Roflumilast is an orally administered phosphodiesterase 4 inhibitor that has potential for use in pediatric patients with asthma. The pharmacokinetics of roflumilast and roflumilast N-oxide were examined in adolescents and children with stable mild to moderate asthma in an open-label crossover study with age-stratification and 2 treatment periods (100-microg dose in period 1, 250-microg dose in period 2) separated by a washout period. Plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using standard noncompartmental methods and compared between study groups and within the entire cohort. Roflumilast was well tolerated. Linear relationships were evident for dose and area under the plasma drug concentration-time curve extrapolated to infinity for both roflumilast (r(2) = 0.36, P < .01) and roflumilast N-oxide (r(2) = 0.39, P < .01). With the exception of dose-normalized maximum plasma concentration (mean 1.1 and 0.8 microg/L per 1 microg/kg dose for adolescents and children, respectively), pharmacokinetic parameters for roflumilast and roflumilast N-oxide were not different between age groups and were similar to adults.

Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide.

OBJECTIVE: To investigate the effects of steady-state dosing of fluvoxamine, an inhibitor of cytochrome P450 (CYP) 1A2 and CYP2C19, on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor and its pharmacodynamically active metabolite roflumilast N-oxide. METHODS: In an open-label, non-randomised, one-sequence, two-period, two-treatment crossover study, 14 healthy subjects received a single oral dose of roflumilast 500 microg on study day 1. After a 6-day washout period, repeated doses of fluvoxamine 50 mg once daily were given from days 8 to 21. On day 15, roflumilast 500 microg and fluvoxamine 50 mg were taken concomitantly. Percentage ratios of test/reference (reference: roflumilast alone; test: roflumilast plus steady-state fluvoxamine) of geometric means and their 90% confidence intervals for area under the plasma concentration-time curve, maximum plasma concentration (roflumilast and roflumilast N-oxide) and plasma clearance of roflumilast were calculated. RESULTS: Upon co-administration with steady-state fluvoxamine, the exposure to roflumilast as well as roflumilast N-oxide increased by a factor of 2.6 and 1.5, respectively. Roflumilast plasma clearance decreased by a factor of 2.6, from 9.06 L/h (reference) to 3.53 L/h (test). The combined effect of fluvoxamine co-administration on roflumilast and roflumilast N-oxide exposures resulted in a moderate (i.e. 59%) increase in total PDE4 inhibitory activity. CONCLUSION: Co-administration of roflumilast and fluvoxamine affects the disposition of roflumilast and its active metabolite roflumilast N-oxide most likely via a potent dual pathway inhibition of CYP1A2 and CYP2C19 by fluvoxamine. The exposure increases observed for roflumilast N-oxide are suggested to be attributable to CYP2C19 co-inhibition by fluvoxamine and thus, are not to be expected to occur when roflumilast is co-administered with more selective CYP1A2 inhibitors.

Steady-state pharmacokinetics of roflumilast and roflumilast N-oxide in patients with mild and moderate liver cirrhosis.

BACKGROUND: Roflumilast and its primary N-oxide metabolite are targeted phosphodiesterase 4 (PDE4) inhibitors with similar in vivo potency. Roflumilast is being developed for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease and asthma. OBJECTIVE: To investigate the effects of mild and moderate liver cirrhosis on the steady-state pharmacokinetics of roflumilast and roflumilast N-oxide. METHODS: Patients with mild (n = 8, Child-Pugh A) and moderate (n = 8, Child-Pugh B) liver cirrhosis and healthy subjects (n = 8) matched with patients with cirrhosis with regard to sex, age and bodyweight received oral roflumilast 250 microg once daily for 14 days. Blood samples were collected for 24 hours after the last dose on day 14. Steady-state plasma concentrations of roflumilast and roflumilast N-oxide were determined using a validated high-performance liquid chromatography with tandem mass spectrometry assay. The pharmacokinetics were compared between groups using ANOVA. RESULTS: In patients with liver cirrhosis, the average total exposure (area under the plasma concentration-time curve from 0 to 24 hours [AUC(24)]) of roflumilast was approximately 51% (Child-Pugh A) and 92% (Child-Pugh B) higher than in healthy subjects. In contrast, roflumilast maximum plasma concentration (C(max)) was unaltered in Child-Pugh A patients and was increased by 27% in Child-Pugh B patients. Changes in the AUC(24) of roflumilast N-oxide were less distinct, with 24% and 41% increases and corresponding C(max) increases of 26% and 40% in Child-Pugh A and B patients, respectively, compared with healthy subjects. Overall, changes in average potency-corrected exposure to the sum of the free fractions of both compounds were estimated to result in approximately 26% and 46% increases in total PDE4 inhibitory capacity (tPDE4i) in Child-Pugh A and B patients, respectively, relative to healthy subjects. Roflumilast was well tolerated. CONCLUSIONS: Mild and moderate liver cirrhosis resulted in distinct alterations of exposure to roflumilast but only in modest alterations of exposure to roflumilast N-oxide. The integrated exposure-weighted assessment of the observed pharmacokinetic changes of roflumilast and roflumilast N-oxide (tPDE4i) indicates modest average exposure increases to the sum of both compounds. These findings and the favourable tolerability profile suggest that roflumilast can be safely used in patients with mild and moderate liver cirrhosis without special precautions or dose adjustment.

Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects.

This open, randomized, single-dose crossover study investigated effects of a high-fat meal on the pharmacokinetics of roflumilast and its major active N-oxide metabolite. Twelve healthy subjects received oral roflumilast 500 microg (2 x 250 microg) after overnight fasting and after breakfast. Blood was sampled up to 54 hours for pharmacokinetic profiling of roflumilast and N-oxide. Geometric mean ratios (fed/fasted) for point estimates (PE) and 90% confidence intervals (CI) were calculated for AUC(0-last), AUC(0-infinity), and C(max) of both compounds. After the meal, roflumilast C(max) (PE, 0.59; 90% CI, 0.49-0.70) was modestly reduced; N-oxide C(max) (PE, 0.95; 90% CI, 0.90-1.01) was unchanged. Roflumilast t(max) was delayed in fed state (2.0 +/- 0.4 hours) versus fasted state (1.0 +/- 0.2 hours); N-oxide t(max) was unaltered. No significant food effect on roflumilast AUC(0-last) (PE, 1.04; 90% CI, 0.90-1.21), AUC(0-infinity) (PE, 1.12; 90% CI, 1.00-1.25), and respective N-oxide AUCs (PE, 0.91; 90% CI, 0.79-1.04; PE, 0.99; 90% CI, 0.92-1.06) occurred. Because roflumilast N-oxide is the major contributor to roflumilast's overall pharmacologic effects, these findings suggest that roflumilast can be taken with or without food.

Sensitive quantification of roflumilast and roflumilast N-oxide in human plasma by LC-MS/MS employing parallel chromatography and electrospray ionisation.

A high throughput bioanalytical method based on semi-automated liquid extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the sensitive quantification of roflumilast and its metabolite roflumilast N-oxide, a phosphodiesterase (PDE) inhibitor in human plasma and serum. The sample work-up procedure comprised liquid extraction using penta-deuterated analogues of both analytes as internal standards. Chromatography was performed on C18 revered phase analytical columns at a flow rate of 0.5 mL/min in the dual column mode employing a column switching technique and a linear gradient from 18% to 54% acetonitrile in 0.005 M aqueous ammonium acetate containing 0.006% formic acid. Mass spectrometry was performed on an API 4000 instrument in the positive ion SRM-mode (selected reaction monitoring) with the Turbo-V ionspray interface. The method showed linear detector responses over the entire calibration range between 0.1 ng/mL (lower limit of quantification (LLOQ)) and 50 ng/mL (upper limit of quantification (ULOQ)) for both analytes. Linear regression analysis with concentration-squared weighting (1/x(2) for roflumilast and 1/x for roflumilast N-oxide) yielded inaccuracy and precision values <15% and coefficients of correlation (r) for the calibration curves >0.99 for both analytes.

Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.

Roflumilast is an oral phosphodiesterase 4 (PDE4) inhibitor for the treatment of chronic obstructive pulmonary disease (COPD). It is metabolized by CYP1A2 and CYP3A4 to its primary metabolite, roflumilast N-oxide, through which >90% total PDE4 inhibitory activity (tPDE4i) is mediated. Fluoroquinolones, of which enoxacin is the most potent CYP1A2 inhibitor, are used to treat COPD exacerbations. This phase I, open, nonrandomized, fixed-sequence, 2-period study evaluated the effects of steady-state enoxacin on the single-dose pharmacokinetics of roflumilast and roflumilast N-oxide. Twenty healthy participants received roflumilast, 500 µg once daily, on days 1 and 12, and enoxacin, 400 mg twice daily, on days 7 to 18. Pharmacokinetic profiles were obtained for days 1 to 6 and 12 to 19. The safety and tolerability of all treatments were also assessed. In 19 evaluable participants, coadministration led to 56% higher mean systemic exposure, 20% higher mean peak concentrations, and 36% lower mean apparent oral clearance compared with roflumilast alone. For roflumilast N-oxide, 23% higher mean systemic exposure and 14% lower mean peak concentrations were seen after coadministration. Roflumilast was well tolerated both alone and in combination with enoxacin. A weak interaction was shown between roflumilast and enoxacin, as mean tPDE4i increased by 25%, but is unlikely to have clinical relevance.

Pharmacokinetics of ciclesonide and desisobutyryl ciclesonide after administration via aqueous nasal spray or hydrofluoroalkane nasal aerosol compared with orally inhaled ciclesonide: an open-label, single-dose, three-period crossover study in healthy volunteers.

BACKGROUND: Ciclesonide, an intranasal corticosteroid, is administered as a prodrug and is converted to the active metabolite, desisobutyryl ciclesonide, in the upper and lower airways. Previous studies have assessed systemic exposure with the ciclesonide hydrofluoroalkane metered dose inhaler (CIC HFA-MDI) and the ciclesonide aqueous nasal spray (CIC-AQ) formulations. However, systemic exposure with ciclesonide HFA nasal aerosol (CIC-HFA) developed for the treatment of allergic rhinitis has not been investigated. OBJECTIVE: This study compared the systemic exposure of ciclesonide and desisobutyryl ciclesonide after administration of ciclesonide formulated as an aqueous nasal spray, an HFA nasal aerosol, or as an orally inhaled HFA-MDI. METHODS: Healthy adults (aged 18-60 years) were randomly assigned in an open-label, singledose, 3-period crossover design to CIC-AQ 300 microg, CIC-HFA 300 microg, or CIC HFA-MDI 320 microg. Serum samples were collected before study drug administration and at 5, 15, and 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 18, 22, and 24 hours after dosing. The primary pharmacokinetic parameters were AUC(0-infinity) and C(max) of desisobutyryl ciclesonide. Adverse events were elicited by direct questioning of participants throughout the study. RESULTS: Thirty volunteers were randomly assigned. Most of the volunteers were male (63% [19/30]) and white (83% [25/30]); the mean age was 36 years and mean weight was 68 kg. Concentrations of desisobutyryl ciclesonide were quantifiable (lower limit of quantitation [LLOQ] = 10 ng/L) in the serum samples of only 5 volunteers (of 30) receiving CIC-AQ, and the highest C(max) value of desisobutyryl ciclesonide was 26.7 ng/L (mean C(max), 15.2 ng/L). The AUC(0-infinity) of desisobutyryl ciclesonide for CIC-AQ was below the LLOQ of the bioanalytic assay. Mean C(max) and AUC(0-infinity) of desisobutyryl ciclesonide were 59.1 ng/L and 397.5 ng . h/L, respectively, for CIC-HFA; and 586.2 ng/L and 2685.0 ng . h/L, respectively, for CIC HFA-MDI. Concentrations of the parent compound, ciclesonide, were below the LLOQ in serum samples after administration of CIC-AQ; they were detectable up to 2 hours after administration of CIC-HFA and up to 4 hours after administration of CIC HFA-MDI. Treatment-emergent adverse events occurred with a low frequency in all 3 treatment groups (30% [9/30] overall) and were mild in intensity as determined by the study investigator. CONCLUSIONS: In this study, compared with that of CIC HFA-MDI, the systemic exposure of desisobutyryl ciclesonide was 10-fold lower after administration of CIC-HFA and at least 40-fold lower after administration of CIC-AQ. All treatments were well tolerated.