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PEDIATRICS |
From the Department of Pediatrics, University of Missouri–Kansas City and the Children's Mercy Hospitals and Clinics, Kansas City, Missouri (Dr Neville, Dr Abdel-Rahman, Dr Kearns); National Jewish Medical and Research Center, Denver, Colorado (Dr Szefler, Ms Gleason); and Nycomed GmbH, Konstanz, Germany (Mr Lahu, Dr Zech, Mr Herzog, Dr Bethke).
Address for reprints: Gregory L. Kearns, PharmD, PhD, FCP, Division of Pediatric Pharmacology and Medical Toxicology, The Children's Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64079; e-mail: gkearns{at}cmh.edu.
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ABSTRACT |
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Key Words: Roflumilast • pharmacokinetics • children • adolescents • phosphodiesterase inhibitor
Inhibition of phosphodiesterases (PDEs), a group of 11 families of metallophosphohydrolases that rapidly break down adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate, increases the cellular concentrations of these second messengers and as a result can modulate inflammation.4-6 Roflumilast is an orally administered phosphodiesterase 4 (PDE4) inhibitor that has been developed for the treatment of chronic obstructive pulmonary disease and asthma because of its anti-inflammatory properties.3,7,8 In vitro and in vivo experiments in animals have demonstrated that the anti-inflammatory properties of roflumilast are selective for multiple inflammatory cells including mast cells, eosinophils, neutrophils, T-lymphocytes, and macrophages.9-11 Both roflumilast and its major metabolite, roflumilast N-oxide, are pharmacologically active,3 with roflumilast N-oxide accounting for approximately 90% of roflumilast's overall pharmacologic effect.8,12
The pharmacokinetics of roflumilast and its metabolite have been well described in adults following both single and multiple doses.8,13-15 However, data examining pharmacokinetic effects of roflumilast in pediatrics are lacking. Given the potential utility of this drug in the treatment of asthma in pediatric patients, it is critical that the pharmacokinetics of roflumilast be characterized in this particular subpopulation. The purpose of this study was to investigate the single-dose pharmacokinetics of roflumilast and roflumilast N-oxide in adolescents and children with stable mild to moderate asthma and to assess tolerability of roflumilast through examination of changes in vital signs, electrocardiographic findings, clinical laboratory parameters, and adverse events.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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7 years of age), by patient assent to protocols approved by the institutional review boards of Children's Mercy Hospital and Clinics, Kansas City, Missouri, and National Jewish Medical and Research Center, Denver, Colorado. Mild to moderate asthma was defined as cough and/or wheeze 2 times per week or nocturnal symptoms 2 times per month, on average, during the period before the study or a prebronchodilator forced expiratory volume in the first second of expiration of 60% to 95% of predicted at some time during the 18 months preceding enrollment or PEF variability of <20%. Subjects who were either less than the fifth percentile or greater than the 100th percentile for the weight to height ratio were excluded from participation. Patients were also excluded if they were not in a stable clinical state, if they had features of severe persistent asthma or a history of respiratory tract infection within the 4 weeks prior to the screening visit, or if they had a history of a significant asthma exacerbation within 4 weeks prior to the screening visit or greater than 4 significant exacerbations within the year prior to the study. Treatment with concomitant steroids and leukotriene antagonists was not allowed. Subjects each received a single oral dose of roflumilast in tablet form: 100 µg on day 1 of treatment period 1 and 250 µg on day 1 of period 2. Each dose was given with a fixed volume of tap water (120 mL) at a constant temperature (25°C). The test article was administered in fasting conditions (6- to 8-hour fast), which were maintained for 2 hours post dose. Clear liquids, such as apple juice, were permitted until 1 hour before the dose and at 1 hour after the dose. For both strengths of study medication, medication was derived from a single lot of roflumilast to minimize variability in drug potency between patients and/or study periods.
Pharmacokinetic Evaluation
Repeated blood samples (2.0 mL each) were obtained predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 32, and 48 hours postdose for the 100-µg dose with an additional sample obtained at 60 hours for the 250-µg dose. These samples were drawn through an indwelling venous catheter placed in an upper extremity or by phlebotomy when the catheter was no longer in place. Blood samples were collected into glass tubes containing calcium EDTA anticoagulant (BD, Franklin Lakes, NJ), mixed by inversion, and were immediately centrifuged at 2500 rpm for 10 minutes at 4°C. Plasma was removed by manual aspiration, placed into screw-capped polypropylene vials, and immediately frozen and stored at –70°C or less until shipped to the study sponsor for analysis.
Plasma concentrations of roflumilast and roflumilast N-oxide were measured by high-performance liquid chromatography tandem mass spectrometry using a previously published validated method.8 The method had a range of linearity from 0.1 to 20 µg/L for roflumilast and 0.1 to 40 µg/L for roflumilast N-oxide, and the inter- and intra-assay precision values (expressed as percentage coefficient of variation) were consistently less than 15% for all concentrations in the range of linearity. The limit of quantification for the assay was determined to be 0.1 µg/mL. The accuracy of the method was reflected by measured concentrations of the quality control samples that were consistently within ±15% of the target concentrations. Stability of samples (defined as <15% loss of initial concentration) was previously verified through 2 years when maintained at about –20°C (data on file, Nycomed GmbH, Konstanz, Germany).
Roflumilast plasma concentration–time data were analyzed by standard noncompartmental methods. The maximum plasma concentration (Cmax) and time to Cmax (tmax) values were obtained by visual inspection of the plasma drug concentration versus time data for each subject. The area under the plasma drug concentration–time curve (AUC) was obtained by the linear trapezoidal rule up to the final measurable concentration (Cplast) and was extrapolated to infinity (AUC0–
), calculated as AUC0-last + Cplast/
z, where z is the terminal elimination rate constant (ie, the slope of the plasma concentration vs time profile at the terminal loglinear phase, as determined by least-squares linear regression), and AUC0-last is the AUC from 0 hours to the time corresponding to Cplast. Apparent total body clearance (Cl/F) and apparent volume of distribution (Vz/F, Vdss/F) for the parent compound were calculated from the AUC and area under the moment curve (AUMC) estimates. The terminal plasma elimination half-life (t1/2) for both roflumilast and roflumilast N-oxide was calculated as 0.693/z. Finally, the roflumilast N-oxide formation ratio was estimated as AUC0– roflumilast N-oxide/AUC0– roflumilast.
Roflumilast and roflumilast N-oxide pharmacokinetic data for the study cohort were examined using standard descriptive statistics. Normality of distribution for pharmacokinetic parameters was assessed by application of the Wilk-Shapiro test. Within- and between-group comparisons were conducted using paired and unpaired (as appropriate) t tests (2-tailed). Univariate analysis of variance estimates and nonlinear regression techniques were used to evaluate the relationship between demographic variables and pharmacokinetic parameter estimates. The significance limit for all statistical analyses was set at 
= .05. All analyses were performed in SPSS version 9.0 (SPSS, Chicago, Ill).
Tolerability was evaluated by assessment of adverse events, clinical laboratory tests, vital signs, and physical examinations. Complete physical examinations were performed within 72 hours before and after dosing. Vital signs were obtained immediately before study drug administration, at selected intervals during pharmacokinetic blood sampling, and at the end of the study. Clinical laboratory tests were performed prior to roflumilast administration and at 24 hours postdose. These included hemoglobin, hematocrit, red blood cell, white blood cell, and platelet counts; aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, total bilirubin, blood urea nitrogen, serum albumin, serum creatinine, sodium, potassium, and chloride concentrations; and gross and microscopic urinalyses. Also, a standard 12-lead electrocardiograph was determined prior to study article administration and after completion of the pharmacokinetic blood sampling.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics
Mean plasma concentration versus time profiles of roflumilast and roflumilast N-oxide in adolescents and children after single oral roflumilast doses of 100 µg and 250 µg are illustrated in Figure 1. The shape of the curves between each dose/subject group was similar, with the apparent time of peak plasma concentration (tmax) for roflumilast N-oxide lagging behind that of the parent compound, as would be expected for metabolite formation. Given that the roflumilast dose was fixed (ie, 100 µg and 250 µg) and mean total body weights of the 2 subpopulations varied by almost 2-fold (Table 1), the differences in the mean plasma concentration versus time curves for roflumilast and roflumilast N-oxide (Figure 1) were expected. When corrected for body weight, dose proportionality was apparent for roflumilast (Figure 2A).
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The pharmacokinetic parameters for roflumilast and roflumilast N-oxide are summarized in Table 2. With the exception of a significantly higher weight-corrected Cmax in adolescents compared with children at the 100-µg dose (P < .01), pharmacokinetic characteristics of roflumilast were not significantly different with regard to age. With respect to dose, a statistically significant difference in the apparent volume of distribution (Vd/F) between the 100- and 250-µg doses was observed in adolescents. No significant differences were observed for any of the other pharmacokinetic parameters when compared within each age cohort on the basis of dose.
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Elimination half-life was comparable between adolescents and children for both roflumilast (11.7 ± 9.7 hours vs 13.7 ± 14.6 hours) and roflumilast N-oxide (31.1 ± 17.3 hours vs 27.5 ± 24.5 hours). A statistically significant difference for the apparent terminal elimination rate constant (z) for roflumilast N-oxide was observed between children and adolescents for the 250-µg dose period. A difference in this parameter between adolescents and children was not observed for the 100-µg dose period. Finally, as reflected by the roflumilast N-oxide formation ratios, the conversion of roflumilast into its N-oxide metabolite did not appear to differ significantly between adolescents and children (Table 2).
A significant linear relationship was found between weight-normalized (µg/kg) roflumilast dose and AUC0- of both roflumilast (r2 = 0.36, P < .01; Figure 2) and roflumilast N-oxide (r2 = 0.39, P < .01). When pharmacokinetic parameters for roflumilast were examined for an association with patient age across the entire study cohort, no linear or nonlinear relationships were evident for z, Cl/F, or Vdss/F. Similarly, when z for roflumilast N-oxide was examined as a function of age, no statistically significant linear or nonlinear relationships were observed.
Safety and Tolerability
No clinically relevant changes in vital signs, electrocardiographic findings, or clinical laboratory parameters were observed. Four adverse events related to administration of study drug were recorded: ear pain, gastrointestinal disorder, infection, and pruritus (1 event each). All events were mild to moderate in intensity and were assessed as unrelated or unlikely related to roflumilast.
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DISCUSSION |
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There is considerable experience with roflumilast in adult patients. In phase I studies, more than 1000 adult patients received repeated roflumilast doses of 500 µg/d, a dose that was found to be safe and well tolerated in healthy volunteers. The drug was shown to have an oral bioavailability of approximately 80% that was unaffected by food intake.3,15 As well, the elimination half-life of the parent drug and active metabolite was approximately 7 to 25 hours and 15 to 36 hours, respectively, with a total exposure (AUC) of roflumilast N-oxide that is approximately 10-fold greater than that of the parent drug.8 Our data suggest that in adolescents and in children, the AUC of roflumilast N-oxide is approximately 20-fold greater than the AUC of the parent drug (Table 2). This is greater than the ratio that has been observed in adults and may be attributable, in part, to enhanced biotransformation.
In adult phase II/III studies involving patients with allergic asthma, more than 1600 patients received roflumilast with approximately 400 patients receiving 500 µg/d for a total duration of more than 9 months. In these studies, the most common adverse events were mild and included headache, nausea, and gastrointestinal complaints. No clinically significant abnormalities occurred at this dose level.11 Studies have also shown that although CYP3A4 and CYP1A2 are involved in the biotransformation of roflumilast, neither the parent drug nor roflumilast N-oxide inhibited the activity of these drug-metabolizing enzymes.8,21 As well, they did not produce an apparent pharmacokinetic interaction with warfarin as a probe drug for CYP1A222 and midazolam as a probe drug for CYP3A4.21 Finally, both roflumilast and roflumilast N-oxide at clinically relevant plasma concentrations did not appear to have an effect on common drug transporters.8
As in adult studies, single doses of both 100 µg and 250 µg were well tolerated by adolescents and children and caused no significant adverse events. With regard to the safety and tolerability of roflumilast, mild to moderate adverse events (diarrhea, nausea, headache, dizziness) and no clinically significant changes in vital signs or electrocardiographic parameters were observed.3,23,24
The pharmacologic profile and accumulated adult clinical experience with roflumilast suggest that it may have utility in the treatment of pediatric patients with asthma.5,25-27 Given the potential for developmental differences in the activity of enzymes involved in the biotransformation of roflumilast (ie, CYP1A2 and CYP3A4) and also body composition capable of altering the apparent volume of distribution for many drugs,28 it was important to examine the pharmacokinetics of roflumilast in a pediatric subject cohort with a diagnosis of asthma.
Following administration of either a fixed 100-µg or 250-µg single oral dose of roflumilast, the observed apparent peak plasma concentrations of roflumilast and roflumilast N-oxide varied by approximately 4- and 5-fold, respectively (Figure 1). To a great degree, this variability appeared to be associated with expected age-associated differences in body weight between adolescents and children (Table 1). Absorption of the drug appeared to be rapid, with tmax values ranging from 0.5 to 1.1 hours across the study cohort (Table 2). As previously reported in adults,8,22 the pharmacokinetics of roflumilast in pediatric subjects ranging in age from 6 to 16 years exhibited dose proportionality. In the current study, relative bioavailability of roflumilast could not be assessed given that only a single formulation of the drug was administered.
When pharmacokinetic parameters for roflumilast (Table 2) were compared between patient subgroups as a function of age (adolescents vs children), statistically significant differences were not apparent except for Cmax values at the 100-µg dose level. Although the comparison for Cmax was not significantly different between adolescents and children at the 250-µg dose level, a trend toward a higher value for adolescents was noted. Although apparent differences in the dose-normalized Cmax values cannot be readily explained on the basis of expected developmental differences in drug absorption, they may be temporally associated with intersubject variability in the extent of drug absorption as it relates to roflumilast dose size. Finally, such variability in the extent of drug absorption could explain the observed difference for roflumilast Vd/F in the adolescent cohort when the parameter was compared between the 100-µg and 250-µg dose periods.
Examination of mean apparent oral clearance values for roflumilast suggested a possible trend for higher values in children (0.37-0.38 L/h/kg) compared with adolescents (0.26-0.29 L/h/kg). Likewise, mean elimination t1/2 values in adolescents were approximately 19% to 34% higher than those observed in children. However, when both Cl/F and z values for roflumilast were examined as a function of subject age across the study cohort, no significant associations were found (data not shown). When the data from both of the age-based cohorts are considered collectively, the apparent elimination half-life values for roflumilast in children and adolescents were lower than values for this parameter previously reported from adult studies.8,13,14 It should be noted, however, that any finding suggestive of age dependence in roflumilast disposition must be tempered by the caveats of small sample size and considerable variability in the pharmacokinetic parameters across the study cohort, the latter being anticipated given the expected degree of intersubject variability in the activity of drug-metabolizing enzymes in normal children and adolescents.28
As previously noted, roflumilast N-oxide, the major pharmacodynamically active metabolite of roflumilast, exhibits anti-inflammatory action and consequently contributes to the overall pharmacologic effect of the drug.8,10,15 In the current study, roflumilast N-oxide formation was assessed by examination of its AUC following a single roflumilast dose relative to that of the parent drug (ie, roflumilast N-oxide formation ratio). As reflected by the data contained in Table 2, the roflumilast N-oxide formation ratio was very consistent across the study cohort, ranging from 0.91 to 0.95, values reflective of extensive parent drug biotransformation over a 48- to 50-hour period after administration of either a 100-µg dose or a 250-µg dose.
The mean apparent elimination half-life of roflumilast N-oxide (29 ± 21 hours) was 2- to 3-fold greater than that for the parent drug, a finding similar to that reported previously from adult studies.8,15 Although the apparent terminal elimination rate constant for roflumilast N-oxide was significantly greater in children receiving the 250-µg dose compared with adolescents (mean difference approximately 53%), this difference must be interpreted with caution in that the postdose sampling period used in the current study was relatively short compared with the roflumilast N-oxide elimination t1/2. Finally, our data do not permit us to address the pharmacodynamic consequences of roflumilast N-oxide pharmacokinetics in pediatric patients. Given the adult data reported previously,8,12 our findings suggest that careful consideration of roflumilast N-oxide disposition is warranted in future studies.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was funded by Nycomed GmbH (formerly ALTANA Pharma AG), Konstanz, Germany. Supported in part by grant 1 U10 HD31313-12 (Dr Kearns partial salary support), Pediatric Pharmacology Research Unit Network, National Institute of Child Health and Human Development; grant K23 HL077684-01A2 (Dr Neville), National Heart Lung and Blood Institute, Bethesda, Maryland; and a clinical study award from ALTANA Pharma AG.
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REFERENCES |
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