Karl Zech

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

AIMSnTo 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.nnnMETHODSnSixteen 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.nnnRESULTSnDuring 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).nnnCONCLUSIONSnCo-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.

Pharmacology, Clinical Efficacy, and Tolerability of Phosphodiesterase-4 Inhibitors: Impact of Human Pharmacokinetics

Since more than two decades anti-inflammatory effects of inhibitors of phosphodiesterase-4 have been described in numerous cellular and animal studies and were finally confirmed in clinical trials. The path from an early, pioneering study with Ro20-1724 showing reduction of psoriatric plaque size in 1979 to modern PDE4 inhibitors such as oral apremilast in development for psoriasis, the inhaled PDE4 inhibitor GSK256066 in development for asthma and COPD and finally roflumilast, the first PDE4 inhibitor approved and currently marketed as an oral, once-daily remedy for severe COPD was marked by large progress in chemical optimization based on improved understanding of PDE4 biology and drug-like properties determining the appropriate pharmacokinetic profile. In this chapter aspects of the pharmacology and clinical efficacy of PDE4 inhibitors, which have been in clinical development over the years are summarized with specific emphasis on their clinical pharmacokinetic properties.

Population Pharmacokinetic Modelling of Roflumilast and Roflumilast N-Oxide by Total Phosphodiesterase-4 Inhibitory Activity and Development of a Population Pharmacodynamic-Adverse Event Model

Background:Roflumilast is an oral, selective phosphodiesterase (PDE)-4 inhibitor in development for the treatment of chronic obstructive pulmonary disease (COPD). Both roflumilast and its metabolite roflumilast N-oxide have anti-inflammatory properties that contribute to overall pharmacological activity.Objectives:To model the pharmacokinetics of roflumilast and roflumilast N-oxide, evaluate the influence of potential covariates, use the total PDE4 inhibitory activity (tPDE4i) concept to estimate the combined inhibition of PDE4 by roflumilast and roflumilast N-oxide, and use individual estimates of tPDE4i to predict the occurrence of adverse events (AEs) in patients with moderate-to-severe COPD.Methods:We modelled exposure to roflumilast and roflumilast N-oxide (21 studies provided the index dataset and five separate studies provided the validation dataset), extended the models to COPD (using data from two studies) and assessed the robustness of the parameter estimates. A parametric bootstrap estimation was used to quantify tPDE4i in subpopulations. We established logistic regression models for each AE occurring in >2% of patients in a placebo-controlled trial that achieved a p-value of <0.2 in a permutation test. The exposure variables were the area under the plasma concentration-time curve (AUC) of roflumilast, the AUC of roflumilast N-oxide and tPDE4i. Individual AUC values were estimated from population models.Results:Roflumilast pharmacokinetics were modelled with a two-compartment model with first-order absorption including a lag time. A one-compartment model with zero-order absorption was used for roflumilast N-oxide. The final models displayed good descriptive and predictive performance with no appreciable systematic trends versus time, dose or study. Posterior predictive checks and robustness analysis showed that the models adequately described the pharmacokinetic parameters and the covariate effects on disposition. For roflumilast, the covariates of sex, smoking and race influenced clearance; and food influenced the absorption rate constant and lag time. For roflumilast N-oxide, age, sex and smoking influenced clearance; age, sex and race influenced the fraction metabolized; bodyweight influenced the apparent volume of distribution; and food influenced the apparent duration of formation. The COPD covariate increased the central volume of distribution of roflumilast by 184% and reduced its clearance by 39%; it also reduced the estimated volume of distribution of roflumilast N-oxide by 21% and reduced its clearance by 7.9%. Compared with the reference population (male, non-smoking, White, healthy, 40-year-old subjects), the relative geometric mean [95%CI] tPDE4i was higher in patients withCOPD(12.6%[−6.6, 35.6]), women (19.3%[8.2, 31.6]), Black subjects (42.1% [16.4, 73.4]), Hispanic subjects (28.2% [4.1, 57.9]) and older subjects (e.g. 8.3% [−11.2, 32.2] in 60-year-olds), and was lower in smokers (−19.1% [−34.0, −0.7]). Among all possible subgroups in this analysis, the subgroup with maximal tPDE4i comprised elderly, Black, female, non-smoking, COPD patients (tPDE4i 217% [95% CI 107, 437] compared with the value in the reference population). The probability of a patient with tPDE4i at the population geometric mean [95% CI] was 13.0% [7.5, 18.5] for developing diarrhoea, 6.0% [2.6, 9.4] for nausea and 5.1% [1.9, 8.6] for headache.Conclusions:Covariate effects have a limited impact on tPDE4i. There was a general association between tPDE4i and the occurrence of common AEs in patients with COPD.

Sensitive simultaneous determination of ciclesonide, ciclesonide-M1-metabolite and fluticasone propionate in human serum by HPLC–MS/MS with APPI

A new and very sensitive analytical method has been developed and validated to jointly determine the anti-inflammatory drug ciclesonide (CIC), its active principle metabolite M1 (CIC-M1) and fluticasone propionate (FP) in human serum, in the low concentration range from 10 to 1000 pg/mL. This was accomplished by high-performance liquid chromatography and tandem mass spectrometry using atmospheric pressure photo ionisation (HPLC-MS/MS with APPI) using 0.5 mL of serum. Serum was mixed with the internal standards (IS) D11-CIC and D11-CIC-M1 and extracted with diisopropylether. A gradient with acetonitrile (containing 10 mM of acetic acid and 10% of acetone) was used. HPLC-MS/MS of the acetic acid adducts of the analytes was performed in negative mode. The novel aspect of this method is that instead of the dopant being introduced directly into the source by means of an external HPLC pump, it was added to the mobile phase. This provided significantly better sensitivity than the usual method of in-source addition of the dopant, and with no loss in HPLC performance. Sensitivity for the analytes was about four times greater than with either APCI or ESI. Validation was performed in three batches. The inter-batch precision (CV) of the quality control samples in human serum ranged from 4.08% to 6.78% for CIC, from 2.57% to 7.74% for CIC-M1, and from 2.38% to 9.61% for FP. The inter-batch accuracy (with reference to the mean value) of the quality control samples in human serum ranged from 99.3% to 110.0% for CIC, from 101.8% to 104.7% for CIC-M1, and from 100.4% to 101.8% for FP. Calibration data and LLOQ data are also presented in this paper. The analytes were stable in human serum over three freeze/thaw cycles, or for 4h at room temperature, or for at least 18 months when stored at below -20 degrees C. This method was used for quantifying the analytes after inhalation of low-mug amounts of the drugs by patients.

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.

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‐μg dose in period 1, 250‐μg 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 (r2 = 0.36, P < .01) and roflumilast N‐oxide (r2 = 0.39, P < .01). With the exception of dose‐normalized maximum plasma concentration (mean 1.1 and 0.8 μg/L per 1 μg/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.