What is already known about this subject• Cytochrome P450 (CYP) 3A4 plays a prominent role in the metabolism of many drugs, which in turn implies, that changes in the activity of this enzyme caused by, for example, co-administered drugs, might result in clinically significant drug interactions.• Roflumilast, a targeted PDE4 inhibitor in clinical development for the treatment of COPD and asthma, is partly metabolized by CYP3A4, and thus may have the potential to inhibit its activity.
What this study adds• The results of this study show that therapeutic steady-state concentrations of roflumilast and its active metabolite roflumilast N-oxide do not alter the disposition of the CYP3A substrate midazolam.• Therefore, roflumilast treatment has a low susceptibility to alter the clearance of drugs metabolized by CYP3A4.
AimsThe aim of this study was to investigate the effects of roflumilast, an investigational PDE4 inhibitor for the treatment of COPD and asthma, on the pharmacokinetics of the CYP3A probe drug midazolam and its major metabolites.
MethodsIn an open, randomized (for midazolam treatment sequence) study, 18 healthy male subjects received single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart) alone, repeated doses of roflumilast (500 µ g once daily for 14 days) alone, and repeated doses of roflumilast together with single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart).
ResultsA comparison of clearance and peak and systemic exposure to midazolam following administration of roflumilast indicated no effect of roflumilast dosed to steady state on the pharmacokinetics of midazolam. Point estimates (90% CI) were 0.97 (0.84, 1.13) for the AUC of i.v. midazolam and 0.98 (0.82, 1.17) for that of oral midazolam with and without roflumilast.
ConclusionsTherapeutic steady state concentrations of roflumilast and its N-oxide do not alter the disposition of the CYP3A substrate midazolam in healthy subjects. This finding suggests that roflumilast is unlikely to alter the clearance of drugs that are metabolized by CYP3A4.OnlineOpen: This article is available free online at www.blackwell-synergy.com N. Nassr et al.
This open-label, randomized, 3-period crossover study evaluated the pharmacokinetic interaction potential of roflumilast and budesonide following repeated coadministration to healthy male subjects (N = 12). Treatments consisted of oral roflumilast 500 mug, once daily, orally inhaled budesonide 800 mug, twice daily, and concomitant administration of both treatments for 7 days each. Roflumilast and roflumilast N-oxide in plasma and budesonide serum levels were measured by specific assays. Geometric mean test/reference ratios of steady-state pharmacokinetic parameters were evaluated by analysis of variance. Safety and tolerability were monitored. Pharmacokinetic parameters of roflumilast, roflumilast N-oxide, and budesonide after coadministration of roflumilast and budesonide were similar to those after mono-treatment. Compared with budesonide and roflumilast mono-treatments, slightly lower maximum serum/plasma concentration (C(max)) and area under the curve (AUC) values of roflumilast N-oxide and budesonide (ranging from -8% to -16%) were observed with combined treatment. All test/reference ratios were within predefined equivalence acceptance ranges for roflumilast AUC (0.80, 1.25) and C(max) (0.70, 1.43) and for roflumilast N-oxide and budesonide AUC and C(max) (all 0.67, 1.50). Coadministration of roflumilast and budesonide did not alter the steady-state disposition of each other and did not affect safety and tolerability of either drug.
1 Isoprostanes comprise a group of free radical-catalyzed products of arachidonic acid. However, there is recent evidence pointing towards an enzyme-dependent formation of isoprostanes. 2 With the use of isolated rat glomeruli we addressed the mechanisms of isoprostane generation. Synthesis of prostanoids and isoprostanes, including 8-epi-PGF 2a , was studied under conditions favouring radical formation. 3 Cultured glomeruli formed dierent prostanoids including 8-epi-PGF 2a . Upon LPS challenge cyclo-oxygenase (COX)-2 expression was enhanced, and this was paralleled by a 2 ± 9-fold increase in prostanoid formation, including isoprostanes. Addition of COX-isoform unselective inhibitors (diclofenac, indomethacin) or a selective inhibitor (NS-398) suppressed the synthesis of prostanoids, 8-epi-PGF 2a and total isoprostane fraction; however, inhibition of the latter was less pronounced. 4 Antioxidants such as butylated hydroxytoluene (BHT), nordihydroguaiaretic acid (NDGA), or dimethylurea exhibited an only minimal inhibitory eect on 8-epi-PGF 2a synthesis. Moreover, ROSgenerating drugs (menadione, methylviologen) or NADPH-driven radical formation were unable to cause the generation of signi®cant amounts of 8-epi-PGF 2a by rat glomeruli. In contrast, the total isoprostane fraction could be increased by menadione addition. 5 These data provide further evidence for a radical-independent, but COX-dependent formation of 8-epi-PGF 2a in renal tissue. Regarding the other isoprostanes, both radicals and COX enzymes contribute to their formation. Based on our data we assume that elevated release of vasoactive 8-epi-PGF 2a has to be expected under conditions when the prostanoid system in the kidney is stimulated, e.g. under in¯ammatory conditions. Regarding renal oxidative injuries, the usefulness of 8-epi-PGF 2a as a representative marker molecule of oxidative stress has to be questioned.
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