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Prostacyclins are routinely used to treat vascular features of systemic sclerosis (SSc, scleroderma) but require parenteral infusion or inhalation. This study evaluated the safety and efficacy of oral treprostinil in digital ulcers secondary to SSc. Methods: This was a randomized (1:1) placebo-controlled, multicenter study in adults with SSc and at least one active digital ulcer at entry. Oral treprostinil was administered twice daily and titrated to maximum tolerated dose with clinical assessments at Weeks 5, 10, 15 and 20. The primary endpoint was change in net digital ulcer burden. Secondary outcomes included ulcer healing and prevention, measures of hand function, quality of life, Raynaud phenomenon and global assessments. Simplified data were gathered during open-label follow up. Results: Enrolled were 147 patients (109F/38M), mean age 48.8 years with SSc of mean duration 10.5 years. At week 20, mean net ulcer burden was reduced-0.43 ulcers on treprostinil (1.80 vs. 1.37) and-0.10 ulcers on placebo (1.61 vs. 1.51; p = 0.20). There were no effects on ulcer healing or prevention, and small, inconsistent effects on Raynaud phenomenon, global assessment, hand function and quality-of-life measures. In open-label follow-up, there was a continued, small reduction in net ulcer burden (-0.52 month 3, n = 104;-0.64 month 12, n = 36). Common adverse effects were headache, nausea, diarrhea, jaw pain, flushing and other gastrointestinal symptoms. Conclusions: Administration of oral treprostinil twice daily over 20 weeks was associated with small and statistically insignificant reduction in net ulcer burden in comparison to placebo.

IntroductionTreprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet. The availability of a formulation permitting convenient systemic delivery might have applicability to scleroderma vascular complications. We evaluated pharmacokinetics and perfusion in scleroderma patients with digital ischemia following escalating twice-daily doses of treprostinil diethanolamine SR.MethodsScleroderma patients with digital ulcers were enrolled in this dual-center, open-label, phase I pharmacokinetic study. Drug concentrations and perfusion, quantified by laser Doppler imaging, were measured over 12 hours at the 2 mg and 4 mg (or maximally tolerated) doses. Pharmacokinetic parameters were determined from individual plasma concentration versus time profiles using non-compartmental analysis methods. Digital perfusion and skin temperature were modeled as a function of log-transformed drug concentration and other covariates by performing repeated measures analyses using random effects models.ResultsNineteen scleroderma patients (84% female, 53% limited scleroderma) received treprostinil diethanolamine SR with dose titration up to 4 mg twice daily as tolerated. Peak concentrations (mean maximum plasma concentration (Cmax) = 1,176 and 2,107 pg/mL) occurred approximately 3.6 hours after dose administration, and overall exposure (under the plasma concentration-time curve from time 0 to 12 hours post dose (AUC0-12) = 7,187 and 12,992 hr*pg/mL) was linear between the 2 mg and 4 mg doses. Perfusion and digital skin temperature were positively associated with log-transformed plasma concentration at the 4 mg dose (P = 0.015 and P = 0.013, respectively). The most frequent adverse events were similar to those seen with prostacyclin analogues.ConclusionsOral treprostinil diethanolamine was effectively absorbed in patients with scleroderma. Drug administration was temporally associated with improved cutaneous perfusion and temperature. Treprostinil diethanolamine may provide a new therapeutic option for Raynaud's phenomenon and the peripheral vascular disease of scleroderma.Trial RegistrationClinicalTrials.gov NCT00848939.Electronic supplementary materialThe online version of this article (doi:10.1186/ar4216) contains supplementary material, which is available to authorized users.

ABSTRACT:The CYP3A5*1 allele has been associated with differences in the metabolism of some CYP3A substrates. CYP3A5 polymorphism may also influence susceptibility for certain drug interactions. We have previously noted a correlation between basal CYP3A activity and the inductive effects of dexamethasone using the erythromycin breath test (ERBT). To determine whether CYP3A5 polymorphism influences induction of CYP3A activity, we examined the effect of an antiemetic regimen of dexamethasone, and the prototypical inducer rifampin, on the ERBT in African American volunteers prospectively stratified by CYP3A5*1 allele carrier status.Mean basal ERBTs were significantly higher in CYP3A5*1 carriers (2.71 ؎ 0.53%) versus noncarriers (2.12 ؎ 0.37%, P ‫؍‬ 0.006). Rifampin increased ERBTs in CYP3A5*1 carriers (4.68 versus 2.60%, P ‫؍‬ 0.0008) and noncarriers (3.55 versus 2.11%, P ‫؍‬ 0.0017), whereas dexamethasone increased ERBTs only in CYP3A5*1 noncarriers (3.03 versus 2.14%, P ‫؍‬ 0.031). CYP3A5 polymorphism appears to influence susceptibility to induction-type drug interactions for some inducers, and CYP3A5*1 noncarriers may be more susceptible to the inductive effects of dexamethasone as a result of lower basal CYP3A activity.Members of the cytochrome P450 3A (CYP3A) subfamily of drug-metabolizing enzymes are the most abundantly expressed cytochrome P450 enzymes in human liver and are involved in the metabolism of nearly 50% of clinically used drugs (Wilkinson, 2005). In adults, hepatic CYP3A activity reflects primarily the net contributions of CYP3A4 and CYP3A5, which share overlapping substrate specificities but differ with regard to tissue expression and transcriptional regulation (Gibson et al., 2002;Goodwin et al., 2002;. Recent efforts to understand interindividual variability in CYP3A activity have focused primarily on CYP3A5 polymorphisms because variability in the contribution of functional CYP3A5 activity could influence an individual's susceptibility to inducer-or inhibitor-mediated drug interactions. The major CYP3A5 polymorphisms include the CYP3A5*3, *6, and *7 alleles, which are functionally inactive because of single nucleotide polymorphisms that result in either splice defects or the introduction of an early stop codon that results in reduced production of the full-length active protein Wojnowski, 2004;Xie et al., 2004). CYP3A5*1 is the only functional CYP3A5 allele known to contribute to total CYP3A activity, and the frequency of the CYP3A5*1 allele has been shown to differ among ethnic groups (Kuehl et al., 2001). The CYP3A5*1 allele has been associated with higher midazolam systemic clearance and tacrolimus dose requirements (Kuehl et al., 2001;Wong et al., 2004) and greater metabolism of quinidine and saquinavir (Mouly et al., 2005;Mirghani et al., 2006).Less is known about the influence of the CYP3A5*1 allele on susceptibility for drug interactions caused by different CYP3A inducers and inhibitors. Recently, the CYP3A5*1 allele was shown to influence susceptibility to the inhibitory effects of fl...