BackgroundLung remodeling and pulmonary fibrosis are serious, life‐threatening conditions resulting from diseases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Preclinical evidence suggests that JNK enzyme function is required for key steps in the pulmonary fibrotic process. However, a selective JNK inhibitor has not been investigated in translational models of lung fibrosis with clinically relevant biomarkers, or in IPF patients. MethodsThe JNK inhibitor CC‐930 was evaluated in the house dust mite‐induced fibrotic airway mouse model, in a phase I healthy volunteer pharmacodynamic study, and subsequently in a phase II multicenter study of mild/moderate IPF (n = 28), with a 4‐week, placebo‐controlled, double‐blind, sequential ascending‐dose period (50 mg QD, 100 mg QD, 100 mg BID) and a 52‐week open‐label treatment‐extension period. ResultsIn the preclinical model, CC‐930 attenuated collagen 1A1 gene expression, peribronchiolar collagen deposition, airway mucin MUC5B expression in club cells, and MMP‐7 expression in lung, bronchoalveolar lavage fluid, and serum. In the phase I study, CC‐930 reduced c‐Jun phosphorylation induced by UV radiation in skin. In the phase II IPF study, there was a CC‐930 dose‐dependent trend in reduction of MMP‐7 and SP‐D plasma protein levels. The most commonly reported adverse events were increased ALT, increased AST, and upper respiratory tract infection (six subjects each, 21.4 %). A total of 13 subjects (46.4 %) experienced adverse events that led to discontinuation of study drug. Nine out of 28 subjects experienced progressive disease in this study. The mean FVC (% predicted) declined after 26–32 weeks at doses of 100 mg QD and 100 mg BID. Changes in MMP‐7, SP‐D, and tenascin‐C significantly correlated with change in FVC (% predicted). ConclusionsThese results illustrate JNK enzymatic activity involvement during pulmonary fibrosis, and support systemic biomarker use for tracking disease progression and the potential clinical benefit of this novel intervention in IPF. Trial registration ClinicalTrials.gov NCT01203943

Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors.

Lenalidomide is a thalidomide analog and an immunomodulatory drug with demonstrated efficacy in various hematological malignancies. The distribution of lenalidomide into semen was evaluated in healthy subjects. Twenty-four male subjects were randomized into 4 equal groups for semen collection. All subjects received lenalidomide 25 mg once daily for 4 days. After the last dose, a single semen sample was collected from subjects, at approximately 2, 24, 72, and 168 hours for groups 1, 2, 3, and 4, respectively, and serial blood sampling was performed for 24 hours in all groups. The mean lenalidomide concentration in semen was 478 ng/mL at 2 hours and 10.0 ng/mL at 24 hours, which was higher than was the corresponding drug concentration in plasma (219 ng/mL at 2 hours and undetectable at 24 hours) but roughly paralleled the time course in plasma for drug elimination. The mean amount of lenalidomide was 1379 ng/ejaculate at 2 hours and 35 ng/ejaculate at 24 hours. The maximal drug content in a single ejaculate was <2000 ng (<0.01% of the daily 25-mg dose). Lenalidomide was undetectable in semen at 72 and 168 hours. Therefore, lenalidomide is essentially eliminated from seminal reservoirs by 72 hours postdose.

The effect of lenalidomide on the corrected QT (QTc) interval was evaluated in healthy men and extended to patients based on the lenalidomide concentration–QTc (C–QTc) relationship. A rigorous assessment of the effect of lenalidomide on QTc intervals was conducted in healthy volunteers who each received, in randomized order, a single oral dose of 10 mg lenalidomide, 50 mg lenalidomide, 400 mg moxifloxacin (positive control) and placebo. Plasma lenalidomide exposure was compared between healthy volunteers and patients with multiple myeloma or myelodysplastic syndromes. In healthy volunteers, moxifloxacin produced the expected significant prolongation in QTcI (individual correction). For lenalidomide 10 mg and 50 mg, the time-matched changes from placebo in the baseline-adjusted least-squares mean QTcI were <3 ms with the upper limit of the two-sided 90% confidence interval for the change <10 ms at all time-points. No subjects experienced QTcI >450 ms or change from baseline >60 ms after lenalidomide administration. Similar results were seen with QT interval data corrected by Fridericia and Bazett methods. The C–QTc analysis yielded no significant association between lenalidomide concentrations and QTcI changes up to 1522 ng/mL; this range was close to that observed in patients receiving lenalidomide doses up to 50 mg, including those with reduced drug clearance due to renal impairment. In conclusion, single doses of lenalidomide up to 50 mg were not associated with prolonged QTc intervals in healthy males. The C–QTc analysis further assured that lenalidomide doses up to 50 mg are not expected to prolong QTc intervals in patients.

The pharmacokinetics of apremilast and its major metabolite M12 were evaluated in subjects with varying degrees of renal impairment. Men and women with renal impairment (estimated glomerular filtration rate, 60‒89 mL/min [mild, n = 8], 30‒59 mL/min [moderate, n = 8], or <30 mL/min [severe, n = 8]) or demographically healthy matched (control) subjects (n = 24) received a single oral dose of apremilast 30 mg. Plasma apremilast and metabolite M12 concentrations were determined, and pharmacokinetic parameters were calculated from samples obtained predose and up to 72 hours postdose. In subjects with mild to moderate renal impairment, apremilast pharmacokinetic profiles were similar to healthy matched subjects. In subjects with severe renal impairment, apremilast elimination was significantly slower, and exposures based on area under the plasma concentration‐versus‐time curve from time zero extrapolated to infinity and maximum observed plasma concentration were increased versus healthy matched subjects. Metabolite M12 pharmacokinetic profiles for subjects with mild renal impairment were similar to those of the healthy matched subjects; however, they were increased in both the moderate and severe renally impaired subjects. Dose reduction of apremilast is recommended in individuals with severe renal impairment, but not in those with mild to moderate renal impairment.