***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension . We investigated the effect of cyclosporine ( Cs ) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects . In addition , in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides ( OATPs ) . The clinical study ( AC-055 - 111 ) was conducted as a two-part , one-sequence , crossover study . Ten subjects in each part  received multiple-dose macitentan followed by multiple-dose co-administration of Cs ( part A ) or rifampin ( part B ) . In the presence of Cs , steady-state area under the plasma concentration – time profiles during a dose interval ( AUCτ ) for macitentan and ACT-373898 increased 10 % and 7 % , respectively , and decreased 3 % for ACT-132577 . Steady-state AUCτ of macitentan and ACT-373898 in the presence of rifampin decreased 79 % and 64 % , respectively . For ACT-132577 , no relevant difference in AUCτ between the two treatments was observed . Macitentan co-administered with Cs or rifampin was well tolerated . The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested . Concomitant treatment with Cs did not have any clinical ly relevant effect on the exposure to macitentan or its metabolites , at steady-state . Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinical ly relevant extent OBJECTIVE To investigate the effect of eslicarbazepine acetate ( ESL ) on the pharmacokinetics of simvastatin  ( SMV ) , a known CYP3A4 substrate , in healthy subjects . METHODS Single centre , two-way cross-over , r and omized , open-label study in 24 healthy volunteers . The volunteers received an oral single-dose of SMV 80 mg on two occasions ( once administered alone and once after treatment with an oral once-daily dose of 800 mg of ESL for 14 days ) , separated by a wash-out period of 3 weeks or more . The analysis of variance ( ANOVA ) was used to test for differences between Test ( SMV under co-administration with ESL ) and Reference ( SMV administered alone ) treatments for AUC0-∞ , AUC0-t and Cmax of SMV and SMV-acid . RESULTS Mean systemic exposure ( AUC ) measurements for both SMV and SMV-β-hydroxyacid ( SMV-acid ) were up to 54 % lower during ESL use . The Test/Reference geometric mean ratios ( GMR ) ( 90 % CI ) for the AUC0-t of SMV and SMV-acid were 46 % ( 38 % ; 55 % ) and 49 % ( 44 % ; 55 % ) , respectively . Mean peak concentrations ( Cmax ) of both SMV and SMV-acid were reduced by 60 % and 41 % , respectively , when SMV was administered with ESL . CONCLUSIONS A significant effect of repeated ESL administration on the pharmacokinetics of SMV and its metabolite SMV-acid was observed . Therefore , dose adjustment of SMV may be required when used concomitantly with ESL , if a clinical ly significant change in lipids is noted 
    Output:
    
As perpetrators , the overall effects for NMEs were much less pronounced , compared with when they served as victims .