E subject had a grade 2 glucose measurement of 8.05 mmol/L (144.9 mg
E subject had a grade 2 glucose measurement of 8.05 mmol/L (144.9 mg/dL). This subject, on one prior measurement during period 2, day-1, had a grade 1 glucose elevation of 6.22 mmol/L (112 mg/dL) that occurred after he completed DCV dosing and before he received DTG. Attempts to contact him afterfollow-up for additional follow-up testing were unsuccessful, and he was considered lost to follow-up.Pharmacokinetics of DTGThe mean plasma concentration-time profiles of DTG after administration of DTG alone and in combination with DCV are presented in Fig. 1. Coadministration of DTG 50 mg once daily with DCV 60 mg once daily increased DTG AUC0-, Cmax, and C by 33, 29, and 45 , respectively, compared with DTG administered alone. Dolutegravir CL/F decreased by 25 , while the t1/2 increased by 17 when coadministered with DCV compared with DTG administered alone (Table 1).Pharmacokinetics of DCVThe plasma concentration-time profiles after administration of DCV alone and in combination with DTG are presented in Fig. 2. DCV exposure did not appear to be meaningfully affected by coadministration with DTG 50 mg once daily (Table 2). DCV AUC0-, decreased by 2.2 , Cmax increased by 3 , and C increased by 6 compared with DCV administered alone. DCV CL/F increased by 2 , while the t1/2 increased by 1.8 whenTable 1 Statistical comparison of DTG PK parameters when administered with and without DCVPlasma DTG PK parameter Geometric mean (CV ) DTG alone (treatment A) (N = 12) AUC0- (hr ?g/mL) Cmax (g/mL) C (g/mL) CL/F (L/hr) t1/2 (hr) 35.7 (34.7) 2.65 (32.0) 0.771 (41.3) 1.40 (34.7) 13.9 (32.8) DTG + DCV (treatment C) (N = 12) 47.3 (26.3) 3.43 (24.5) 1.11 (36.6) 1.06 (26.3) 16.2 (32.6) Geometric least-squares mean ratio (90 CI) DTG + DCV vs DTG alone PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27488460 1.33 (1.11?.59) 1.29 (1.07?.57) 1.45 (1.25?.68) 0.753 (0.627?.905) 1.17 (1.01?.35)Abbreviations: AUC0- area under the concentration-time curve over the dosing interval, C Ixazomib citrate price concentration at the end of the dosing interval, CI confidence interval, CL/F apparent clearance following oral dosing, Cmax maximum observed concentration, DCV daclatasvir, DTG dolutegravir, PK pharmacokinetic, t1/2 terminal phase half-life Treatment A = DTG 50 mg once daily; treatment C = DTG 50 mg once daily plus DCV 60 mg once dailyRoss et al. BMC Infectious Diseases (2016) 16:Page 5 of10,000 Concentration ?SD, ng/mL1,100 DCV 60 mg q24h ?5 days PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28914615 DCV 60 mg q24h + DTG 50 mg q24h ?5 days 10 0 5 10 15 20 25 Planned relative time, hours post dosingFig. 2 Mean plasma concentration-time profiles of daclatasvir (DCV) administered with and without dolutegravir (DTG). Abbreviations: q24h, every 24 h; SD, standard deviationcoadministered with DTG compared with DCV administered alone.Discussion The results from this study demonstrated that plasma exposure of DCV did not appear to be meaningfully affected when coadministered with DTG as compared with DCV administered alone. This result is consistent with the preclinical findings for DCV and DTG. Daclatasvir is a substrate of cytochrome P450 (CYP) 3A4 and the transporter P-glycoprotein (P-gp) [8, 9]. In vitro, DTG demonstrates minimal or no direct inhibition of CYP isozymes or of P-gp; and DTG is not considered an inducer of CYP3A4 [13]. Coadministration of DTG with DCV increased DTG AUC0-, Cmax, and C by approximately 33, 29, and 45 , respectively, compared with DTG administered alone. Dolutegravir is metabolized primarily through UDPglucuronosyltransferase 1A1 with a minor component ( 10 ).
