Dolutegravir versus Simeprevir
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Study Design
This was a prospective, single center, open-label, three arm, three-period, crossover study to evaluate the drug interaction potential between DTG and SMV in healthy volunteers ages 18-60 years. Subjects received (1) SMV 150mg once daily for 7 days, (2) DTG 50mg once daily for 7 days, and (3) SMV 150mg once daily plus DTG 50mg once daily for 7 days with ≥ 14-day “washout” between sequences. Subjects were randomized to sequence order. Intensive PK sampling was performed on day 7 of each sequence following observed dosing and a standardized meal. SMV and DTG were quantified using a validated, simultaneous LC/MS/MS assay. PK parameters were determined using non-compartmental methods, log transformed, and compared using paired t-tests. There were no adjustments for multiple comparisons. Bioequivalence for area under the curve (AUCtau) and maximum concentration (Cmax) were also assessed. Bioequivalence was declared when the 90% CI for the geometric mean ratio (GMR) of combination vs. individual drug fell within 80%-125%.
Study Results
Twenty-four subjects completed all 3 sequences (15 female, 21 Caucasian/3 Hispanic, mean age 35 yrs and weight 69.4 kg). DTG trough was increased 24% (p=0.0003) with SMV. DTG AUCtau was increased 15% (p=0.002), but was deemed bioequivalent as the 90% CI for the GMR was 107%-123%. DTG Cmax was bioequivalent (GMR 106%; 90% CI 100%- 114%). DTG Tmax increased by 0.5 hours while
DTG CL/F decreased by ~100mL/hr. SMV AUCtau (GMR 99%; 90% CI 82%-119%) and Cmax (GMR 105%; 90% CI 88% to 125%) were bioequivalent with DTG. There were no significant differences in any other SMV PK parameters with DTG. There were no discontinuations due to adverse events and all adverse events were mild to moderate in severity. The most common clinical adverse events were gastrointestinal upset and headache reported by 7/24 (29.2%) of participants. The most common laboratory abnormality was a decline in creatinine clearance (CrCl) due to an increase in serum creatinine by an average of 18.2 mL/min (average baseline CrCl was 113.8 mL/min for all participants) which occurred in 6/24 (25%) of participants while taking DTG, consistent with DTG’s inhibition of renal creatinine transporters.
Study Conclusions
The author’s concluded that while the DTG trough was increased slightly with SMV, the total AUC was bioequivalent. The delayed DTG Tmax suggests SMV may inhibit P-gp in the gut, but this alone cannot account for the increased DTG trough so there may be additional inhibition of hepatic clearance via either UGT1A1 or CYP3A. Despite the increase in trough, DTG concentrations were well within the range with established safety data. Thus, SMV and DTG can be safely coadministered.
References
Macbrayne C, Castillo-Mancilla J, Burton J, MaWinney S, Wagner C, Micke K. Small increase in dolutegravir trough, but equivalent total exposure with simeprevir. International Workshop On Clinical Pharmacology Of Antiviral Therapy. Chicago, IL, USA. 18; June 2017.
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