



No Pharmacokinetic Interaction Between HCV NS5A Inhibitor Elbasvir and Buprenorphine/Naloxone in Healthy Volunteers



Reported by Jules Levin
AASLD Liver Meeting 2015 San Francisco, CA
November 1317
William L. Marshall1; Ted Marenco2; HwaPing Feng1; April M. Barbour1; Jocelyn Gilmartin1; Fang Liu1; Deborah Panebianco1; Angela Mirzac2; Mike Di Spirito2; Daria Stypinski2; Ziv Machnes2; Michael Gartner2; Marian Iwamoto1; Joan R. Butterton1; Wendy W. Yeh1
1Merck & Co., Inc., Kenilworth, NJ, USA; 2Celerion, Lincoln, NE, USA
Figure 2. Arithmetic mean plasma concentrationtime profiles of buprenorphine following the administration of a single sublingual dose of 8 mg buprenorphine/2 mg naloxone with and without a single oral dose of 50 mg elbasvir in healthy volunteers (N = 16 for buprenorphine + naloxone alone; N = 15 for elbasvir + buprenorphine + naloxone) (Linear and semilog scales)
Table 3. Statistical comparison and summary statistics of buprenorphine plasma pharmacokinetics following the administration of a single sublingual dose of 8 mg buprenorphine/2 mg naloxone with and without a single oral dose of 50 mg elbasvir in healthy volunteers
Buprenorphine + naloxone alone: A single sublingual dose of 8 mg buprenorphine/2 mg naloxone (with naltrexone blockade administered as 50 mg naltrexone HCl q12h starting 14 hours prior to the buprenorphine/naloxone dose, for a total of 3 naltrexone doses).
Elbasvir + buprenorphine + naloxone: A single oral dose of 50 mg elbasvir coadministered with a single sublingual dose of 8 mg buprenorphine/2 mg naloxone (with naltrexone blockade administered as 50 mg naltrexone HCl q12h starting 14 hours prior to the buprenorphine/naloxone dose, for a total of 3 naltrexone doses).
One subject was discontinued by the Investigator on Day 1 of Period 1 (buprenorphine +naloxone alone) due to vomiting within 3 hours of dosing.
* Two subjects were discontinued from the study by the Investigator on Day 1 of Period 3 (elbasvir + buprenorphine + naloxone) due to vomiting within 8 hours of dosing.
Pseudo withinsubject %CV = 100*sqrt((σA2 + σB2  2σAB)/2), where σA2 and σB2 are the estimated variances on the log scale for the 2 treatments and σAB is the corresponding estimated covariance, each obtained from the linear mixedeffects model.
Backtransformed leastsquares mean and confidence interval from the linear mixedeffects model performed on natural logtransformed values.
Median (minimum, maximum) reported for Tmax.
Geometric mean and geometric coefficient of variation reported for apparent terminal t.
GM = Geometric leastsquares mean; CI = Confidence interval; GMR = Geometric leastsquares mean ratio; CV = Coefficient of variation.
NOR exhibited similar PK following singledose administration of BUP/NAL with or without coadministration of EBR (Figure 3, Table 4)
 GMRs [90% CIs] for the NOR AUC0∞, Cmax, C24, and the molecular weightadjusted parent/metabolite AUC0∞ ratio were 0.97 [0.86, 1.09], 1.10 [0.98, 1.23], 0.97 [0.87, 1.09], and 1.01 [0.88, 1.16], respectively
 Relative to when BUP + NAL was administered alone, coadministration with EBR resulted in a median Tmax of NOR that occurred approximately 0.5 hours earlier, ie, 1.01 hours postdose compared to 1.51 hours postdose
 The GM apparent terminal t1/2 of NOR was comparable following EBR + BUP + NAL (33.92 hours) and following BUP + NAL alone (38.81 hours)
Figure 3. Arithmetic mean plasma concentrationtime profiles of norbuprenorphine following the administration of a single sublingual dose of 8 mg buprenorphine/2 mg naloxone with and without a single oral dose of 50 mg elbasvir in healthy volunteers (N = 16 for buprenorphine + naloxone alone; N = 15 for elbasvir + buprenorphine + naloxone) (Linear and semilog scales)
Table 4. Statistical comparison and summary statistics of norbuprenorphine plasma pharmacokinetics following the administration of a single sublingual dose of 8 mg buprenorphine/2 mg naloxone with and without a single oral dose of 50 mg elbasvir in healthy volunteers
Buprenorphine + naloxone alone: A single sublingual dose of 8 mg buprenorphine/2 mg naloxone (with naltrexone blockade administered as 50 mg naltrexone HCl q12h starting 14 hours prior to the buprenorphine/naloxone dose, for a total of 3 naltrexone doses).
Elbasvir + buprenorphine + naloxone: A single oral dose of 50 mg elbasvir coadministered with a single sublingual dose of 8 mg buprenorphine/2 mg naloxone (with naltrexone blockade administered as 50 mg naltrexone HCl q12h starting 14 hours prior to the buprenorphine/naloxone dose, for a total of 3 naltrexone doses).
^One subject was discontinued by the Investigator on Day 1 of Period 1 (buprenorphine +naloxone alone) due to vomiting within 3 hours of dosing.
*Two subjects were discontinued from the study by the Investigator on Day 1 of Period 3 (elbasvir + buprenorphine + naloxone) due to vomiting within 8 hours of dosing.
Pseudo withinsubject %CV = 100*sqrt((σA2 + σB2  2σAB)/2), where σA2 and σB2 are the estimated variances on the log scale for the 2 treatments and σAB is the corresponding estimated covariance, each obtained from the linear mixedeffects model.
Backtransformed leastsquares mean and confidence interval from the linear mixedeffects model performed on natural logtransformed values.
Median (minimum, maximum) reported for Tmax.
Geometric mean and geometric coefficient of variation reported for apparent terminal t.
GM = Geometric leastsquares mean; CI = Confidence interval; GMR = Geometric leastsquares mean ratio; CV = Coefficient of variation;
AUC0∞ ratio = Molecular weightadjusted AUC0∞ ratio of norbuprenorphine/buprenorphine.






