PMID- 27872071
OWN - NLM
STAT- MEDLINE
DCOM- 20170918
LR  - 20201209
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 61
IP  - 2
DP  - 2017 Feb
TI  - Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study.
LID - 10.1128/AAC.01364-16 [doi]
LID - e01364-16
AB  - Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase 
      inhibitor that is administered once daily and that is in development for the 
      treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine 
      is unlikely to cause significant drug-drug interactions via major 
      drug-metabolizing enzymes or transporters. As a common HIV-1 infection 
      comorbidity, hypercholesterolemia is often treated with statins, including the 
      commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug 
      interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due 
      to CYP3A4 inhibition may lead to serious adverse events (AEs), including 
      rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer 
      resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may 
      increase atorvastatin exposure. The potential of doravirine to affect 
      atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence 
      study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg 
      was administered followed by a 72-h washout. In period 2, doravirine at 100 mg 
      was administered once daily for 8 days, with a single dose of atorvastatin at 20 
      mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 
      14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The 
      atorvastatin area under the curve from time zero to infinity was similar with and 
      without doravirine (geometric mean ratio [GMR] for 
      doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 
      1.06), while the maximum concentration decreased by 33% (GMR for 
      doravirine-atorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes 
      were deemed not to be clinically meaningful. Both of the study drugs were 
      generally well tolerated. Doravirine had no clinically relevant effect on 
      atorvastatin pharmacokinetics in healthy subjects, providing support for the 
      coadministration of doravirine and atorvastatin.
CI  - Copyright (c) 2017 American Society for Microbiology.
FAU - Khalilieh, Sauzanne
AU  - Khalilieh S
AD  - Merck & Co., Inc., Kenilworth, New Jersey, USA sauzanne.khalilieh@merck.com.
FAU - Yee, Ka Lai
AU  - Yee KL
AD  - Merck & Co., Inc., Kenilworth, New Jersey, USA.
FAU - Sanchez, Rosa I
AU  - Sanchez RI
AD  - Merck & Co., Inc., Kenilworth, New Jersey, USA.
FAU - Triantafyllou, Ilias
AU  - Triantafyllou I
AD  - Merck & Co., Inc., Kenilworth, New Jersey, USA.
FAU - Fan, Li
AU  - Fan L
AD  - Merck & Co., Inc., Kenilworth, New Jersey, USA.
FAU - Maklad, Noha
AU  - Maklad N
AD  - Merck & Co., Inc., Kenilworth, New Jersey, USA.
FAU - Jordan, Heather
AU  - Jordan H
AD  - Pharma Medica Research Inc., St. Charles, Missouri, USA.
FAU - Martell, Maureen
AU  - Martell M
AD  - Pharma Medica Research Inc., Mississauga, ON, Canada.
FAU - Iwamoto, Marian
AU  - Iwamoto M
AD  - Merck & Co., Inc., Kenilworth, New Jersey, USA.
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
DEP - 20170124
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Pyridones)
RN  - 0 (Reverse Transcriptase Inhibitors)
RN  - 0 (Triazoles)
RN  - 913P6LK81M (doravirine)
RN  - A0JWA85V8F (Atorvastatin)
SB  - IM
MH  - Adult
MH  - Area Under Curve
MH  - Atorvastatin/blood/*pharmacokinetics
MH  - Drug Interactions
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Pyridones/blood/*pharmacokinetics
MH  - Reverse Transcriptase Inhibitors/pharmacokinetics
MH  - Triazoles/blood/*pharmacokinetics
PMC - PMC5278756
OTO - NOTNLM
OT  - CYP3A4
OT  - atorvastatin
OT  - doravirine
OT  - human immunodeficiency virus
OT  - hypercholesterolemia
OT  - pharmacokinetics
EDAT- 2016/11/23 06:00
MHDA- 2017/09/19 06:00
PMCR- 2017/07/24
CRDT- 2016/11/23 06:00
PHST- 2016/06/27 00:00 [received]
PHST- 2016/11/05 00:00 [accepted]
PHST- 2016/11/23 06:00 [pubmed]
PHST- 2017/09/19 06:00 [medline]
PHST- 2016/11/23 06:00 [entrez]
PHST- 2017/07/24 00:00 [pmc-release]
AID - AAC.01364-16 [pii]
AID - 01364-16 [pii]
AID - 10.1128/AAC.01364-16 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2017 Jan 24;61(2):e01364-16. doi: 
      10.1128/AAC.01364-16. Print 2017 Feb.