PMID- 25760671
OWN - NLM
STAT- MEDLINE
DCOM- 20160331
LR  - 20191210
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 55
IP  - 8
DP  - 2015 Aug
TI  - Clinical drug interaction profile of idelalisib in healthy subjects.
PG  - 909-19
LID - 10.1002/jcph.495 [doi]
AB  - Idelalisib, a potent phosphatidylinositol-3-kinase delta (PI3Kdelta) inhibitor, is 
      metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser 
      extent by cytochrome P450 (CYP) 3A and uridine 
      5'-diphospho-glucuronosyltransferase 1A4. In vitro, idelalisib inhibits 
      P-glycoprotein (P-gp) and organic anion transporting polypeptides 1B1 and 1B3, 
      and GS-563117 is a time-dependent CYP3A inhibitor. This study enrolled 24 healthy 
      subjects and evaluated (1) the effect of idelalisib on the pharmacokinetics (PK) 
      of digoxin, a P-gp probe substrate, rosuvastatin, a breast cancer resistance 
      protein, and OATP1B1/OATP1B3 substrate, and midazolam, a CYP3A substrate; and (2) 
      the effect of a strong inducer, rifampin, on idelalisib PK. On treatment, the 
      most common clinical adverse events (AEs) were headache and pyrexia. Grade 3 
      transaminase increases were observed in 5 of 24 subjects and were reversible. Two 
      subjects had serious AEs after treatment completion (grade 3 pyrexia and/or 
      drug-induced liver injury). Idelalisib coadministration did not affect digoxin 
      and rosuvastatin PK. Coadministration with idelalisib increased plasma exposures 
      of midazolam (138% and 437% for maximum observed plasma concentration [Cmax ] and 
      area under the plasma concentration-time curve from time 0 extrapolated to 
      infinity [AUCinf ], respectively), consistent with the in vitro finding of CYP3A 
      inhibition by GS-563117. Rifampin caused a substantial decrease in idelalisib 
      (58% and 75%, Cmax and AUCinf , respectively) and GS-563117 exposures, indicating 
      an enhanced contribution of CYP3A to idelalisib metabolism under a strongly 
      induced state.
CI  - (c) 2015, The American College of Clinical Pharmacology.
FAU - Jin, Feng
AU  - Jin F
AD  - Gilead Sciences, Inc., Foster City, CA, USA.
FAU - Robeson, Michelle
AU  - Robeson M
AD  - Gilead Sciences, Inc., Seattle, WA, USA.
FAU - Zhou, Huafeng
AU  - Zhou H
AD  - Gilead Sciences, Inc., Seattle, WA, USA.
FAU - Moyer, Candra
AU  - Moyer C
AD  - Gilead Sciences, Inc., Foster City, CA, USA.
FAU - Wilbert, Sibylle
AU  - Wilbert S
AD  - Gilead Sciences, Inc., Seattle, WA, USA.
FAU - Murray, Bernard
AU  - Murray B
AD  - Gilead Sciences, Inc., Foster City, CA, USA.
FAU - Ramanathan, Srini
AU  - Ramanathan S
AD  - Gilead Sciences, Inc., Foster City, CA, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150506
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Purines)
RN  - 0 (Quinazolinones)
RN  - 73K4184T59 (Digoxin)
RN  - 83MVU38M7Q (Rosuvastatin Calcium)
RN  - R60L0SM5BC (Midazolam)
RN  - VJT6J7R4TR (Rifampin)
RN  - YG57I8T5M0 (idelalisib)
SB  - IM
MH  - Adult
MH  - Antineoplastic Agents/blood/*pharmacokinetics/*pharmacology
MH  - Digoxin/blood/pharmacokinetics
MH  - Drug Interactions
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Midazolam/blood/pharmacokinetics
MH  - Middle Aged
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Purines/blood/*pharmacokinetics/*pharmacology
MH  - Quinazolinones/blood/*pharmacokinetics/*pharmacology
MH  - Rifampin/pharmacology
MH  - Rosuvastatin Calcium/blood/pharmacokinetics
MH  - Young Adult
OTO - NOTNLM
OT  - PI3Kdelta
OT  - drug interaction
OT  - idelalisib
OT  - pharmacokinetics
OT  - safety
EDAT- 2015/03/12 06:00
MHDA- 2016/04/01 06:00
CRDT- 2015/03/12 06:00
PHST- 2015/03/12 06:00 [entrez]
PHST- 2015/03/12 06:00 [pubmed]
PHST- 2016/04/01 06:00 [medline]
AID - 10.1002/jcph.495 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2015 Aug;55(8):909-19. doi: 10.1002/jcph.495. Epub 2015 May 6.