PMID- 26224203
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20181202
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 56
IP  - 3
DP  - 2016 Mar
TI  - Drug-metabolism mechanism: Knowledge-based population pharmacokinetic approach 
      for characterizing clobazam drug-drug interactions.
PG  - 365-74
LID - 10.1002/jcph.603 [doi]
AB  - A metabolic mechanism-based characterization of antiepileptic drug-drug 
      interactions (DDIs) with clobazam in patients with Lennox-Gastaut syndrome (LGS) 
      was performed using a population pharmacokinetic (PPK) approach. To characterize 
      potential DDIs with clobazam, pharmacokinetic (PK) data from 153 patients with 
      LGS in study OV-1012 (NCT00518713) and 18 healthy participants in bioavailability 
      study OV-1017 were pooled. Antiepileptic drugs (AEDs) were grouped based on their 
      effects on the cytochrome P450 (CYP) isozymes responsible for the metabolism of 
      clobazam and its metabolite, N-desmethylclobazam (N-CLB): CYP3A inducers 
      (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, 
      phenobarbital, phenytoin, and carbamazepine), or CYP2C19 inhibitors (felbamate, 
      oxcarbazepine). CYP3A4 inducers-which did not affect the oral clearance of 
      clobazam-significantly increased the formation of N-CLB by 9.4%, while CYP2C19 
      inducers significantly increased the apparent elimination rate of N-CLB by 10.5%, 
      resulting in a negligible net change in the PK of the active metabolite. CYP2C19 
      inhibitors did not affect N-CLB elimination. Because concomitant use of AEDs that 
      are either CYP450 inhibitors or inducers with clobazam in the treatment of LGS 
      patients had negligible to no effect on clobazam PK in this study, dosage 
      adjustments may not be required for clobazam in the presence of the AEDs 
      investigated here.
CI  - (c) 2015, The American College of Clinical Pharmacology.
FAU - Tolbert, Dwain
AU  - Tolbert D
AD  - Lundbeck LLC, Deerfield, IL, USA.
FAU - Bekersky, Ihor
AU  - Bekersky I
AD  - Lundbeck LLC, Deerfield, IL, USA.
FAU - Chu, Hui-May
AU  - Chu HM
AD  - Anoixis Corporation, Natick, MA, USA.
FAU - Ette, Ene I
AU  - Ette EI
AD  - Anoixis Corporation, Natick, MA, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20150929
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (Anticonvulsants)
RN  - 0 (Cytochrome P-450 CYP2C19 Inducers)
RN  - 0 (Cytochrome P-450 CYP2C19 Inhibitors)
RN  - 0 (Cytochrome P-450 CYP3A Inducers)
RN  - 12794-10-4 (Benzodiazepines)
RN  - 2MRO291B4U (Clobazam)
RN  - MZ4L647O2H (N-desmethylclobazam)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Anticonvulsants/adverse effects
MH  - Benzodiazepines/blood/*pharmacokinetics
MH  - Biological Availability
MH  - Child
MH  - Child, Preschool
MH  - Clobazam
MH  - Cytochrome P-450 CYP2C19 Inducers/*pharmacology
MH  - Cytochrome P-450 CYP2C19 Inhibitors/*pharmacology
MH  - Cytochrome P-450 CYP3A Inducers/*pharmacology
MH  - *Drug Interactions
MH  - Female
MH  - Humans
MH  - Lennox Gastaut Syndrome/blood
MH  - Male
MH  - Middle Aged
MH  - Models, Biological
MH  - Young Adult
OTO - NOTNLM
OT  - Lennox-Gastaut syndrome
OT  - clobazam
OT  - drug-drug interaction
OT  - epilepsy
OT  - population pharmacokinetics
EDAT- 2015/08/01 06:00
MHDA- 2016/12/15 06:00
CRDT- 2015/07/31 06:00
PHST- 2015/04/03 00:00 [received]
PHST- 2015/07/28 00:00 [accepted]
PHST- 2015/07/31 06:00 [entrez]
PHST- 2015/08/01 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
AID - 10.1002/jcph.603 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2016 Mar;56(3):365-74. doi: 10.1002/jcph.603. Epub 2015 Sep 29.