PMID- 26149244
OWN - NLM
STAT- MEDLINE
DCOM- 20161018
LR  - 20181113
IS  - 1179-1926 (Electronic)
IS  - 0312-5963 (Linking)
VI  - 55
IP  - 1
DP  - 2016 Jan
TI  - Population Pharmacokinetic Model of Cabozantinib in Patients with Medullary 
      Thyroid Carcinoma and Its Application to an Exposure-Response Analysis.
PG  - 93-105
LID - 10.1007/s40262-015-0295-x [doi]
AB  - BACKGROUND AND OBJECTIVES: Cabozantinib is a tyrosine kinase inhibitor approved 
      in the USA and EU for the treatment of patients with progressive, metastatic 
      medullary thyroid cancer (MTC). The indicated cabozantinib dose is 140 mg/day, 
      with dose modifications allowed for patients who develop adverse events (AEs). 
      The analysis objective was to develop a population pharmacokinetic (PopPK) model 
      in MTC patients and to use the model for exposure-response (ER) analysis of dose 
      modifications. METHODS: A PopPK model for cabozantinib was developed using data 
      from three clinical trials (2079 evaluations from 289 patients), including a 
      randomized, double-blind, placebo-controlled phase III study of patients with 
      progressive, metastatic MTC. The PopPK model predictions [model-predicted 
      steady-state area under the plasma concentration-time curve (AUCss,pred)] were 
      used for an ER analysis of the time to first dose modification. RESULTS: The 
      final PopPK model was a one-compartment model with first-order absorption and 
      first-order elimination. Estimated cabozantinib apparent oral clearance (CL/F) 
      and apparent volume of distribution (V c/F) were 106 L/day [+/-2.98 % relative 
      standard error (RSE)] (males) and 349 L (+/-2.73 % RSE), respectively. CL/F was 
      reduced by 22 % (to 83 L/day) in females. Sex and body mass index (BMI) were 
      significant covariates that combined contributed 15 % to the variability in 
      cabozantinib CL/F, but did not warrant dose adjustment. Higher cabozantinib 
      AUCss,pred was correlated to an increased risk of early dose modification and a 
      lower average dose through to Day 85. Early cabozantinib dose modification was 
      not associated with a reduction in progression-free survival (PFS). CONCLUSION: A 
      PopPK model was developed for cabozantinib pharmacokinetics in MTC patients. 
      Higher cabozantinib exposure was associated with earlier first dose modification 
      and a lower average administered dose through to Day 85. Early first dose 
      modification did not appear to impact PFS.
FAU - Miles, Dale
AU  - Miles D
AD  - Genentech (A member of the Roche Group), South San Francisco, CA, USA.
AD  - Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA.
FAU - Jumbe, Nelson L
AU  - Jumbe NL
AD  - Pharmactuarials LLC, Mountain View, CA, USA.
FAU - Lacy, Steven
AU  - Lacy S
AD  - Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA. 
      slacy@exelixis.com.
FAU - Nguyen, Linh
AU  - Nguyen L
AD  - Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA.
AD  - Medivation Inc., San Francisco, CA, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Switzerland
TA  - Clin Pharmacokinet
JT  - Clinical pharmacokinetics
JID - 7606849
RN  - 0 (Anilides)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - 1C39JW444G (cabozantinib)
RN  - Thyroid cancer, medullary
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Anilides/*administration & dosage/*pharmacokinetics
MH  - Carcinoma, Neuroendocrine/*drug therapy/*metabolism
MH  - Clinical Trials as Topic
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Models, Biological
MH  - Protein Kinase Inhibitors/*administration & dosage/*pharmacokinetics
MH  - Pyridines/*administration & dosage/*pharmacokinetics
MH  - Randomized Controlled Trials as Topic
MH  - Thyroid Neoplasms/*drug therapy/*metabolism
MH  - Treatment Outcome
MH  - Young Adult
EDAT- 2015/07/08 06:00
MHDA- 2016/10/19 06:00
CRDT- 2015/07/08 06:00
PHST- 2015/07/08 06:00 [entrez]
PHST- 2015/07/08 06:00 [pubmed]
PHST- 2016/10/19 06:00 [medline]
AID - 10.1007/s40262-015-0295-x [pii]
AID - 10.1007/s40262-015-0295-x [doi]
PST - ppublish
SO  - Clin Pharmacokinet. 2016 Jan;55(1):93-105. doi: 10.1007/s40262-015-0295-x.