PMID- 26031410
OWN - NLM
STAT- MEDLINE
DCOM- 20151103
LR  - 20181113
IS  - 1532-6535 (Electronic)
IS  - 0009-9236 (Print)
IS  - 0009-9236 (Linking)
VI  - 98
IP  - 3
DP  - 2015 Sep
TI  - Physiologically based and population PK modeling in optimizing drug development: 
      A predict-learn-confirm analysis.
PG  - 336-44
LID - 10.1002/cpt.155 [doi]
AB  - Physiologically based pharmacokinetic (PBPK) modeling and classical population 
      pharmacokinetic (PK) model-based simulations are increasingly used to answer 
      various drug development questions. In this study, we propose a methodology to 
      optimize the development of drugs, primarily cleared by the kidney, using 
      model-based approaches to determine the need for a dedicated renal impairment 
      (RI) study. First, the impact of RI on drug exposure is simulated via PBPK 
      modeling and then confirmed using classical population PK modeling of phase 2/3 
      data. This methodology was successfully evaluated and applied to an 
      investigational agent, orteronel (nonsteroidal, reversible, selective 17,20-lyase 
      inhibitor). A phase 1 RI study confirmed the accuracy of model-based predictions. 
      Hence, for drugs eliminated primarily via renal clearance, this modeling approach 
      can enable inclusion of patients with RI in phase 3 trials at appropriate doses, 
      which may be an alternative to a dedicated RI study, or suggest that only a 
      reduced-size study in severe RI may be sufficient.
CI  - (c) 2015 The Authors. Clinical Pharmacology & Therapeutics published by Wiley 
      Periodicals, Inc. on behalf of The American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Suri, A
AU  - Suri A
AD  - Clinical Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, 
      Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company 
      Limited.
FAU - Chapel, S
AU  - Chapel S
AD  - Ann Arbor Pharmacometrics Group, Ann Arbor, Michigan, USA.
FAU - Lu, C
AU  - Lu C
AD  - Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., 
      Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical 
      Company Limited.
FAU - Venkatakrishnan, K
AU  - Venkatakrishnan K
AD  - Clinical Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, 
      Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company 
      Limited.
LA  - eng
SI  - ClinicalTrials.gov/NCT01193244
SI  - ClinicalTrials.gov/NCT01193257
PT  - Journal Article
DEP - 20150714
PL  - United States
TA  - Clin Pharmacol Ther
JT  - Clinical pharmacology and therapeutics
JID - 0372741
RN  - 0 (Cytochrome P-450 Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Naphthalenes)
RN  - EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase)
RN  - UE5K2FNS92 (orteronel)
SB  - IM
MH  - Clinical Trials, Phase I as Topic
MH  - Clinical Trials, Phase III as Topic
MH  - *Computer Simulation
MH  - Cytochrome P-450 Enzyme Inhibitors/administration & dosage/*pharmacokinetics
MH  - Drug Discovery/*methods
MH  - Drug Dosage Calculations
MH  - Humans
MH  - Imidazoles/administration & dosage/*pharmacokinetics
MH  - Kidney/*metabolism/physiopathology
MH  - Kidney Diseases/*metabolism/physiopathology
MH  - *Models, Biological
MH  - Naphthalenes/administration & dosage/*pharmacokinetics
MH  - Nonlinear Dynamics
MH  - Renal Elimination
MH  - Reproducibility of Results
MH  - Steroid 17-alpha-Hydroxylase/antagonists & inhibitors/metabolism
PMC - PMC5039936
EDAT- 2015/06/03 06:00
MHDA- 2015/11/04 06:00
PMCR- 2015/07/14
CRDT- 2015/06/03 06:00
PHST- 2015/03/18 00:00 [received]
PHST- 2015/05/13 00:00 [revised]
PHST- 2015/05/27 00:00 [accepted]
PHST- 2015/06/03 06:00 [entrez]
PHST- 2015/06/03 06:00 [pubmed]
PHST- 2015/11/04 06:00 [medline]
PHST- 2015/07/14 00:00 [pmc-release]
AID - CPT155 [pii]
AID - 10.1002/cpt.155 [doi]
PST - ppublish
SO  - Clin Pharmacol Ther. 2015 Sep;98(3):336-44. doi: 10.1002/cpt.155. Epub 2015 Jul 
      14.