PMID- 24152603
OWN - NLM
STAT- MEDLINE
DCOM- 20140116
LR  - 20190608
IS  - 0946-1965 (Print)
IS  - 0946-1965 (Linking)
VI  - 51
IP  - 11
DP  - 2013 Nov
TI  - Application of population pharmacokinetic modeling to explore the impact of 
      alternative roflumilast dosing regimens on tolerability.
PG  - 832-6
AB  - OBJECTIVE: Roflumilast is the first phosphodiesterase 4 (PDE4) inhibitor approved 
      for the treatment of chronic obstructive pulmonary disease (COPD) associated with 
      chronic bronchitis and history of exacerbations. In clinical practice, side 
      effects such as diarrhea appear to be somewhat more frequent in patients than 
      that observed in clinical trials. We hypothesize that if patients could take a 
      reduced dose for the first few weeks of therapy, the incidence of adverse events 
      (AEs) could be reduced. METHODS: We used previously reported population 
      pharmacokinetic/ pharmacodynamic modeling to simulate three dosing scenarios of 
      roflumilast: 500 mu once daily (OD) (approved dose), 250 mu OD and 500 mu every 
      other day (EoD). RESULTS: These models predicted that the 250 mu and EoD regimens 
      were associated with lower plasma concentrations, lower total PDE4 inhibition, 
      and lower incidence of diarrhea, nausea, and headache, versus the 500 mu OD dose. 
      CONCLUSIONS: Reduction of roflumilast dose in the first few weeks of therapy may 
      be able to reduce the incidence of treatment-related AEs. Clearly, modeling 
      provides only the basis for hypothesis generation, and must be supported with 
      clinical evidence from carefully designed trials.
FAU - Lahu, Gezim
AU  - Lahu G
AD  - Department of Pharmacometrics, Takeda Pharmaceuticals International GmbH, Zurich, 
      Switzerland.
FAU - Facius, Axel
AU  - Facius A
LA  - eng
PT  - Journal Article
PL  - Germany
TA  - Int J Clin Pharmacol Ther
JT  - International journal of clinical pharmacology and therapeutics
JID - 9423309
RN  - 0 (Aminopyridines)
RN  - 0 (Benzamides)
RN  - 0 (Cyclopropanes)
RN  - 0 (Phosphodiesterase 4 Inhibitors)
RN  - 0P6C6ZOP5U (Roflumilast)
SB  - IM
MH  - Aminopyridines/administration & dosage/adverse effects/*pharmacokinetics
MH  - Benzamides/administration & dosage/adverse effects/*pharmacokinetics
MH  - Cyclopropanes/administration & dosage/adverse effects/pharmacokinetics
MH  - Humans
MH  - Logistic Models
MH  - Models, Biological
MH  - Phosphodiesterase 4 Inhibitors/administration & dosage/adverse 
      effects/*pharmacokinetics
MH  - Pulmonary Disease, Chronic Obstructive/*drug therapy
EDAT- 2013/10/25 06:00
MHDA- 2014/01/17 06:00
CRDT- 2013/10/25 06:00
PHST- 2013/10/25 06:00 [entrez]
PHST- 2013/10/25 06:00 [pubmed]
PHST- 2014/01/17 06:00 [medline]
AID - 10997 [pii]
AID - 10.5414/cp201906 [doi]
PST - ppublish
SO  - Int J Clin Pharmacol Ther. 2013 Nov;51(11):832-6. doi: 10.5414/cp201906.