Objective. There is evidence supporting a therapeutic range for methotrexate polyglutamate ( Conclusion. There is wide interpatient variability of RBC MTXGlu 1-5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu 1-5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered.

The developed model enabled acceptable description of the intracellular kinetics of MTX and MTXGlu(2-5) in RBCs. In the future it can form the basis of a full pharmacokinetic-pharmacodynamic model to assess the time-RBC concentration-effect relationship of low-dose MTX treatment in RA.

The developed model describes a longitudinal relationship between RBC MTXGlu(3-5) concentrations and DAS28-3v (CRP) in patients with RA commencing MTX. Further work is required to determine whether measurement of RBC MTX polyglutamates might be useful for dose individualisation in patients with RA.

AIMTo assess the similarities in intracellular pharmacokinetics (PK) of methotrexate (MTX) in red blood cells (RBCs) and other cell lines. METHODSThree previously published PK models for intracellular MTX and MTX polyglutamate (MTXGlu2-5) concentrations were used: (i) a model for the kinetics in RBCs, (ii) a model for the kinetics in human breast cancer cells (HBCCs) and (iii) a model for the kinetics in various white blood cell (WBC) lines. All three models were used to simulate the response in a typical individual receiving 10 mg oral MTX once weekly and the predicted steady-state concentrations (Css) and time to Css (tss) were compared. RESULTSThe HBCC model showed a lower Css for MTXGlu2 and 3 and higher Css for MTXGlu 4 and 5 compared with the RBC PK model, while tss and overall intracellular MTX exposure appeared similar. The WBC PK model showed much lower Css for the parent MTXGlu1 and of tss for all MTXGlun, as well as a much lower cumulative Css for MTXGlu2-7 for the majority of the WBC cell lines.

To the best of our knowledge, there have been no published studies of doxazosin transfer into human milk. In rats, milk concentrations twentyfold higher than in plasma have been reported. Based on these animal data, some references advise to avoid breastfeeding during doxazosin therapy. However, the physicochemical properties of doxazosin suggest low transfer into human milk. A 37-year-old breastfeeding woman who was administered doxazosin 4 mg daily for 2 doses was studied. Doxazosin concentrations in milk and plasma were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The milk/plasma area under the concentration-time curve (AUC0-18 hours) ratio was 0.1. This finding is consistent with what could be predicted based on the physicochemical properties of doxazosin. The average and maximum milk concentrations were 2.9 and 4.2 µg/L. These values correspond to estimated relative infant doses of 0.06% and 0.09%, respectively, assuming standard infant milk intake. These values are well below the generally accepted cutoff of 10% for predicting safety during breastfeeding. A low relative infant dose of < 0.1% suggests that maternal doxazosin therapy may be compatible with breastfeeding after careful individual risk-benefit analysis.