4 research outputs found
Quantification of afatinib, alectinib, crizotinib and osimertinib in human plasma by liquid chromatography/triple-quadrupole mass spectrometry; focusing on the stability of osimertinib
The development and full validation of a sensitive and selective ultra-performance liquid chromatography/
tandem mass spectrometry (UPLC–MS/MS) method are described for the simultaneous analysis of afatinib,
alectinib, crizotinib and osimertinib in human lithium heparinized plasma. Afatinib-d6, crizotinib-d5 and erlotinib-d6 were used as internal standards. Given osimertinib's instability in plasma and whole blood at ambient
temperature, samples should be solely processed on ice (T = 0 °C). Chromatographic separation was obtained on
an Acquity UPLC ® BEH C18; 2.1 × 50 mm, 1.7 μm column, which was eluted with 0.400 mL/minute flow on a
linear gradient, consisting of 10 mM ammonium formate (pH 4.5) and acetonitrile. Calibration curves for all
compounds were linear for concentration ranges of 1.00 to 100 ng/mL for afatinib and 10.0 to 1000 ng/mL for
alectinib, crizotinib and osimertinib, herewith validating the lower limits of quantification at 1.00 ng/mL for
afatinib and 10.0 ng/mL for alectinib, crizotinib and osimertinib. Within-run and between-run precision measurements fell within 10.2%, with accuracy ranging from 89.2 to 110%
Clinically relevant drug interactions with multikinase inhibitors: a review
Multikinase inhibitors (MKIs), including the tyrosine kinase inhibitors (TKIs), have
rapidly become an established factor in daily (hemato)-oncology practice. Although the oral
route of administration offers improved flexibility and convenience for the patient, challenges
arise in the use of MKIs. As MKIs are prescribed extensively, patients are at increased risk for
(severe) drug–drug interactions (DDIs). As a result of these DDIs, plasma pharmacokinetics
of MKIs may vary significantly, thereby leading to high interpatient variability and subsequent
risk for increased toxicity or a diminished therapeutic outcome. Most clinically relevant
DDIs with MKIs concern altered absorption and metabolism. The absorption of MKIs may be
decreased by concomitant use of gastric acid-suppressive agents (e.g. proton pump inhibitors)
as many kinase inhibitors show pH-dependent solubility. In addition, DDIs concerning
drug (uptake and efflux) transporters may be of significant clinical relevance during MKI
therapy. Furthermore, since many MKIs are substrates for cytochrome P450 isoenzymes
(CYPs), induction or inhibition with strong CYP inhibitors or inducers may lead to significant
alterations in MKI exposure. In conclusion, DDIs are of major concern during MKI therapy
and need to be monitored closely in clinical practice. Based on the current knowledge and
available literature, practical recommendations for management of these DDIs in clinical
practice are presented in this review