TY - JOUR
T1 - A Review of CYP3A Drug-Drug Interaction Studies
T2 - Practical Guidelines for Patients Using Targeted Oral Anticancer Drugs
AU - Molenaar-Kuijsten, Laura
AU - Van Balen, Dorieke E.M.
AU - Beijnen, Jos H.
AU - Steeghs, Neeltje
AU - Huitema, Alwin D.R.
N1 - Publisher Copyright:
© Copyright © 2021 Molenaar-Kuijsten, Van Balen, Beijnen, Steeghs and Huitema.
Copyright © 2021 Molenaar-Kuijsten, Van Balen, Beijnen, Steeghs and Huitema.
PY - 2021/8/30
Y1 - 2021/8/30
N2 - Many oral anticancer drugs are metabolized by CYP3A. Clinical drug-drug interaction (DDI) studies often only examine the effect of strong CYP3A inhibitors and inducers. The effect of moderate or weak inhibitors or inducers can be examined using physiologically based pharmacokinetic simulations, but data from these simulations are not always available early after approval of a drug. In this review we provide recommendations for clinical practice on how to deal with DDIs of oral anticancer drugs if only data from strong CYP3A inhibitors or inducers is available. These recommendations were based on reviewed data of oral anticancer drugs primarily metabolized by CYP3A and approved for the treatment of solid tumors from January 1st, 2013 to December 31st, 2015. In addition, three drugs that were registered before the new EMA guideline was issued (i.e., everolimus, imatinib, and sunitinib), were reviewed. DDIs are often complex, but if no data is available from moderate CYP3A inhibitors/inducers, a change in exposure of 50% compared with strong inhibitors/inducers can be assumed. No a priori dose adaptations are indicated for weak inhibitors/inducers, because their interacting effect is small. In case pharmacologically active metabolites are involved, the metabolic pathway, the ratio of the parent to the metabolites, and the potency of the metabolites should be taken into account.
AB - Many oral anticancer drugs are metabolized by CYP3A. Clinical drug-drug interaction (DDI) studies often only examine the effect of strong CYP3A inhibitors and inducers. The effect of moderate or weak inhibitors or inducers can be examined using physiologically based pharmacokinetic simulations, but data from these simulations are not always available early after approval of a drug. In this review we provide recommendations for clinical practice on how to deal with DDIs of oral anticancer drugs if only data from strong CYP3A inhibitors or inducers is available. These recommendations were based on reviewed data of oral anticancer drugs primarily metabolized by CYP3A and approved for the treatment of solid tumors from January 1st, 2013 to December 31st, 2015. In addition, three drugs that were registered before the new EMA guideline was issued (i.e., everolimus, imatinib, and sunitinib), were reviewed. DDIs are often complex, but if no data is available from moderate CYP3A inhibitors/inducers, a change in exposure of 50% compared with strong inhibitors/inducers can be assumed. No a priori dose adaptations are indicated for weak inhibitors/inducers, because their interacting effect is small. In case pharmacologically active metabolites are involved, the metabolic pathway, the ratio of the parent to the metabolites, and the potency of the metabolites should be taken into account.
KW - cancer
KW - CYP3A inducer
KW - CYP3A inhibitor
KW - cytochrome P450 enzyme
KW - drug interaction
KW - kinase inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85114821503&partnerID=8YFLogxK
U2 - 10.3389/fphar.2021.670862
DO - 10.3389/fphar.2021.670862
M3 - Review article
C2 - 34526892
AN - SCOPUS:85114821503
SN - 1663-9812
VL - 12
SP - 1
EP - 20
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 670862
ER -