Table 4.

Possible Mechanisms, Types of Interactions, and Management of X-Category Drug–Drug Interactions

	Types of Interaction	Mechanism of Interaction	Interaction Management
Lopinavir/Ritonavir or Atazanavir plus Clopidogrel	Pharmacokinetic	Ritonavir and atazanavir might inhibit clopidogrel (a pro-drug) metabolism to its active metabolite so it result in the diminished antiplatelet activity.	Avoid combinations and consider possible alternatives.
Lopinavir/Ritonavir or Atazanavir plus Ticagrelor	Pharmacokinetic	Strong CYP3A4a inhibitors would enhance the serum concentration of ticagrelor and reduce the serum concentration of its active metabolites.	Avoid a combination of ticagrelor with strong CYP3A4 inhibitors and consider alternatives.
Lopinavir/Ritonavir or Atazanavir plus Rivaroxaban	Pharmacokinetic	Since rivaroxaban is a substrate for both CYP3A4 isoenzyme and P-gpb, concomitant administration of this drug with strong inhibitors of CYP3A4 and inhibitors of P-gp may enhance the serum concentration of rivaroxaban and risk of major bleeding.	Avoid a combination of rivaroxaban with strong CYP3A4 inhibitors and P-gp inhibitors.
Lopinavir/Ritonavir or Atazanavir plus Apixaban	Pharmacokinetic	These concomitant administrations might result in inhibition of CYP3A4 mediated metabolism and P-gp induced efflux of apixaban which may cause enhanced serum concentration of apixaban and bleeding complications.	A combination of apixaban with strong CYP3A4 inhibitors and P-gp inhibitors is contraindicated.
Lopinavir/Ritonavir or Atazanavir plus Edoxaban	Pharmacokinetic	Inhibitors of P-gp/ABCB1c might enhance the Cmaxd, AUCe, and anticoagulant effect of edoxaban.	A combination of edoxaban with P-gp/ABCB1 inhibitors should be avoided or dose adjustment should be considered in patients with venous thromboembolism. No dosage modification is available in patients with non-valvular atrial fibrillation.
Lopinavir/Ritonavir or Atazanavir plus Dabigatran etexilate	Pharmacokinetic	Inhibitors of P-gp/ABCB1 could enhance the serum concentration of active metabolites of dabigatran etexilate, which is a pro-drug agent. These drug–drug interactions would be significantly precipitated in patients with moderate to severe renal failure.	Avoid combination or consider therapy modification. Dose adjustment may also be considered according to the patients’ renal function, dabigatran etexilate indications, and labeling recommendations.

Notes: ^aCytochrome P450 (CYP) 3A4. ^bP-glycoprotein. ^cATP-binding cassette sub-family B member 1. ^dMax serum concentration. ^eArea under the curve.