Examkin

Question

Difficulty: MediumPharmacokinetic and Pharmacodynamic Principles

A 34-year-old woman comes to the clinic for follow-up evaluation of right leg pain and swelling. She has a history of an unprovoked left pulmonary embolism six months ago, for which she has been taking rivaroxaban. Her symptoms had completely resolved until three days ago, when she developed worsening right calf pain. Two weeks ago, she was diagnosed with active pulmonary tuberculosis and began treatment with a four-drug regimen containing rifampin, isoniazid, pyrazinamide, and ethambutol. Vital signs are within normal limits. Physical examination shows a swollen, erythematous, and tender right calf. A venous duplex ultrasound confirms a new acute deep vein thrombosis in the right popliteal vein. Which of the following pharmacokinetic principles best explains this patient's current presentation?

  1. Accelerated systemic elimination via hepatic enzyme inductionAnswer
  2. B
    Competitive displacement from plasma protein binding sites
  3. C
    Decreased gastrointestinal absorption due to altered intraluminal pH
  4. D
    Reduced enterohepatic recirculation secondary to intestinal flora eradication
  5. E
    Compensatory increase in the synthesis of targeted coagulation factors

Answer

Accelerated systemic elimination via hepatic enzyme induction
The correct answer identifies that the patient's recurrent thrombosis is due to a well-known pharmacokinetic drug interaction. Rifampin is a potent inducer of the cytochrome P450 system (particularly CYP3A4) and the P-glycoprotein (P-gp) efflux transporter. Rivaroxaban relies heavily on CYP3A4 for metabolism and P-gp for excretion. The induction of these pathways markedly accelerates the clearance of rivaroxaban, dropping its plasma concentration below the therapeutic threshold and leaving the patient vulnerable to recurrent thromboembolic events.

Step-by-Step Solution

1
Analyze the patient's clinical presentation.
The patient developed a new deep vein thrombosis while supposedly fully anticoagulated on rivaroxaban.
Identifying a therapeutic failure (recurrent thrombosis) establishes that the anticoagulant effect is currently subtherapeutic.
2
Identify any recent changes to the patient's medication regimen.
The patient recently started a four-drug regimen for active tuberculosis, which includes rifampin.
New medications are the most common cause of sudden pharmacokinetic shifts leading to loss of efficacy.
3
Recall the pharmacokinetic properties of the involved medications.
Rivaroxaban is metabolized by CYP3A4 and is a substrate for the P-glycoprotein (P-gp) efflux transporter. Rifampin is a potent inducer of both CYP3A4 and P-gp.
Understanding the specific metabolic pathways allows for the identification of the exact drug-drug interaction mechanism.
4
Determine the clinical consequence of this interaction.
Induction of CYP3A4 and P-gp significantly accelerates the clearance of rivaroxaban, leading to subtherapeutic drug concentrations and subsequent clot formation.
This confirms that accelerated systemic elimination is the definitive cause of the patient's presentation.

Key Concept

Rifampin is a potent inducer of cytochrome P450 enzymes (specifically CYP3A4) and P-glycoprotein. Co-administration with direct oral anticoagulants (DOACs) like rivaroxaban accelerates their clearance, resulting in subtherapeutic levels and an increased risk of thromboembolism.
Rate this question

Topics

Pharmacokinetic and Pharmacodynamic Principles

More questions from this topic