A 38-year-old woman on warfarin for atrial fibrillation is started on rifampicin for tuberculosis. After 2 weeks, her INR drops from 2.8 to 1.5 despite unchanged warfarin dose. Which investigation is most appropriate to confirm the suspected drug–drug interaction and guide therapeutic adjustment?

Question

Accepted Answer

A. Serum warfarin concentration and INR. ## Investigation of Choice for Warfarin–Rifampicin Interaction

### Why Serum Warfarin Concentration and INR is Correct

**Key Point:** The combination of serum warfarin concentration (pharmacokinetic parameter) and INR (pharmacodynamic parameter) directly confirms the suspected interaction. Rifampicin induces CYP2C9 and CYP3A4, increasing warfarin metabolism and clearance, leading to reduced plasma concentration and subtherapeutic anticoagulation.

**High-Yield:** This is a classic example of enzyme induction:
  - Rifampicin induces hepatic cytochrome P450 enzymes
  - Warfarin clearance increases → plasma concentration falls
  - INR decreases → loss of anticoagulation
  - Serum warfarin level confirms reduced concentration

**Clinical Pearl:** The drop in INR from 2.8 to 1.5 is the clinical clue; measuring serum warfarin concentration confirms the pharmacokinetic mechanism (increased clearance) rather than poor adherence or other causes.

**Mnemonic:** **RIFE** — **Rifampicin Induces Enzyme** metabolism, reducing the plasma concentration of CYP-metabolized drugs like warfarin, phenytoin, and oral contraceptives.

### Why Other Investigations Are Suboptimal

| Investigation | Limitation |
|---|---|
| **Liver function tests & PT** | LFTs are non-specific; PT is already reflected in INR. Neither directly measures warfarin concentration or confirms the induction mechanism. |
| **Plasma protein binding assay** | Warfarin is highly protein-bound (~99%), but protein binding is not the issue here. The problem is increased hepatic metabolism (clearance), not displacement from protein. |
| **CYP2C9 genetic testing** | Useful for predicting warfarin sensitivity at baseline, but does not explain the acute drop in INR after rifampicin initiation. The interaction is pharmacokinetic (enzyme induction), not genetic. |

### Pathophysiology of the Interaction

```mermaid
flowchart TD
  A[Rifampicin started]:::action --> B[Induces CYP2C9 & CYP3A4]:::outcome
  B --> C[Warfarin metabolism ↑]:::outcome
  C --> D[Plasma warfarin concentration ↓]:::outcome
  D --> E[INR drops]:::urgent
  E --> F[Loss of anticoagulation]:::urgent
  F --> G[Measure serum warfarin + INR]:::action
  G --> H{Warfarin level low?}:::decision
  H -->|Yes| I[Increase warfarin dose]:::action
  H -->|No| J[Investigate other causes]:::action
```

### Management Implication

Once the induction is confirmed by low serum warfarin concentration and low INR, the warfarin dose must be increased (typically by 30–50%) and INR monitored closely. When rifampicin is stopped, the dose must be reduced again to prevent over-anticoagulation.

[cite:KD Tripathi 8e Ch 6; Harrison 21e Ch 297]

Answer

B. Genetic testing for CYP2C9 polymorphisms

Answer

C. Liver function tests and prothrombin time

Answer

D. Plasma protein binding assay for warfarin

A 38-year-old woman on warfarin for atrial fibrillation is started on rifampicin for tuberculosis. After 2 weeks, her INR drops from 2.8 to 1.5 despite unchanged warfarin dose. Which investigation is most appropriate to confirm the suspected drug–drug interaction and guide therapeutic adjustment?

Explanation

Investigation of Choice for Warfarin–Rifampicin Interaction

Why Serum Warfarin Concentration and INR is Correct

Why Other Investigations Are Suboptimal

Pathophysiology of the Interaction

Management Implication

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Investigation	Limitation
Liver function tests & PT	LFTs are non-specific; PT is already reflected in INR. Neither directly measures warfarin concentration or confirms the induction mechanism.
Plasma protein binding assay	Warfarin is highly protein-bound (~99%), but protein binding is not the issue here. The problem is increased hepatic metabolism (clearance), not displacement from protein.
CYP2C9 genetic testing	Useful for predicting warfarin sensitivity at baseline, but does not explain the acute drop in INR after rifampicin initiation. The interaction is pharmacokinetic (enzyme induction), not genetic.