What are the implications of rifampin's CYP 450 enzyme inducer properties on the treatment regimen of a patient with isoniazid-resistant tuberculosis (TB) taking other medications metabolized by the CYP 450 enzyme system, such as antiretroviral medications or warfarin?

Rifampin's CYP 450 Enzyme Induction: Critical Management in Isoniazid-Resistant TB

Rifampin is a potent CYP450 inducer that markedly reduces serum concentrations of antiretrovirals and warfarin, requiring either dose adjustments of affected medications, substitution with rifabutin, or selection of specific antiretroviral combinations that can tolerate rifampin's enzyme induction. 1

Mechanism and Duration of CYP450 Induction

• Rifampin is the most potent CYP450 inducer among rifamycins, affecting CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4, as well as UDP-glucuronyltransferases, P-glycoprotein, and MRP2 transporters 2, 1
• Full enzyme induction develops within approximately 1 week of starting rifampin and persists for at least 2 weeks after discontinuation 1, 3
• This prolonged effect requires a mandatory 2-week washout period before initiating protease inhibitors or NNRTIs after stopping rifampin 1, 4

Management with Antiretroviral Medications

Contraindicated Combinations

The following combinations are absolutely contraindicated and must be avoided: 1, 2

• Rifampin with any protease inhibitor except specific ritonavir-based regimens
• Rifampin with NNRTIs (except efavirenz in specific combinations)
• Rifampin with ritonavir-boosted saquinavir (causes severe hepatocellular toxicity) 2
• Rifabutin with ritonavir (at standard doses), hard-gel saquinavir, or delavirdine 1

Permitted Antiretroviral Combinations with Rifampin

Three specific antiretroviral regimens can be used with rifampin: 1, 4

1. Efavirenz + 2 NRTIs: Rifampin can be used at standard doses 1
2. Ritonavir (alone) + 1 or more NRTIs: Rifampin can be used at standard doses 1
3. Ritonavir + saquinavir (dual protease inhibitor therapy): Rifampin can be used at standard doses 1

Rifabutin as Alternative Strategy

When rifampin cannot be used, rifabutin is the preferred alternative as it is a less potent CYP450 inducer: 1

• Rifabutin with indinavir: Increase indinavir from 800 mg every 8 hours to 1,200 mg every 8 hours 1
• Rifabutin with nelfinavir: Some experts recommend increasing nelfinavir from 750 mg three times daily to 1,000 mg three times daily 1
• Rifabutin with ritonavir: Drastically reduce rifabutin dose to 150 mg two or three times per week (not daily) 1, 4
• Rifabutin with efavirenz: Increase rifabutin dose to 450-600 mg daily or 600 mg two or three times per week 1
• Rifabutin with nevirapine: Can be used with dose adjustments 1

NRTIs: No Interaction

All nucleoside reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir) can be used with any rifamycin without dose adjustment because they are not metabolized by CYP450 1, 4

Management with Warfarin

Rifampin significantly reduces warfarin concentrations through CYP2C9 induction, requiring: 1, 5, 3

• Substantially increased warfarin doses during rifampin therapy (specific increases determined by INR monitoring)
• Frequent INR monitoring (at least weekly initially, then every 2-4 weeks)
• Anticipate INR elevation when rifampin is discontinued, as enzyme induction wears off over 2 weeks 3
• Reduce warfarin dose preemptively when stopping rifampin to avoid supratherapeutic INR and bleeding risk 3

Other Critical Drug Interactions

Many commonly used medications require dose adjustments or alternative therapies: 1, 2

• Hormonal contraceptives: Use alternative contraceptive methods (barrier methods, IUDs) as rifampin renders oral contraceptives ineffective 1, 2, 5
• Corticosteroids: Substantially increased doses may be needed; monitor for adrenal insufficiency 1, 2
• Methadone: Expect opioid withdrawal symptoms; increase methadone dose based on clinical response 1, 3
• Cardiac glycosides (digoxin): Monitor levels and increase dose as needed 1, 2
• Sulfonylureas: Monitor glucose closely; may need dose increases 1, 5
• Azole antifungals (ketoconazole, itraconazole, fluconazole): Consider alternative antifungals or substantially increased doses 1, 3
• Immunosuppressants (cyclosporin): Risk of acute transplant rejection; requires intensive monitoring and dose adjustments 3, 6

Clinical Algorithm for Decision-Making

Follow this stepwise approach: 1, 4

1. Identify all current medications metabolized by CYP450 (protease inhibitors, NNRTIs, warfarin, etc.)
2. For HIV-coinfected patients:
   • If on efavirenz + 2 NRTIs, ritonavir + NRTIs, or ritonavir + saquinavir → use rifampin at standard doses 1
   • If on other protease inhibitors or NNRTIs → substitute rifabutin with appropriate dose adjustments 1
   • If on NRTIs only → use rifampin at standard doses 4
3. For warfarin patients:
   • Increase warfarin dose based on INR monitoring
   • Check INR weekly initially, then every 2-4 weeks
   • Plan for dose reduction 2 weeks before stopping rifampin 3
4. For other interacting medications:
   • Review Table 1 in rifampin FDA label for specific management 2
   • Consider therapeutic drug monitoring when available 1

Critical Pitfalls to Avoid

• Never start protease inhibitors or NNRTIs within 2 weeks of stopping rifampin due to persistent enzyme induction 1, 4
• Do not compromise TB treatment by avoiding rifampin when appropriate antiretroviral regimens can be selected; active TB requires optimal treatment for mortality reduction 1, 4
• Do not use rifapentine in HIV-infected patients as safety and efficacy are not established 1
• Monitor for paradoxical reactions when initiating antiretrovirals in TB patients (worsening symptoms despite appropriate therapy); these usually require only symptomatic management, not treatment changes 1
• Remember that rifampin affects drug absorption and hepatic uptake in addition to metabolism, particularly in HIV-infected patients where malabsorption can lead to treatment failure 1
• Counsel patients about discoloration of body fluids, permanent staining of contact lenses, and the need to report hepatotoxicity symptoms immediately 2