Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of calcium channel antagonists. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with ritonavir.

When ritonavir is coadministered with nifedipine, plasma concentrations of nifedipine may be increased and a decrease in dose may be needed. The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Caution is warranted and clinical monitoring of patients is recommended.

PBPK/PD models for 3 formations of nifedipine were developed based on the Simcyp nifedipine model and the models were verified using published data. The effects of ritonavir on nifedipine exposure and systolic blood pressure (SBP) were assessed for instant-release, sustained-release and controlled-release formulations in patients. The predicted maximum concentration (Cmax), area under plasma concentration-time curve (AUC), maximum reduction in SBP and area under effect-time curve were all within 0.5-2.0-fold of the observed data. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmax of nifedipine 17.92-48.85-fold and the AUC 63.30-84.01-fold at steady state and decreased the SBP by >40 mmHg. Thus, the combination of nifedipine and ritonavir could lead to severe hypotension. It is not recommended for patients to take nifedipine- and ritonavir-containing regimens simultaneously.

A 51-year-old man with HIV infection who was receiving extended-release nifedipine (60 mg/day) developed symptomatic orthostasis and heart block after starting antiretroviral therapy that included nelfinavir (1250 mg twice daily). Other medication included losartan-hydrochlorothiazide (100/25 mg per day), atenolol (100 mg/day), clopidogrel (75 mg/day), aspirin (325 mg/day), zidovudine (300 mg twice daily) and lamivudine (150 mg twice daily). He experienced dizziness, fatigue, and hypotension and developed complete heart block with a junctional escape rhythm. Electrocardiogram abnormalities abated within 24 hours of discontinuing antiretroviral therapy. Medication was changed to nifedipine (60 mg/day), losartan (50 mg/day), aspirin (81 mg/day) and atenolol (50 mg/day), however, the patient developed orthostatic symptoms after restarting nelfinavir. He was switched successfully to an efavirenz-based regimen (efavirenz 600 mg once daily, stavudine 40 mg twice daily, didanosine 400 mg/day). Subsequent administration of antiretroviral therapy containing indinavir/ritonavir (800/100 mg twice daily) with extended-release nifedipine resulted in recurrence of his orthostatic symptoms. Drug therapy at that time consisted of nifedipine (60 mg/day), atenolol (100 mg/day), losartan (50 mg twice daily) and zidovudine (300 mg twice daily) and abacavir (300 mg twice daily). Discontinuation of atenolol, and nifedipine dosage reduction to 30 mg/day were effective in managing his orthostatic changes.