Nifedipine–lopinavir/ritonavir severe interaction: a case report

Abstract

Lopinavir is administered co-formulated with a low ritonavir dose (a potent cytochrome P450(CYP)3A4 inhibitor). As lopinavir is predominantly metabolized via cytochrome P450(CYP)34A, the subtherapeutic dose of ritonavir inhibits lopinavir metabolism resulting in higher lopinavir concentrations, especially higher trough levels [1,2]. Nifedipine (a dihydropyridine calcium antagonist) is also a cytochrome P450(CYP)34A substrate [3]. The co-administration of ritonavir with nifedipine may significantly increase serum concentrations of nifedipine resulting in toxicity: headache, peripheral oedema, hypotension and tachycardia. Although this interaction has only a theoretical substantiation, it is well described as a low grade, usually clinically irrelevant interaction [3]. We report a case of a nifedipine–low-dose ritonavir interaction with severe hypotension and renal failure confirmed with an unintended re-exposition to the drugs. A 47-year-old man was diagnosed with HIV infection in 1992. His medical history included two bouts of Pneumocystis jiroveci pneumonia, chronic hepatitis C and hypertension treated with nifedipine 30 mg/12 h, doxazosine 1 mg/12 h and furosemide 40 mg/8 h. HAART (estavudine 40 mg/12 h, lamivudine 300 mg/24 h and lopinavir/ritonavir three pills/12 h) was begun in 2002. In March 2005, hypotension and progressive renal failure were noted; HAART was withdrawn, when the CD4 cell count was 105 cells/μl, and a kidney biopsy confirmed membranoproliferative glomerulonephritis. In May 2005, during his follow-up, lopinavir/ritonavir re-introduction was decided when he was receiving nifedipine 30 mg/12 h, doxazosine 1 mg/12 h and furosemide 40 mg/8 h.On the second day the patient developed malaise, severe hypotension (90/50 mmHg), oliguria, and progressive generalized oedemas. Serum creatinine was 5 mg/dl (creatinine before HAART re-introduction was 1.7 mg/dl). All antihypertensive and antiretroviral drugs were discontinued, and the patient was managed with symptomatic treatment and hydroelectrolitic repletion. Renal function progressively improved, the creatinine level lowered to 3 mg/dl, the clinical symptoms vanished and blood pressure normalized. The episode was diagnosed as prerenal acute kidney failure and antihypertensive drugs were re-introduced one week later, first nifedipine 30 mg/12 h, and later enalapril 5 mg/12 h and losartan 50 mg/12 h. At that time the patient was clinically stable, with good control of blood pressure and a serum creatinine level of 1.7 mg/dl. One week later the re-introduction of lopinavir/ritonavir was decided. Again, after 48 h another hypotension episode occurred, with malaise, oedemas and renal insufficiency (creatinine peak 7 mg/dl). Every drug was stopped and in approximately 72 h a progressive clinical and biochemical improvement was noted. As an interaction between HAART and antihypertensive drugs was suspected, in June 2005 only HAART was re-introduced. The patient went on improving, reaching a creatinine level of 2.5 mg/dl. Amlodipine 15 mg/24 h, a dihydropiridine calcium antagonist metabolized via CYP314, was substitued for nifedipine. Two week later the patient was discharged with creatinine 2.8 mg/dl and a diagnosis of severe hypotension with secondary renal failure caused by a pharmacologic interaction between nifedipine and HAART. During a 6-month follow-up the patient was clinically stable with well-controlled hypertension and a creatinine level of 2 mg/dl. We describe a case of acute renal insufficiency with severe hypotension and oedema caused by a pharmacokinetic interaction. When nifedipine is administered to a patient receiving ritonavir, CYP450 is inhibited and this can lead to a high nifedipine trough level, resulting in hypotension and renal failure, especially in patients with some degree of renal insufficiency. Hypotension can induce a quick and severe renal failure in patients with mild renal insufficiency. As we could not find a suitable cause for the first hypotension episode, HAART and antihypertensive drugs were re-introduced after clinical improvement. This fuelled another hypotension episode that confirmed the pharmacokinetic interaction between ritonavir and nifedipine through an unintended re-exposition. At this point we decided to associate stavudine, lamivudine and lopinavir/ritonavir with amlodipine, a drug with a metabolism not affected by ritonavir [3] and it was well tolerated. Pharmacokinetic ritonavir interactions can result in clinically meaningful problems, at least with ketoconazole, itraconazole, amiodarone, quinidine, atovaquone, nicardipine and methadone. The levels of all those drugs, and their effects, can be greatly heightened by ritonavir. As has been shown, a nifedipine–ritonavir interaction can lead to serious clinical problems. At this time it is not known whether there is any nifedipine dose that can be used safely when co-administered with ritonavir. As lopinavir is available only co-formulated with ritonavir, it is difficult to ascertain the differential CYP inhibitory effects of lopinavir (if any) and ritonavir in this interaction. Further research, especially in patients receiving many drugs and with co-morbidities, is needed if ritonavir and nifedipine are going to be used together in the future [4]. To the best of our knowledge, this is the first description of a severe interaction between nifedipine and ritonavir leading to prerenal kidney failure induced through severe hypotension.