Clinical Pharmacokinetics of Rifabutin

Abstract

The clinical effectiveness of rifabutin for prophylaxis of disseminated Mycobacterium avium complex infection has recently been demonstrated in HIV-positive patients with low CD4 counts. Rifabutin is a newly marketed, semisynthetic antimycobacterial agent similar to rifampicin (rifampin) in structure and activity. However, rifabutin has important pharmacokinetic differences compared with rifampicin. Rifabutin has relatively low oral bioavailability; about 20% after single dose administration. With long term administration rifabutin induces its own metabolism and the metabolism of some other drugs. The elimination half-life of rifabutin is long (45 hours) but, as a result of a very large volume of distribution (> 9 L/kg), average plasma concentrations remain relatively low after repeated administration of standard doses. In vitro rifabutin is more active against M. avium-intracellulare complex and at least as active against M. tuberculosis as rifampicin. In vivo the advantage of rifabutin is less apparent due to its lower plasma concentrations at equivalent doses. Adverse effects are unusual at the recommended oral dosage of 300 mg/day, but become common as the total daily dose approaches 1 g. Dose-limiting toxicity consists of a polyarthralgia/arthritis syndrome, possibly complicated by uveitis. More clinical studies are needed to establish the role of rifabutin in combination therapy for M. avium-intracellulare complex and other mycobacterial infections.

Effect of Rifampin and Rifabutin on the Pharmacokinetics of Lersivirine and Effect of Lersivirine on the Pharmacokinetics of Rifabutin and 25-O-Desacetyl-Rifabutin in Healthy Subjects

“…Rifabutin has an apparent terminal half-life of 45 h (range, 16 to 69 h) (32). Due to the potent CYP induction liability of rifampin, rifabutin is used as an alternative to rifampin in individuals infected with HIV who are coinfected with Mycobacterium tuberculosis (3).…”

Rifabutin Induced Uveitis in HIV-Dangers of Drug Interactions in Patients on ART

“…Co-administration of rifabutin with ritonavir, as is common in patients with HIV disease, increases the Area Under the Concentration-time curve (AUC) of Rifabutin by 35 times, compared with administration of rifabutin alone [5,6]. This increases the propensity for rifabutin to exert its ocular idiosyncratic effect.…”

“…The onset of symptoms can occur as early as 2 weeks to 7 months following initiation of therapy [4]. It can be seen with doses that range from as low as 300mg a day to 1800mg a day [4], although side effects are less common in the standard prophylactic dose of 300mg [5,6]. It is usually under diagnosed, and the patient is subjected to various laboratory tests to establish an etiology for the uveitis.…”

Rifabutin Low Dose-Induced Intermediate Uveitis in a Patient with Acquired Immunodeficiency Syndrome

“…The dose range of rifabutin associated with uveitis goes between 300 and 1800 mg daily [5,9]. Shafran and colleagues demonstrated that patients on 300 mg/day of rifabutin rarely developed uveitis, and when it occurred, it took at least 7 months of medication use for the uveitis to develop [3].…”

“…Shafran and colleagues demonstrated that patients on 300 mg/day of rifabutin rarely developed uveitis, and when it occurred, it took at least 7 months of medication use for the uveitis to develop [3]. Skinner and Blaschke later confirmed that drug related uveitis was unusual at the recommended dose of 300 mg/day [9]. Our patient was on 150 mg daily of rifabutin for 4 months before he developed uveitis but he was also taking ritonavir 100 mg/d and fluconazole 200 mg/week.…”