The management of HIV-associated tuberculosis (TB) is complicated by the
pharmacokinetic interactions between rifampicin (RMP) and co-administered
protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors.
Rifabutin (RBT) is an alternative rifamycin, preferred in patients requiring PIs.
Recent studies suggest the current recommended dose of RBT in
combination with boosted lopinavir (LPV/r) is suboptimal and there are
insufficient pharmacokinetic data evaluating the interaction between RBT coadministered
with efavirenz (EFV) and nevirapine (NVP). Pharmacogenomic
studies have shown that RMP concentrations are lower in patients from sub-Saharan Africa with polymorphisms of the SLCO1B1gene but there is
currently no data on the pharmacogenetic determinants of RBT exposure.
The pharmacokinetics of RBT were evaluated at two different doses in HIV
co-infected patients before and after the introduction of LPV/r, EFV and NVPbased antiretroviral therapy (ART). After six weeks of standard TB therapy, RBT 300 mg daily was started for four weeks. Thereafter patients were randomized to receive either RBT 150 mg daily or RBT 150 mg three times a week (TPW) with LPV/r, RBT 300mg or 450mg with NVP or RBT- 450mg or 600mg with efavirenz. After four weeks on the first RBT dose, patients switched to the alternate dose and continued until the end of TB treatment. Serial RBT and 25-O-desacetylrifabutin (dRBT) concentrations were measured during a dose interval before patients switched RBT doses.
The median AUC0-24 and Cmax, of RBT in patients taking 150mg RBT TPW
was significantly reduced when compared to the other treatment arms. 86% of patients whilst on this intermittent RBT arm had an AUC0-24 < 4.5 μg.h/mL, level that has been associated with acquired rifamycin resistance. Rifabutin exposure was maintained within the range of AUCs that have been shown to
prevent acquired rifamycin resistance (ARR) with 150mg daily dosing in
combination with LPV/r. In addition, the combination of RBT with NVP 300mg
resulted in significantly increased exposure of RBT, with significantly higher
exposure observed with 600mg RBT. However, the combination of RBT
450mg with EFV resulted in RBT exposure lower than 300mg RBT given
alone in the same patients, whereas RBT 600mg plus NVP results in
bioavailability of RBT equivalent to 300mg given alone.
Rifabutin was well tolerated at all doses. Only three grade 4 laboratory
toxicities, elevated transaminases, neutropenia, and uveitis, possibly related
to RBT were reported in patients taking NVP. SLCO1B1 rs4149032 C>T
polymorphism occurs frequently in African patients in Durban and may be
associated with low RBT bioavailability. These findings support
recommendations for the higher dose of RBT in combination with LPV and
EFV but not with NVP. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2012.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ukzn/oai:http://researchspace.ukzn.ac.za:10413/9814 |
| Date | 23 October 2013 |
| Creators | Naiker, Suhashni. |
| Contributors | Pym, Alexander S., Mcilleron, Helen. |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
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