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. 2016 May;71(5):1330-40.
doi: 10.1093/jac/dkv470. Epub 2016 Jan 31.

Population Pharmacokinetic Drug-Drug Interaction Pooled Analysis of Existing Data for Rifabutin and HIV PIs

Free PMC article

Population Pharmacokinetic Drug-Drug Interaction Pooled Analysis of Existing Data for Rifabutin and HIV PIs

Stefanie Hennig et al. J Antimicrob Chemother. .
Free PMC article


Objectives: Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV PIs and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated TB, with concurrently administered PIs.

Methods: Individual-level data from 13 published studies were pooled and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin) and drug-drug interaction with PIs in healthy volunteers and patients who had HIV and TB (TB/HIV).

Results: Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation of the metabolite (increased by 224% in patients), volume of distribution (increased by 606%) and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, clearance was reduced by 35%-76% and volume of distribution increased by 67%-240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of PIs and 280% with ritonavir-boosted PIs.

Conclusions: Given together with non-boosted or ritonavir-boosted PIs, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant PIs and may achieve peak concentrations within an acceptable therapeutic range. Although 300 mg of rifabutin every 3 days with boosted PI achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.

Trial registration: NCT00000877.


Figure 1.
Figure 1.
Schematic of the final pharmacokinetic model for rifabutin, des-rifabutin and PIs, including all parameters and covariates associated with specific parameters. Parameters affected by drug interaction with PIs are shown in grey. Covariate relations were included before performing lin-SCM. All disposition parameters were allometrically scaled with the factor FCLbody weight = (body weight/70)0.75 on all clearance parameters and FVbody weight = body weight/70 on all volume parameters. CL, systemic clearance of rifabutin to routes other than to des-rifabutin; CLe, systemic metabolism to des-rifabutin; CLm, systemic clearance of des-rifabutin; COAD, coadministration with a PI; COADTB/HIV, coadministration with a PI in TB/HIV patients; F, bioavailability; Fm, fraction first-pass metabolism; TB/HIV, patients with HIV and TB; ka, absorption rate constant; MTT, mean transit time; N, number of transit compartments; Q, intercompartmental clearance rate for rifabutin; Qm, intercompartmental clearance rate for des-rifabutin; RTV, coadministration with ritonavir or ritonavir-boosted PI; RTVTB/HIV, coadministration with ritonavir or ritonavir-boosted PI in TB/HIV patients; V2, volume of distribution, central compartment, rifabutin; V3, volume of distribution, peripheral compartment, rifabutin; V4, volume of distribution, central compartment, des-rifabutin; V5, volume of distribution, peripheral compartment, des-rifabutin.
Figure 2.
Figure 2.
pvcVPC for rifabutin (left-hand panels) and des-rifabutin (right-hand panels) for the final model. The pvcVPC was stratified to present data separately for healthy volunteers (top panels) and TB/HIV patients (bottom panels). Raw data are represented as grey dots. Top, middle and bottom lines represent 95th, 50th and 5th percentiles of the observations. Grey shaded areas are 90% CIs for the 95th, 50th and 5th percentiles of the simulated data.

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