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Antimicrobial Agents and Chemotherapy, September 2007, p. 3104-3110, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00341-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Effect of Concomitantly Administered Rifampin on the Pharmacokinetics and Safety of Atazanavir Administered Twice Daily{triangledown} ,{dagger}

Edward P. Acosta,1 Michelle A. Kendall,2 John G. Gerber,3 Beverly Alston-Smith,4 Susan L. Koletar,5 Andrew R. Zolopa,6 Sangeeta Agarwala,7 Michael Child,7 Richard Bertz,7 Lara Hosey,8 and David W. Haas9*

University of Alabama at Birmingham, Birmingham, Alabama,1 Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts,2 University of Colorado Health Sciences Center, Denver, Colorado,3 DAIDS, NIAID, NIH, Bethesda, Maryland,4 Ohio State University, Columbus, Ohio,5 Stanford University, Stanford, California,6 Bristol-Myers Squibb, Princeton, New Jersey,7 Social & Scientific Systems Inc., Silver Spring, Maryland,8 Vanderbilt University School of Medicine, Nashville, Tennessee9

Received 13 March 2007/ Returned for modification 9 June 2007/ Accepted 11 June 2007


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The potent induction of hepatic cytochrome P450 3A isoforms by rifampin complicates therapy for coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. We performed an open-label, single-arm study to assess the safety and pharmacokinetic interactions of the HIV protease inhibitor atazanavir coadministered with rifampin. Ten healthy HIV-negative subjects completed pharmacokinetic sampling at steady state while receiving 300 mg atazanavir every 12 h without rifampin (period 1), 300 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 2), and 400 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 3). During period 1, the mean concentration of drug in serum at 12 h (C12 h) was 811 ng/ml (range, 363 to 2,484 ng/ml) for atazanavir, similar to historic seronegative data for once-daily treatment with 300 mg atazanavir boosted with 100 mg ritonavir. During periods 2 and 3, the mean C12 h values for atazanavir were 44 ng/ml (range, <25 to187 ng/ml) and 113 ng/ml (range, 39 to 260 ng/ml), respectively, well below historic seronegative data for once-daily treatment with 400 mg atazanavir without ritonavir. Although safe and generally well tolerated, 300 mg or 400 mg atazanavir administered every 12 h did not maintain adequate plasma exposure when coadministered with rifampin.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Tuberculosis is a leading cause of mortality in human immunodeficiency virus (HIV)-infected individuals and accounts for about 13% of all AIDS deaths worldwide (19). Rifampin is a cornerstone of effective antituberculosis therapy. Unfortunately, potent induction of hepatic cytochrome P450 3A (CYP3A) expression by rifampin markedly lowers plasma concentrations of HIV protease inhibitors (13). The antituberculosis drug rifabutin induces CYP3A activity less than rifampin and may therefore be coadministered with many HIV protease inhibitors (13), but rifabutin is not available in most resource-limited countries. Although rifampin may be coadministered with the nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine, there are many situations in which efavirenz and nevirapine may not be appropriate. Additional safe and effective strategies are urgently needed to treat coinfection with HIV and Mycobacterium tuberculosis.

Atazanavir is a widely prescribed HIV protease inhibitor. It undergoes metabolism by hepatic CYP3A, which generates two metabolites that lack antiviral activity (3). Approved dosages are 400 mg once daily when prescribed without ritonavir and 300 mg once daily when boosted with 100 mg ritonavir once daily (3). In antiretroviral therapy-naïve individuals, atazanavir-containing regimens have activity that is broadly similar to those of regimens that contain nelfinavir (10, 15) or efavirenz (18). When administered with low-dose ritonavir, atazanavir has shown efficacy similar to other ritonavir-enhanced protease inhibitor regimens in antiretroviral-experienced patients (8). Atazanavir has a lower propensity to cause insulin resistance or dyslipidemia than most other HIV protease inhibitors (10, 11, 16, 18). The most frequent laboratory abnormality seen with atazanavir is asymptomatic hyperbilirubinemia (13), but this infrequently requires treatment discontinuation (6, 9, 16). Minimum plasma concentration (Ctrough) is the pharmacokinetic parameter most strongly linked to the atazanavir virologic response (17).

The primary objective of this AIDS Clinical Trials Group (ACTG) study was to characterize the steady-state pharmacokinetics and safety of concurrently administered atazanavir and rifampin in healthy, HIV-seronegative subjects and to address whether higher-than-approved, twice-daily dosing of atazanavir without ritonavir could maintain adequate plasma concentrations with the concomitant administration of rifampin.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study subjects and design. ACTG study 5213 enrolled 15 HIV-seronegative subjects. Eligible participants were at least 18 but no more than 55 years of age, with acceptable screening electrocardiogram, hematology, and chemistry studies, which included normal aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin values. Exclusion criteria included the concomitant use of medications known or predicted to interact with CYP3A and acid-reducing agents (H2 receptor blockers, proton pump inhibitors, and antacids) and suspicion of active tuberculosis. The study was approved by the institutional review boards at each of the three sites at which participants were enrolled (Ohio State University, Stanford University, and Vanderbilt University); all subjects provided written informed consent.

This phase I, open-label, single-arm pharmacokinetic interaction study involved three sequential periods of atazanavir administration with or without rifampin. Participants underwent serial plasma sampling for pharmacokinetic analyses on the last day of each study period. Atazanavir was administered orally every 12 h, and rifampin was administered orally every 24 h with the morning atazanavir dose. During period 1, participants received 300 mg atazanavir (two 150-mg capsules) every 12 h for at least 8 days but no more than 11 days. During period 2, participants received 300 mg atazanavir every 12 h and 600 mg rifampin (two 300-mg capsules) every 24 h for at least 11 days but no more than 14 days. During period 3, participants received 400 mg atazanavir (two 200-mg capsules) every 12 h and 600 mg rifampin every 24 h for at least 8 days but no more than 11 days. Subjects fasted prior to entering the general clinical research center at each respective institution; study drug was administered with a standardized meal. Safety assessments, including ALT and AST determinations, were performed during pharmacokinetic sampling visits, at the midpoint of each study period, and 14 to 21 days after the last dose of study drug.

Bioanalytical and pharmacokinetic methods. Pharmacokinetic sampling for atazanavir and rifampin occurred in general clinic research centers. Study drugs were administered directly with food by study personnel during each pharmacokinetic sampling visit. Plasma was collected into EDTA tubes within 15 min before the morning dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 h after the morning dose. The 12-h sample was collected before the 12-h atazanavir dose, and the 24-h sample was collected before the next morning's atazanavir and rifampin doses. Plasma was separated by centrifugation at 4°C and stored at –70°C until assayed. Atazanavir was quantitated from plasma samples using a validated high-performance liquid chromatography method at the University of Alabama at Birmingham Antiviral Pharmacology Laboratory. Briefly, a rapid, sensitive, and specific high-performance liquid chromatography assay was used for the simultaneous quantification of eight antiretroviral agents in 200 µl of human plasma. Following liquid-liquid extraction in 2 ml of tert-butyl methyl ether at basic pH, samples were separated via reversed-phase liquid chromatography on a YMC C8 (4.6 by 100 mm, 3 µm) analytical column under isocratic conditions (55% 20 mM NaAc [pH 4.88], 45% acetonitrile) with a total run time of 25 min. UV detection at 212 nm provided adequate sensitivity with minimal interference from endogenous matrix components. The assay was linear over a concentration range of 25 to 20,000 ng/ml with intra-assay coefficients of variation ranging from 2.0 to 7.1% and an interassay variation of 5.6% for atazanavir.

Rifampin and desacetyl rifampin assays were performed at Covance (Princeton, NJ). Plasma samples were assayed using a validated liquid chromatography-tandem mass spectrometry method from plasma treated with K3 EDTA. Rifampin, desacetyl rifampin, and the internal standard, rifabutin, were extracted from human plasma using solid-phase extraction. The standard curve range for this assay is from 50 to 35,000 ng/ml for both rifampin and desacetyl rifampin using a plasma sample volume of 0.1 ml. The inter- and intra-assay coefficients of variation ranged from 1.1 to 9.8% and 2.4 to 7.2%, respectively, for rifampin; these same values for desacetyl rifampin were 0.9 to 6.4% and 1.5 to 5.1%, respectively.

Pharmacokinetic parameter estimates were determined using a noncompartmental approach (WinNonlin version 4.01; Pharsight Corp., Mountain View, CA). Calculated pharmacokinetic parameters were area under the concentration-time curve at 12 h (AUC12), AUC24, maximum concentration of drug in plasma (Cmax), time to Cmax (Tmax), oral clearance (CL/F), terminal apparent distribution volume (Vz/F), and elimination half-life (t1/2). AUC12 (AUC24) was determined using the linear/log trapezoidal method. The atazanavir AUC24 was estimated by doubling the AUC12. Cmax, Tmax, and mean concentration of drug in serum at 12 h (C12 h) were taken directly from the observed concentration-time data. CL/F was calculated as dose/AUC12 (AUC24). Vz/F was calculated as dose divided by the product of the elimination rate constant ({lambda}z) and AUC12 (AUC24). The elimination rate constant was determined by linear regression of the terminal elimination phase concentration-time points; t1/2 was calculated as ln2/{lambda}z. Measured samples below the assay limit of quantitation were assigned a value equal to one-half the lower limit of quantification, and the partial area method was utilized to determine the AUC12 (AUC24)for each subject.

Statistical design. Sample size calculations for the primary objective assumed the use of a standard one-sided, two-sample t test applied to natural log-transformed AUCs and fixing the type I and type II error rates at 5% and 10%, respectively. The sample size of 18 had 90% power to test if the estimated atazanavir AUC24 values were at least 70% of the historic mean AUC24 for 400 mg atazanavir every 24 h (3). The Wilcoxon signed-rank test was applied to the within-subject differences in the untransformed atazanavir AUC and C12 h values to test the null hypothesis of no difference in these parameters before the initiation of rifampin (period 1) versus after dosing to steady state (period 2 and period 3). The paired t test was used on log-transformed AUC and C12 h values as a confirmatory test. For rifampin, the Wilcoxon rank sum test was applied to the untransformed AUC, Cmin, and Cmax values to test the null hypothesis of no difference in these parameters compared to historic controls. The t test was used on the log-transformed AUC, Cmin, and Cmax values as a confirmatory test. In addition, geometric mean ratios (GMRs) for the pharmacokinetic parameters with 90% confidence intervals were derived to compare exposures during each treatment period. Continuous bilirubin data were compared by the exact Kruskal-Wallis test. An exact 95% confidence interval was constructed on the rate of adverse events. Reported P values are one sided and not adjusted for multiple comparisons.

Additional measurements. Determination of Gilbert's genotype (UDP-glucuronosyltransferase 1A1 [UGT1A1]) was performed using a PCR-based assay that discriminates between the relevant promoter alleles A(TA)6TAA and A(TA)7TAA (University of Chicago Genetic Services Laboratories, Chicago, IL). Serum bilirubin and other safety laboratory assays were performed at commercial laboratories. Electrocardiograms were obtained at baseline and 2 h postdose during each pharmacokinetic sampling visit.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Participant characteristics. Fifteen participants received at least one dose of study drug. Ten individuals completed all three pharmacokinetic sampling visits; demographic characteristics of these individuals are presented in Table 1. Accrual was suspended for a preplanned interim analysis of period 3 data after 15 subjects were enrolled; an evaluable sample size of 10 had an 80% power to test if the estimated atazanavir AUC24 values were at least 70% of the historic mean AUC24 for 400 mg atazanavir administered every 24 h. Participants ranged in age from 23 to 51 years, 9 were white, 2 were African American, and 7 were female. One participant discontinued the study due to intolerance to study drugs. Four participants discontinued the study because of nonadherence with the study protocol. One subject had extremely low desacetyl rifampin concentrations (<50 ng/ml) throughout the dosing interval and was censored from the calculations of desacetyl rifampin pharmacokinetic parameters. Demographic characteristics of the subjects excluded from the pharmacokinetic analyses were not different.


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  		TABLE 1. Study participant demographics

 
Pharmacokinetic results. Steady-state atazanavir concentration-versus-time profiles over 12 h following the morning dose during each dosing period for the 10 fully evaluable participants are shown in Fig. 1. A summary of atazanavir pharmacokinetic parameters is provided in Table 2. Concomitantly administered rifampin markedly reduced plasma atazanavir exposure, which is reflected in the C12 h values more so than in AUC12 values. Compared to the mean atazanavir C12 h during period 1, the mean plasma atazanavir C12 h during period 2 was 97% lower, and that during period 3 was 83% lower (both P = 0.002). Mean atazanavir AUC12 values were reduced by 77% (P = 0.002) and 55% (P = 0.002) during periods 2 and 3, respectively. Plasma C12 h values during periods 2 and 3 were considerably lower than 159 ng/ml (the historic mean C24 h value for 400 mg atazanavir administered every 24 h in healthy subjects) (3). Plasma atazanavir concentrations at 12 h following the morning dose (just prior to the evening dose) were significantly higher than concentrations at 0 h and 24 h (before morning doses), especially during period 3. Mean atazanavir concentrations at 12 h and 24 h during periods 2 and 3 were as follows: period 2, 44 ng/ml and 27 ng/ml; period 3, 113 ng/ml and 67 ng/ml, respectively. Pharmacokinetic results were also characterized as GMRs with 90% confidence intervals. The atazanavir Cmax (period 2/period 1 and period 3/period 1) GMRs were 0.344 (0.235, 0.502) and 0.585 (0.436, 0.786), respectively. Similarly, for period 2/period 1 and period 3/period 1, the AUC12 GMRs were 0.199 (0.134, 0.296) and 0.408 (0.295, 0.565), respectively, and the C12 h GMRs were 0.054 (0.032, 0.089) and 0.139 (0.092, 0.211), respectively.


Figure 1
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  		FIG. 1. Steady-state plasma concentration curves for atazanavir. Mean values are shown. Error bars indicate standard deviations. Closed circles represent period 1 (300 mg atazanavir administered every 12 h without rifampin), open circles represent period 2 (300 mg atazanavir administered every 12 h with 600 mg rifampin every administered 24 h), and open squares represent period 3 (400 mg atazanavir every administered 12 h with 600 mg rifampin administered every 24 h). The 24-h time points for periods 2 and 3 represent the atazanavir C12 h following the second dose during the 24-h interval. The horizontal dashed line indicates 159 ng/ml, the historic mean C12 h for healthy volunteers given 400 mg atazanavir every 24 h (3).

 

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  		TABLE 2. Atazanavir pharmacokinetic parameters during each study perioda

 
Plasma pharmacokinetics of rifampin and its desacetyl metabolite in individuals receiving concomitantly administered atazanavir twice daily were examined. Concentration-versus-time profiles at steady state over 24 h during periods 2 and 3 for the evaluable participants are shown in Fig. 2. Detailed pharmacokinetic results for rifampin and desacetyl rifampin are provided in Table 3. Plasma rifampin exposure did not differ significantly between periods 2 and 3. The AUC24 values from period 2 were higher than historic data (P = 0.03), whereas the AUC24 values from period 3 were not different (P = 0.08). The Cmax values for rifampin from periods 2 and 3 were not different from historic data (P = 0.08 and 0.23, respectively) (5). However, desacetyl rifampin exposure was somewhat higher during period 3 than during period 2. The AUC24 and Cmax values for desacetyl rifampin from periods 2 and 3 were significantly higher than historic data (both P = 0.004) (5). The mean plasma concentration-versus-time profile for rifampin is similar to what has been described for rifampin alone at steady state. For rifampin and desacetyl rifampin, the GMRs were calculated using period 2 and period 3 results versus historic control data (5). The rifampin AUC24 GMRs for periods 2 and 3 versus historic controls were 1.322 (1.059, 1.651) and 1.215 (0.964, 1.531), respectively, and the Cmax GMRs were 1.144 (0.974, 1.345) and 1.169 (0.915, 1.494), respectively. The desacetyl rifampin AUC24 GMRs for periods 2 and 3 versus historic controls were 2.886 (2.118, 3.933) and 3.371 (2.546, 4.463), respectively, and the Cmax GMRs were 2.291 (1.776, 2.955) and 2.431 (1.968, 3.001), respectively.


Figure 2
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  		FIG. 2. Steady-state plasma concentration curves for rifampin and desacetyl rifampin. Mean values are shown. Error bars indicate standard deviations. Open circles represent period 2 (300 mg atazanavir administered every 12 h with 600 mg rifampin administered every 24 h), and open squares represent period 3 (400 mg atazanavir administered every 12 h with 600 mg rifampin administered every 24 h). Solid lines represent rifampin, and dashed lines represent desacetyl rifampin.

 

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  		TABLE 3. Rifampin and desacetyl rifampin pharmacokinetic parameters during each study perioda

 
Data from period 1 allowed a comparison between plasma exposure with 300 mg atazanavir administered twice daily and historic seronegative data for approved once-daily atazanavir dosages. Concentration-versus-time profiles for 300 mg atazanavir administered every 12 h (present study), 400 mg atazanavir administered every 24 h (historic data), and 300 mg atazanavir and 100 mg ritonavir administered every 24 h (historic data) are shown in Fig. 3. Mean pharmacokinetic parameters are presented in Table 4. With 300 mg atazanavir administered every 12 h, the mean C12 h exceeded historic data for 400 mg atazanavir administered every 24 h (P = 0.002) and was similar to that of 300 mg atazanavir boosted with 100 mg ritonavir administered every 24 h (P = 0.23) (3). The Cmax value with 300 mg atazanavir administered every 12 h was somewhat less than those for 400 mg atazanavir administered every 24 h (P = 0.03) and 300 mg atazanavir plus 100 mg ritonavir administered every 24 h (P = 0.004). The estimated mean AUC24 value with 300 mg atazanavir administered every 12 h appeared to be higher than those of historic data for 400 mg atazanavir administered every 24 h and appeared to be lower than those for 300 mg atazanavir and 100 mg ritonavir administered every 24 h. As noted above, the estimated mean AUC24 values for 300 mg atazanavir administered every 12 h should be interpreted with some caution since samples were not obtained throughout the second 12-h dosing interval.


Figure 3
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  		FIG. 3. Steady-state plasma concentration curves for atazanavir in HIV-negative subjects. Mean values are shown. Error bars indicate standard deviations. Rifampin was not coadministered. Closed circles represent 300 mg atazanavir administered every 12 h without ritonavir (period 1 of the present study), open triangles represent historic data for 400 mg atazanavir administered every 24 h, and open squares represent historic data for 300 mg atazanavir and 100 mg ritonavir, both given every 24 h.

 

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  		TABLE 4. Atazanavir pharmacokinetic parameters in the present study and previous studies involving seronegative volunteersa

 
Safety and tolerability. The study drugs were safe and generally well tolerated. One (7%) of 15 individuals discontinued study participation because of grade 3 fatigue (95% confidence interval, 0.2% to 32%). There were no elevations of ALT, creatinine, or hemoglobin levels above the normal range in any participant while receiving study drugs and no clinically significant electrocardiogram changes. As expected, study participants experienced elevations of unconjugated bilirubin while receiving 300 mg atazanavir every 12 h without rifampin. Bilirubin values normalized during periods 2 and 3. During period 1, peak bilirubin values ranged from 5.00 to 7.30 mg/dl in the two Gilbert's genotype homozygotes, from 4.10 to 7.30 mg/dl in the six heterozygotes, and from 2.60 to 5.40 mg/dl in five individuals lacking Gilbert's genotype (P = 0.23).


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Treatment of coinfection with M. tuberculosis and HIV is a major challenge, largely because rifampin enhances the clearance of HIV protease inhibitors (13). Studies are needed to identify antiretroviral regimens that are safe and effective in HIV-infected patients who require therapy for tuberculosis. The present study demonstrates that 300 mg or 400 mg atazanavir administered every 12 h without ritonavir will not provide adequate plasma atazanavir exposure to effectively treat HIV infection when coadministered with 600 mg rifampin once daily. Coadministration of atazanavir with rifampin was safe and generally well tolerated, without untoward symptoms or laboratory abnormalities. These data support the need for additional studies to identify a strategy to allow atazanavir-containing regimens to be coadministered with rifampin. Among subjects not receiving rifampin, 300 mg atazanavir administered every 12 h provided plasma drug exposure similar to that of 300 mg atazanavir and 100 mg ritonavir administered once daily.

This study was designed before there were data available regarding the pharmacokinetic interaction between atazanavir and rifampin. It was clear a priori that rifampin would likely decrease plasma atazanavir exposure, but due to atazanavir's ability to inhibit the metabolism of some other drugs (2), we hypothesized that an inhibitory effect of high-dose atazanavir on drug metabolism might provide adequate drug exposure despite concomitantly administered rifampin. Since Ctrough is an important pharmacokinetic parameter for the efficacy of HIV protease inhibitors, we chose twice-daily dosing to increase the likelihood that adequate minimum atazanavir concentrations would be maintained throughout 24 h. We chose not to include concomitantly administered ritonavir in this study because a pharmacokinetic interaction study of atazanavir, rifampin, and ritonavir was already in progress (5).

A recent report supports the concept that any strategy involving concomitantly administered atazanavir and rifampin will require twice-daily dosing, even if atazanavir is boosted with ritonavir (5). Ritonavir is a potent inhibitor of CYP3A, and coadministration of ritonavir with atazanavir increases atazanavir plasma Ctrough by over 600% (3). However, among HIV-negative subjects who received 400 mg atazanavir, 200 mg ritonavir, and 600 mg rifampin once daily, plasma atazanavir concentrations were substantially decreased at the end of the dosing interval, with a mean C24 h of 53 ng/ml (5).

The absence of hepatotoxicity in the present study is in contrast with what occurred in a study of healthy subjects given saquinavir (1,000 mg), ritonavir (100 mg), and rifampin (600 mg) once daily (7). In that study, elevations of levels of hepatic transaminase were profound, particularly among individuals who received rifampin for 14 days before saquinavir and ritonavir were added. While the mechanism is not known, such toxicity may have been favored by rifampin preinduction of CYP3A expression before saquinavir and ritonavir were added. The design of future studies involving HIV protease inhibitors concomitantly administered with rifampin must consider the sequence in which these drugs are initiated and not just steady-state concentrations.

Rifampin undergoes enterohepatic circulation, during which time the drug is progressively deacetylated. The desacetyl metabolite retains full antibacterial activity, but its reduced intestinal reabsorption facilitates elimination. In the present study, plasma rifampin Cmax and AUC24 values with concomitantly administered atazanavir were remarkably similar to historic values from healthy subjects receiving rifampin alone, while desacetyl rifampin Cmax and AUC24 values with concomitantly administered atazanavir were significantly higher than historic values. In a previous study of 14 healthy subjects receiving 600 mg rifampin every 24 h, steady-state plasma rifampin Cmax and AUC24 values were 8,058 ng/ml and 31,268 ng·h/ml, respectively, while values for desacetyl rifampin were 674 ng/ml and 2,493 ng·h/ml, respectively (5). Thus, atazanavir use should not compromise the antituberculosis efficacy of rifampin.

Efficient elimination of bilirubin, the primary product of heme metabolism, requires conjugation with glucuronic acid catalyzed by hepatic UGT1A1. Many individuals have decreased bilirubin-conjugating activity caused by a TA insertion into the UGT1A1 promoter (Gilbert's genotype) (1, 14). Atazanavir commonly causes unconjugated hyperbilirubinemia by competing with bilirubin for binding to UGT1A1. Among 138 healthy subjects who participated in phase I studies of atazanavir, those homozygous for Gilbert's genotype had significantly higher median total bilirubin concentrations than heterozygous or wild-type subjects (12). In contrast with that previous report, we found no significant association between Gilbert's genotype and hyperbilirubinemia, possibly due to the small sample size.

In summary, atazanavir administered twice daily at the doses used in the present study does not provide adequate plasma drug exposure when coadministered with rifampin administered once daily. Based on data from our study and previous work, we are optimistic that a safe and effective regimen can be devised to allow the coadministration of atazanavir and rifampin. A strategy that warrants careful investigation would combine atazanavir (300 mg or 400 mg) with ritonavir (100 mg), both given twice daily, with rifampin, given once daily.


   ACKNOWLEDGMENTS
 
We acknowledge Carol Suckow, our team data manager, Robin DiFrancesco, the laboratory technologist, Mary Dobson, our laboratory data manager, and Laura Laughlin, our field representative, for their outstanding professional contributions to this work. We are also grateful to the persons who volunteered for this study.

This study was conducted through the ACTG (grants AI38858 and AI68636), Division of AIDS, National Institutes of Health, and was supported in part by NIH grants AI068636 (E.P.A.), AI32775 (J.G.G.), AI38855 (M.A.K.), AI069474 and RR000034 (S.L.K.), and AI069439 and RR00095 (D.W.H.). Bristol-Myers Squibb provided rifampin and rifampin concentration analysis, partial stipends to the participants, and study drugs.


   FOOTNOTES
 
* Corresponding author. Mailing address: Division of Infectious Diseases, Vanderbilt University School of Medicine, 345 24th Avenue North, Suite 105, Nashville, TN 37203. Phone: (615) 467-0154. Fax: (615) 467-0158. E-mail: david.w.haas{at}vanderbilt.edu Back

{triangledown} Published ahead of print on 18 June 2007. Back

{dagger} This is ACTG study A5213. Back


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Antimicrobial Agents and Chemotherapy, September 2007, p. 3104-3110, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00341-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.




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