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JAC Advance Access originally published online on December 19, 2007
Journal of Antimicrobial Chemotherapy 2008 61(2):389-393; doi:10.1093/jac/dkm484
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Effect of rifampicin-based antitubercular therapy on nevirapine plasma concentrations in South African adults with HIV-associated tuberculosis

Karen Cohen1,*, Gilles van Cutsem2, Andrew Boulle3, Helen McIlleron1, Eric Goemaere2, Peter J. Smith1 and Gary Maartens1

1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa 2 Médecins Sans Frontières, Khayelitsha, Cape Town, South Africa 3 Department of Public Health, University of Cape Town, South Africa

* Corresponding author. Tel: +27-21-4066293; Fax: +27-21-4481989; E-mail: karen.cohen{at}uct.ac.za

Received 26 July 2007; returned 7 October 2007; revised 16 November 2007; accepted 21 November 2007


   Abstract
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Background and objectives: Nevirapine-containing antiretroviral therapy (ART) and rifampicin-based antitubercular therapy are commonly co-administered in Africa, where nevirapine is often the only available non-nucleoside reverse transcriptase inhibitor. Rifampicin induces the metabolism of nevirapine, but the extent of the reduction in nevirapine concentrations has varied widely in previous studies. We describe the steady-state pharmacokinetics of nevirapine during and after antitubercular therapy in South African patients.

Methods: Sixteen patients receiving ART including standard doses of nevirapine were admitted twice for intensive pharmacokinetic sampling: during and after rifampicin-based antitubercular therapy.

Results: Geometric mean ratios for nevirapine pharmacokinetic parameters during versus after antitubercular therapy were 0.61 [90% confidence interval (CI) 0.49–0.79] for Cmax, 0.64 (90% CI 0.52–0.80) for area under the curve up to 12 h (AUC0–12) and 0.68 (90% CI 0.53–0.86) for Cmin. Nevirapine Cmin was subtherapeutic (<3 mg/L) in six patients during antitubercular therapy (one of whom developed virological failure) and in none afterwards. There was no correlation between rifampicin concentrations and the degree of nevirapine induction assessed by the proportional change in nevirapine concentrations between the two admissions. The ratio of nevirapine AUC0–12 to the AUC0–12 of its 12-hydroxy metabolite was significantly lower in the presence of antitubercular therapy, consistent with induced metabolism.

Conclusions: Nevirapine concentrations were significantly decreased by concomitant rifampicin-based antitubercular therapy and a high proportion of patients had subtherapeutic plasma concentrations. Further study in African patients is required to determine the implications for treatment outcomes.

Keywords: pharmacokinetics , interaction , 12-hydroxynevirapine


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Tuberculosis (TB) is the leading cause of morbidity and mortality in HIV-infected patients in Africa.1 As access to antiretroviral therapy (ART) expands, a substantial number of patients will require treatment for TB while receiving ART. Nevirapine-based combination ART is used extensively in resource-limited settings, where few alternative regimens are available. Nevirapine is metabolized by cytochrome P450 isoenzymes, predominantly CYP3A4 and CYP2B6, to the hydroxymetabolites 2-, 3-, 8- and 12-hydroxynevirapine.2 Rifampicin is a key component of antitubercular regimens. Rifampicin induces the metabolism of many drugs, including nevirapine. Previous pharmacokinetic studies have shown a variable reduction in nevirapine trough concentrations with concomitant rifampicin, ranging from 10% to 68%.3–6

The largest studies of the interaction between nevirapine and rifampicin have been in Thai patients.6,7 Despite some reassuring data suggesting that more than 86% of Thai patients on concomitant rifampicin-based antitubercular therapy attain therapeutic nevirapine concentrations,8 their low body weight and slower nevirapine clearance9 cast doubt on the generalizability of the results.

We report the steady-state pharmacokinetics of nevirapine during and after rifampicin-based antitubercular therapy in a group of South African patients with HIV-associated TB.


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Study design and setting

HIV-infected adults (≥18 years) on a combination ART regimen consisting of two nucleoside reverse transcriptase inhibitors and nevirapine who were in the continuation phase of rifampicin-based antitubercular therapy were recruited at a donor-funded (Médecins Sans Frontières) ART clinic in Khayelitsha, Cape Town, South Africa. Participants were admitted for intensive pharmacokinetic blood sampling while taking rifampicin-based antitubercular therapy, and again 10 days or more after completion of antitubercular therapy. Nevirapine was administered throughout at standard doses of 200 mg 12 hourly. Rifampicin was dosed at 600 mg 5 days a week in those weighing ≥55 kg and 450 mg for those <55 kg.

An estimated sample size of 16 participants had 80% power at a 5% level of significance to detect a 25% reduction in nevirapine Cmin when administered concomitantly with rifampicin, calculated based on previously published pharmacokinetic parameters.5 Patients were excluded if they had poor venous access, a Karnofsky score <70, known severe renal, hepatic or intestinal disease (malabsorption or severe diarrhoea), pregnancy, or were taking any other medication known to have a pharmacokinetic interactions with nevirapine. Adherence to ART and antitubercular therapy was assessed by means of self-report, using a structured questionnaire which recorded any doses of ART or antitubercular treatment omitted in the 4 days before admission. Haemoglobin, alanine transaminase (ALT) and albumin were measured on both admissions. CD4+ lymphocyte counts and quantitative HIV-1 RNA (viral loads) were obtained from the participants’ 6 monthly routine monitoring results.

The protocol was approved by the research Ethics Committee of the University of Cape Town. All participants gave signed informed consent.

Pharmacokinetic assessment

An observed dose of nevirapine was given and the exact time of administration recorded. Antitubercular therapy was administered together with nevirapine at the first sampling occasion. Venous blood was collected at –0.5, 0.5, 1, 1.5, 2, 4, 6, 10 and 12 h on both admissions. The exact times of sampling were recorded. Blood was immediately centrifuged and the plasma was stored at –80°C until analysis.

Assay methodologies for quantifying nevirapine and 12-hydroxynevirapine were derived from a previously published method.10 Plasma concentrations of nevirapine were determined by Liquid Chromatography Mass Spectrometry methods using a Waters Alliance 2690 High Pressure Liquid Chromatograph (HPLC) coupled to a Waters/Micromass ZMD single quadrapole mass spectrometer. The mobile phase consisted of 50% acetonitrile in 4 mM ammonium acetate and 0.1% trifluoroacetic acid. A 20 by 2.1 mm Hypersil Gold C18 column (Thermo) was used at a flow rate of 0.3 mL/min. Neostigmine served as internal standard. Detection in positive ionization mode of nevirapine was at 276.2 (m/z) and neostigmine at 223.2 (m/z). Acetonitrile (50 µL) containing 1 mg/L internal standard was added to 20 µL of each sample or control to precipitate protein. Samples were vortexed for 30 s, centrifuged for 5 min at 750 g and 2 µL of the supernatant was injected onto the column. The standard curve was linear in the range 0.2–20 mg/L. The lower limit of quantification (LLQ) was set at 0.2 mg/L.

Plasma concentrations of 12-hydroxynevirapine were quantified by tandem mass spectrometry using an Applied Biosystems API 3200 linear ion trap. HPLC was performed on an Agilent 12000 series instrument using a Gemini C18 3 µm particle size, 50 by 2.1 mm column (Phenomonex). The mobile phase comprised 15% acetonitrile and 85% ammonium formate. The flow rate was 0.3 mL/min and injection volume 5 µL. The following SRM transitions of [M-H]+ precursor ions to product ions were selected: 12-hydroxynevirapine m/z 283.2–265.2; physostigmine (internal standard) m/z 276.3–162.3. The internal standard was made up to a concentration of 0.5 mg/L in acetonitrile. One hundred microlitres of plasma was transferred to a 1.5 mL polypropylene tube and 300 µL of internal standard solution was added. After mixing for 10 s, the tube was centrifuged for 5 min at 750 g. Supernatant (10 µL) was transferred to a new 1.5 mL tube and 1000 µL of the mobile phase was added; 5 µL was injected onto the column. The standard curve was linear in the range 0.025–5 mg/L. LLQ was set at 0.025 mg/L.

Plasma concentrations of rifampicin were determined using an Applied Biosystems API 2000 tandem mass spectrometer, using a previously published method.11 The mobile phase consisted of 50% methanol, 20% acetonitrile and 30% formic acid (0.1%). A 20 by 2.1 mm Hypersil Gold C18 column (Thermo) was used at a flow rate of 0.3 mL/min. Rifapentine served as internal standard. Detection of rifampicin in positive ionization mode was at 823.5–791.5 (m/z) and rifapentine at 877.27–845.30 (m/z). Acetonitrile (150 µL) containing 1 mg/L internal standard was added to 50 µL of each sample or control to precipitate protein. Samples were vortexed for 30 s, and centrifuged for 5 min at 750 g. Supernatant (2 µL) was injected onto the column. The standard curve was linear in the range 0.1–30 mg/L. LLQ was set at 0.1 mg/L.

Quality control samples covering the range of the standard curve were included with each assay run. Inter- and intra-day percentage coefficients of variation were <10% for all controls. The laboratory is a member of the Association for Quality Assessment in Therapeutic Drug Monitoring and Toxicology international inter-laboratory quality control programme.

Observed peak plasma concentration (Cmax), time to peak plasma concentration (Tmax) and minimum plasma concentration (Cmin) in the dosing interval were determined by inspection of individual concentration–time curves. Cmin was defined as the lowest concentration after Tmax. Non-compartmental analysis was performed (using WinNonlin version 4, Pharsight Corporation, Mountain View, CA, USA) to calculate area under the curve to 12 h (AUC0–12) using the linear trapezoidal rule with linear interpolation and half-life (t1/2). The target minimum plasma concentration for nevirapine was ≥3 mg/L, based on the trough concentration recommended in current antiretroviral therapeutic monitoring guidelines.12

Statistical analysis

Statistical analysis was performed using STATA version 9.2 (Stata corp. College Station, TX, USA). Descriptive statistics of patient characteristics and pharmacokinetic data were summarized using means and standard deviations if normally distributed, and medians and interquartile ranges if non-normally distributed. Comparison of participant characteristics, laboratory results and pharmacokinetic parameters in the presence and absence of antitubercular therapy was performed using a paired t-test or Wilcoxon signed rank test. Geometric means and geometric mean ratios with 90% confidence intervals (CIs) were calculated for Cmax, AUC0–12 and Cmin. Spearman’s rank correlation coefficients were calculated to explore correlation between nevirapine and rifampicin pharmacokinetic parameters.


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There were 16 participants (13 women) with a median age of 35 years (IQR 27–39). Median CD4 count closest to the first pharmacokinetic sampling was 115 cells/mm3 (IQR 63–252). Twelve participants had World Health Organization stage 4 HIV disease. All participants were taking an ART regimen comprising nevirapine, lamivudine and either stavudine or zidovudine throughout. At the time of first pharmacokinetic sampling, all participants were taking rifampicin and isoniazid, and five participants were taking ethambutol. Median duration of ART at the time of first pharmacokinetic sampling was 165 days (IQR 114–221); 3/16 participants were established on ART before initiating antitubercular therapy and 13 participants had commenced ART during antitubercular therapy. Median time from completion of antitubercular therapy to the second admission for intensive sampling was 56 days (IQR 32.5–98.5). ALT was moderately elevated in 3/16 participants at the first admission and 4/16 participants at the second admission (less than four times the upper limit of normal in all instances). One participant reported having missed a single dose of nevirapine 2 days before the first admission. All other participants reported 100% adherence in the 4 days prior to both admissions.

Participant characteristics and pharmacokinetic parameters of nevirapine during and after antitubercular therapy are given in Table 1. Median weight gain between admissions was 2.5 kg (IQR 0.1–6.9). When participants were receiving antitubercular therapy, Cmax, Cmin and AUC0–12 were significantly lower. The mean reduction in nevirapine Cmin in the presence of rifampicin-based antitubercular therapy was 26.3% (95% CI 6.4–46.3). Geometric mean ratios for nevirapine pharmacokinetic parameters during versus after antitubercular therapy were 0.61 (90% CI 0.49–0.79) for Cmax, 0.64 (90% CI 0.52–0.80) for AUC0–12 and 0.68 (90% CI 0.53–0.86) for Cmin.


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  		Table 1. Participant characteristics and nevirapine pharmacokinetic parameters for 16 participants intensively sampled during and after rifampicin-based antitubercular therapy

 
Nevirapine concentration–time curves during and after antitubercular therapy are shown in Figure 1. Nevirapine Cmin was subtherapeutic (<3 mg/L) in 6/16 participants taking rifampicin and in none after antitubercular therapy (Figure 2).


Figure 1
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  		Figure 1. Nevirapine median concentration–time profile during and after rifampicin-based antitubercular therapy. Bars represent interquartile ranges.

 


Figure 2
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  		Figure 2. Nevirapine Cmin in 16 participants during and after rifampicin-based antitubercular therapy.

 
Three participants, with a nevirapine Cmin while on antitubercular therapy of 1.3, 5.9 and 6.4 mg/L, respectively, had a detectable viral load (>400 copies/mL) within 6 months of the first admission. In all of the other participants, including five with a Cmin<3 mg/L, viral loads measured during the 6 months after the first admission were suppressed (<400 copies/mL).

Median (IQR) AUC0–12 of 12-hydroxynevirapine was similar during and after antitubercular therapy at 3.2 mg·h/L (2.5–3.9) and 3.0 mg·h/L (2.6–4.1), respectively (P = 0.5). However, there was a significant change in the ratio of nevirapine AUC0–12 to the 12-hydroxy metabolite AUC0–12, with a median ratio of 14.7 (IQR 12.1–18.0) in the presence of rifampicin-based antitubercular therapy and 20.4 (IQR 18.3–25.3) after rifampicin-based antitubercular therapy (P = 0.0004).

Median rifampicin Cmax was 7.8 mg/L (IQR 5.9–9.6) and median rifampicin AUC0–12 was 34.7 mg·h/L (IQR 26.3–56.6). There was no evidence of an association between rifampicin AUC0–12 and the proportional change in nevirapine concentrations between the two admissions.


   Discussion
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We found significant reductions in nevirapine Cmin, Cmax and AUC0–12 in participants while they were taking rifampicin-based antitubercular therapy. Nevirapine Cmin concentration was below the recommended lower limit of 3 mg/L in 6/16 (38%) participants taking antitubercular therapy. Although five of these six participants had a good short-term virological outcome, this is nevertheless a worrying finding, as the trough concentration is the key pharmacokinetic parameter for efficacy.12 We found a significant decrease in the ratio between the AUC0–12 of nevirapine and its inactive 12-hydroxymetabolite (produced primarily by CYP3A42) in the presence of rifampicin-based antitubercular therapy. This indicates that the change in nevirapine pharmacokinetic parameters is due to enhanced metabolism of nevirapine by CYP3A4, with increased flux through the metabolic pathway in the presence of rifampicin. Half of the participants had rifampicin peak concentrations lower than the recommended reference range of 8–24 mg/L. This is in keeping with the findings of two recent African studies, which showed low rifampicin concentrations in a high proportion of TB patients,13,14 which was associated with HIV infection in one study.13 A previous pharmacokinetic study found that nevirapine did not affect rifampicin concentrations.5

The reduction in nevirapine trough concentrations with concomitant rifampicin has varied widely in previous studies. This variability is due in part to differing study designs. The largest reductions of nevirapine trough concentrations of 53%6 and 68%3 were found in HIV-infected patients without TB, who were receiving rifampicin without other concomitant antitubercular therapy. It is likely that the inducing effect of rifampicin is ameliorated by isoniazid, which is an inhibitor of CYP3A—the major cytochrome P450 isoenzyme involved in nevirapine metabolism.15 In addition, CYP2B6 polymorphisms are known to influence nevirapine pharmacokinetics16,17 and may influence the magnitude of the inducing effect of rifampicin; thus another source of variability in study results may be differences in the frequencies of CYP2B6 polymorphisms in different populations.

Two adequately powered Thai studies conducted in patients with TB reported reductions of nevirapine trough concentrations of 15.6%18 and 37.2%,8 which are similar to the 26.3% that we found. However, the mean trough nevirapine concentrations with concomitant rifampicin-based antitubercular therapy in the Thai studies were 5.5 and 5.4 mg/L,8,18 considerably higher than the 3.2 mg/L that we found. The likely explanation for the higher nevirapine trough concentrations is their lower body weight (~10 kg lower than our patients’ mean weight of 65.8 kg), given that nevirapine clearance is similar in Thai and South African patients.9

One approach to compensate for the reduction in nevirapine concentrations when co-administered with rifampicin is to increase the nevirapine dose. In an Indian study, a 50% dose increase, selectively given to a small group of seven patients who had subtherapeutic trough nevirapine concentrations when the standard dose was co-administered with rifampicin, resulted in trough concentrations in the therapeutic range.6 However, given the variability in nevirapine concentrations, this dosing strategy may result in very high nevirapine concentrations in some individuals with resultant toxicity and requires further study.

The key question is whether the observed reduction in nevirapine concentrations with concomitant rifampicin results in an increased risk of virological failure. A retrospective Spanish study of 32 patients reported that 74% of patients treated with concomitant nevirapine- and rifampicin-based antitubercular therapy attained undetectable viral loads, but there was no control group.19 A Thai cohort study of 70 patients on nevirapine-based combination ART and concomitant rifampicin-based antitubercular therapy found that virological suppression was similar to a control group,7 with virological suppression rates remaining similar up to 60 weeks.18 However, as mentioned above, Thai patients have lower body weight and higher trough nevirapine concentrations.

A limitation of our study is that the majority of the patients are women; there may be sex differences in the pharmacokinetics of both nevirapine and rifampicin. Although pharmacokinetic sampling was performed after observed drug dosing, dosing in the days prior to admission was not directly observed, and adherence cannot be guaranteed. Our study is also not powered to explore the association between nevirapine trough concentration and virological outcomes.

In conclusion, concomitant rifampicin-based antitubercular therapy significantly reduces nevirapine concentrations, and subtherapeutic trough nevirapine concentrations occur in a significant proportion of patients. Our data together with that from other small studies suggest that virological responses are reasonable, but there is a need for larger cohort studies, particularly in sub-Saharan Africa.


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Funding for this study was provided by Médecins Sans Frontières and the South African National Department of Health.


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G. M. is the recipient of an unrestricted educational grant from Merck, Sharp & Dohme, South Africa. The other authors have none to declare.


   Acknowledgements
 
Thanks to Médecins Sans Frontières and the South African National Department of Health for providing funding for this study. Britt Jansson, Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, assisted in the development of the 12-hydroxynevirapine assay and provided us with its reference standard.


   References
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1 Corbett EL, Marston B, Churchyard G, et al. Tuberculosis in sub-Saharan Africa: opportunities, challenges and change in the era of antiretroviral treatment. Lancet (2006) 367:926–37.[CrossRef][Web of Science][Medline]

2 Erikson DA, Mather G, Trager WF, et al. Characterisation of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos (1999) 27:1488–95.[Abstract/Free Full Text]

3 Robinson P, Lamson M, Gigliotti M, et al. Pharmacokinetic interaction between nevirapine and rifampicin. Programme and Abstracts of the Twelfth World AIDS Conference, 1998: Geneva, Switzerland. Abstract 60623.

4 Dean GL, Back DJ, de Ruiter A. Effect of tuberculosis therapy on nevirapine trough plasma concentrations. AIDS (1999) 13:2489.[CrossRef][Web of Science][Medline]

5 Ribera DE, Pou L, Lopez RM, et al. Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr (2001) 28:450–3.[Web of Science][Medline]

6 Ramachandran G, Hemanthkumar AK, Rajeskaran S, et al. Increasing nevirapine dose can overcome reduced bioavailability due to rifampicin coadministration. J Acquir Immune Defic Syndr (2004) 42:36–41.

7 Manosuthi W, Sungkanurparph S, Thakkinstian A, et al. Plasma nevirapine levels and 24-week efficacy in HIV-infected patients receiving nevirapine-based highly active antiretroviral therapy with or without rifampicin. Clin Infect Dis (2006) 43:253–5.[CrossRef][Web of Science][Medline]

8 Autar RS, Wit FWNM, Sankote J, et al. Nevirapine plasma concentrations and concomitant use of rifampin in patients coinfected with HIV-1 and tuberculosis. Antivir Ther (2005) 10:937–43.[Web of Science][Medline]

9 Kappelhoff BS, van Leth F, MacGregor TR, et al. Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study. Antivir Ther (2005) 10:145–55.[Web of Science][Medline]

10 Chi J, Jayewardene A, Stone J, et al. An LC-MS-MS method for the determination of nevirapine, a non-nucleoside reverse transcriptase inhibitor, in human plasma. J Pharm Biomed Anal (2003) 31:953–9.[CrossRef][Web of Science][Medline]

11 McIlleron H, Norman J, Kanyok TP, et al. Elevated gatifloxacin and reduced rifampicin concentrations in a single-dose interaction study amongst healthy volunteers. J Antimicrob Chemother (2007) 60:1398–401.[Abstract/Free Full Text]

12 la Porte CJL, Back D, Blaschke T, et al. Updated guidelines to perform therapeutic monitoring for antiretroviral agents. Rev Antivir Ther (2006) 3:4–12.

13 McIlleron H, Wash P, Burger A, et al. Determinants of rifampin, isoniazid, pyrazinamide and ethambutol pharmacokinetics in a cohort of tuberculosis patients. Antimicrob Agents Chemother (2006) 50:1170–7.[Abstract/Free Full Text]

14 Tappero JW, Bradford WZ, Agerton TB, et al. Serum concentrations of antimycobacterial drugs in patients with pulmonary tuberculosis in Botswana. Clin Infect Dis (2005) 41:461–9.[CrossRef][Web of Science][Medline]

15 Desta Z, Soukhova NV, Flockhart DA. Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: potent inhibition of CYP2C19 and CYP3A. Antimicrob Agents Chemother (2001) 45:382–9.[Abstract/Free Full Text]

16 Penzak SR, Kabuye G, Mugyenyi P, et al. Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV-infected patients in Uganda. HIV Med (2007) 8:86–91.[CrossRef][Web of Science][Medline]

17 Rotger M, Colombo S, Furrer H, et al. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics (2005) 15:1–5.[Medline]

18 Manosuthi W, Ruxrungtham K, Likanosakul S, et al. Nevirapine levels after discontinuation of rifampicin therapy and 60-week efficacy of nevirapine-based antiretroviral therapy in HIV-infected patients with tuberculosis. Clin Infect Dis (2007) 44:141–4.[CrossRef][Web of Science][Medline]

19 Oliva J, Moreno S, Sanz J, et al. Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis. AIDS (2003) 17:637–8.[Web of Science][Medline]


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