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doi: 10.1097/QAD.0b013e3283189c07
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Efavirenz–rifampicin interaction: therapeutic drug monitoring to efavirenz dosage optimization in HIV/TBC patients

Cabrera, Salvador Ea,b; Cordero, Miguelc; Iglesias, Aliciac; Valverde, María Pa; Domínguez-Gil, Alfonsoa,d; García, María Jd

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aPharmacy Service, University Hospital of Salamanca, Salamanca, Spain

bPharmacy Institute, University Austral of Chile, Valdivia, Chile

cInfectious Disease Service, University Hospital of Salamanca, Spain

dDepartment of Pharmacy and Pharmaceutical Technology, University of Salamanca, Salamanca, Spain.

Correspondence to Salvador Cabrera Figueroa, Servicio de Farmacia, Hospital Universitario de Salamanca, Paseo de San Vicente 58, 37007 Salamanca, España, Spain. Tel: +34 923291172; fax: +34923291174; e-mail: farpacex@husa.sacyl.es

Rifampicin (RFP) is known to decrease efavirenz (EFV) plasma concentrations by about 30% in healthy volunteers and HIV-1 patients [1]. Thus, a daily dose change from 600 to 800 mg is usually recommended, especially in patients weighing more than 60 kg [2,3].

The high variability in EFV pharmacokinetic behaviour justifies the use of therapeutic drug monitoring (TDM) as an approach to optimizing EFV dosages, especially when drugs with known or suspected clinically relevant interactions are used.

A 40-year-old woman (patient 1) and a 59-year-old man (patient 2) were diagnosed with disseminated tuberculosis and HIV-1 infection. Both patients started treatment with RFP, isoniazid, pyrazinamide and ethambutol as antituberculosis drugs. Two weeks later, they began to receive antiretroviral therapy (ART) with lamivudin, abacavir and EFV, following current guidelines [4].

Follow-up determinations carried out every 2 months included plasma viral load, CD4 cell count and steady-state EFV plasma concentrations. ART adherence was evaluated monthly by the dispensation records and simplified medication adherence questionnaire (SMAQ) [5].

Written informed consent of patients and ethical approval was obtained from the Institutional Review Board of the University Hospital of Salamanca.

The adherence to ART in both patients was optimal (100%) along the period analysed. In light of the results of the clinical evolution of the patients and their EFV plasma concentrations, the doses were individualized in order to achieve concentrations within the currently accepted therapeutic range (1–4 mg/l) [6]. The results concerning clinical efficacy, CD4 cell count and viral load, together with the evolution of the plasma concentrations determined in each control, are shown in Fig. 1.

Fig. 1
Fig. 1
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In both patients, the CYP2B6 and CYP3A4 isoenzymes and the multidrug resistance (MDRI) gene did not exhibit polymorphisms, which prevents the higher dosage requirement observed in patient 2 with respect to the general population from being ascribed to a genetic cause. However, in this patient, a new mutation was found in the N-acetyl transferase 2 (NAT2; 191G/G, 282T/T, 341T/T, 481T/C, 590A/A, 803A/A, 857G/G). This combination has hitherto not been described as an allelic form.

As can be seen from the results shown in Fig. 1, the infra-therapeutic levels of EFV can be attributed to the increase in the clearance of the drug, which demands a dosage correction for EFV concentrations within the therapeutic range to be reached. These concentrations were accompanied by virological and immunological efficacy.

A difference of 100% was observed in the doses of EFV required in both patients (800 vs. 1600 mg/day) during its association with RFP; this could be a result of different intensities in the interaction between the two drugs. However, the withdrawal of the RFP from the patients' treatments made it necessary to have a 33% decrease in the EFV dose in both of them; thus, the difference between necessary doses (600 vs. 1200 mg/day) is maintained in 100% when the RFP inducer effect had disappeared. In this sense, it should be noted that a certain period of time is necessary for this to occur, estimated at approximately 1 month. This counsels a gradual reduction in the dose of EFV in order to avoid periods with infra-therapeutic concentrations that might favour the development of resistances, which are of special relevance in the case of EFV, characterized by having a low-genetic barrier [7].

The different doses of EFV required by the patients, regardless of whether RFP was present or not in the treatment, are due to a different type of pharmacokinetic behaviour that could be attributed to genetic differences in the isoenzymes responsible for EFV metabolism or drug transport phenomena. However, the genotypes observed in these patients indicated a normal activity of them. The finding of an allelic combination of NAT2 in patient 2 could account for the high dose that he required. However, this gene is responsible for N-acetylation, a metabolic process to which, theoretically, EFV is not subject to, such that it does not account for this difference either.

Accordingly, the pharmacogenetic factors described to date in the literature do not seem to be responsible for the broad pharmacokinetic variability of EFV between the two patients studied here, which would be due to hitherto unidentified factors. Thus, TDM in clinical practice continues to be the best tool for optimizing the dosing of EFV, as it reflects the phenotype of each patient. Although TDM has still not been proposed for EFV dosage adjustment in HIV-1/TBC coinfection, our results demonstrate its usefulness during the treatment and post-treatment period with RFP, allowing the drug dose to be adapted according to the pharmacokinetic changes and thereby favouring the efficacy and safety of ART.

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Acknowledgements

Salvador Cabrera contributed to the design of the study, pharmacokinetics analyses and drafting/completion of the manuscript. María J García was the lead investigator of this study, conceived the design, and contributed to the pharmacokinetics analyses, interpretation and writing of the manuscript. María P Valverde contributed to the data management and completion of the manuscript. Miguel Cordero contributed to the design of the study and drafting/completion of the manuscript. Alicia Iglesias contributed to the design of the study and interpretation of data. Alfonso Domínguez-Gil contributed to the pharmacokinetics analyses and drafting/completion of the manuscript. The authors have no conflicts of interest to disclose.

Efavirenz, as a pure compound, was kindly provided by Bristol Myers Squibb laboratories. This substance was used both as a standard for the analytical technique validation and as a standard in all quantitative determinations.

The present research was supported by funding granted by the project FIS PI070714, the Ministry of Health and Consumption of Spain, in the frame of the National Plan of I+D+I 2004–2007.

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References

1. Soy D, Lopez E, Sarasa M, Lopez-Pua Y, Lopez-Cortes L, Ruiz-Valderas R, et al. Population pharmacokinetic modeling in HIV patients with tuberculosis treated with efavirenz and rifampicin [abstract #15]. In: 6th International Workshop on Clinical Pharmacology of HIV Therapy, Quebec, Canada, 28–30 April 2005.

2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 29 January 2008. pp. 1–128. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. [Accessed 29 May 2008].

3. Updated Guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2004; 53:37.

4. American Thoracic Society; Centers for Disease Control; Infectious Disease Society of America. Treatment of tuberculosis. MMWR 2003; 52:1–77.

5. Knobel H, Alonso J, Casado JL, Collazos J, González J, Ruiz I, et al. Validation of a simplified medication adherence questionnaire in a large cohort of HIV-infected patients: the GEEMA Study Group. AIDS 2002; 16:605–613.

6. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001; 15:71–75.

7. Joly V, Yeni P. Non nucleoside reverse transcriptase inhibitors. AIDS Rev 1999; 1:37–44.

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