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Etravirine-raltegravir, a marked interaction in
HIV-1-infected patients: about four cases
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AIDS:
27 April 2009 - Volume 27 - Issue 7 - p 869-871
doi: 10.1097/QAD.0b013e328329915f
Correspondence
Menard, Amelie; Solas, Caroline; Mokthari, Saadia; Bregigeon, Sylvie; Drogoul, Marie-Pierre; Tamalet, Catherine; Lacarelle, Bruno; Martin, Isabelle Poizot
aCenter of Clinical Care and Research on HIV Infectious Disease, P™le Oncologie Specialites Medicales et Chirurgicales, Universite de la Mediterranee, Sainte Marguerite University Hospital, France
bLaboratoire de Pharmacologie et de Toxicologie, Hopital La Timone, France
cService des maladies infectieuses et tropicales, P™le des maladies infectieuses, Hopital Nord, France
dFederation de Microbiologie Clinique, Timone University Hospital, Marseille, France.
Recently, new compounds, capable of overcoming the extensive class resistances observed in multitreated patients, became available for HIV-infected patients. Raltegravir (RAL) is the first compound of a new class of antiretrovirals, the integrase inhibitors. Etravirine (ETV), a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), has been demonstrated to be active against HIV strains presenting resistance to first-generation NNRTI.
ETV and RAL are both extensively metabolized, mainly by cytochrome P450-3A (CYP3A) for ETV and by glucuronidation through uridine-diphosphate-glucuronosyl-transferase-1A1 (UGT1A1) for RAL. Recently, a two-way interaction study [1] of ETV and RAL, undertaken in healthy volunteers, reported that ETV had an overall modest suppressive effect on RAL pharmacokinetics.. In contrast, we report here four cases demonstrating a significant drug-drug interaction between RAL and ETV in HIV-1 B-subtype monoinfected patients followed in an HIV-outdoor unit.
Case one was a 49-year-old patient, staged A3, diagnosed in 1985. From 1987 to 2006, he received 19 therapeutic regimens [combination antiretroviral therapy (cART)]. In April 2008, enfuvirtide (T20), RAL and darunavir/ritonavir (DRV/r) were initiated. High-treatment adherence was supported by plasma trough concentrations (Ctrough) in the expected range for RAL and DRV. In August 2008, T20 was switched for ETV because of virological failure and patient request. Therapeutic drug monitoring (TDM) realized 1 month later indicated a drastically decrease of the RAL Ctrough (10 ng/ml) with therapeutic ETV and DRV concentrations. These results were confirmed 1 month later (Table 1).
Case two was a 53-year-old patient, staged C3, diagnosed in 1985. He received 42 therapeutic regimens from 1994 to 2007 without virological success.. In April 2007, cART was changed for ETV, RAL, tenofovir (TDF) and emtricitabine. Although plasma Ctrough for TDF was in the expected range, RAL Ctrough was subtherapeutic. RAL dose was increased from 800 mg/day to 1200 mg/day, resulting in an optimal RAL Ctrough (Table 1).
Case three was a 51-year-old patient, staged B2, diagnosed in 1987. He received 17 cART from 1994 to 2007 without achieving virological success. In September 2007, RAL and DRV/r were initiated, and therapeutic DRV Ctrough was observed. RAL TDM was not available at this time. In April 2008, cART was intensified by ETV, and again TDM showed a low RAL Ctrough (12 ng/ml). Two months later, this result was confirmed by the concomitant expected Ctrough for ETV and DRV (Table 1).
Case four was a 50-year-old patient, staged C3, diagnosed in 1992. From February 1994 to September 2008, he received 20 cART that resulted in an immunological recovery, although the viral load was still detectable. In October 2008, ETV-RAL and TDF were initiated, and again TDM results displayed an unusual low RAL Ctrough (29 ng/ml), whereas ETV Ctrough was in the appropriate range (Table 1).
A significant and dramatic decrease in the RAL Ctrough was reported for these four patients. In case one, the drop of RAL Ctrough was observed after ETV was introduced. The mean ± SD RAL plasma Ctrough was 16.7 ± 10..2 ng/ml and always lower than the mean RAL Ctrough of 63 ng/ml (range 29-118 ng/ml), expected at 400 mg twice daily (b.i.d.) [2]. Moreover, 4/7 RAL Ctrough was lower than the in-vitro IC95 of 14.6 ng/ml [3], which may explain the reduced virological efficacy observed in the four patients.
ETV is known to be a potent inducer of CYP3A4, and therefore may induce UGT1A1. This could result in a decreased plasma concentration of UGT1A1 substrates such as RAL. Although, in healthy volunteers, the mean RAL area under the concentration-time curve (AUC0-12) was not significantly affected by ETV [1], a mean decrease of 34% in the Ctrough was reported with a 90% confidence interval of the geometric mean ratio ranging from 0.34-1.26, exhibiting a significant interindividual variability.
The wide pharmacokinetic variability of RAL was also recently reported in HIV-1-infected patients [4]. Moreover, pharmacokinetic-pharmacodynamic relationship was identified for RAL, suggesting a possible interest of TDM for this drug [5].
Our results underline the need for monitoring RAL concentrations to rapidly detect suboptimal concentrations, in particular in heavily pretreated patients for which future therapeutic options are very restraint. The proportion of patients in which this drug-drug interaction may happen is currently unknown and should be estimated by investigating large cohorts. These results should draw attention to the fact that drug-drug interaction studies conducted in healthy volunteers may not always accurately predict the results obtained in patients.
References
1. Anderson MS, Kakuda TN, Hanley W, Miller J, Kost JT, Stoltz R, et al. Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. Antimicrob Agents Chemother 2008; 52:4228-4232.
2. Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, Cooper DA, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr 2006; 43:509-515.
3. Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, et al. Safety, tolerability and pharmokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharmacol Ther 2008; 83:293-299.
4. Rahal A, Soulie C, Schneider L, Ghosn J, Boue F, Reynes J, et al. Therapeutic drug monitoring of raltegravir (MK-0518) in experienced HIV-infected patients. In: 9th International Workshop on Clinical Pharmacology of HIV Therapy; 7-9 April 2008; New Orleans, LA. Oral presentation #O25..
5. Wenning L, Hwang E, Nguyen BY, Teppler H, Danovich R, Iwamoto M, et al. Pharmacokinetic/pharmacodynamic (PK/PD) analyses for raltegravir (RAL) in phase III studies in treatment experienced HIV-infected patients following 48 weeks of treatment. In: 48th Interscience Conference on Antimicrobial Agents and Chemotherapy; 28 October 2008; Washington, DC. Poster presentation #H-4054.
6. Kakuda TN, Schšller-GyŸre M, Peeters M, Corbett C, De Smedt G, Woodfall BJ, et al. Pharmacokinetics of etravirine (ETR; TMC125) are not affected by sex, age, race, use of enfuvirtide (ENF) or treatment duration in HIV-I-infected subjects. In: 9th International Workshop on Clinical Pharmacology of HIV Therapy; 7-9 April 2008; New Orleans, LA. Poster presentation #P34.
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