Deleterious pharmacokinetic interaction between bexarotene and efavirenzписьмо
Аннотация: Efavirenz (Sustiva, EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV1 with a long half-life (∼45 h) allowing once-daily oral administration. EFV is highly bound to plasma proteins (>99%) and is able to induce CYP2B6, CYP2C19 and CYP3A4 [1]. The recommended daily dosage of EFV is 600 mg. The therapeutic EFV plasma concentration range is 1000–4000 ng/ml [2]. Bexarotene (Targretin, BXR) is a X-receptor-selective retinoid (a rexinoid), which is approved in Europe for the treatment of patients with skin manifestations of advanced-stage cutaneous T-cell lymphoma refractory to at least one systemic therapy. It is recommended as a second-line therapy for the treatment of mycosis fungoides [3]. Despite the established impact of highly active antiretroviral therapy (HAART) in reducing HIV-related morbidity and mortality, malignancy remains an important cause of death. Patients who receive the combination of cancer chemotherapy and HAART may achieve better response rates and higher rates of survival than patients who receive antineoplastic therapy alone. However, the likelihood of drug interactions with combined therapy is high, since protease inhibitors and NNRTIs are substrates and potent inhibitors or inducers of the CYP450 system. Since many antineoplastic drugs are also metabolized by the CYP450 system, co-administration with HAART could result in either drug accumulation and possible toxicity, or decreased efficacy of one or both classes of drugs. No formal studies to evaluate interactions with BXR have been conducted. On the basis of the oxidative metabolism of BXR by CYP3A4, co-administration with CYP3A4 inducers such as rifampicin or phenobarbital may theoretically cause a reduction in plasma BXR concentrations. Moreover, repeated administration of BXR may result in an auto-induction of its own metabolism and, particularly at dosages above 300 mg/m2/day, may increase the rate of metabolism and reduce plasma concentrations of other substances metabolized by CYP3A4. We report a virological failure occurring in a 70-year-old HIV-1-infected patient (body area 1.77 m2) who received HAART for 14 years. At the first time of immuno-virological test availability (1996), plasma HIV-1 RNA (pVL) was 3.65 log10 copies/ml and CD4 and CD8 cell counts (%) were 236 (12%) and 1280 (65%)/μl, respectively. He had always been very drug-compliant with undetectable pVL over the past 12 years while receiving seven successive different multidrug regimens containing nucleoside reverse transcriptase inhibitors [zalcitabine (ddC), zidovudine (ZDV), stavudine (d4T), abacavir (ABC), lamivudine (3TC)] and indinavir, switched for intolerance (nephrolithiasis, lipodystrophy, haematologic toxicity, neuropathy) or simplification. In 2006, he was treated with EFV/3TC/ABC at respective standard doses, and then the EFV dosage was reduced from 600 to 400 mg once daily because of neuropsychiatric adverse effects, based on therapeutic drug monitoring. After this dose adjustment and until March 2009, pVL remained below 50 copies/ml. In February 2003, a neoplastic disorder (mycosis fungoides) was diagnosed on his cheek. He was successively treated with local radiation therapy, puvatherapy, topical chlormethine hydrochloride, topical corticosteroids and alpha-interferon. After an acute exacerbation of his lesions, therapy and maintenance with BXR (300 mg once daily) was initiated in October 2009. Two months after the initiation of BXR, two consecutive pVL above 50 copies/ml confirmed virological failure. During this period, CD4 cell count (%) was relatively stable (Table 1) but BXR-related adverse effects (hypertriglyceridaemia, hypercholesterolaemia, hypothyroidism, anaemia and pruritus) most often reported in patients starting at 300 mg/m2/day occurred.Table 1: Immunovirological and pharmacological findings.Determinations of EFV and BXR plasma concentrations were performed [prospectively for EFV using Acquity UPLC-Acquity TQD (LOQ ∼1 ng/ml) and retrospectively for BXR using LC-Photodiode Array UV detector (LOQ ∼10 ng/ml), Waters Corp. Milford, Massachusetts, USA] according to validated and previously published methods [4,5]. The virological failure was associated with two sub-therapeutic EFV plasma concentrations (<1000 ng/ml), justifying a double dose to reach the therapeutic range. Surprisingly, no mutation associated with EFV resistance was detected at time of failure using bulk sequencing. However, the K103N mutation, which confers a high level of resistance to EFV, might be present as a minority population at the time of early virological failure and could emerge rapidly thereafter. At the same time, BXR plasma exposure was decreased, with concentrations approximately 50% lower compared with steady-state reference pharmacokinetic data (Table 1). Consequently, only a partial efficacy of BXR on neoplastic lesions was observed [6]. In this case, we believe that there was a negative pharmacokinetic interaction between BXR and EFV resulting from induction of either CYP3A4 or P-glycoprotein by BXR. We also conclude that co-administration of BXR can decrease EFV plasma exposure, may result in virological failure and resistance mutations, and should be discouraged. Concomitant drugs that induce CYP3A4 (e.g. nevirapine, phenobarbital, phenytoin, prednisone, rifampicin) and also EFV may increase the clearance of BXR, resulting in decreased clinical effectiveness [7]. Acknowledgements Dr Aude Desnoyer (intern in Clinical Pharmacy Department) was responsible for the data collection of this case and also the primary author of the paper. Dr Firas Al Kaied and Professor Patrick Yeni cared for the HIV-infectious disease of the patient. Professor Diane Descamps was the virologist responsible for the plasma HIV-RNA monitoring and HIV genotype testing. Professor Vincent Descamps monitored the dermatological neoplastic lesions and its treatment. Dr Christine Le Beller was Pharmacovigilant and reviewed the paper. Dr Gilles Peytavin was responsible for the pharmacological analysis, and wrote the paper. Dr A. Desnoyer, Dr F. Al Kaied, Professor D. Descamps, Professor P. Yeni, Professor V. Descamps and Dr C. Le Beller have not accepted honoraria or research grants from any pharmaceutical company and do not accept gifts from, nor hold an equity position in any such company. Dr G. Peytavin has received travel grants, consultancy fees, honoraria and study grants from various pharmaceutical companies, including Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Pfizer and Roche.
Год издания: 2010
Авторы: Aude Desnoyer, Firas Al Kaied, Diane Descamps, Patrick Yéni, V. Descamps, Christine Le Beller, Gilles Peytavin
Издательство: Lippincott Williams & Wilkins
Источник: AIDS
Ключевые слова: Cutaneous lymphoproliferative disorders research, Retinoids in leukemia and cellular processes, Lymphoma Diagnosis and Treatment
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Открытый доступ: bronze
Том: 24
Выпуск: 14
Страницы: 2296–2298