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Delavirdine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Delavirdine is approved in many countries for treatment of HIV infection in combination with other antiretroviral drugs (e.g. zidovudine and lamivudine, or tenofovir and emtricitabine). It is now rarely used. There are insufficient clinical data comparing antiretroviral drug combinations including delavirdine with currently recommended combinations containing logical comparator drugs (e.g. nevirapine, efavirenz, or a ritonavir-boosted protease inhibitor). Further, most of the prospective clinical trials of delavirdine compared treatment with two nucleoside reverse transcriptase inhibitors (e.g. zidovudine plus lamivudine) with the same nucleoside analog combination plus delavirdine (Table 237.4).
Antituberculous Drugs
Published in Thomas T. Yoshikawa, Shobita Rajagopalan, Antibiotic Therapy for Geriatric Patients, 2005
In HIV-infected persons, most protease inhibitors or delavirdine should not be administered concurrendy with rifampin. Rifabutin with appropriate dose adjustments can be used with protease inhibitors (saquinavir should be augmented with ritonavir) and NNRTIs (except delavirdine). Clinicians should consult web-based updates for the latest specific recommendations
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Delavirdine is a potent and selective nonnucleoside reverse transcriptase inhibitor (Dueweke et al. 1993) used in the treatment of HIV-1 infection. The major metabolic pathway of delavirdine in rats involves N-dealkylation, pyridine ring 6′-hydroxylation, pyridine ring cleavage, and amide bond cleavage (Figure 3.85) (Chang et al. 1997). Desalkyl delavirdine is the major metabolite in rat urine and plasma, which could be further hydroxylated or sulfated to form M15d and M4d, respectively. Cleavage of the amide bond in delavirdine to give N-isopropylpyridinepiperazine (M12) and indole carboxylic acid (M10) constituted a minor pathway. Degradation of 6′-hydroxy delavirdine (M7) generated despyridinyl delavirdine (M2) and the pyridine ring–opened product (M14). M7 also underwent sulfation or glucuronidation to form M8 and M6, respectively. The major metabolite in rat bile is M6, whereas M7 and M8 are observed as minor metabolites. In human liver microsomes, at least four metabolites are formed from delavirdine: desalkyl derivative (M5), despyridinyl delavirdine (M2), M7, and M7a (Figure 3.85) (Voorman et al. 1998b). Desalkyl delavirdine is not active against HIV-1 reverse transcriptase (Genin et al. 1996). Since 6′-O-glucuronyl delavirdine (M6) is a major metabolite of delavirdine in rats (Chang et al. 1997), M7 could be the 6′-hydroxylated metabolite of delavirdine and M7a and M7 are tautomers, with M7 representing the enol form, which slowly converts to M7a, the keto form. Delavirdine is mainly metabolized by CYP3A4 and, to a lesser extent, by 2D6 (Voorman et al. 1998b). Only CYP2D6 and 3A4 ex hibit significant desalkylation of delavirdine; incubation of delavirdine with increasing concentrations of CYP3A4 shows increased formation of dealkylated delavirdine as well as the formation of M7 and M7a. Desalkyl delavirdine is also catalyzed by CYP2C8 and 3A5 at a low activity.
Infection-related stillbirth: an update on current knowledge and strategies for prevention
Published in Expert Review of Anti-infective Therapy, 2021
Samia Aleem, Zulfiqar A. Bhutta
Studies from sub-Saharan Africa have found an association between maternal HIV infection during pregnancy, and adverse pregnancy outcomes, including stillbirth [36]. The risk of stillbirth in HIV-infected women is significantly higher than that in women without HIV (RR 3.34, 95% CI: 1.80, 6.20, p < 0.001), as shown in a study from Mozambique [37]. A high maternal viral load is a strong risk factor for vertical transmission, which may occur during pregnancy, labor, or delivery [38]. There is increasing evidence to suggest that higher viral loads increase the risk of stillbirth [36]. Antiretroviral drugs (ARVs) are recommended during pregnancy to reduce maternal viral load, thereby reducing the risk of maternal-to-child transmission [38]. Commonly used classes of ARVs include nucleoside analogue reverse transcriptase inhibitors (including zidovudine, lamivudine, didanosine, stavudine), non‐nucleoside analogue reverse transcriptase inhibitors (including nevirapine, delavirdine, efavirenz), and protease inhibitors (including indinavir, ritonavir, nelfinavir) [38]. Without appropriate therapy, 15–30% of infants born to HIV-positive women will become HIV-infected during gestation and delivery, and another 5–15% of infants will be infected through breastfeeding [39]. At this time, the WHO recommends that ARV therapy should be initiated in all HIV-positive pregnant women, and in those who are breastfeeding, regardless of clinical stage and CD4 cell count [40].
Allosteric activation of cytochrome P450 3A4 by efavirenz facilitates midazolam binding
Published in Xenobiotica, 2018
Tomohiko Ichikawa, Hirofumi Tsujino, Takahiro Miki, Masaya Kobayashi, Chiaki Matsubara, Sara Miyata, Taku Yamashita, Kohei Takeshita, Yasushige Yonezawa, Tadayuki Uno
Efavirenz belongs to a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and is combined with other antiretroviral agents for the treatment of HIV-1 infections (Vrouenraets et al., 2007). Keubler et al. (2012) showed that both efavirenz and ketoconazole, a representative inhibitor of CYP3A4, affect the formation of 1-hydroxymidazolam. Von Moltke et al. (2001) reported that efavirenz and delavirdine, another clinically available NNRTI, affects CYP3A4-mediated 4-hydroxylation of triazolam. Studies on drug interactions and substrate specificity of CYP3A4 with efavirenz have also been conducted (Kosugi & Takahashi, 2015), and all reports suggest that while efavirenz acts as both an inducer and inhibitor of CYP3A4, it also acts as an activator in vivo and in vitro. Remarkably, a recent clinical study showed that concentrations of midazolam in plasma were significantly decreased one day after administration of efavirenz as a single oral dose (Mikus et al., 2017), implying that efavirenz facilitates the acute metabolic activation of midazolam. Although the in vivo observations were supported by in vitro studies using human liver microsomes and recombinant human CYP3A4 as mentioned above, it remains unclear whether efavirenz binds to a distinct allosteric site of the enzyme, leading to enhanced midazolam turnover attributable to changes at the active site.
The dawn of precision medicine in HIV: state of the art of pharmacotherapy
Published in Expert Opinion on Pharmacotherapy, 2018
Ying Mu, Sunitha Kodidela, Yujie Wang, Santosh Kumar, Theodore J. Cory
Hyperlipidemia is defined as abnormally elevated levels of any or all lipids or lipoproteins in the blood, and in individuals with HIV occurs due to high triglycerides and low HDL levels [115]. Enhanced levels of TNF and IL-6 and down regulated clearance of lipids may contribute to high triglycerides levels in people with HIV. Increased hepatic synthesis of very low-density lipoprotein could be responsible for the low level of HDL [116]. Moreover, a viral infection could induce dyslipidemia by interferon-α in acute-phase reactants [117]. On the other hand, the incidence of dyslipidemia can be increased by some drugs in ART treatment, particularly PI-containing regimens. PIs inhibit lipogenesis and adipocyte differentiation [118]. Furthermore, the PK enhancer RTV increases hepatic synthesis and plasma circulation of triglyceride [119]. TFV is recommended to avoid dyslipidemia [120,121]. The drug–drug interaction between statins and ART regimens should be observed as well, however [122]. PIs significantly increase serum statin level by inhibiting statin metabolism. The increased statin level leads to the risks of myopathy and rhabdomyolysis. For patients who are on simvastatin and lovastatin should be avoided to be administered with PIs and boosters. The NNRTI delavirdine increases statin level by inhibiting CYPs metabolism. Efavirenz reduces serum statin level by increasing statin metabolism [81]. Patients who are on statin need to be monitored when prescribed with ARVs like delavirdine or efavirenz.