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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (C(min,ss)) was 1.92 microg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 microg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (C(max,ss)) was 7.12 microg/ml, the area under the concentration-time curve from 0 to 10 h (AUC(0-10)) was 32.06 microg. h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUC(ss)) was 35.74 microg. h/ml. Decreases in the mean values of C(min,ss) (29%), C(max,ss) (42%), AUC(0-10) (42%), and AUC(ss) (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir C(min,ss) markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir C(min,ss) above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.
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PMID:Steady-state pharmacokinetics of amprenavir coadministered with ritonavir in human immunodeficiency virus type 1-infected patients. 1249 78

HIV/AIDS has become a chronic disease thanks to the availability of antiretroviral drugs. Many of these antiretroviral drugs are available in India. Many more will soon become available. The cost of these drugs is being reduced gradually and their use is increasing. However, there are both short term and long term side effects. This review focuses on the common potential toxicities of antiretroviral drugs and their management. The potential toxicities include gastrointestinal effects, hepatitis, hypersensitivity reactions, cytochrome P450 interactions, mitochondrial toxicity and lipodystrophy syndrome as well as more drug-specific adverse effects.
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PMID:Antiretroviral therapy: are we aware of adverse effects? 1251 2

Amprenavir is a human immunodeficiency virus-1 (HIV-1) protease inhibitor intended to be used to treat HIV-infected children. Although a pediatric dosage is proposed by the manufacturer, no data are currently available on the pharmacokinetics of amprenavir in neonates and infants. Amprenavir being primarily eliminated after oxidative biotransformation, we explored its in vitro metabolism by cytochrome P450 (P450)-dependent monooxygenases. In our conditions, five metabolites were formed in vitro and subsequently analyzed by liquid chromatography-mass spectrometry; P450-dependent oxidations occurred either on the tetrahydrofuran ring (M3 and M4), the aniline ring (M5), and the aliphatic chain (M2) or resulted from the N-dealkylation and loss of the tetrahydrofuran ring (M1). The two major metabolites, respectively M3 and M2 were formed by human liver microsomes with K(m) between 10 and 70 microM. CYP3A4 and to a lesser extent CYP3A5 were major contributors for the formation of M2, M3, and M5 metabolites, whereas CYP3A7 had no or little activity. This assumption was confirmed by inhibition with ketoconazole and ritonavir (two potent inhibitors of CYP3A) whereas sulfaphenazole (2C9 inhibitor) and quinidine (2D6 inhibitor) were inefficient. The metabolism of amprenavir was negligible in microsomes from either fetuses or neonates and steadily increased after the first weeks of life in relation with the maturation of CYP3A4/5. In conclusion, results demonstrated that the capacity of the human liver to oxidize amprenavir is low during the first weeks after birth and that dosage could be substantially reduced during the early neonatal period.
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PMID:Oxidative metabolism of amprenavir in the human liver. Effect of the CYP3A maturation. 1258 53

HIV-infected individuals usually receive a wide variety of drugs in addition to their antiretroviral drug regimen. Since both non-nucleoside reverse transcriptase inhibitors and protease inhibitors are extensively metabolised by the cytochrome P450 system, there is a considerable potential for pharmacokinetic drug interactions when they are administered concomitantly with other drugs metabolised via the same pathway. In addition, protease inhibitors are substrates as well as inhibitors of the drug transporter P-glycoprotein, which also can result in pharmacokinetic drug interactions. The nucleoside reverse transcriptase inhibitors are predominantly excreted by the renal system and may also give rise to interactions. This review will discuss the pharmacokinetics of the different classes of antiretroviral drugs and the mechanisms by which drug interactions can occur. Furthermore, a literature overview of drug interactions is given, including the following items when available: coadministered agent and dosage, type of study that is performed to study the drug interaction, the subjects involved and, if specified, the type of subjects (healthy volunteers, HIV-infected individuals, sex), antiretroviral drug(s) and dosage, interaction mechanism, the effect and if possible the magnitude of interaction, comments, advice on what to do when the interaction occurs or how to avoid it, and references. This discussion of the different mechanisms of drug interactions, and the accompanying overview of data, will assist in providing optimal care to HIV-infected patients.
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PMID:Drug interactions between antiretroviral drugs and comedicated agents. 1260 74

Having changed the landscape in the treatment of HIV infection, the functional efficacy of current protease inhibitors (PIs) remains limited by their pharmacokinetic and pharmacodynamic profiles. Complex metabolism by the cytochrome P450 system (particularly the 3A4 isoenzyme), action of membrane drug transporter elements (such as P-glycoprotein and multi-drug resistance-associated proteins) and activation of the nuclear receptor steroid xenobiotic receptor may alter exposures and compromise the antiretroviral activity of these drugs. These factors, as well as inadequate adherence, can facilitate the emergence of PI resistance and lead to regimen failure. Coadministration of ritonavir can enhance exposures of a primary PI by inhibiting CYP3A4 metabolism, P-glycoprotein activity and multi-drug resistance protein-1-mediated efflux. Adding ritonavir, however, is not without cost. Dyslipidaemia (possibly increasing the risk of cardiovascular events), gastrointestinal intolerance, multiple drug-to-drug interactions and activation of steroid xenobiotic receptor can all result and must be balanced against the pharmacokinetic improvement rendered by the addition of ritonavir. Understanding the pharmacological origins for the variations in exposures of PIs, both between and within patients, is important for the successful use of these agents.
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PMID:The role of pharmacological enhancement in protease inhibitor-based highly active antiretroviral therapy. 1260 63

A population-based pharmacokinetic (PK) model has been developed for efavirenz based on 16 phase I studies. The combined data set consisted of 334 healthy volunteers, 2,907 efavirenz dose administrations and 9,342 measured plasma concentrations across a range of doses from 100-600 mg. The pharmacokinetic structural model was a 2-compartment model with first-order absorption with differentiation between single- and multiple-dose exposure to account for known hepatic cytochrome P450 induction of efavirenz metabolism. Model-building was performed on the index data set (66% of the total database), as a data-splitting technique was used to validate the final model using NONMEM. The final model confirmed the appropriateness of separate clearance terms for single and multiple dose administration (2.65 versus 10.2 l/h, respectively). Clearance increased with dose and frequency of administration. A lower clearance was predicted in Asians and Blacks relative to Caucasians. A slightly lower clearance was observed in females relative to males (9.08 compared to 10.2 l/h in males) and interactions on clearance due to co-administration of fluconazole, ritonavir, rifampin, indinavir and azithromycin were identified. The magnitudes of these effects were small and did not suggest dose adjustment in the various subpopulations. With little exception, these results agree with the findings from the non-compartmental analyses. The residual variability was 21% CV and the intersubject variation in CL/F and V/F was 48 and 85%, respectively. The phase I meta-analysis was able to substantiate the pharmacokinetic characteristics of efavirenz derived from the composite of individual well-defined studies. The model was deemed adequate for subsequent evaluation in HIV-infected patients. Covariates and outlier classes identified in this phase I meta-analysis were similarly identified in subsequent analyses of patient data.
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PMID:Population pharmacokinetic meta-analysis with efavirenz. 1269 88

Despite the efficiency of the present polytherapies against AIDS, HIV replication continues indicating difficulties in drug adherence, drug-drug interactions, resistance issues, and the existence of reservoirs or sanctuaries for the virus. Moreover, most of the current FDA-approved HIV protease inhibitors (PIs) display disadvantageous physicochemical and pharmacological properties such as low water solubility, low oral bioavailability and/or low level of penetration into the HIV sanctuaries resulting from their in vivo binding to the plasma proteins and to the Multi-Drug-Resistant P-glycoprotein, their rapid metabolization and inactivation by the liver cytochrome P450 enzymes. To overcome these suboptimal pharmacokinetics, high daily doses must be ingested, which complicate patient adherence to the prescribed regimen and contribute to the appearance of serious long-term metabolic complications and to the decrease of the viral treatment outcome. Another attractive alternative aimed at improving the safety, pharmacokinetics, and therapeutic potency of the current PIs is to modify these PIs into pharmacologically inactive prodrugs which are converted in vivo into their parent active drug. The present review is dedicated to the different prodrug approaches, including the "lipophilic", "hydrophilic", "active transport" and "double-drug" prodrug strategies, which have been applied more particularly to the current HIV PIs used in clinic. Among the strategies explored up to now, the most successful one was the "hydrophilic" prodrug approach which has led to the discovery of fosamprenavir, a phosphate ester prodrug of amprenavir, which has reached phase III clinical trials. This success gives strong support for the search of PI prodrugs as a therapeutic alternative in addition to the development of new and well-tolerated PIs.
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PMID:Prodrugs of HIV protease inhibitors. 1287 Nov 95

Highly active antiretroviral therapy (HAART) significantly prolongs the lives of HIV-infected patients. Current regimens may consist of a protease inhibitor (PI) combined with at least two or more other antiretroviral drugs. PI administration has been shown to be associated with alterations in plasma lipids (i.e. prompt and sustained increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides) and insulin levels that place PI-treated patients at risk for coronary heart disease (CHD). Because PI-associated dyslipidemia is generally asymptomatic and occurs in patients who are often younger than those traditionally at risk for CHD, the need for primary prevention of acute coronary events in these patients is often unappreciated. Statins form a significant component of pharmacotherapy for PI-associated dyslipidemia. However, because PIs and all statins except pravastatin are metabolized by the cytochrome P450 (CYP) system, co-administration of these agents produces a significant risk of drug interactions and statin-induced hepatotoxicity and myopathy. This risk can be greatly reduced by administering a statin not metabolized by CYP. The need for lipid reduction therapy may be minimized with the use of new PIs that are comparable in efficacy to current PIs but do not negatively affect lipid levels.
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PMID:HIV protease inhibitors and dyslipidemia. 1287 4

The antituberculosis drug rifampicin (rifampin) induces a number of drug-metabolising enzymes, having the greatest effects on the expression of cytochrome P450 (CYP) 3A4 in the liver and in the small intestine. In addition, rifampicin induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein. Full induction of drug-metabolising enzymes is reached in about 1 week after starting rifampicin treatment and the induction dissipates in roughly 2 weeks after discontinuing rifampicin. Rifampicin has its greatest effects on the pharmacokinetics of orally administered drugs that are metabolised by CYP3A4 and/or are transported by P-glycoprotein. Thus, for example, oral midazolam, triazolam, simvastatin, verapamil and most dihydropyridine calcium channel antagonists are ineffective during rifampicin treatment. The plasma concentrations of several anti-infectives, such as the antimycotics itraconazole and ketoconazole and the HIV protease inhibitors indinavir, nelfinavir and saquinavir, are also greatly reduced by rifampicin. The use of rifampicin with these HIV protease inhibitors is contraindicated to avoid treatment failures. Rifampicin can cause acute transplant rejection in patients treated with immunosuppressive drugs, such as cyclosporin. In addition, rifampicin reduces the plasma concentrations of methadone, leading to symptoms of opioid withdrawal in most patients. Rifampicin also induces CYP2C-mediated metabolism and thus reduces the plasma concentrations of, for example, the CYP2C9 substrate (S)-warfarin and the sulfonylurea antidiabetic drugs. In addition, rifampicin can reduce the plasma concentrations of drugs that are not metabolised (e.g. digoxin) by inducing drug transporters such as P-glycoprotein. Thus, the effects of rifampicin on drug metabolism and transport are broad and of established clinical significance. Potential drug interactions should be considered whenever beginning or discontinuing rifampicin treatment. It is particularly important to remember that the concentrations of many of the other drugs used by the patient will increase when rifampicin is discontinued as the induction starts to wear off.
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PMID:Pharmacokinetic interactions with rifampicin : clinical relevance. 1288 88

The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is the drug of choice for preventing maternal-fetal HIV transmission during pregnancy. Our aim was to assess the cytotoxic effects of AZT on human placenta in vitro. The mechanisms of AZT-induced effects were investigated using JEG-3 choriocarcinoma cells and primary explant cultures from term and first-trimester human placentas. Cytotoxicity measures included trypan blue exclusion, MTT, and reactive oxygen species (ROS) assays. Apoptosis was measured with an antibody specific to cleaved caspase-3 and by rescue of cells by the general caspase inhibitor Boc-D-FMK. The effect of AZT on the activities of glutathione-S-transferase, beta-glucuronidase, UDP-glucuronosyl transferase, cytochrome P450 (CYP) 1A, and CYP reductase (CYPR) in the placenta was assessed using biochemical assays and immunoblotting. AZT increased ROS levels, decreased cellular proliferation rates, was toxic to mitochondria, and initiated cell death by a caspase-dependent mechanism in the human placenta in vitro. In the absence of serum, the effects of AZT were amplified in all the models used. AZT also increased the amounts of activity of GST, beta-glucuronidase, and CYP1A, whereas UGT and CYPR were decreased. We conclude that AZT causes apoptosis in the placenta and alters metabolizing enzymes in human placental cells. These findings have implications for the safe administration of AZT in pregnancy with respect to the maintenance of integrity of the maternal-fetal barrier.
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PMID:3'-azido-3'-deoxythymidine (AZT) induces apoptosis and alters metabolic enzyme activity in human placenta. 1455 Jul 50


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