Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART

Bertrand, Julie; Tréluyer, Jean‐Marc; Panhard, Xavière; Tran, A.; Auleley, Solange; Rey, Elisabeth; Salmon‐Céron, Dominique; Duval, Xavier; Mentré, France

doi:10.1007/s00228-009-0660-5

Cited by 38 publications

(22 citation statements)

References 50 publications

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“…(51,52). It is uncertain whether interindividual differences in drug metabolism can be attributed to the allelic variant CYP3A4*1B (47,49,(53)(54)(55)(56)(57)(58); it has also been suggested that a linkage disequilibrium between CYP3A4*1B and CYP3A5*1A (and thus increased CYP3A5 expression) could be the actual cause of the altered metabolism (47,58,59). No effect of CYP3A5*3 could be detected in our study.…”

Section: Discussioncontrasting

confidence: 44%

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

Hodel

Csajka

Ariey

et al. 2013

Antimicrob Agents Chemother

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The pharmacogenetics of antimalarial agents are poorly known, although the application of pharmacogenetics might be critical in optimizing treatment. This population pharmacokinetic-pharmacogenetic study aimed at assessing the effects of single nucleotide polymorphisms (SNPs) in cytochrome P450 isoenzyme genes (CYP, namely, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) and the N-acetyltransferase 2 gene (NAT2) on the pharmacokinetics of artemisininbased combination therapies in 150 Tanzanian patients treated with artemether-lumefantrine, 64 Cambodian patients treated with artesunate-mefloquine, and 61 Cambodian patients treated with dihydroartemisinin-piperaquine. The frequency of SNPs varied with the enzyme and the population. Higher frequencies of mutant alleles were found in Cambodians than Tanzanians for CYP2C9*3, CYP2D6*10 (100C¡T), CYP3A5*3, NAT2*6, and NAT2*7. In contrast, higher frequencies of mutant alleles were found in Tanzanians for CYP2D6*17 (1023C¡T and 2850C¡T), CYP3A4*1B, NAT2*5, and NAT2*14. For 8 SNPs, no significant differences in frequencies were observed. In the genetic-based population pharmacokinetic analyses, none of the SNPs improved model fit. This suggests that pharmacogenetic data need not be included in appropriate first-line treatments with the current artemisinin derivatives and quinolines for uncomplicated malaria in specific populations. However, it cannot be ruled out that our results represent isolated findings, and therefore more studies in different populations, ideally with the same artemisininbased combination therapies, are needed to evaluate the influence of pharmacogenetic factors on the clearance of antimalarials.

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Section: Discussioncontrasting

confidence: 44%

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

Hodel

Csajka

Ariey

et al. 2013

Antimicrob Agents Chemother

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“…Patients received a combination of two NRTIs plus one PI as antiretroviral therapy. Population PK analyses of the data from the nelfinavir group and the ritonavir-boosted indinavir group obtained in this trial were performed to evaluate the impact of genetic polymorphisms on nelfinavir and indinavir pharmaco-kinetics (PK) and the link between concentrations and shortterm efficacy (10,21). A substudy of the COPHAR2-ANRS111 trial consisted of measuring plasma and intracellular concentrations of AZT and 3TC in patients whose treatment contained AZT and 3TC as NRTIs with a PI.…”

mentioning

confidence: 99%

Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

Bazzoli

Bénech

Rey

et al. 2011

Antimicrob Agents Chemother

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The population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once-versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.Zidovudine (AZT) and lamivudine (3TC) are common antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection, which causes AIDS. AZT and 3TC are nucleoside reverse transcriptase inhibitors (NRTIs) that are often used in highly active antiretroviral therapy (HAART) along with one protease inhibitor (PI) boosted with ritonavir in general or along with a non-NRTI. The 2009 recommendations of the World Health Organization recommended the use of AZT as a preferred first-line therapy option, a less toxic alternative to the use of stavudine (38). As AZT and 3TC are frequently prescribed together, they are combined in one tablet (Combivir).All NRTIs undergo a series of three sequential phosphorylation reactions producing monophosphates, diphosphates, and then triphosphates (TP) within the cell. AZT and 3TC are thus metabolized intracellularly to their active metabolites (AZT-TP and 3TC-TP, respectively), which block DNA synthesis by reverse transcriptase inhibition and chain termination. These active moieties are the determinants of the efficacy and toxicity of AZT and 3TC. Several studies have demonstrated that the antiviral activity of NRTIs does not always correlate with plasma concentrations of the parent nu...

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“…The functional significance of CYP3A4*1B mutation has recently been reported. CYP3A4*1B/ CYP3A4*1B genotype has been reported to reduce the absorption of indinavir in patients initiating Highly Active Anti-Retroviral Treatment (HAART) naïve patients [14]. This SNP has also been associated with the more aggressive forms and advanced clinical stages of prostate cancer in African-Americans but not in Portugese victims [31].…”

Section: Discussionmentioning

confidence: 99%

“…Substrates of CYP3A4 include methadone, anti-depressants, immunosuppressive agents, macrolide antibiotics, benzodiazepines, calcium channel blockers [12], and several antiretroviral [4,13,14] used in HIV/AIDS. Also importantly, CYP3A4 is involved in the metabolism of endogenous substances that include testosterone [15], progesterone [16], cortisol [17], and 17β-estradiol [18], and this may be important in the patho physiology of diseases including drug dependence.…”

Section: Introductionmentioning

confidence: 99%

High Frequency of CYP3A4*1B among Opiate Dependent Patients in Malaysia

M¹,

A²

2012

J Addict Res Ther

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Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART

Abstract: The CYP3A4*1B polymorphism was found to influence the pharmacokinetics of indinavir and, to some extent, the biochemical safety of indinavir.

Cited by 38 publications

References 50 publications

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

High Frequency of CYP3A4*1B among Opiate Dependent Patients in Malaysia

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