carbovir-triphosphate and abacavir

Here, we aimed to investigate the pharmacokinetics of abacavir and carbovir triphosphate (CBV-TP) with darunavir/ritonavir 900/100 mg once daily or raltegravir 400 mg twice daily.. HIV-infected subjects on abacavir (600 mg once daily) underwent steady-state pharmacokinetic assessments without and with darunavir/ritonavir or raltegravir. Within-subject changes in plasma and intracellular pharmacokinetic parameters were evaluated by geometric mean ratios (GMRs) and 90% CIs.. A total of 19 patients completed the study. With darunavir/ritonavir (versus abacavir alone), abacavir GMRs (90% CI) were 0.73 (0.66, 0.80), 0.62 (0.50, 0.77) and 0.78 (0.69, 0.87) for area under the curve (AUC), trough concentration (C(trough)) and maximum concentration (C(max)), respectively. With raltegravir, they were 1.03 (0.97, 1.10), 0.83 (0.62, 1.11) and 1.06 (0.95, 1.18), respectively. Intracellular CBV-TP GMRs (90% CI) were 0.88 (0.72, 1.07), 0.68 (0.48, 0.95) and 0.98 (0.79, 1.23) for AUC, C(trough) and C(max), respectively, with darunavir/ritonavir, and 0.96 (0.76, 1.20), 0.57 (0.33, 1.00) and 1.07 (0.85, 1.35), respectively, with raltegravir.. There was a 27% decrease in abacavir plasma exposure with darunavir/ritonavir and no changes with raltegravir. CBV-TP C(trough) was significantly decreased with darunavir/ritonavir (32%) and showed a high inter-individual variability with raltegravir.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Cross-Over Studies; Darunavir; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

To evaluate a potential pharmacodynamic/pharmacokinetic interaction between abacavir (ABC) and tenofovir disoproxil fumarate (TDF).. This randomized trial compared 7 days of ABC or TDF monotherapy, separated by a 35-day washout, with 7 days of ABC + TDF dual-therapy in treatment-naive, HIV-1-infected patients. During each 7-day course, the slope of the phase I viral decay was estimated and steady-state intracellular concentrations of carbovir triphosphate (CBV-TP), deoxyguanosine triphosphate (dGTP), tenofovir diphosphate (TFV-DP) and deoxyadenosine triphosphate (dATP) were determined.. Twenty-one participants were randomized to initial monotherapy with ABC (n = 11) or TDF (n = 10). The addition of TDF did not increase the slope of viral decay compared to ABC alone (-0.15 log10 per day vs. -0.16 log10 per day, respectively). No decrease in CBV-TP or TFV-DP between monotherapy and dual-therapy was observed. However, intracellular dATP concentrations increased between monotherapy and dual-therapy [median dATP (fmol/10 cells) 3293 vs. 4638; P = 0.08], although this difference was significant only among patients randomized to TDF [median dATP (fmol/10 cells) 3238 vs. 4534; P = 0.047]. A lower TFV-DP-to-dATP ratio was associated with reduced viral decay during dual-therapy (rho = -0.529; P = 0.045).. In this study, the viral decay during ABC and TDF dual-therapy was similar to that during ABC therapy alone, suggesting a nonadditive antiviral effect. This negative pharmacodynamic interaction was not explained by changes in CBV-TP or TFV-DP concentrations. Rather, modest increases in endogenous dATP pools were associated with reduced antiviral potency of TDF during co-administration with ABC.

Topics: Adenine; Adult; Anti-HIV Agents; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Organophosphonates; RNA, Viral; Tenofovir; Treatment Outcome

Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days -1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC(0-24)) and comparable CBV-TP concentrations at the end of the dosing interval (C(tau)). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma (C(max)) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC(0-24) and 99% higher CBV-TP C(max) than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC(0-24) and 81% higher weight-adjusted CBV-TP AUC(0-24) than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP C(tau) values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exposure than did men.

Topics: Adult; Aged; Anti-HIV Agents; Area Under Curve; Cross-Over Studies; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Administration Schedule; Female; HIV Infections; Humans; Male; Middle Aged

Topics: Adult; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Administration Schedule; Female; HIV Infections; Humans; Leukocytes, Mononuclear; Male

Abacavir (ABC) has been associated with ischaemic cardiovascular events in HIV-infected patients, but the pathogenic mechanisms are unknown. Aim of our study was to assess whether ABC induces in vivo platelet activation and ex vivo platelet hyper-reactivity. In a retrospective, case-control study, in vivo platelet activation markers were measured in 69 HIV-infected patients, before starting therapy and after 6-12 months of either ABC (n=35) or tenofovir (TDF) (n=34), and compared with those from 20 untreated HIV-infected patients. A subgroup of patients was restudied after 28-34 months for ex vivo platelet reactivity. In vivo platelet activation markers were assessed by ELISA or flow cytometry, ex vivo platelet reactivity by light transmission aggregometry (LTA) and PFA-100®. Thein vitro effects of the ABC metabolite, carbovir triphosphate, on aggregation and intra-platelet cGMP were also studied. sPLA2, sPsel and sGPV increased significantly 6-12 months after the beginning of ABC, but not of TDF or of no treatment. Ex vivo platelet function studies showed enhanced LTA, shorter PFA-100® C/ADP closure time and enhanced platelet expression of P-sel and CD40L in the ABC group. The intake of ABC blunted the increase of intraplatelet cGMP induced by nitric oxide (NO) and acutely enhanced collagen-induced aggregation. Preincubation of control platelets with carbovir triphosphate in vitro enhanced platelet aggregation and blunted NO-induced cGMP elevation. In conclusion, treatment with ABC enhances in vivo platelet activation and induces platelet hyperreactivity by blunting the inhibitory effects of NO on platelets. These effects may lead to an increase of ischaemic cardiovascular events.

Topics: Adenine; Adult; Anti-HIV Agents; Blood Platelets; Case-Control Studies; CD40 Ligand; Cyclic GMP; Deoxyguanine Nucleotides; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Nitric Oxide; Organophosphonates; P-Selectin; Phospholipases A2, Secretory; Platelet Activation; Platelet Aggregation; Retrospective Studies; Tenofovir

Topics: Adult; Blood Specimen Collection; Clinical Laboratory Techniques; Deoxyguanine Nucleotides; Dideoxynucleosides; HIV Infections; Humans; Intracellular Fluid; Leukocytes, Mononuclear; Male; Middle Aged; Reproducibility of Results

We describe an unusual pathway of human immunodeficiency virus type 1 reverse transcriptase resistance during therapy with tenofovir-emtricitabine, characterized initially by the mutations K70E and M184V and later by K70G and M184V, with the two mutations coexisting on the same viral genome. Phenotypic resistance to lamivudine, emtricitabine, abacavir, didanosine, and tenofovir was observed, whereas susceptibility to zidovudine and stavudine was preserved.

Topics: Adenine; Amino Acid Substitution; Deoxycytidine; Didanosine; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Emtricitabine; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Molecular Sequence Data; Mutation; Organophosphonates; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir; Zidovudine

The anti-human immunodeficiency virus (HIV) activity of abacavir (ABC; 1-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol) could be markedly enhanced by administering the aryloxymethoxyalaninyl phosphoramidate prodrug derivative of ABC (pro-ABC-MP) to virus-infected cell cultures. Metabolic studies with radiolabeled ABC and pro-ABC-MP in human T-lymphocyte and primary macrophage cell cultures revealed a significantly increased delivery of the activated (phosphorylated) metabolite of ABC (ABC-MP) by pro-ABC-MP, and the concomittant appearance of markedly higher intracellular levels of carbovir 5'-triphosphate (CBV-TP), which represents the eventual antivirally active metabolite of ABC. The intracellular amounts of ABC-MP and appearance of CBV-TP closely correlated with the extracellular pro-ABC-MP concentrations that were administered to the cell cultures within a concentration range between 0.5 and 100 microM. The highest amounts of CBV-TP were observed within 6-24 h after drug administration. The improved delivery of ABC-MP and metabolic conversion to CBV-TP explain the markedly enhanced antiviral activity of the prodrug of ABC, and warrant further exploration of this prodrug technology on ABC and related compounds to further enhance and optimize their antiviral efficacy.

Topics: Anti-HIV Agents; Cell Line; Deoxyguanine Nucleotides; Dideoxynucleosides; HIV-1; Humans; Macrophages; Monocytes; Prodrugs; Purine Nucleotides

A capillary electrophoresis-ion trap mass spectrometry method with a time-segment program was developed to simultaneously analyze Ziagen and its phosphorylated metabolites such as carbovir monophosphate, carbovir diphosphate, and carbovir triphosphate. By using the time-segment program, the positively charged nucleoside analog and negatively charged nucleotides were separated and detected in a single electrophoretic run. The limits of detection were less than 2 micro M for all of the analytes. Calibration curves of the compounds showed excellent linearity over the range of 2-100 micro M. The capability of the method was demonstrated by analyzing Ziagen and its phosphorylated metabolites that were spiked in cellular extracts of human peripheral blood mononuclear cells at 20 micro M levels. Some endogenous nucleotides such as adenosine 5'-triphosphate, adenosine 5'-diphosphate, and adenosine 5'-monophosphate, were also detected in the cellular extracts.

Topics: Adenosine Triphosphate; Anti-HIV Agents; Cell Extracts; Deoxyguanine Nucleotides; Dideoxynucleosides; Electrophoresis, Capillary; Humans; Leukocytes, Mononuclear; Nucleosides; Nucleotides; Phosphorylation; Spectrometry, Mass, Electrospray Ionization; Stereoisomerism

Mycophenolic acid (MPA) enhances the in vitro activity of abacavir (ABC) and other nucleoside analog reverse transcriptase inhibitors (NRTIs) against sensitive and NRTI-resistant HIV-1. This may occur via depletion of intracellular deoxyguanosine triphosphate (dGTP). Mycophenolate mofetil (MMF) 500 mg twice daily was added as a single agent to the antiretroviral regimens of five patients failing maximal available therapy. Therapy included ABC, and in most cases didanosine (DDI) and tenofovir (TDF). At entry, mean plasma HIV-1 RNA (VL) was 5.02 log copies/mL (median 4.78, range 4.71-5.63) and mean CD4 count was 106/microL (median 117, range 11-174). MMF was well tolerated. CD4 cell counts did not change significantly from baseline for up to 60 weeks of follow-up. Three of five subjects had VL declines of >0.5 log copies/mL immediately after adding MMF; a fourth subject had a sustained decline of >0.5 log copies/mL after week 8. Declines of >0.5 log copies/mL were lost in two patients at 6 and 8 weeks, and persisted in two patients at 36 and 60 weeks of follow-up, respectively. An increase in the ratio of carbovir triphosphate (CBV-TP), the active antiviral metabolite of ABC, to dGTP was documented in 3 of 4 subjects in temporal association with decreased VL. Trough plasma MPA levels ranged from 0.26-1.67 microg/mL; peak levels 90 minutes after dosing from 1.20-7.77 microg/mL. AUC of MPA appeared little changed when measured over 28 weeks of therapy. Declines in VL were observed in association with measurable changes in the CBV-TP/dGTP ratio in some patients, whereas MPA AUC was below the 30-60 microg*hr/mL range targeted in organ transplantation. The possibility that MMF may enhance the effect of selected NRTIs and be tolerated in late stage HIV disease deserves careful randomized study.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Apoptosis; CD4 Lymphocyte Count; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; HIV-1; Humans; Mycophenolic Acid; RNA, Viral

An ion-paring HPLC-MS-MS method with positive ion mode electrospray ionization has been developed to simultaneously quantify Ziagen, carbovir monophosphate, carbovir diphosphate and carbovir triphosphate. N',N'-Dimethylhexylamine was used as the ion-pairing agent. The presence of this ion-pairing agent allowed the retention and separation of the four compounds on a reversed-phase HPLC column as well as the detection of the nucleotides with positive ion mode electrospray ionization. The limits of detection were found to be better than 25 nM for all the analytes. Calibration curves of the analytes showed excellent linearity over the range of 25 nM to 5 microM. The relative standard deviations and accuracies for replicate analyses of quality control samples were less than 15%. The method has been successfully applied to the analysis of these compounds in human liver cells treated with Ziagen.

Topics: Anti-HIV Agents; Cell Extracts; Chromatography, High Pressure Liquid; Deoxyguanine Nucleotides; Dideoxynucleosides; Humans; Leukocytes, Mononuclear; Nucleosides; Nucleotides; Phosphorylation; Spectrometry, Mass, Electrospray Ionization