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Biomedical subjects

Peter L Anderson

Publications and source records attributed to Peter L Anderson.

17 recordsLinked to original sources
PubMed2006

Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study.

OBJECTIVE: The aim of the study was to investigate relationships among indinavir, lamivudine-triphosphate, and zidovudine-triphosphate pharmacokinetics and pharmacodynamics with polymorphisms in CYP3A5, MDR1, MRP2, MRP4, BCRP, and UGT1A1 genes. STUDY DESIGN: Retrospective pilot investigation among 33 subjects who participated in a randomized pharmacological study of indinavir, lamivudine, and zidovudine. Subjects were defined as genetic variant carriers or not. Relationships were investigated with multivariable regression. Indinavir clearance was adjusted for African American race; triphosphates for sex; and HIV-response for study arm, drug exposure, and baseline HIV-RNA. RESULTS: Genetically determined CYP3A5 expressors had 44% faster indinavir oral clearance versus nonexpressors (P = 0.002). MRP2-24C/T variant carriers had 24% faster indinavir oral clearance (P = 0.05). Lamivudine-triphosphate concentrations were elevated 20% in MRP4 T4131G variant carriers (P = 0.004). A trend for elevated zidovudine-triphosphates was observed in MRP4 G3724A variant carriers (P = 0.06). The log10 changes in HIV-RNA from baseline to week 52 were -3.7 for MDR1 2677 TT, -3.2 for GT, and -2.2 for GG (P < 0.05). Bilirubin increases were 2-fold higher in UGT1A1 [TA]7/[TA]7 genotypes. No relationships were identified with BCRP. DISCUSSION: Novel relationships were identified among genetic variants in drug transporters and indinavir, lamivudine-triphosphate, and zidovudine-triphosphate concentrations. CYP3A5 expression was associated with faster indinavir oral clearance. These pilot data provide a scientific basis for more rational utilization of antiretroviral drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Liquid chromatography-tandem mass spectrometric determination of tenofovir-diphosphate in human peripheral blood mononuclear cells.

To facilitate the evaluation of drug safety, virologic activity, and pharmacokinetics, an anion exchange isolation of tenofovir-diphosphate (TFV-DP) from human peripheral blood mononuclear cells (hPBMCs), coupled with dephosphorylation, desaltation, and detection by LC-MS-MS was validated. hPBMCs were harvested from whole blood, lysed, and a suspension of intracellular tenofovir moieties was produced. TFV-DP was isolated from TFV-monophosphate (TFV-MP) and tenofovir (TFV), dephosphorylated with acid phosphatase to form TFV and then desalted and concentrated, making it possible for tandem mass spectral detection. An LC-MS-MS methodology was developed and validated for the determination of TFV concentrations, which directly correspond with the intra-hPBMC TFV-DP concentration. The assay was linear in the range of 50-10,000 fmol per sample. The lower limit of quantitation (LLOQ) of the method is 10 fmol per million cells with 5 million hPBMCs used. This paper outlines the development and validation of the determination of TFV-DP concentrations in femtomoles per million hPBMCs.

Adenine↗
PubMed2006

Multiplex PCR-pyrosequencing assay for genotyping CYP3A5 polymorphisms.

BACKGROUND: The cytochrome P450 (CYP) 3A5 enzyme contributes to the metabolism of many drugs. Single nucleotide polymorphisms in the CYP3A5 gene (CYP3A5(*)3C and CYP3A5(*)6) are associated with decreased CYP3A5 expression in the liver. We designed a multiplex genotyping assay to detect the CYP3A5(*)3C and CYP3A5(*)6 polymorphisms in a single polymerase chain reaction (PCR) and a single pyrosequencing reaction. METHODS: A multiplex PCR assay was designed to simultaneously amplify 2 fragments, one containing the CYP3A5(*)3C polymorphism and the other containing the CYP3A5(*)6 polymorphism. Following PCR, multiplex genotyping was performed with pyrosequencing analysis. RESULTS: Patient samples (n=69) were analyzed for the CYP3A5(*)3C and CYP3A5(*)6 polymorphisms using the multiplex PCR-pyrosequencing assay. Genotypes obtained by the multiplex reaction were in 100% concordance with genotypes obtained using simplex PCR-pyrosequencing (n=69) and direct DNA sequencing (n=29). CONCLUSIONS: The advantage of this method is that the CYP3A5(*)3C and CYP3A5(*)6 polymorphism can be amplified in a single PCR reaction and genotyped in a single pyrosequencing reaction. This combined approach improves the time-efficiency and decreases the cost of CYP3A5 genotyping.

Alleles↗
PubMed2006

Quantitation of zidovudine triphosphate concentrations from human peripheral blood mononuclear cells by anion exchange solid phase extraction and liquid chromatography-tandem mass spectroscopy; an indirect quantitation methodology.

To facilitate the assessment of drug safety and determination of phamacokinetics, an anion exchange isolation of zidovudine triphosphate (ZDV-TP) from human peripheral blood mononuclear cells (hPBMC), coupled with dephosphorylation, desaltation, and detection by liquid chromatography-tandem mass spectroscopy (LC-MS-MS) was validated. hPBMCs were harvested from whole blood, lysed, and a suspension of intracellular ZDV-TP was produced. ZDV-TP was isolated from ZDV, ZDV-monophosphate (ZDV-MP), and ZDV-diphosphate (ZDV-DP), which were all present in the cell lysate, by performing a salt gradient anion exchange SPE. Isolated ZDV-TP was dephosphorylated with acid phosphatase to its parent drug form, ZDV. ZDV was then desalted and concentrated for tandem mass spectral detection. An LC-MS-MS methodology was developed and validated for the determination of molar ZDV directly corresponding to the intra-hPBMC molar ZDV-TP concentration. ZDV-TP concentrations were determined in femtomoles per million hPBMCs (fmol/10(6)cells). The assay was able to determine ZDV-TP concentrations accurately and precisely within the range of 5-640 fmol/10(6)cells with 10 million cells per sample analyzed. Inter- and intra-day accuracy and precision data for back calculated standards and quality controls fell within 15% of nominal. The assay correlated well with a previous ELISA method developed and validated in our laboratory, and has been successfully used to quantitate ZDV-TP concentrations in patients being routinely monitored and treated with ZDV.

Chemical Fractionation↗
PubMed2006

6th International Workshop on Clinical Pharmacology of HIV Therapy.

The 6th International Workshop on Clinical Pharmacology of HIV Therapy convened at the Fairmont Le Château Frontenac in Québec, Canada on April 28-30, 2005. More than 170 participants registered for this workshop, demonstrating the continued interest in exploring and understanding the complexities of antiretroviral pharmacology. The purpose of this meeting was to present and discuss research related to antiretroviral pharmacokinetics, pharmacodynamics, drug interactions, therapeutic drug monitoring and the assays necessary for measuring antiretroviral concentrations. This article highlights some of the 22 oral and 98 poster presentations that were presented at this meeting.

Anti-HIV Agents↗
PubMed2006

Effects of esomeprazole on the pharmacokinetics of atazanavir and fosamprenavir in a patient with human immunodeficiency virus infection.

The effects of proton pump inhibitors on the pharmacokinetics of atazanavir and amprenavir (administered as fosamprenavir) were rigorously evaluated in healthy volunteers in two studies, but formal studies in persons infected with human immunodeficiency virus (HIV) are lacking. We describe a 65-year-old man with HIV who underwent a 12-hour intensive pharmacokinetic study while receiving esomeprazole with atazanavir-ritonavir and subsequently, an 8-hour study while receiving esomeprazole with fosamprenavir-ritonavir. Consistent with the data in healthy volunteers, a major interaction between esomeprazole and atazanavir-ritonavir was observed in this patient-marked reductions in atazanavir trough plasma concentration and in the area under the concentration-time curve from 0-24 hours-whereas an interaction between esomeprazole and fosamprenavir-ritonavir was not apparent in this patient.

Aged↗
PubMed2005

Therapeutic drug monitoring: pharmacologic considerations for antiretroviral drugs.

Therapeutic drug monitoring (TDM) is the process by which a patient's dosing regimen is guided by repeated measures of plasma drug concentrations. An enormous challenge with regard to TDM of antiretroviral drugs (ARV) is that the concentration goals can be moving targets. Well-designed prospective studies demonstrating that prospectively altering ARV doses based on TDM leads to virologic success and increased tolerability are needed. Nevertheless, there are specific clinical instances where this experimental intervention should be considered to potentially reduce toxicity and improve therapeutic outcomes.

Adolescent↗
PubMed2004

Pharmacologic perspectives for once-daily antiretroviral therapy.

OBJECTIVE: To contrast available once-daily antiretroviral agents and combinations of these agents from a clinical pharmacologic viewpoint. DATA SOURCES: Data were extracted from publications and major HIV conference proceedings cited in MEDLINE (1966-March 2004) using the search terms antiretroviral therapy, combination therapy, once-daily therapy, and pharmacokinetics. Additional references were obtained from the bibliographies of these sources. STUDY SELECTION AND DATA EXTRACTION: Information pertaining to pharmacologic perspectives for once-daily antiretroviral agents was selected. DATA SYNTHESIS: Maximal and durable suppression of plasma HIV RNA, the principal goal of therapy, depends on the intrinsic antiviral activity of the antiretroviral regimen. A favorable tolerability/toxicity profile is also fundamentally important. All once-daily agents exhibit some pharmacologic limitations or lack adequate long-term follow-up. Of available agents, efavirenz has a long and distinguished efficacy record, with reasonable safety and moderate tolerability. Lamivudine, and newer agents such as atazanavir (or atazanavir/ritonavir), emtricitabine, fosamprenavir/ritonavir, and tenofovir, may offer pharmacologic advantages in the current state of once-daily therapy. Important considerations exist for coadministering once-daily agents including drug-drug interactions, drug-food incompatibilities, and synergistic toxicities. Few controlled studies have compared once-daily regimens with conventional regimens. CONCLUSIONS: Progress has been made toward once-daily therapy, but more clinical experience with available agents is needed, including comparative studies of entirely once-daily regimens versus conventional regimens. Limitations of currently available agents signify a need for improved antiretroviral utilization or new alternative agents.

Anti-HIV Agents↗
PubMed2004

The cellular pharmacology of nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors and its relationship to clinical toxicities.

Nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors (NRTIs) require intracellular phosphorylation for anti-human immunodeficiency virus (HIV) activity and toxicity. Long-term toxicities associated with NRTIs may be related to overactivation of this process. In vitro experiments have shown increased rates of NRTI and endogenous nucleoside phosphorylation to be associated with cellular activation. Patients with advanced HIV disease often have overexpression of cytokines, which corresponds to an elevated cellular activation state. These patients also have higher rates of NRTI phosphorylation and NRTI toxicity, suggesting an interaction between a proinflammatory biological state, NRTI phosphorylation, and toxicity. Studies suggest that women may have higher rates of NRTI phosphorylation than do men, as well as increased risk for NRTI-induced toxicity. Future research is needed to understand the NRTI activation process and improve the long-term toxicity profile of NRTIs. Such research should include comparisons of NRTI phosphorylation according to sex and cellular activation state (i.e., elevated vs. low).

Antiviral Agents↗
PubMed2004

Updated clinical pharmacologic considerations for HIV-1 protease inhibitors.

Many data associate low protease inhibitor plasma concentrations with suboptimal virologic responses, whereas fewer data associate high plasma concentrations with toxicity. Knowledge of relationships between concentrations and virologic response is important because significant variability in concentrations exists among patients. For antiretroviral-naïve patients, target trough concentrations have been suggested on the basis of retrospective associations with virologic responses. Two prospective studies demonstrated improved virologic responses when indinavir and nelfinavir doses were managed based on these troughs. Investigations among antiretroviral-experienced patients have identified a relationship between the trough concentration and the in-vitro susceptibility of the patient's virus with virologic outcome. However, differences in virologic response may further depend on other pharmacologic factors, such as protein binding, intracellular kinetics, function of drug transporters, and the activity of other drugs in the regimen. In the future, dosing strategies that accommodate the variability in pharmacokinetics and pharmacodynamics may improve virologic outcomes.

HIV Infections↗
PubMed2003

Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals.

OBJECTIVES: Nucleoside analog reverse transcriptase inhibitors (NRTI) are used in virtually all anti-HIV regimens. Clinical response depends on the intracellular formation of the pharmacologically active triphosphate moiety. Our objective was to quantify the pharmacological characteristics of zidovudine and lamivudine triphosphate in HIV-infected individuals. METHODS: Peripheral blood mononuclear cells were obtained at multiple planned intervals from antiretroviral-naive adults participating in a study of zidovudine, lamivudine and indinavir, and triphosphate levels were determined by immunoassay and high-performance liquid chromatography/mass spectrometry. Plasma HIV-RNA, CD4 cell counts, and plasma drug concentrations were collected over 18 months. Data were analysed using non-parametric, regression and time-to-event methods. RESULTS: Thirty-three subjects were evaluated. The estimated half-lives of zidovudine and lamivudine triphosphate were 7 and 22 h, respectively. Triphosphate concentrations were elevated in individuals with low baseline CD4 cell counts. Triphosphate concentrations in women were higher than in men by 2.3 and 1.6-fold for zidovudine and lamivudine, respectively. Women reached an HIV-RNA level under 50 copies/ml twice as fast as men. Zidovudine triphosphate above 30 fmol/10(6) cells was independently predictive of the time to under 50 copies/ml. Lamivudine triphosphate above 7017 fmol/10(6) cells was independently predictive of a longer virological response. Indinavir concentrations were related to antiviral responses in univariate analyses. CONCLUSION: Zidovudine and lamivudine triphosphate concentration thresholds were independently associated with the antiviral activity of zidovudine, lamivudine, and indinavir. The significantly elevated triphosphate concentrations in women and individuals with low baseline CD4 cell counts, groups that historically experience high rates of serious NRTI toxicities, provide a hypothesis for the pathogenesis of these events.

Adult↗
PubMed2002

Concentration-controlled compared with conventional antiretroviral therapy for HIV infection.

OBJECTIVES: To demonstrate the feasibility of a concentration-controlled approach to combination antiretroviral therapy, and to compare the virological responses and safety of this strategy versus conventional fixed-dose therapy. DESIGN: A prospective, randomized, 52 week, open-label trial of concentration-controlled compared with conventional dose zidovudine, lamivudine, and indinavir therapy conduced in a university-based general clinical research center in the United States. PATIENTS: Forty antiretroviral-naive individuals with plasma HIV-RNA levels > 5000 copies/ml. INTERVENTIONS: Zidovudine, lamivudine, and indinavir plasma concentrations were measured in all participants. Doses were adjusted in those assigned to concentration-controlled therapy to achieve levels equal to or greater than target values. MAIN OUTCOME MEASURES: The proportion of patients who achieved the desired drug concentrations, the proportion of patients with HIV-RNA levels < 50 copies/ml at week 52, and safety and tolerance in the concentration-controlled versus conventional therapy arms. RESULTS: Significantly more concentration-controlled recipients achieved the desired concentration targets for all three drugs: 15 of 16 concentration-controlled recipients compared with nine of 17 conventional recipients (P = 0.017) had HIV-RNA levels < 50 copies/ml at week 52. No difference was observed in the occurrence of drug-related clinical events or laboratory abnormalities between the two treatment arms. CONCLUSION: Concentration-controlled therapy implemented simultaneously for three antiretroviral agents was feasible, as well tolerated as conventional therapy, and resulted in a greater proportion of recipients with HIV-RNA levels < 50 copies/ml after 52 weeks. These findings provide a scientific basis to challenge the accepted practice of administering the same dose of antiretroviral agents to all adults, ignoring the concentrations actually achieved.

Adult↗
PubMed2002

CD4 response is correlated with peak plasma concentrations of indinavir in adults with undetectable human immunodeficiency virus ribonucleic acid.

We retrospectively evaluated correlates of increases in CD4 cell count in antiretroviral agent-naive subjects with fewer than 50 copies per milliliter of plasma human immunodeficiency virus ribonucleic acid who were participating in a study of indinavir, lamivudine, and zidovudine therapy. Pharmacologic data from intensive pharmacokinetic studies and baseline patient characteristics were evaluated as predictors of the increase in CD4 count from baseline to weeks 24, 56, and 80. Relations were investigated with regression analysis. Of all covariates, maximum plasma concentration (C(max)) of indinavir was significantly and uniquely associated with increases in CD4 count from baseline to all end points (P =.002 at week 80; n = 20). At week 80, subjects with a C(max) greater than the overall group median value of 7 microg/ml had an increase in CD4 count of 358 cells/microl versus 197 cells/microl for those with a C(max) less than 7 microg/ml (P =.006). These data suggest distinct pharmacodynamic relations exist for immune reconstitution and suppression of plasma human immunodeficiency virus ribonucleic acid. We hypothesize this new finding may be associated with expression of P-glycoprotein.

Adult↗