Edward P Acosta

University of Alabama at Birmingham, Birmingham, Alabama, United States

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Publications (151)817.26 Total impact

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    ABSTRACT: Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed.
    Clinical pharmacokinetics. 08/2014;
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    ABSTRACT: IMPAACT P1097 was a multicenter trial to determine washout pharmacokinetics and safety of in utero/intrapartum exposure to raltegravir in infants born to HIV-infected pregnant women receiving raltegravir-based antiretroviral therapy. Twenty-two mother-infant pairs were enrolled; evaluable pharmacokinetic data was available from 19 mother-infant pairs. Raltegravir readily crossed the placenta, with median cord blood/maternal delivery plasma raltegravir concentration ratio 1.48 (range, 0.32-4.33). Raltegravir elimination was highly variable and extremely prolonged in some infants; [median t½ 26.6 hours (range 9.3-184 hours)]. Prolonged raltegravir elimination likely reflects low neonatal UGT1A1 enzyme activity and enterohepatic recirculation. Excessive raltegravir concentrations must be avoided in the neonate, since raltegravir at high plasma concentrations may increase the risk of bilirubin neurotoxicity. Sub-therapeutic concentrations, which could lead to inadequate viral suppression and development of raltegravir resistance, must be avoided as well. Two ongoing IMPAACT studies are investigating further the pharmacology of raltegravir in neonates.
    Journal of acquired immune deficiency syndromes (1999). 08/2014;
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    ABSTRACT: Efavirenz is widely prescribed for HIV-1 infection, and CYP2B6 polymorphisms 516G→T and 983T→C define efavirenz slow metabolizer genotypes. To identify genetic predictors of higher plasma efavirenz concentrations beyond these two common functional alleles, we characterized associations with mid-dosing interval efavirenz concentrations in 84 HIV-infected adults, all carrying two copies of these major loss-of-function CYP2B6 alleles. Study participants had been randomized to efavirenz-containing regimens in prospective clinical trials and had available plasma efavirenz assay data. Analyses focused on secondary metabolism pathway polymorphisms CYP2A6 -48T→G (rs28399433), UGT2B7 735A→G (rs28365062) and UGT2B7 802T→C (rs7439366). Exploratory analyses also considered 196 polymorphisms and 8 copy number variants in 41 drug metabolism/transport genes. Mid-dosing interval efavirenz concentrations at steady-state were obtained ≥8 h but <19 h post-dose. Linear regression was used to test for associations between polymorphisms and log-transformed efavirenz concentrations. Increased efavirenz concentrations were associated with CYP2A6 -48T→G in all subjects (P = 3.8 × 10(-4)) and in Black subjects (P = 0.027) and White subjects (P = 0.0011) analysed separately; and with UGT2B7 735 G/G homozygosity in all subjects (P = 0.006) and in Black subjects (P = 0.046) and White subjects (P = 0.062) analysed separately. In a multivariable model, CYP2A6 -48T→G and UGT2B7 735 G/G homozygosity remained significant (P < 0.05 for each). No additional polymorphisms or copy number variants were significantly associated with efavirenz concentrations. Among individuals with a CYP2B6 slow metabolizer genotype, CYP2A6 and possibly UGT2B7 polymorphisms contribute to even higher efavirenz concentrations.
    Journal of Antimicrobial Chemotherapy 04/2014; · 5.34 Impact Factor
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    ABSTRACT: HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS(®) Taqman(®) 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06-0.12] than DRV, 0.04 (95%CI 0.03-0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50 ) in all ATV and 1 DRV-treated subjects (P < 0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P = 0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation.
    The Journal of Clinical Pharmacology 04/2014; · 2.84 Impact Factor
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    ABSTRACT: The impact of raltegravir-resistant HIV-1 minority variants (MVs) on raltegravir treatment failure is unknown. Illumina sequencing offers greater throughput than 454, but sequence analysis tools for viral sequencing are needed. We evaluated Illumina and 454 for the detection of HIV-1 raltegravir-resistant MVs. A5262 was a single-arm study of raltegravir and darunavir/ritonavir in treatment-naïve patients. Pre-treatment plasma was obtained from 5 participants with raltegravir resistance at the time of virologic failure. A control library was created by pooling integrase clones at predefined proportions. Multiplexed sequencing was performed with Illumina and 454 platforms at comparable costs. Illumina sequence analysis was performed with the novel snp-assess tool and 454 sequencing was analyzed with V-Phaser. Illumina sequencing resulted in significantly higher sequence coverage and a 0.095% limit of detection. Illumina accurately detected all MVs in the control library at ≥0.5% and 7/10 MVs expected at 0.1%. 454 sequencing failed to detect any MVs at 0.1% with 5 false positive calls. For MVs detected in the patient samples by both 454 and Illumina, the correlation in the detected variant frequencies was high (R2 = 0.92, P<0.001). Illumina sequencing detected 2.4-fold greater nucleotide MVs and 2.9-fold greater amino acid MVs compared to 454. The only raltegravir-resistant MV detected was an E138K mutation in one participant by Illumina sequencing, but not by 454. In participants of A5262 with raltegravir resistance at virologic failure, baseline raltegravir-resistant MVs were rarely detected. At comparable costs to 454 sequencing, Illumina demonstrated greater depth of coverage, increased sensitivity for detecting HIV MVs, and fewer false positive variant calls.
    PLoS ONE 01/2014; 9(3):e90485. · 3.73 Impact Factor
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    ABSTRACT: Lopinavir (LPV)/ritonavir (RTV) co-formulation (LPV/RTV) is a widely used protease inhibitor (PI)-based regimen to treat HIV-infection. As with all PIs, the trough concentration (C trough) is a primary determinant of response, but the optimum exposure remains poorly defined. The primary objective was to develop an integrated LPV population pharmacokinetic model to investigate the influence of α-1-acid glycoprotein and link total and free LPV exposure to pharmacodynamic changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters. Data from 35 treatment-naïve HIV-infected patients initiating therapy with LPV/RTV 400/100 mg orally twice daily across two studies were used for model development and simulations using ADAPT. Total LPV (LPVt) and RTV concentrations were measured by high-performance liquid chromatography with ultraviolet (UV) detection. Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry. The LPVt typical value of clearance ([Formula: see text]) was 4.73 L/h and the distribution volume ([Formula: see text]) was 55.7 L. The clearance ([Formula: see text]) and distribution volume (V f/F) for LPVf were 596 L/h and 6,370 L, respectively. The virion clearance rate was 0.0350 h(-1). The simulated [Formula: see text] C trough values at 90 % (EC90) and 95 % (EC95) of the maximum response were 316 and 726 ng/mL, respectively. The pharmacokinetic-pharmacodynamic model provides a useful tool to quantitatively describe the relationship between LPV/RTV exposure and viral response. This comprehensive modelling and simulation approach could be used as a surrogate assessment of antiretroviral (ARV) activity where adequate early-phase dose-ranging studies are lacking in order to define target trough concentrations and possibly refine dosing recommendations.
    Clinical Pharmacokinetics 12/2013; · 5.49 Impact Factor
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    ABSTRACT: Background. Our goals were to describe azithromycin (AZI) pharmacokinetics in maternal plasma (MP), fetal plasma (FP), and amniotic fluid (AF) following intra-amniotic infection (IAI) with Ureaplasma in pregnant rhesus monkeys and explore concentration-response relationships.Methods. Following intra-amniotic inoculation of Ureaplasma parvum, rhesus monkeys received AZI (12.5 mg/kg every 12 hours intravenously for 10 days; n=10). Intensive pharmacokinetic sampling of MP, FP and AF was scheduled following the first (SD) and last (MD) dose. Noncompartmental and pharmacokinetic modeling methods were used.Results. AF AUC12 was 0.22 µgxh/mL following a SD and 6.3 µgxh/mL at day 10. MP and AF accumulation indices were 8.4 and 19, respectively. AZI AF half-life following SD and MD were 156 and 129 hours, respectively. The median (range) MP:FP ratio of concomitantly drawn samples was 3.2 (1.3-9.6; n=9). Eradication of U. parvum occurred at 6.6 days with a 95% effective concentration (EC95) of 39 ng/mL for the maximum AZI AF concentration.Conclusions. Our study demonstrates a maternal AZI regimen is effective in eradicating U.parvum IAI by virtue of intra-amniotic accumulation and suggests that antenatal therapy has the potential to mitigate complications associated with U. parvum infection in pregnancy, such as preterm labor and fetal sequelae.
    The Journal of Infectious Diseases 10/2013; · 5.85 Impact Factor
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    ABSTRACT: Background. IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate safety, pharmacokinetics (PK), tolerability and efficacy of multiple raltegravir (RAL) formulations in HIV-infected youth. Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to<12 years; and III: 2 to<6 years) was based on review of short term safety (4 weeks) and intensive pharmacokinetic (PK) evaluation. Safety data through Weeks 24 and 48, and Grade >3 or serious adverse events (AE) were assessed. The primary virologic endpoint was achieving HIV RNA<400 copies/mL or ≥1 log10 reduction between baseline and week 24. Results. The targeted PK parameters (AUC0-12 hr and C12 hr) were achieved for each cohort allowing dose selection for two formulations. Of 96 final dose subjects, there were 15 subjects with Grade 3+ clinical AEs (1 subject with drug related [DR] psychomotor hyperactivity and insomnia); 16 subjects with Grade 3+ laboratory AEs (1 with DR transaminase elevation); 15 subjects with serious clinical AEs (1 with DR rash); 2 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at Week 48 were observed in 78.9%, with a mean CD4 increase of 156 cells/uL (4.6%). Conclusions. 400 mg BID of RAL film-coated tablet (6 to <19 years, and ≥25 kg) and 6 mg/kg BID (maximum dose 300 mg) of RAL chewable tablet (2 to<12 years) were well-tolerated and showed favorable virologic and immunologic responses.
    Clinical Infectious Diseases 10/2013; · 9.37 Impact Factor
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    ABSTRACT: Objective. Define viral kinetics with raltegravir (RAL)-based antiretroviral therapy (ART).Methods. ART-naïve patients received RAL, tenofovir, emtricitabine for 72 weeks. HIV-1 RNA by ultrasensitive and single-copy assays estimated first (d1)-, second (d2)-, and, third (d3)-phase decay by mixed-effects models. Decay data were compared to historical estimates for efavirenz (EFV)- and ritonavir/lopinavir (LPV/r)-based regimens.Results. Bi- and tri-exponential models for ultrasensitive (n=38) and single-copy assay (n=8) data, respectively, provided the best fits over 8 and 72 weeks. Median d1 with ultrasensitive data was 0.563/day (interquartile range [IQR], 0.501 to 0.610/day), significantly slower than d1 for EFV-based regimens [p<0.001]). Median duration of d1 was 15.1 days, transitioning to d2 at a HIV-1 RNA of 91 c/ml, indicating longer duration of d1 and d2 transition at lower viremia than with EFV. Median decays with single-copy assay were: d1, 0.607/day (Q1-Q3, 0.582-0.653); d2, 0.070/day (0.042-0.079); and d3, 0.0016/day (0.0005-0.0022); median d1 duration was 16.1 days transitioning to d2 at 69 c/ml. d3 transition occurred at 110 days at 2.6 c/mL, similar to LPV/r-based regimens.Conclusions. Models using single-copy assay data revealed 3 phases of decay with RAL-containing ART with a longer duration of first-phase decay consistent with RAL-mediated blockade of productive infection from pre-integration complexes.
    The Journal of Infectious Diseases 06/2013; · 5.85 Impact Factor
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    ABSTRACT: To address the need for nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens, we explored the virologic and pharmacokinetic characteristics of maraviroc plus ritonavir-boosted darunavir in a single-arm, open-label, 96-week study. 24 antiretroviral-naïve R5 HIV-1-infected participants received maraviroc 150 mg and DRV/r 800/100 mg (MVC/DRV/r) once-daily. The primary outcome was virologic failure (VF) = confirmed viral load (VL) >50 copies/mL at week 24 in the modified intent-to-treat population. To determine viral dynamics, participant-specific first- and second-phase empirical Bayes estimates were compared to decay rates from efavirenz plus lopinavir/ritonavir, lopinavir/ritonavir plus 2NRTIs and efavirenz plus 2NRTIs. Maraviroc plasma concentrations were determined at weeks 2, 4,12, 24 and 48. Baseline median (Q1, Q3) CD4 count and VL were 455 (299, 607) cells/mm and 4.62 (4.18, 4.80) log10copies/mL, respectively. VF occurred in 3/24 participants (12.5 % [95% CI 2.7, 32.4]) at week 24. One of these resuppressed, yielding a week 48 VF rate of 2/24 (8.3 % [95% CI 1.0, 27.0]). The week 48 failures were 2 of the 4 (50%) participants with baseline VL >100,000 copies/mL. Week 96 VF rate was 2/20 (10 % [95% CI 1.2, 31.7]). Phase 1 decay was faster with MVC/DRV/r than reported for ritonavir-boosted lopinavir plus 2 NRTIs (p=0.0063) and similar to efavirenz-based regimens. Individual maraviroc trough concentrations collected between 20-28 hours post dose (n=59) was 13.7 to 130 ng/mL (Q1, 23.4 ng/mL; Q3, 46.5 ng/mL), and modeled steady-state concentration was 128 ng/mL. MVC/DRV/r 150/800/100 mg once-daily has potential for treatment-naïve patients with R5 HIV-1.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 06/2013; · 4.65 Impact Factor
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    ABSTRACT: Objective. Nevirapine is metabolized by cytochrome P450 (CYP) 2B6 and CYP3A4, We characterized relationships between clinical parameters, human genetics, pharmacokinetics, and HIV-1 drug resistance mutations in pregnant women following single-dose intrapartum nevirapine.Methods. In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor, and were randomized to lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir, for 7 or 21 days. Plasma nevirapine was quantified at post-partum day 1 and weeks 1, 3 and 5. We assayed 214 polymorphisms in CYP2B6 and other genes and evaluated associations with pharmacokinetic parameters included elimination constant, time to protein-adjusted 50% inhibitory concentration (IC50), and week 5 nevirapine below quantification limit.Results. Among 301 women with evaluable pharmacokinetic and genotype data, lower body mass index and randomization to lopinavir/ritonavir were associated with more rapid nevirapine elimination. Among those of African ancestry, longer time to IC50 was associated with CYP2B6 983T→C (p=0.004) but not with CYP2B6 516G→T (p=0.8). Among Indians, slower nevirapine elimination was associated with CYP2B6 516G→T (p=0.04). Emergent resistance was infrequent and not associated with pharmacokinetics or CYP2B6 genotype.Conclusions. Effects on plasma drug exposure following single-dose nevirapine may be greater for CYP2B6 983T→C than 516G→T, and are less pronounced than at steady state.
    The Journal of Infectious Diseases 05/2013; · 5.85 Impact Factor
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    Kajal B Larson, Jennifer R King, Edward P Acosta
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    ABSTRACT: Raltegravir was the first HIV integrase strand-transfer inhibitor to be approved by the US FDA, in October 2007, for the treatment of HIV-1 infection in combination with other antiretroviral agents. Raltegravir can be used in treatment-naïve and -experienced patients, as well as for the treatment of multidrug-resistant infection. Raltegravir exists in two formulations: a film-coated tablet administered orally at 400 mg twice daily, and a chewable tablet administered orally at 300 mg twice daily. In 2011, raltegravir was also approved for the treatment of children and adolescents, ages 2-18 years. For adolescents (ages 12-18 years), the recommended dose is 400 mg twice daily (film-coated tablet). If children (ages 6-12 years) weigh at least 25 kg, the film-coated tablet is recommended at 400 mg twice daily. Otherwise, patients receive the chewable tablet according to weight-based dosing at approximately 6 mg/kg/dose. Studies are ongoing for children ages 4 weeks to 2 years, and preliminary efficacy and safety data are promising. This article reviews current studies on the efficacy, safety, and pharmacokinetics of raltegravir in the pediatric population and the challenges of treating HIV in children and adolescents.
    Adolescent Health, Medicine and Therapeutics 01/2013; 4:79-87.
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    ABSTRACT: Antiretroviral drugs vary in their central nervous system penetration, with better penetration possibly conferring neurocognitive benefit during human immunodeficiency virus (HIV) therapy. The efflux transporter gene ABCB1 is expressed in the blood-brain barrier, and an ABCB1 variant (3435C→T) has been reported to affect ABCB1 expression. The integrase inhibitor raltegravir is a substrate for ABCB1. We examined whether ABCB1 3435C→T affects raltegravir disposition into cerebrospinal fluid (CSF), and explored associations with polymorphisms in other membrane transporter genes expressed in the blood-brain barrier. Forty healthy, HIV-negative adults of European descent (20 homozygous for ABCB1 3435 C/C, 20 homozygous for 3435 T/T, each group divided equally between males and females) were given raltegravir 400 mg twice daily for 7 days. With the final dose, plasma was collected for pharmacokinetic analysis at 9 timepoints over 12 hours, and CSF collected 4 hours post dose. The 4-hour CSF concentration correlated more strongly with 2-hour (r(2)=0.76, P=1.12x10(-11)) than 4-hour (r(2)=0.47, P=6.89x10(-6)) single timepoint plasma concentration, and correlated strongly with partial plasma area-under-the-curve values (AUC0-4h r(2)=0.86, P=5.15x10(-16)). There was no significant association between ABCB1 3435C→T and ratios of CSF-to-plasma AUC or concentration (p>0.05 for each comparison). In exploratory analyses, CSF-to-plasma ratios were not associated with 276 polymorphisms across 16 membrane transporter genes. Among HIV-negative adults, CSF raltegravir concentrations do not differ by ABCB1 3435C→T genotype but strongly correlate with plasma exposure. ClinicalTrials.gov NCT00729924 http://clinicaltrials.gov/show/NCT00729924.
    PLoS ONE 01/2013; 8(12):e82672. · 3.73 Impact Factor
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    ABSTRACT: Background. Children under 2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children under 2 years of age is unknown.Methods. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants from birth to 2 years of age in an age-deescalation, adaptive design with a targeted systemic exposure.Results. From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0&emsp14;mg/kg produced drug exposures within the target range in subjects 0 through 8 months of age, although there was a greater degree of variability in infants under 3 months of age. In subjects 9 through 11 months of age, a dose of 3.5&emsp14;mg/kg produced drug exposures within the target range. Six of ten subjects 12 through 23 months of age receiving the FDA-approved unit dose for this age group of 30&emsp14;mg had oseltamivir carboxylate exposures below the target range. Virus from three subjects developed oseltamivir resistance during antiviral treatment.Conclusions. The appropriate twice-daily oral oseltamivir dose for infants birth through 8 months of age is 3.0&emsp14;mg/kg, while the dose for infants 9 through 11 months is 3.5&emsp14;mg/kg.
    The Journal of Infectious Diseases 12/2012; · 5.85 Impact Factor
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    ABSTRACT: OBJECTIVES: Prior candidate gene studies have associated CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499] with increased plasma efavirenz exposure. We sought to identify novel variants associated with efavirenz pharmacokinetics. MATERIALS AND METHODS: Antiretroviral therapy-naive AIDS Clinical Trials Group studies A5202, A5095, and ACTG 384 included plasma sampling for efavirenz pharmacokinetics. Log-transformed trough efavirenz concentrations (Cmin) were previously estimated by population pharmacokinetic modeling. Stored DNA was genotyped with Illumina HumanHap 650Y or 1MDuo platforms, complemented by additional targeted genotyping of CYP2B6 and CYP2A6 with MassARRAY iPLEX Gold. Associations were identified by linear regression, which included principal component vectors to adjust for genetic ancestry. RESULTS: Among 856 individuals, CYP2B6 516G→T was associated with efavirenz estimated Cmin (P=8.5×10). After adjusting for CYP2B6 516G→T, CYP2B6 983T→C was associated (P=9.9×10). After adjusting for both CYP2B6 516G→T and 983T→C, a CYP2B6 variant (rs4803419) in intron 3 was associated (P=4.4×10). After adjusting for all the three variants, non-CYP2B6 polymorphisms were associated at P-value less than 5×10. In a separate cohort of 240 individuals, only the three CYP2B6 polymorphisms replicated. These three polymorphisms explained 34% of interindividual variability in efavirenz estimated Cmin. The extensive metabolizer phenotype was best defined by the absence of all three polymorphisms. CONCLUSION: Three CYP2B6 polymorphisms were independently associated with efavirenz estimated Cmin at genome-wide significance, and explained one-third of interindividual variability. These data will inform continued efforts to translate pharmacogenomic knowledge into optimal efavirenz utilization.
    Pharmacogenetics and Genomics 10/2012; · 3.61 Impact Factor
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    ABSTRACT: INTRODUCTION:: There is limited pediatric information on the complex relationships among the dose of tenofovir disoproxil fumarate (TDF), plasma concentrations of tenofovir (TFV), and intracellular TFV-diphosphate (TFV-DP) concentrations. Our objectiveswere to describe TFV-DP pharmacokinetics in children and adolescents and investigate the effect of age on TFV and TFV-DP concentrations. METHODS:: TFV-DP pharmacokinetics were determined in 47 children and adolescents. TFV and TFV-DP were quantified with validated LC/MS/MS methods. Data were pooled with other studies in HIV-infected adults (N = 55). Nonlinear mixed effects modeling was used to develop the population model and explore the influence of covariates on TFV. A two-compartment model,partitioned for slow and fast absorbers by age, with weight allometrically scaled for children and adolescents best described TFV pharmacokinetics. An indirect stimulation of response model best described TFV-DP formation. RESULTS:: Apparent oral TFV clearance (CL/F) was significantly faster in patients <25 versus ≥25 years. The most significant covariate on CL/F and central distribution volume was creatinine clearance. The TFV plasma concentration producing 50% of maximal TFV-DP concentrations (EC50) was almost 2-fold lower in patients <25 versus ≥25 years. The estimated intracellular TFV-DP half-life for these groups was 70 and87 hours,respectively. CONCLUSIONS:: These data demonstrate children and adolescents receiving standard TDF dosing of 300 mg once daily achieve higher intracellular TFV-DP concentrations than adults, despite lower plasma TFV concentrations. This age-related difference appears to arise from an increased sensitivity to formation ofTFV-DP.
    AIDS (London, England) 10/2012; · 4.91 Impact Factor
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    ABSTRACT: Durable suppression of HIV-1 replication requires the establishment of antiretroviral drug concentrations that exceed the susceptibility of the virus strain(s) infecting the patient. Minimum plasma drug concentrations (C(trough)) are correlated with response, but determination of target C(trough) values is hindered by a paucity of in vivo concentration-response data. In the absence of these data, in vitro susceptibility measurements, adjusted for serum protein binding, can provide estimations of suppressive in vivo drug concentrations. We derived serum protein binding correction factors (PBCF) for protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and an integrase inhibitor by measuring the effect of a range of human serum concentrations on in vitro drug susceptibility measured with the PhenoSense HIV assay. PBCFs corresponding to 100% HS were extrapolated using linear regression and ranged from 1.4 for nevirapine to 77 for nelfinavir. Using the mean 95% inhibitory concentration (IC(95)) for ≥1,200 drug-susceptible viruses, we calculated protein-bound IC(95) (PBIC(95)) values. PBIC(95) values were concordant with the minimum effective C(trough) values that were established in well-designed pharmacodynamic studies (e.g., indinavir, saquinavir, and amprenavir). In other cases, the PBIC(95) values were notably lower (e.g., darunavir, efavirenz, and nevirapine) or higher (nelfinavir and etravirine) than existing target recommendations. The establishment of PBIC(95) values as described here provides a convenient and standardized approach for estimation of the minimum drug exposure that is required to maintain viral suppression and prevent the emergence of drug-resistant variants, particularly when in vivo concentration-response relationships are lacking.
    Antimicrobial Agents and Chemotherapy 09/2012; 56(11):5938-45. · 4.57 Impact Factor
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    ABSTRACT: AIMS: To determine pharmacokinetic and pharmacogenomic correlates of efavirenz central nervous system (CNS) side effects following a single dose. METHODS: Thirty-four healthy HIV-negative African Americans were administered a 600 mg dose of efavirenz. Blood samples for pharmacokinetics were drawn serially from 0 to 12 hours post-dose. Neuropsychometric testing with drowsiness visual analogue scale, grooved pegboard, and letter digit substitution tests was done the day prior to dosing and at 1, 2, 3, 4, and 6 hours post-dose. Subjective CNS symptoms were assessed at 6 hours post-dose. Composite CYP2B6 516/983 genotype was determined. RESULTS: Pharmacokinetic indices reflecting increased plasma efavirenz exposure were associated with slower non-dominant hand grooved pegboard task completion (C(max) , P(1hr) =0.01, P(2hr) =0.05, P(3hr) =0.03, P(4hr) =0.01; AUC, P(1hr) =0.04; clearance P(1hr) =0.05, P(2hr) =0.02, P(6hr) =0.01). In a repeated measures model analysis that adjusted timing of neuropsychometric testing for timing of peak drug concentration, clearance (P<0.001), AUC(0→312h) (P=0.001) and C(max) (P=0.008) were associated with non-dominant grooved pegboard test performance. CYP2B6 genotype trended to correlate with non-dominant hand grooved pegboard at 4 and 6 hours (P=0.07 and 0.06). Decreased drowsiness at 6 hours was associated with higher C(max) (P= 0.02). CONCLUSIONS: Following a single dose of efavirenz, an association between pharmacokinetics and neuropsychometric performance was discernable. A weaker association between genotype and neurocognitive test performance likely is mediated by effect of genotype on plasma clearance. Strategies that lower C(max) during initial dosing may decrease CNS side effects.
    British Journal of Clinical Pharmacology 09/2012; · 3.58 Impact Factor
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    ABSTRACT: Paired plasma and intracellular samples were obtained from 12 HIV-infected adults taking raltegravir twice-daily (BID), and after switching to once daily (QD). With BID dosing, no plasma trough concentrations were below the IC95, in contrast to 33% for QD dosing. 50% of the QD group had intracellular trough concentrations below the IC95; 25% in the BID group. Lower plasma and intracellular concentrations may contribute to inferior virologic suppression rates observed with QD raltegravir dosing.
    AIDS (London, England) 08/2012; · 4.91 Impact Factor
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    ABSTRACT: Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used worldwide as part of combination antiretroviral therapy in infants and children to treat HIV infection. Dosing based on either weight or body surface area has been approved by the U.S. Food and Drug Administration (FDA) but can be difficult to implement in resource-limited settings. The World Health Organization (WHO) has developed simplified weight band dosing for NVP, but it has not been critically evaluated. NVP pharmacokinetic data were combined from eight pediatric clinical trials (Pediatric AIDS Clinical Trials Group [PACTG] studies 245, 356, 366, 377, 403, 1056, and 1069 and Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens [CHAPAS]) representing subjects from multiple continents and across the pediatric age continuum. A population pharmacokinetic model was developed to characterize developmental changes in NVP disposition, identify potential sources of NVP pharmacokinetic variability, and assess various pediatric dosing strategies and their impact on NVP exposure. Age, CYP2B6 genotype, and ritonavir were independent predictors of oral NVP clearance. The Triomune fixed-dose tablet was an independent predictor of bioavailability compared to the liquid and other tablet formulations. Monte Carlo simulations of the final model were used to assess WHO weight band dosing recommendations. The final pharmacokinetic model indicated that WHO weight band dosing is likely to result in a percentage of children with NVP exposure within the target range similar to that obtained with FDA dosing. Weight band dosing of NVP proposed by the WHO has the potential to provide a simple and effective dosing strategy for resource limited settings.
    Antimicrobial Agents and Chemotherapy 08/2012; 56(10):5374-80. · 4.57 Impact Factor

Publication Stats

4k Citations
817.26 Total Impact Points

Institutions

  • 2001–2014
    • University of Alabama at Birmingham
      • • Department of Pharmacology and Toxicology
      • • Division of Clinical Pharmacology
      • • Department of Medicine
      Birmingham, Alabama, United States
  • 2013
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2005–2013
    • Vanderbilt University
      • Department of Medicine
      Nashville, Michigan, United States
    • University of Colorado
      • Department of Clinical Pharmacy
      Denver, CO, United States
  • 2012
    • Monogram Biosciences
      San Francisco, California, United States
    • University of Nebraska Medical Center
      Omaha, Nebraska, United States
    • University of Nebraska at Omaha
      • Department of Internal Medicine
      Omaha, NE, United States
  • 2011
    • Northwestern University
      • Division of Infectious Diseases (Dept. of Medicine)
      Evanston, IL, United States
  • 2010–2011
    • University of South Florida
      • Department of Epidemiology and Biostatistics
      Tampa, FL, United States
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 2007–2011
    • Emory University
      • Division of Infectious Diseases
      Atlanta, GA, United States
  • 2006–2010
    • Harvard University
      • Department of Biostatistics
      Cambridge, Massachusetts, United States
    • University at Buffalo, The State University of New York
      • Department of Pharmacy Practice
      Buffalo, NY, United States
  • 2009
    • University of Oklahoma Health Sciences Center
      • College of Pharmacy
      Oklahoma City, OK, United States
  • 2007–2009
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 2005–2009
    • University of Washington Seattle
      • Department of Neurology
      Seattle, WA, United States
  • 2008
    • Brigham and Women's Hospital
      • Center for Brain Mind Medicine
      Boston, MA, United States
  • 2004–2008
    • Weill Cornell Medical College
      New York City, New York, United States
  • 2006–2007
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2005–2006
    • University of Rochester
      • Department of Biostatistics and Computational Biology
      Rochester, NY, United States
  • 2003–2004
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 2002–2004
    • University of North Carolina at Chapel Hill
      • Division of Infectious Diseases
      North Carolina, United States
  • 1995–1996
    • University of Minnesota Duluth
      • College of Pharmacy
      Duluth, Minnesota, United States
  • 1994
    • University of Minnesota Twin Cities
      • College of Pharmacy
      Minneapolis, MN, United States