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ABSTRACT: PURPOSE OF REVIEW: Current antiretroviral treatment regimens represent significant improvements in the management of HIV-1 infection; however, these regimens have not achieved a functional or sterilizing cure. One barrier to achieving a cure may be suboptimal antiretroviral concentrations in sanctuary sites throughout the body, including the central nervous system, gut-associated lymphoid tissue, lymph nodes, and tissue macrophages. This review will focus on the problems associated with achieving effective concentrations in these restricted sanctuary sites, and potential strategies to overcome these barriers. RECENT FINDINGS: Sufficient data exist to conclude that antiretroviral drug distribution is not uniform throughout the body. Low tissue/reservoir concentrations may be associated with viral replication. Multiple means to increase drug concentrations in sanctuary sites are being investigated, including modification of currently utilized drugs, blockade of transporters and enzymes that affect drug metabolism and pharmacokinetics, and local drug administration. Accumulating data suggest these methods increase antiretroviral concentrations in reservoirs of viral replication. No method has yet resulted in the complete clearance of HIV. SUMMARY: New strategies for increasing antiretroviral concentrations in predominant sites of viral replication may provide more effective means for elimination of viral sanctuaries. Additional research is necessary to optimize antiretroviral tissue distribution in order to inhibit virus replication fully, and avoid resistance and replenishment of viral reservoirs that may persist in the face of antiretroviral therapy.
Current opinion in HIV and AIDS 02/2013; · 4.75 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: 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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Jennifer J Kiser,
Rui Zhu,
David Z DʼArgenio,
Mark F Cotton,
Raziya Bobat,
George D McSherry,
Shabir A Madhi,
Vincent J Carey,
Heiner I Seifart,
Cedric J Werely, Courtney V Fletcher
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ABSTRACT: There are limited data on isoniazid (INH) pharmacokinetics in infants and young children and, therefore, uncertainty on appropriate dosing.
Pharmacokinetic data were obtained from perinatally HIV-exposed South African infants aged 3-24 months receiving INH 10-20 mg·kg·d orally for Mycobacterium tuberculosis prophylaxis. INH pharmacokinetic parameters were characterized using a population pharmacokinetic approach. Dosing simulations were performed to evaluate weight-based INH doses in children based on N-acetyltransferase 2 enzyme (NAT2) genotype, age, maximum concentrations (Cmax) ≥3 mg/L, and area under the curve (AUC0-24) ≥10.52 mg·h/L.
In 151 infants (53% female, 48% HIV positive) receiving a mean INH dose of 14.5 mg·kg·d, mean (±SD) Cmax at 3, 6, and 23 months of age were 10.0 (3.5), 8.6 (2.6), and 9.3 (3.8) mg/L, respectively, mean (±SD) AUC0-24 were 53.6 (26.8), 42 (19.9), and 44 (30.7) mg·h/L, respectively, and mean (±SD) half-lives were 2.1 (0.7), 1.9 (0.6), and 1.8 (0.9) hours, respectively. A trimodal apparent oral clearance of INH as a function of the NAT2 genotype was apparent as early as 3 months. INH was well tolerated. At an average INH dose of 14.5 mg·kg·d, 99% of infants aged 3-24 months have an INH Cmax ≥3 mg/L, and 98% have an INH AUC0-24 ≥10.52 mg·h/L.
INH at an average dose of 14.5 mg/kg once daily was well tolerated in infants and achieved INH Cmax values ≥3 mg/L and AUC0-24 values ≥10.52 mg·h/L.
Therapeutic drug monitoring 06/2012; 34(4):446-51. · 2.43 Impact Factor
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ABSTRACT: An assay using ultrahigh pressure liquid chromatography and mass spectrometry detection was developed and validated for measurement of the HIV integrase inhibitor raltegravir (MK-0518) in human cell extracts. The assay is designed to utilize 200μl of 70% MeOH cell extract derived from human peripheral blood mononuclear cells or human tissue samples. The assay is linear over a range from 0.0023 to 9.2ngml(-1). The average %CV (SD/Mean)*100 and %deviation ((observed-target)/target)*100 were less than 20% at the lower limit of quantification and less than 15% over the range of the curve. This assay is an accurate and highly sensitive method for determining raltegravir concentrations in cellular extracts with a lower limit 40 to over 100-fold lower than other methods in the literature. We also present a new processing method where a rapid spin through oil produced a significant increase in apparent intracellular raltegravir concentration compared with conventional processing.
Journal of pharmaceutical and biomedical analysis 06/2012; 70:378-87. · 2.45 Impact Factor
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ABSTRACT: Many data associate low protease inhibitor plasma concentrations with suboptimal virologic responses, whereas relatively few
data associate high plasma concentrations with increased likelihood of toxicity. Knowledge of relationships between concentrations
and virologic response is important because significant variability in plasma concentrations exists among HIV-infected persons.
Unfortunately, a prospectively confirmed therapeutic range that reduces the risk of virologic failure has not been established
for the protease inhibitors. Recent investigations have identified a relationship between the measured minimum plasma concentration,
the in vitro susceptibility of the subject’s virus, and virologic outcome. However, differences in virologic response may
further depend on other pharmacologic factors such as protein binding, intracellular kinetics, expression of drug transporters,
and drug synergies or antagonisms. In the future, dosing strategies that accommodate the variability in both pharmacokinetics
and pharmacodynamics may improve virologic outcomes. In summary, clinical pharmacologic considerations for protease inhibitors
can be used to promote their optimal use.
Current Infectious Disease Reports 04/2012; 3(4):381-387.
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ABSTRACT: To determine whether the absorption of four antiretroviral agents-raltegravir, etravirine, emtricitabine, and tenofovir-is compromised when administered by gastrostomy tube.
Pharmacokinetic analysis.
University medical center.
A 52-year-old African-American man coinfected with advanced multidrug-resistant human immunodeficiency virus (HIV) and chronic hepatitis B, who was receiving treatment with raltegravir, etravirine, emtricitabine, and tenofovir, and developed ulcerative esophagitis with perforation, requiring a gastrostomy tube.
Due to the patient's esophageal perforations, all nutrition and drug therapy had to be provided by gastrostomy tube. As his antiretroviral regimen of raltegravir, etravirine, and emtricitabine-tenofovir was not available in liquid or powder formulations, the oral tablets were crushed or dispersed and mixed with water, then administered by gastrostomy tube. To ensure that the absorption of the drugs was sufficient for antiretroviral response, plasma samples were collected at 2 hours and 12 hours after dosing, and drug concentrations were quantitated by using validated assays. The 2- and 12-hour postdose plasma concentrations were 1220 and 446 ng/ml for raltegravir, 212 and 274 ng/ml for etravirine, 1148 and 164 ng/ml for emtricitabine, and 320 and 94 ng/ml for tenofovir, respectively. The patient's plasma concentrations were then compared with those in published pharmacokinetic studies of oral regimens administered to HIV-infected persons and healthy volunteers. Overall, the plasma concentrations of the antiretrovirals administered by gastrostomy tube were similar to published values. No drug toxicities were observed in this patient.
These pharmacokinetic data suggest that absorption of raltegravir, etravirine, emtricitabine, and tenofovir was not compromised when the drugs were administered by gastrostomy tube. These findings provide a basis for further investigation of the pharmacokinetics, safety, tolerance, and antiretroviral response to raltegravir, etravirine, and emtricitabine-tenofovir when the oral route of administration is not possible.
Pharmacotherapy 02/2012; 32(2):142-7. · 2.90 Impact Factor
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ABSTRACT: The relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n = 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h(-1); apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (E(max)), the TFV concentration producing 50% of E(max) (EC(50)), and the intracellular elimination rate constant (k(out)) of 300 fmol/10(6) cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h(-1), respectively. The estimated k(out) gave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.
Antimicrobial Agents and Chemotherapy 09/2011; 55(11):5294-9. · 4.84 Impact Factor
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The Journal of Infectious Diseases 09/2011; 204(5):669-74. · 6.41 Impact Factor
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Jennifer J Kiser,
Richard M Rutstein,
Pearl Samson,
Bobbie Graham,
Grace Aldrovandi,
Lynne M Mofenson,
Elizabeth Smith,
Steven Schnittman,
Terry Fenton,
Richard C Brundage, Courtney V Fletcher
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ABSTRACT: To describe the pharmacokinetics of atazanavir (ATV) and ritonavir-boosted ATV (ATV/r) in children aged 91 days to 21 years.
A phase I/II, open-label, multicenter study of once-daily ATV and ATV/r as part of combination antiretroviral treatment in HIV-infected treatment-experienced and treatment-naive children.
Sites in the United States and South Africa.
One hundred and ninety-five children enrolled; 172 had evaluable ATV pharmacokinetics on day 7.
Children were entered in age, dose, and formulation (powder or capsule) cohorts. Intensive pharmacokinetic sampling occurred 7 days after starting ATV. ATV doses were increased or decreased if the 24-h area under the concentration time curves (AUC0-24hr) were less than 30 or more than 90 μg × h/ml, respectively.
Cohorts satisfied protocol-defined pharmacokinetic criteria if the median ATV AUC0-24hr was 60 μg × h/ml or less, and AUC0-24hr and ATV concentrations 24-h postdose (C24) were more than 30 μg × h/ml and at least 60 ng/ml, respectively, in at least 80% of the children, with no individual AUC0-24hr less than 15 μg × h/ml.
Unboosted ATV capsules satisfied pharmacokinetic criteria at a dose of 520 mg/m for those aged more than 2 to 13 years or less and 620 mg/m for those aged more than 13 to 21 years or less. ATV/r capsules satisfied criteria at a dose of 205 mg/m for those aged more than 2 to 21 years or less. ATV/r powder satisfied criteria at a dose of 310 mg/m for those aged more than 2 to 13 years or less, but pharmacokinetics in those aged 2 years or less were highly variable.
Body surface area-determined doses of ATV capsules and of ATV/r powder and capsules provide ATV exposures in children of more than 2 years that approximate concentrations in adults receiving ATV/r.
AIDS (London, England) 05/2011; 25(12):1489-96. · 4.91 Impact Factor
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ABSTRACT: The roles of the NAT2 genotype and enzyme maturation on isoniazid pharmacokinetics were investigated in South African infants with perinatal HIV exposure enrolled in a randomized, double-blind, controlled trial of isoniazid for prevention of tuberculosis disease and latent infection. Plasma concentration-time measurements of isoniazid from 151 infants (starting at 3-4 months of age) receiving isoniazid 10 to 20 mg/kg/d orally during the course of the 24-month study were incorporated in a population analysis along with NAT2 genotype, body weight, age, and sex. The results showed a different NAT2 enzyme maturation profile for each of the 3 acetylation groups, with the 70-kg body weight-normalized typical apparent clearance for the fast and intermediate acetylators increasing from 14.25 L/h and 10.88 L/h at 3 months of age to 22.84 L/h and 15.58 L/h at 24 months of age, respectively, with no significant change in the apparent clearance of the slow group during this period. A hypothesis is proposed to explain the genotype-dependent enzyme maturation processes for the NAT2 enzyme.
The Journal of Clinical Pharmacology 05/2011; 52(4):511-9. · 2.91 Impact Factor
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ABSTRACT: Current procedures for obtaining and measuring plasma concentrations of HIV protease inhibitors (PIs) are technically challenging. Dried blood spot (DBS) assays offer a way to overcome many of the obstacles. We sought to develop a DBS assay for quantitation of the PI atazanavir (ATV) and to compare this method with a previously validated plasma assay. We prospectively enrolled 48 patients with well-controlled HIV disease who had been on ATV for at least 7 days. ATV was quantified from plasma by use of high-performance liquid chromatography (HPLC). A reversed-phase ultrahigh-performance liquid chromatography (UPLC) assay was utilized for DBS samples. The concentrations of ATV quantified in a DBS matrix showed very strong agreement with those measured in plasma (r(2) = 0.988). The mean difference in ATV concentration between the two methods was -10.8% (95% confidence interval [95% CI], -7.65% to -13.95%), indicating that the DBS method has a slight negative bias. A majority (97.8%) of the differences in concentration between the two assays fell within ±2 standard deviations. ATV concentrations were lower in subjects who had detectable HIV RNA in plasma (mean, 543 ng/ml) than in those with HIV RNA of <50 copies/ml (mean, 1,582 ng/ml) (P = 0.03, Wilcoxon rank-sum test). In conclusion, our study demonstrated that ATV quantitation in a DBS matrix is feasible and accurate. DBS use offers a convenient alternative for measuring plasma concentrations of ATV and may have utility in monitoring of drug concentrations in clinical practice and in future studies.
Antimicrobial Agents and Chemotherapy 10/2010; 54(10):4124-8. · 4.84 Impact Factor
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ABSTRACT: An LC/MS/MS assay we published for tenofovir (TFV) plasma levels is a useful tool for monitoring the pharmacotherapy of HIV-positive individuals [T. Delahunty, L. Bushman, C.V. Fletcher, J. Chromatogr. B 830 (2006) 6-12]. A new combination therapy consisting of the TFV pro-drug (300 mg) and another reverse transcriptase inhibitor, emtricitabine (FTC, 200 mg) has become available in a convenient once-daily dosage form (Truvada). This widely used medication has prompted us to develop and validate a convenient assay to determine simultaneously TFV and FTC plasma concentrations. In view of their chemical similarity to the analytes, stable isotope internal standards (IS) were chosen. These consisted of TFV labeled uniformly with (13)C in the adenine moiety (Iso-TFV) and FTC labeled with 13C and 15N in the cytosine moiety (Iso-FTC). Trifluoroacetic acid was added to the patient's EDTA plasma (containing the IS) to produce a de-proteinated extract after high speed centrifugation. The extracts were directly injected into the mobile phase (3% acetonitrile/1% acetic acid, aq.) stream flowing at 200 microL/min. A Synergi Polar-RP, 2.0 mm x 150 mm, reversed-phase analytical column was used to achieve the chromatographic separation. Detection of the analytes was achieved by ESI positive ionization tandem mass spectrometry. The precursor/product transitions (m/z) in the positive ion mode were 288/176 and 293/181 ions for TFV and Iso-TFV, respectively and the precursor/product transitions (m/z) were 248/130 and 251/133 ions for FTC and Iso-FTC, respectively. When the analyte/IS abundance ratios were plotted against the specified concentrations, the linearity of the concentration curves were in the range 10 ng/mL to 1500 ng/mL for both analytes (250 microL plasma extracted), with a minimum quantifiable limit of 10 ng/mL for both analytes. The inter- and intra-day accuracy and precision for both TFV and FTC were within +/-20% at the LLOQ and +/-15% at the other QC levels. We have expanded the method originally designed for the assay of TFV alone to incorporate the simultaneous determination of the latter and FTC using stable isotope IS. This assay has been successfully used for the periodic monitoring of 678 HIV-positive patients being treated with the combination therapy.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 08/2009; 877(20-21):1907-14. · 2.78 Impact Factor
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Courtney V Fletcher
The Pediatric Infectious Disease Journal 06/2009; 28(5):429-30. · 3.58 Impact Factor
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Timothy J Wilkin,
John E McKinnon,
A Gregory DiRienzo,
Katie Mollan, Courtney V Fletcher,
David M Margolis,
Barbara Bastow,
Gary Thal,
William Woodward,
Catherine Godfrey,
Ann Wiegand,
Frank Maldarelli,
Sarah Palmer,
John M Coffin,
John W Mellors,
Susan Swindells
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ABSTRACT: Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/RTV) alone is attractive because of nucleoside reverse-transcriptase inhibitor (NRTI)-sparing benefits, low pill burden, once-daily dosage, and safety.
Subjects with virologic suppression after > or = 48 weeks of initial antiretroviral therapy with 2 NRTIs and a protease inhibitor (PI) were enrolled. Subjects switched to ATV/RTV at entry and discontinued NRTIs after 6 weeks. The primary end point was time to virologic failure (confirmed HIV-1 RNA level > or = 200 copies/mL). Drug resistance at virologic failure was evaluated by standard genotyping and single-genome sequencing (SGS). Residual viremia (1.1-49 copies/mL) was measured by single-copy assay.
Thirty-four subjects simplified to ATV/RTV alone, of whom 30 (88%) did not experience virologic failure by 48 weeks after simplification. Residual viremia did not change significantly after NRTI discontinuation among those without virologic failure but did increase 4-12 weeks before confirmed virologic failure. No major PI-resistance mutations were identified at virologic failure by standard genotyping or SGS.
In this pilot study, simplified maintenance therapy with ATV/RTV alone maintained viral suppression in most subjects through 48 weeks. PI resistance was not detected among subjects experiencing virologic failure. Larger, randomized trials are warranted to further define the efficacy and safety of this strategy.
The Journal of Infectious Diseases 03/2009; 199(6):866-71. · 6.41 Impact Factor
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ABSTRACT: Efavirenz, a nonnucleoside reverse transcriptase inhibitor, is a highly effective and widely prescribed antiretroviral agent. It is recommended as first-line treatment of human immunodeficiency virus (HIV) infection. The standard dose of efavirenz is 600 mg/day; however, adverse central nervous system effects limit its use. Few data citing use of efavirenz at lower doses have been published. We describe a 35-year-old man with HIV infection whose virologic suppression was maintained after 18 months of treatment with efavirenz 400 mg/day. Genetic testing for cytochrome P450 (CYP) 2B6 showed that the patient was a heterozygous variant; patients with this polymorphism tend to have higher plasma efavirenz concentrations and slower plasma efavirenz clearance (prolonged elimination half-lives). Therapeutic drug monitoring also supported the dose reduction in this patient. Even with the 400-mg dose, the patient's plasma trough concentrations exceeded the upper limit of the therapeutic range. However, as he remained completely asymptomatic with this dose, no further dose reduction was necessary. This case report provides evidence that reduced efavirenz doses may be effective in the treatment of HIV infection. In addition, this case demonstrates that pharmacogenetic and pharmacokinetic testing combined with therapeutic drug monitoring may be used to guide reduced-dose, efavirenz-based therapy.
Pharmacotherapy 07/2008; 28(6):782-7. · 2.90 Impact Factor
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ABSTRACT: Nucleos(t)ide reverse transcriptase inhibitors (NRTIs), such as tenofovir, require intracellular phosphorylation for pharmacologic activity. Drug transporters may contribute to the intracellular disposition of NRTIs.
We characterized intracellular tenofovir diphosphate (TFV-DP) concentrations in HIV-infected patients (n = 30), and investigated associations between TFV-DP concentrations and polymorphisms in the drug transporter genes SLC22A6, ABCC2, and ABCC4.
Subjects were genotyped for 6 single-nucleotide polymorphisms: 2 in SLC22A6 (encodes influx transporter, human organic anion transporter 1), 728G>A and 453G>A; 2 in ABCC2 (encodes efflux transporter, multidrug resistance protein [MRP] 2), -24C>T and 1249G>A; and 2 in ABCC4 (encodes efflux transporter, MRP4), 3463A>G and 4131T>G.
The mean TFV-DP was 76.1 fmol/10(6) cells (range: 16.3 to 212 fmol/10(6) cells). Tenofovir apparent oral and renal clearances were significantly predictive of intracellular TFV-DP concentrations. For every 1-L/h decrease in tenofovir renal clearance, there was, on average, an 8% increase in TFV-DP (P = 0.002). We identified a novel relation between ABCC4 3463A>G genotype and TFV-DP. ABCC4 3463G variants had TFV-DP concentrations 35% higher (29 fmol/10(6) cells) than wild type (P = 0.04).
This study provides direction for future investigations to elucidate the contribution of clinical characteristics and drug transporter genotype to TFV-DP safety and efficacy.
JAIDS Journal of Acquired Immune Deficiency Syndromes 03/2008; 47(3):298-303. · 4.43 Impact Factor
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ABSTRACT: It is not uncommon in pharmacokinetic (PK) studies that some concentrations are censored by the bioanalytical laboratory and reported qualitatively as below the lower limit of quantification (LLOQ). Censoring concentrations below the quantification limit (BQL) has been shown to adversely affect bias and precision of parameter estimates; however, its impact on structural model decision has not been studied. The current simulation study investigated the impact of the percentage of data censored as BQL on the PK structural model decision; evaluated the effect of different coefficient of variation (CV) values to define the LLOQ; and tested the maximum conditional likelihood estimation method in NONMEM VI (YLO). Using a one-compartment intravenous model, data were simulated with 10-50% BQL censoring, while maintaining a 20% CV at LLOQ. In another set of experiments, the LLOQ was chosen to attain CVs of 10, 20, 50 and 100%. Parameters were estimated with both one- and two-compartment models using NONMEM. A type I error was defined as a significantly lower objective function value for the two-compartment model compared to the one-compartment model using the standard likelihood ratio test at alpha = 0.05 and alpha = 0.01. The type I error rate substantially increased to as high as 96% as the median of percent censored data increased at both the 5% and 1% alpha levels. Restricting the CV to 10% caused a higher type I error rate compared to the 20% CV, while the error rate was reduced to the nominal value as the CV increased to 100%. The YLO option prevented the type I error rate from being elevated. This simulation study has shown that the practice of assigning a LLOQ during analytical methods development, although well intentioned, can lead to incorrect decisions regarding the structure of the pharmacokinetic model. The standard operating procedures in analytical laboratories should be adjusted to provide a quantitative value for all samples assayed in the drug development setting where sophisticated modeling may occur. However, the current level of precision may need to be maintained when laboratory results are to be used for direct patient care in a clinical setting. Finally, the YLO option should be considered when more than 10% of data are censored as BQL.
Journal of Pharmacokinetics and Biopharmaceutics 03/2008; 35(1):101-16. · 2.06 Impact Factor
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Jennifer J Kiser, Courtney V Fletcher,
Patricia M Flynn,
Coleen K Cunningham,
Craig M Wilson,
Bill G Kapogiannis,
Hanna Major-Wilson,
Rolando M Viani,
Nancy X Liu,
Larry R Muenz,
D Robert Harris,
Peter L Havens
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ABSTRACT: The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects > or =18 to <25 years old receiving (> or =28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC(0-24)), maximum concentration of drug in serum (C(max)), concentration at 24 h postdose (C(24)), and total apparent oral clearance (CL/F) values were 35,971 ng x hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC(0-24), C(max), C(24), and CL/F values were 2,762 ng.hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P < or = 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir C(max) and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.
Antimicrobial Agents and Chemotherapy 02/2008; 52(2):631-7. · 4.84 Impact Factor
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ABSTRACT: Mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTIs) has been reported to be responsible for various adverse effects. The relative impact of NRTIs on the mitochondria of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected children receiving highly active antiretroviral therapy (HAART) is unknown. Mitochondrial DNA (mtDNA) levels were quantified longitudinally from peripheral blood mononuclear cells (PBMCs) in 31 HIV-1-infected children from Pediatric AIDS Clinical Trial Group Study 382 who were receiving HAART, including nelfinavir, efavirenz, and different NRTIs, and who had had undetectable plasma HIV-1 RNA levels for >2 years. The median mtDNA levels in PBMCs increased from 137 copies/cell at the baseline to 179 copies/cell at week 48 (P = 0.01) and 198 copies/cell at week 104 (P < 0.001). Before the initiation of HAART, children who received regimens containing didanosine had mtDNA levels persistently lower than those in children not receiving didanosine (106 versus 140 copies/cell; P = 0.008). During HAART, the median increase in the mtDNA level from the baseline to week 104 was the lowest in children who received regimens containing didanosine (+26 copies/cell) compared to those in children who received other regimens (+79 copies/cell) (P = 0.02). A multivariate analysis also demonstrated that didanosine, as part of HAART, was the only NRTI associated with the change in mtDNA levels (P = 0.007). Children receiving didanosine-containing antiretroviral regimens have the lowest mtDNA levels in PBMCs and may be at greater risk for long-term adverse effects due to mitochondrial toxicity. This may be of particular importance in resource-limited countries where didanosine is widely used for the treatment of HIV-infected children.
Antimicrobial Agents and Chemotherapy 12/2007; 51(12):4236-42. · 4.84 Impact Factor
