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Jennifer R King

Publications and source records attributed to Jennifer R King.

14 recordsLinked to original sources
PubMed2006

The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity: pharmacokinetic relationship between expired 13CO2 and plasma [2-13C]dihydrouracil.

PURPOSE: Dihydropyrimidine dehydrogenase (DPD) deficiency is critical in the predisposition to 5-fluorouracil dose-related toxicity. We recently characterized the phenotypic [2-(13)C]uracil breath test (UraBT) with 96% specificity and 100% sensitivity for identification of DPD deficiency. In the present study, we characterize the relationships among UraBT-associated breath (13)CO(2) metabolite formation, plasma [2-(13)C]dihydrouracil formation, [2-(13)C]uracil clearance, and DPD activity. EXPERIMENTAL DESIGN: An aqueous solution of [2-(13)C]uracil (6 mg/kg) was orally administered to 23 healthy volunteers and 8 cancer patients. Subsequently, breath (13)CO(2) concentrations and plasma [2-(13)C]dihydrouracil and [2-(13)C]uracil concentrations were determined over 180 minutes using IR spectroscopy and liquid chromatography-tandem mass spectrometry, respectively. Pharmacokinetic variables were determined using noncompartmental methods. Peripheral blood mononuclear cell (PBMC) DPD activity was measured using the DPD radioassay. RESULTS: The UraBT identified 19 subjects with normal activity, 11 subjects with partial DPD deficiency, and 1 subject with profound DPD deficiency with PBMC DPD activity within the corresponding previously established ranges. UraBT breath (13)CO(2) DOB(50) significantly correlated with PBMC DPD activity (r(p) = 0.78), plasma [2-(13)C]uracil area under the curve (r(p) = -0.73), [2-(13)C]dihydrouracil appearance rate (r(p) = 0.76), and proportion of [2-(13)C]uracil metabolized to [2-(13)C]dihydrouracil (r(p) = 0.77; all Ps < 0.05). CONCLUSIONS: UraBT breath (13)CO(2) pharmacokinetics parallel plasma [2-(13)C]uracil and [2-(13)C]dihydrouracil pharmacokinetics and are an accurate measure of interindividual variation in DPD activity. These pharmacokinetic data further support the future use of the UraBT as a screening test to identify DPD deficiency before 5-fluorouracil-based therapy.

Administration, Oral↗
PubMed2006

Tipranavir: a novel nonpeptidic protease inhibitor of HIV.

Tipranavir is a novel nonpeptidic protease inhibitor (PI) with activity against wild-type and multidrug-resistant HIV-1 both in vitro and in HIV-infected patients. Tipranavir/ritonavir 500 mg/200 mg administered twice daily for 3 weeks to healthy volunteers produced a median (range) maximum plasma concentration and minimum plasma concentration of 79.1 (34.9-111.7) mg/L and 19.5 (0.43-42.8) mg/L, respectively. Concomitant administration with low-dose ritonavir significantly increases tipranavir plasma concentrations; therefore, the recommended dose is tipranavir 500 mg and ritonavir 200 mg twice daily. Tipranavir is a substrate and inducer of cytochrome P450 3A4 isoenzyme, thus is predisposed to interactions with other agents that are substrates, inducers or inhibitors of this enzyme family. Significant drug-drug interactions have been reported with co-administration of tipranavir/ritonavir and other PIs but not with the non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine. Tipranavir/ritonavir 500 mg/200 mg twice daily in combination with an optimised background regimen was more effective than a ritonavir-boosted comparator PI plus an optimised background regimen. The adverse effect profile for tipranavir is similar to other boosted PI regimens and most commonly includes gastrointestinal complaints. Severe adverse events that require close monitoring include hepatotoxicity and lipid abnormalities. Tipranavir retains activity in many highly treatment-experienced patients with a large number of protease mutations. Therefore, this novel PI in combination with ritonavir represents an important new choice in the treatment of multiple-PI-experienced patients.

Adult↗
PubMed2005

Indinavir protein-free concentrations when used in indinavir/ritonavir combination therapy.

OBJECTIVE: To describe the in vivo protein-binding characteristics of indinavir (IDV) in the presence of ritonavir (RTV) relative to total IDV plasma concentrations. DESIGN: The ACTG protocol 5055 was a multicenter study comparing the safety and pharmacokinetics of IDV/RTV at doses of 800/200 and 400/400 mg twice daily in HIV-infected adults. METHODS: Forty-four patients underwent a 12-h intensive pharmacokinetic assessment after 2 weeks of therapy. Three plasma samples from 35 patients at Cmax, 6 and 12 h post dose were used to determine the unbound IDV concentrations. Unbound IDV was separated in plasma samples using ultra-filtration and measured using high-performance liquid chromatography with UV detection. RESULTS: Mean IDV protein-bound fraction across all time points in the 800/200 and 400/400 arm were 53.4 and 51.8%, respectively. In the 800/200 arm, percentage binding at Cmax was 50% compared with 56% at 12 h (P = 0.008). In the 400/400 arm, percentage binding at Cmax was 49% compared with 54% at 12 h (P = 0.008). CONCLUSIONS: The extent of plasma protein binding of IDV in this study was less than in previously published data with IDV alone. Although IDV concentrations differed across the arms, the percentage of IDV protein binding at all time points was not different between the 800/200 and 400/400 arms. However, the percentage of IDV protein binding at Cmax was significantly lower compared with 12 h in each arm, possibly suggesting that IDV protein binding is concentration-dependent. These data suggest that RTV affects IDV protein-binding characteristics and IDV also exhibits concentration dependent binding when administered with RTV.

Adult↗
PubMed2005

Efficacy, tolerability and pharmacokinetics of two nelfinavir-based regimens in human immunodeficiency virus-infected children and adolescents: pediatric AIDS clinical trials group protocol 403.

INTRODUCTION: Few combinations of highly active antiretrovirals have been studied in nucleoside reverse transcription inhibitor (NRTI)-experienced, human immunodeficiency virus (HIV)-infected children. We tested the efficacy, tolerability and pharmacokinetics of 2 combination therapies containing an NRTI, protease inhibitors +/- a nonnucleoside reverse transcription inhibitor (NNRTI). METHODS: This was a phase II, randomized, multicenter study. Forty-one children and youths between 5 months and 21 years with prior NRTI and no prior NNRTI or protease inhibitor experience received either nelfinavir (NFV) 30 mg/kg twice daily (bid), ritonavir (RTV) 400 mg/m bid and buffered didanosine (ddI) 240 mg/m daily (arm A) or NFV 50-55 mg/kg bid, nevirapine (NVP) 120 mg/m bid and stavudine (d4T) 1 mg/kg bid (arm B). Patients were evaluated clinically for 48 weeks after initiation of therapy. Intensive pharmacokinetic sampling occurred after 4 weeks of therapy. RESULTS: : The proportion of children with HIV-1 RNA < or =400 copies/mL and on randomized treatment at 48 weeks was 65% among children assigned NFV + RTV + ddI versus 28% among those assigned NFV + NVP + d4T (P = 0.039). No significant difference in median CD4% change from baseline to week 48 was found (3% versus 1%). No significant differences in safety or tolerability between children randomized to NFV + RTV + ddI versus NFV + NVP + d4T were identified. However, a trend toward a higher rate of permanent discontinuation of study treatment was noted among children assigned to NFV + NVP + d4T compared with NFV + RTV + ddI [7 of 20 (35%) versus 2 of 21 (10%); P = 0.12]. NFV pharmacokinetic measurements were not statistically different between the treatment groups, yet exposure to the NFV metabolite, M8, was significantly higher in subjects receiving RTV. The pharmacokinetics for NVP, RTV and d4T were similar to those of previously reported data. CONCLUSION: : Combination therapy containing NFV + RTV + ddI appears more efficacious in NRTI-experienced children than a regimen containing NFV + NVP + d4T. Differences in tolerability between the 2 treatment groups were not identified. Systemic exposure of these drugs was similar to that reported in other HIV-infected children and adults.

Adolescent↗
PubMed2004

Detection of nevirapine in plasma using thin-layer chromatography.

BACKGROUND: Nevirapine (NVP) is widely prescribed in resource-poor settings to pregnant women for treatment and prevention of HIV infection. High rates of misreported adherence, however, have compelled clinicians to find alternative methods to ensure systemic drug exposure. This report describes a fast, inexpensive thin-layer chromatography (TLC) method to detect the presence of NVP in human plasma. METHODS: Human plasma was spiked with various concentrations of NVP. NVP was subsequently isolated using solid-phase extraction and visualized with TLC. Clinical samples with NVP concentrations predetermined by high-performance liquid chromatography were used to validate the TLC method. RESULTS: NVP was detected at concentrations as low as 60 ng/mL. The lower limit of detection was set at 100 ng/mL due to the clear spot definition at this concentration. The turnaround time for assay results averages several hours, and costs associated with the assay are considerably below standard drug quantitation techniques. CONCLUSION: TLC provides a rapid, sensitive, and economical tool to qualitatively measure NVP in plasma. This method offers clinicians in resource-poor settings an alternative approach for measuring adherence, particularly in developing-world regions where NVP use is common and there is an immediate need to prevent mother-to-child HIV transmission.

Anti-HIV Agents↗
PubMed2004

Pharmacokinetic enhancement of protease inhibitor therapy.

Combination antiretroviral therapy with two or more protease inhibitors has become the standard of care in the treatment of HIV infection. Dual protein inhibitor (PI) regimens, such as lopinavir/ritonavir, are commonly used as initial PI therapy. As viral resistance increases and the development of mechanistically novel protease inhibitors decreases, clinicians turn to ritonavir-enhanced dual PI therapy to treat salvage patients. Potency of these combination regimens is increased while pill burden, food restrictions and often, side effects are decreased. These clinical advantages result from the enhancement of their pharmacological properties, including alterations in the absorption and metabolism process. Alterations in the absorption and metabolism of protease inhibitors when co-administered with a cytochrome P450 (CYP) enzyme inhibitor, such as low dose ritonavir, are reflected by impressive changes in pharmacokinetic parameters. For example, the addition of ritonavir 100 or 200 mg to saquinavir 1200-1800 mg has been shown to increase saquinavir area under the concentration-time curve (AUC) by approximately 300-800% compared with saquinavir alone. The ability of ritonavir to increase plasma trough concentrations (C(min)) of concomitantly administered PIs is perhaps the greatest clinical benefit of dual or ritonavir-enhanced dual PI therapy since inadequate concentrations of antiretrovirals may support long term antiretroviral resistance. For example, lopinavir 400mg alone in healthy volunteers produced plasma concentrations that briefly exceeded the concentration required to inhibit 50% of viral replication (IC(50)). Yet, when low doses of ritonavir were added, C(min) values were 50- to 100-fold greater than the concentration required to produce 50% of the maximum effect for wild-type HIV (EC(50)). The following manuscript will discuss the rationale for combining protease inhibitors and will review pertinent pharmacokinetic and clinical data on these combination regimens.

Anti-HIV Agents↗
PubMed2003

Simultaneous determination of nine antiretroviral compounds in human plasma using liquid chromatography.

A rapid, sensitive and specific high-performance liquid chromatographic (HPLC) method using UV detection was developed for the determination of nine antiretroviral compounds commonly found in plasma from patients receiving antiretroviral therapy. Analytes include indinavir, saquinavir, ritonavir, amprenavir, lopinavir, delavirdine, efavirenz, nelfinavir and its M8 metabolite. Analytes were isolated from plasma using tert.-butyl methyl ether and separation achieved via reversed-phase liquid chromatography on a C(8) column with a gradient mobile phase. Detection at 210 nm provided adequate sensitivity. Limit of quantification is 50 ng/ml and all analytes demonstrated linearity across 50-10000 ng/ml from a single 200-microliter plasma sample. Recovery from plasma was consistently high (>80%). This novel HPLC methodology allows us to simultaneously determine plasma concentrations of nine antiretrovirals, including lopinavir, in HIV-infected patients on a single HPLC system.

Anti-HIV Agents↗
PubMed2003

Methods for integration of pharmacokinetic and phenotypic information in the treatment of infection with human immunodeficiency virus.

Interest in monitoring antiretroviral drug concentrations in human immunodeficiency virus-infected patients has gained considerable momentum in recent years. We present a potential method for integrating pharmacokinetic and phenotypic information that will assist clinicians in choosing optimal treatment regimens for their patients and that will provide an approach for the interpretation of antiretroviral plasma drug concentrations.

Anti-HIV Agents↗
PubMed2003

Evaluation of multiple drug therapy in human immunodeficiency virus-infected pediatric patients.

BACKGROUND: An aggressive therapeutic approach for treatment of HIV in adults consists of combining five or more concurrent antiretrovirals. The clinical benefits of this regimen are often accompanied by increased toxicities. We report the safety and tolerance of multiple drug therapy in HIV-infected children. METHODS: A retrospective chart review was performed to identify HIV-infected children who received > or =5 concurrent antiretrovirals or 4 antiretrovirals plus hydroxyurea. Treatment success was defined as > or =1 log(10) decrease in plasma HIV RNA from baseline any time during multiple drug therapy. Toxicities were defined as a >Grade 2 change from baseline in laboratory values. RESULTS: Twelve patients received multiple drug therapy for 6 months, and 42% of patients continued to receive therapy for at least 1 year. No Grade 3 or 4 toxicities or laboratory abnormalities were reported. Treatment success occurred in 8 (83%) of 12 patients. Adherence was a determining factor in treatment success or failure. CONCLUSIONS: Treatment of HIV-infected children with multiple drug therapy was well-tolerated in this cohort. Treatment success occurred in most patients, with adherence affecting patients' likelihood of success. Larger controlled clinical trials in this patient population are necessary to determine whether the benefit of this therapeutic approach outweighs potential risks.

Adolescent↗
PubMed2002

Antiretroviral pharmacokinetics in the paediatric population: a review.

Characteristics unique to paediatric pharmacotherapy should be considered when treating children infected with human immunodeficiency virus (HIV). Processes of growth and development in the paediatric patient can significantly affect drug absorption and disposition. Immature renal function, altered hepatic enzyme activity and differences in drug absorption lead to variations in systemic exposure of antiretrovirals among children. Paediatric patients are also subject to unique circumstances that may prevent adherence to antiretroviral regimens. The pharmacokinetics of nucleoside reverse transcriptase inhibitors differ significantly among preterm infants, full-term infants and older children. Decreased hepatic glucuronidation activity in neonates results in pharmacokinetic differences in zidovudine disposition when compared with older children. Didanosine, stavudine and lamivudine are renally eliminated, thus resulting in differences among young children with immature renal function. Pharmacokinetic data for non-nucleoside reverse transcriptase inhibitors in children are limited. Decreased elimination of nevirapine among neonates has been observed, primarily due to decreased enzymatic activity. Pharmacokinetic differences across age groups have been noted for efavirenz, but no formal assessments have been conducted in children weighing less than 10kg. Protease inhibitors are metabolised by the cytochrome P450 enzyme system, which is not fully developed in younger children. Decreased metabolism can result in elevated plasma concentrations, thereby increasing the chance of toxicity. Unfortunately, few studies exist evaluating the pharmacokinetics of antiretrovirals in children. As a result, dosage selection of antiretrovirals in children often occurs without adequate data. As the life expectancy of HIV-infected children increases, use of antiretrovirals to prevent disease progression also increases. If prevention of treatment failure continues to be the goal of antiretroviral therapy, the pharmacokinetics of antiretrovirals in children need to be assessed early in the drug development process.

Age Factors↗
PubMed2002

Single-dose pharmacokinetics of enteric-coated didanosine in HIV-infected children.

Didanosine remains a cornerstone nucleoside analogue for the treatment of HIV infection. A potential problem with the buffered formulations of didanosine is the likelihood of interactions with other drugs that require an acidic pH for absorption or can be chelated by cations in the buffer. An encapsulated enteric-coated (EC) bead formulation of didanosine has been approved and is routinely used as an alternative to the chewable/dispersible buffered tablet formulation. The objective of this study was to evaluate the single-dose pharmacokinetics of didanosine EC at 240 mg/m2 in 10 HIV-infected children. Didanosine EC was administered at time 0 on an empty stomach with no other concomitant medications. Blood samples were collected at pre-dose, 0.5, 1, 2, 4, 8 and 12 h post-dose. Didanosine was measured in plasma using radioimmunoassay. Ten subjects completed the intensive pharmacokinetic evaluation; data are available for eight participants. Plasma concentrations of didanosine following EC administration were analysed using non-compartmental methods. Median (range) AUCinfinity, Cmax, Tmax and CL/F for didanosine following EC administration were 2385 (1291, 3966) ng x h/ml, 854 (300, 1799) ng/ml, 3.0 (1.0, 8.1) h and 3.3 (2.7-6.4) l/h/kg, respectively. Results from this study indicate that the didanosine Cmax is decreased and Tmax is prolonged, but total exposure of didanosine in plasma following didanosine EC administration appears similar to previous data collected in HIV-infected children following buffered didanosine administration.

Anti-HIV Agents↗
PubMedDate not supplied

Predisposing factors for self-inflicted burns.

Self-inflicted burn injuries, although uncommon, are a significant source of morbidity and mortality. The purpose of this study was to delineate the characteristics of these burns and to examine their impact on society. Records of 32 adult patients admitted for self-inflicted burns at our regional burn center between January 1996 and August 2001 were retrospectively reviewed. The mean burn size was 34 +/- 29% TBSA, with the majority of burns being the result of self-immolation using a flammable liquid. There was a slight male predominance (59%) and a significant mortality rate (25%). Ninety-one percent of patients had an active psychiatric diagnosis, with 47% having had a previous suicide attempt. Two thirds had a chronic stressor, such as a chronic medical illness and/or long-term disability. Only four patients had private insurance, whereas the remainder relied on underfunded state- and county-sponsored programs or were uninsured. In addition to well-described psychiatric factors, common characteristics predisposing to self-inflicted burns include chronic medical illnesses, long-term disability, and a lack of access to adequate mental health care. Better treatment of mental illness in the underfunded population might ultimately save the high costs of these burn injuries.

Adolescent↗
PubMedDate not supplied

Pharmacokinetics of antiretrovirals administered to HIV-infected children via gastrostomy tube.

BACKGROUND: Surgical placement of a gastrostomy tube (g-tube) directly into a patient's gastrointestinal system to support antiretroviral administration is occasionally used to increase adherence in HIV-infected children. Absorption and distribution characteristics of antiretrovirals after g-tube administration, however, are unknown. The goal of this pilot study was to describe the pharmacokinetic characteristics of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) when administered to HIV-infected children via g-tube. METHOD: Nine HIV-infected children who were receiving a PI- or NNRTI-containing regimen via g-tube were enrolled. All antiretrovirals (excluding efavirenz) were administered under direct observation for the pharmacokinetic evaluation. Blood samples were collected at predose and at 1, 2, 4, 8, and 12 hours postdose. Antiretroviral concentrations were measured in plasma using high performance liquid chromatography with ultraviolet detection. RESULTS: Systemic exposure of PIs and NNRTIs in our 9 patients was similar to data from historical oral administration controls. Due to likely drug interactions, LPV exposure was decreased and one patient had low exposure of all antiretrovirals. When doses were increased, adequate exposure was attained. CONCLUSION: This pilot study suggests that administration of most PIs and NNRTIs by a g-tube to HIV-infected children provides systemic exposure comparable with that achieved after oral administration.

Area Under Curve↗