Sociodemographic and clinical correlates of immune activation in postpartum HIV-1/HSV-2 co-infected Kenyan women

Thesis (Master's)--University of Washington, 2016-06

Cerebellar language and cognitive functions in childhood: A comparative review of the clinical research

Background: Recent research addressing evidence from functional neuroimaging studies, neurophysiological research, and new advances in neuropsychology together with traditional cerebellar lesion studies have recently implicated the cerebellum in adult language and cognitive functions. However, more limited information is currently available in describing the functional connectivity present in the paediatric population. Aims: It is the purpose of this paper to review recent clinical research pertaining to paediatric populations, outlining the impact of site of lesion and specific associated clinical changes in children with cerebellar disturbances. Main contribution: The specific contribution of the right cerebellar hemisphere to language function is identified to also exist in the paediatric population, highlighting the existence of functional connections between this region of the brain and left frontal cortical areas early in development. Conclusions: Implications for future research in paediatric populations are extensive, as a greater awareness and an understanding of the recently acknowledged involvement of the cerebellum in cognition and nonmotor linguistic function is anticipated to also add new dimension and direction to the analysis of childhood language outcomes associated with the cerebellum.

Population pharmacokinetics of hydroxychloroquine in patients with rheumatoid arthritis

Hydroxychloroquine (HCQ) is an antimalarial drug that is also used as a second-line treatment of rheumatoid arthritis (RA). Clinically, the use of HCQ is characterized by a long delay in the onset of action, and withdrawal of treatment is often a result of inefficacy rather than from toxicity. The slow onset of action can be attributed to the pharmacokinetics (PK) of HCQ, and wide interpatient variability is evident. Tentative relationships between concentration and effect have been made, but to date, no population PK model has been developed for HCQ. This study aimed to develop a population PK model including an estimation of the oral bioavailability of HCQ. In addition, the effects of the coadministration of methotrexate on the PK of HCQ were examined. Hydroxychloroquine blood concentration data were combined from previous pharmacokinetic studies in patients with rheumatoid arthritis. A total of 123 patients were studied, giving the data cohort from four previously published studies. Two groups of patients were included: 74 received hydroxychloroquine (HCQ) alone, and 49 received HCQ and methotrexate (MTX). All data analyses were carried out using the NONMEM program. A one-compartment PK model was supported, rather than a three-compartment model as previously published, probably because of the clustering of concentrations taken at the end of a dosing interval. The population estimate of bioavailability of 0.75 (0.07), n = 9, was consistent with literature values. The parameter values from the final model were: (Cl) over bar = 9.9 +/- 0.4 L/h, (V) over bar 605 +/- 91 L, (k(d)) over bar = 0.77 +/- 0.22 hours(-1), (t(tag)) over bar = 0.44 +/- 0.02 hours. Clearance was not affected by the presence of MTX, and, hence, steady-state drug concentrations and maintenance dosage requirements were similar. A population PK model was successfully developed for HCQ.

Principles and clinical application of assessing alterations in renal elimination pathways

Drugs and metabolites are eliminated from the body by metabolism and excretion. The kidney makes the major contribution to excretion of unchanged drug and also to excretion of metabolites. Net renal excretion is a combination of three processes - glomerular filtration, tubular secretion and tubular reabsorption. Renal function has traditionally been determined by measuring plasma creatinine and estimating creatinine clearance. However, estimated creatinine clearance measures only glomerular filtration with a small contribution from active secretion. There is accumulating evidence of poor correlation between estimated creatinine clearance and renal drug clearance in different clinical settings, challenging the 'intact nephron hypothesis' and suggesting that renal drug handling pathways may not decline in parallel. Furthermore, it is evident that renal drug handling is altered to a clinically significant extent in a number of disease states, necessitating dosage adjustment not just based on filtration. These observations suggest that a re-evaluation of markers of renal function is required. Methods that measure all renal handling pathways would allow informed dosage individualisation using an understanding of renal excretion pathways and patient characteristics. Methodologies have been described to determine individually each of the renal elimination pathways. However, their simultaneous assessment has only recently been investigated. A cocktail of markers to measure simultaneously the individual renal handling pathways have now been developed, and evaluated in healthy volunteers. This review outlines the different renal elimination pathways and the possible markers that can be used for their measurement. Diseases and other physiological conditions causing altered renal drug elimination are presented, and the potential application of a cocktail of markers for the simultaneous measurement of drug handling is evaluated. Further investigation of the effects of disease processes on renal drug handling should include people with HIV infection, transplant recipients (renal and liver) and people with rheumatoid arthritis. Furthermore, changes in renal function in the elderly, the effect of sex on renal function, assessment of living kidney donors prior to transplantation and the investigation of renal drug interactions would also be potential applications. Once renal drug handling pathways are characterised in a patient population, the implications for accurate dosage individualisation can be assessed. The simultaneous measurement of renal function elimination pathways of drugs and metabolites has the potential to assist in understanding how renal function changes with different disease states or physiological conditions. In addition, it will further our understanding of fundamental aspects of the renal elimination of drugs.

Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil

Aim To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between- and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. Methods Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler. Results The best base model was a two-compartment model with a lag time (apparent oral clearance was 271 h(-1), and apparent volume of the central compartment 981). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. Conclusions The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.

Toward better outcomes with tacrolimus therapy: Population pharmacokinetics and individualized dosage prediction in adult liver transplantation

Patient outcomes in transplantation would improve if dosing of immunosuppressive agents was individualized. The aim of this study is to develop a population pharmacokinetic model of tacrolimus in adult liver transplant recipients and test this model in individualizing therapy. Population analysis was performed on data from 68 patients. Estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F) using the nonlinear mixed effects model program (NONMEM). Factors screened for influence on these parameters were weight, age, sex, transplant type, biliary reconstructive procedure, postoperative day, days of therapy, liver function test results, creatinine clearance, hematocrit, corticosteroid dose, and interacting drugs. The predictive performance of the developed model was evaluated through Bayesian forecasting in an independent cohort of 36 patients. No linear correlation existed between tacrolimus dosage and trough concentration (r(2) = 0.005). Mean individual Bayesian estimates for CL/F and V/F were 26.5 8.2 (SD) L/hr and 399 +/- 185 L, respectively. CL/F was greater in patients with normal liver function. V/F increased with patient weight. CL/F decreased with increasing hematocrit. Based on the derived model, a 70-kg patient with an aspartate aminotransferase (AST) level less than 70 U/L would require a tacrolimus dose of 4.7 mg twice daily to achieve a steady-state trough concentration of 10 ng/mL. A 50-kg patient with an AST level greater than 70 U/L would require a dose of 2.6 mg. Marked interindividual variability (43% to 93%) and residual random error (3.3 ng/mL) were observed. Predictions made using the final model were reasonably nonbiased (0.56 ng/mL), but imprecise (4.8 ng/mL). Pharmacokinetic information obtained will assist in tacrolimus dosing; however, further investigation into reasons for the pharmacokinetic variability of tacrolimus is required.

Prospective evaluation of a D-optimal designed population pharmacokinetic study

Recently, methods for computing D-optimal designs for population pharmacokinetic studies have become available. However there are few publications that have prospectively evaluated the benefits of D-optimality in population or single-subject settings. This study compared a population optimal design with an empirical design for estimating the base pharmacokinetic model for enoxaparin in a stratified randomized setting. The population pharmacokinetic D-optimal design for enoxaparin was estimated using the PFIM function (MATLAB version 6.0.0.88). The optimal design was based on a one-compartment model with lognormal between subject variability and proportional residual variability and consisted of a single design with three sampling windows (0-30 min, 1.5-5 hr and 11 - 12 hr post-dose) for all patients. The empirical design consisted of three sample time windows per patient from a total of nine windows that collectively represented the entire dose interval. Each patient was assigned to have one blood sample taken from three different windows. Windows for blood sampling times were also provided for the optimal design. Ninety six patients were recruited into the study who were currently receiving enoxaparin therapy. Patients were randomly assigned to either the optimal or empirical sampling design, stratified for body mass index. The exact times of blood samples and doses were recorded. Analysis was undertaken using NONMEM (version 5). The empirical design supported a one compartment linear model with additive residual error, while the optimal design supported a two compartment linear model with additive residual error as did the model derived from the full data set. A posterior predictive check was performed where the models arising from the empirical and optimal designs were used to predict into the full data set. This revealed the optimal'' design derived model was superior to the empirical design model in terms of precision and was similar to the model developed from the full dataset. This study suggests optimal design techniques may be useful, even when the optimized design was based on a model that was misspecified in terms of the structural and statistical models and when the implementation of the optimal designed study deviated from the nominal design.

Modelling the population cost-effectiveness of current and evidence-based optimal treatment for anxiety disorders

Background. The present paper describes a component of a large Population cost-effectiveness study that aimed to identify the averted burden and economic efficiency of current and optimal treatment for the major mental disorders. This paper reports on the findings for the anxiety disorders (panic disorder/agoraphobia, social phobia, generalized anxiety disorder, post-traumatic stress disorder and obsessive-compulsive disorder). Method. Outcome was calculated as averted 'years lived with disability' (YLD), a population summary measure of disability burden. Costs were the direct health care costs in 1997-8 Australian dollars. The cost per YLD averted (efficiency) was calculated for those already in contact with the health system for a mental health problem (current care) and for a hypothetical optimal care package of evidence-based treatment for this same group. Data sources included the Australian National Survey of Mental Health and Well-being and published treatment effects and unit costs. Results. Current coverage was around 40% for most disorders with the exception of social phobia at 21%. Receipt of interventions consistent with evidence-based care ranged from 32% of those in contact with services for social phobia to 64% for post-traumatic stress disorder. The cost of this care was estimated at $400 million, resulting in a cost per YLD averted ranging from $7761 for generalized anxiety disorder to $34 389 for panic/agoraphobia. Under optimal care, costs remained similar but health gains were increased substantially, reducing the cost per YLD to < $20 000 for all disorders. Conclusions. Evidence-based care for anxiety disorders would produce greater population health gain at a similar cost to that of current care, resulting in a substantial increase in the cost-effectiveness of treatment.

Steps and sitting in a working population

This study aimed to assess sitting time and number of steps taken each day, and the relationships between these variables, in a sample of working Australian adults. Workers (N = 185), wore a pedometer for 7 days and recorded the number of steps taken and time spent sitting each day. Average time spent sitting on weekdays was 9.4 (SD = 2.40) hr with about half spent sitting at work. Despite this, the average steps taken each day (M = 8,873, SD = 2,757) was higher on weekdays than on weekend days. There was a clear inverse relationship between sitting time at work and number of steps taken on weekdays, r = -.34, p < .001); those in the highest tertile for sitting time reported about 3,000 fewer daily steps. Workers in managerial and professional occupations reported more time sitting at work (M = 6.2 hr per day) and lower weekday step counts (M = 7,883, N = 43) than technical (M = 3.3 hr sitting at work and 10,731 weekday steps, N = 33) and blue collar workers (M = 1.6 hours sitting and 11,784 steps N = 11). The findings suggest those whose daily work involves long hours of sitting should be the focus of efforts to promote physical activity both within and outside the workplace.

Simultaneous detection and differentiation of human Polyomaviruses JC and BK by a rapid and sensitive PCR-ELAHA assay and a survey of the JCV subtypes within an Australian population

Human polyomaviruses JCV and BKV can cause several clinical manifestations in immunocompromised hosts, including progressive multifocal leukoencephalopathy (PML) and haemorrhagic cystitis. Molecular detection by polymerase chain reaction (PCR) is recognised as a sensitive and specific method for detecting human polyomaviruses in clinical samples. In this study, we developed a PCR assay using a single primer pair to amplify a segment of the VP1 gene of JCV and BKV. An enzyme linked amplicon hybridisation assay (ELAHA) using species-specific biotinylated oligonucleotide probes was used to differentiate between JCV and BKV. This assay (VP1-PCR-ELAHA) was evaluated and compared to a PCR assay targeting the human polyomavirus T antigen gene (pol-PCR). DNA sequencing was used to confirm the polyomavirus species identified by the VP1-PCR-ELAHA and to determine the subtype of each JCV isolate. A total of 297 urine specimens were tested and human polyomavirus was detected in 105 specimens (35.4%) by both PCR assays. The differentiation of JCV and BKV by the VP1-PCR-ELAHA showed good agreement with the results of DNA sequencing. Further, DNA sequencing of the JCV positive specimens showed the most prevalent JCV subtype in our cohort was 2a (27%) followed by 1b (20%), 1a (15%), 2c (14%), 4 (14%) and 2b (10%). The results of this study show that the VP1-PCR-ELAHA is a sensitive, specific and rapid method for detecting and differentiating human polyomaviruses JC and BK and is highly suitable for routine use in the clinical laboratory. (C) 2004 Wiley-Liss, Inc.

A case study of the resolution of paediatric dysphagia following brainstern injury: clinical and instrumental assessment

The coexistance of a swallowing impairment can severely impact upon the medical condition and recovery of a child with traumatic brain injury [ref.(1): Journal of Head Trauma Rehabilitation 9 (1) (1994) 43]. Limited data exist on the progression or outcome of dysphagia in the paediatric population with brainstem injury. The present prospective study documents the resolution of dysphagia in a 14-year-old female post-brainstem injury using clinical, radiological and endoscopic evaluations of swallowing. The subject presented with a pattern of severe oral-motor and oropharyngeal swallowing impairment post-injury that resolved rapidly for the initial 12 weeks, slowed to gradual progress for weeks 12-20, and then plateaued at 20 weeks post-injury. Whilst a clinically functional swallow was present at 10 months post-injury, radiological examination revealed a number of residual physiological impairments, reduced swallowing efficiency, and reduced independence for feeding, indicating a potential increased risk for aspiration. The data highlight the need for early and continued evaluation and intensive treatment programs, to focus on the underlying physiological swallowing impairment post-brainstem injury, and to help offset any potential deleterious effects of aspiration that may affect patient recovery, such as pneumonia. (C) 2003 Elsevier Ltd. All rights reserved.

Clinical progression and outcome of dysphagia following paediatric traumatic brain injury: a prospective study

Objectives : To provide a preliminary clinical profile of the resolution and outcomes of oral-motor impairment and swallowing function in a group of paediatric dysphagia patients post-traumatic brain injury (TBI). To document the level of cognitive impairment parallel to the return to oral intake, and to investigate the correlation between the resolution of impaired swallow function versus the resolution of oral-motor impairment and cognitive impairment. Participants : Thirteen children admitted to an acute care setting for TBI. Main outcome measures : A series of oral-motor (Verbal Motor Production Assessment for Children, Frenchay Dysarthria Assessment, Schedule for Oral Motor Assessment) and swallowing (Paramatta Hospital's Assessment for Dysphagia) assessments, an outcome measure for swallowing (Royal Brisbane Hospital's Outcome Measure for Swallowing), and a cognitive rating scale (Rancho Level of Cognitive Functioning Scale). Results : Across the patient group, oral-motor deficits resolved to normal status between 3 and 11 weeks post-referral (and at an average of 12 weeks post-injury) and swallowing function and resolution to normal diet status were achieved by 3-11 weeks post-referral (and at an average of 12 weeks post-injury). The resolution of dysphagia and the resolution of oral-motor impairment and cognitive impairment were all highly correlated. Conclusion : The provision of a preliminary profile of oral-motor functioning and dysphagia resolution, and data on the linear relationship between swallowing impairment and cognition, will provide baseline information on the course of rehabilitation of dysphagia in the paediatric population post-TBI. Such data will contribute to more informed service provision and rehabilitation planning for paediatric patients post-TBI.

Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation

The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients. Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 'acceptable' ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immuno suppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.

Quantitative justification for target concentration intervention - parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides

Aims [1] To quantify the random and predictable components of variability for aminoglycoside clearance and volume of distribution [2] To investigate models for predicting aminoglycoside clearance in patients with low serum creatinine concentrations [3] To evaluate the predictive performance of initial dosing strategies for achieving an aminoglycoside target concentration. Methods Aminoglycoside demographic, dosing and concentration data were collected from 697 adult patients (>=20 years old) as part of standard clinical care using a target concentration intervention approach for dose individualization. It was assumed that aminoglycoside clearance had a renal and a nonrenal component, with the renal component being linearly related to predicted creatinine clearance. Results A two compartment pharmacokinetic model best described the aminoglycoside data. The addition of weight, age, sex and serum creatinine as covariates reduced the random component of between subject variability (BSVR) in clearance (CL) from 94% to 36% of population parameter variability (PPV). The final pharmacokinetic parameter estimates for the model with the best predictive performance were: CL, 4.7 l h(-1) 70 kg(-1); intercompartmental clearance (CLic), 1 l h(-1) 70 kg(-1); volume of central compartment (V-1), 19.5 l 70 kg(-1); volume of peripheral compartment (V-2) 11.2 l 70 kg(-1). Conclusions Using a fixed dose of aminoglycoside will achieve 35% of typical patients within 80-125% of a required dose. Covariate guided predictions increase this up to 61%. However, because we have shown that random within subject variability (WSVR) in clearance is less than safe and effective variability (SEV), target concentration intervention can potentially achieve safe and effective doses in 90% of patients.