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1.  Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model 
Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.
doi:10.1128/AAC.02006-13
PMCID: PMC3910715  PMID: 24126579
2.  Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis 
Antimicrobial Agents and Chemotherapy  2014;58(11):6879-6885.
Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients and healthy volunteers. The influences of demographic and clinical characteristics, such as mucositis, diarrhea, and drug-drug interactions, on posaconazole pharmacokinetics were investigated using a stepwise forward inclusion/backwards deletion procedure. A total of 905 posaconazole concentration measurements from 102 participants were analyzed. A one-compartment pharmacokinetic model with first-order oral absorption with lag time and first-order elimination best described posaconazole pharmacokinetics. Posaconazole relative bioavailability was 55% lower in patients who received posaconazole than in healthy volunteers. Coadministration of proton pump inhibitors (PPIs) or metoclopramide, as well as the occurrence of mucositis or diarrhea, reduced posaconazole relative bioavailability by 45%, 35%, 58%, and 45%, respectively, whereas concomitant ingestion of a nutritional supplement significantly increased bioavailability (129% relative increase). Coadministration of rifampin or phenytoin increased apparent posaconazole clearance by more than 600%, with a smaller increase observed with fosamprenavir (34%). Participant age, weight, or sex did not significantly affect posaconazole pharmacokinetics. Posaconazole absorption was reduced by a range of commonly coadministered medicines and clinical complications, such as mucositis and diarrhea. Avoidance of PPIs and metoclopramide and administration with food or a nutritional supplement are effective strategies to increase posaconazole absorption.
doi:10.1128/AAC.03777-14
PMCID: PMC4249414  PMID: 25199779
4.  Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials 
Objective To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014.
Eligibility criteria for selecting studies Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee.
Data extraction Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration’s tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions.
Results 12 reports (13 randomised trials) were included. There was “high quality” evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference −0.5, 95% confidence interval −2.9 to 1.9) and disability (0.4, −1.7 to 2.5) or improving quality of life (0.4, −0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was “high quality” evidence that paracetamol provides a significant, although not clinically important, effect on pain (−3.7, −5.5 to −1.9) and disability (−2.9, −4.9 to −0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. “High quality” evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain.
Conclusions Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines.
Systematic review registration PROSPERO registration number CRD42013006367.
doi:10.1136/bmj.h1225
PMCID: PMC4381278  PMID: 25828856
5.  Multicenter Study of Posaconazole Therapeutic Drug Monitoring: Exposure-Response Relationship and Factors Affecting Concentration 
Antimicrobial Agents and Chemotherapy  2012;56(11):5503-5510.
Posaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml; P < 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression (P < 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H2 antagonist ranitidine (P < 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure (P < 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.
doi:10.1128/AAC.00802-12
PMCID: PMC3486529  PMID: 22890761
6.  Clinical pharmacology of analgesic medicines in older people: impact of frailty and cognitive impairment 
Pain is highly prevalent in frail older people who often have multiple co-morbidities and multiple medicines. Rational prescribing of analgesics in frail older people is complex due to heterogeneity in drug disposition, comorbid medical conditions, polypharmacy and variability in analgesic response in this population. A critical issue in managing older people with pain is the need for judicious choice of analgesics based on a comprehensive medical and medication history. Care is needed in the selection of analgesic medicine to avoid drug–drug or drug–disease interactions. People living with dementia and cognitive impairment have suboptimal pain relief which in part may be related to altered pharmacodynamics of analgesics and challenges in the systematic assessment of pain intensity in this patient group. In the absence of rigorously controlled trials in frail older people and those with cognitive impairment a pharmacologically-guided approach can be used to optimize pain management which requires a systematic understanding of the pharmacokinetics and pharmacodynamics of analgesics in frail older people with or without changes in cognition.
doi:10.1111/j.1365-2125.2010.03847.x
PMCID: PMC3045544  PMID: 21284694
frailty; oxycodone; pain; paracetamol; pharmacodynamics; pharmacokinetics
7.  Clinical Pharmacology of Chemotherapy Agents in Older People with Cancer 
Populations around the world are aging, and the associated increase in cancer incidence has led to the recognition of the importance of geriatric oncology. Chronological age is a poor determinant of pharmacological response to cancer chemotherapy agents. Age-associated changes in physiology and organ function have a significant impact on the clinical pharmacology of cancer chemotherapy agents used in cancer treatment. Altered response to medicines in older people is a consequence of changes in body composition, organ function, concomitant pathophysiology, multiple medications, genetic determinants of drug response, and patient's clinical status. These issues highlight the need to individualize the management of cancer in the older people with consideration of age-related changes in the clinical pharmacology of cancer drugs, analgesics, and adjunctive therapies.
doi:10.1155/2011/628670
PMCID: PMC3154497  PMID: 21845189
8.  Hepatic Disposal of Advanced Glycation End Products During Maturation and Aging 
Experimental gerontology  2013;48(6):549-556.
Aging is characterized by progressive loss of metabolic and biochemical functions and accumulation of metabolic by-products, including advanced glycation end products (AGEs), which are observed in several pathological conditions. A number of waste macromolecules, including AGEs are taken up from the circulation by endocytosis mainly into liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs). However, AGEs still accumulate in different tissues with ageing, despite the presence of this clearance mechanism. The aim of the present study was to determine whether the efficiency of LSECs and KCs for disposal of AGEs changes through aging.
Results
After intravenous administration of 14C-AGE-albumin in pre-pubertal, young adult, middle aged and old mice, more than 90% of total recovered 14C-AGE was liver associated, irrespective of age. LSECs and KCs represented the main site of uptake. A fraction of the 14C-AGE degradation products (14C-AGE-DPs) was stored for months in the lysosomes of these cells after uptake. The overall rate of elimination of 14C-AGE-DPs from the liver was markedly faster in pre-pubertal than in all post-pubertal age groups. The ability to eliminate 14C-AGE-DPs decreased to similar extents after puberty in LSECs and KCs. A rapid early removal phase was characteristic for all age groups except the old group, where this phase was absent.
Conclusions
Removal of AGE-DPs from the liver scavenger cells is a very slow process that changes with age. The ability of these cells to dispose of AGEs declines after puberty. Decreased AGE removal efficiency early in life may lead to AGE accumulation.
doi:10.1016/j.exger.2013.03.005
PMCID: PMC3722431  PMID: 23531498
aging; scavenger cell; liver; lysosome; AGE accumulation; AGE disposal
9.  Population pharmacokinetics and dosing regimen design of milrinone in preterm infants 
Aims
To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth.
Methods
A prospective open‐labelled, dose‐escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 μg/kg/min (n = 8) and 0.5 μg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4–5 blood samples for concentration–time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180–300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10).
Results
Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one‐compartment model with first‐order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half‐life of 10 h. The 0.25 and 0.5 μg/kg/min dosage regimens did not achieve optimal milrinone concentration‐time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 μg/kg/min for 3 h) followed by maintenance infusion (0.2 μg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study.
Conclusion
Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology.
doi:10.1136/adc.2005.092817
PMCID: PMC2675339  PMID: 16690639
FOCE; first‐order approximation with condition estimation; HPLC; high performance liquid chromatography; P/IVH; peri/intraventricular haemorrhage; SVC; superior vena cava
10.  Population pharmacokinetics of gemcitabine and its metabolite in patients with cancer: effect of oxaliplatin and infusion rate 
Aims
To characterize the population pharmacokinetics of gemcitabine and its metabolite (dFdU) in patients with cancer and identify factors that are influential in gemcitabine dose regimen design.
Methods
Gemcitabine and dFdU plasma concentration–time and clinical data from 94 patients with cancer and nonlinear mixed effect modelling were used to characterize gemcitabine and metabolite pharmacokinetic variability and identify influential covariates.
Results
Gemcitabine and dFdU pharmacokinetics were described by a two-compartment model with first-order elimination. The population mean (and between-subject variability, CV%) for clearance and volume of distribution of the central compartment (VC) for gemcitabine were 2.7 l min−1 (31%) and 15 l (39%), respectively, and 0.04 l min−1 (35%) and 46 l (15%), respectively, for dFdU. Oxaliplatin co-administration significantly decreased dFdU VC by 35% when gemcitabine was administered first and by 46% when oxaliplatin was administered first compared with patients who received gemcitabine alone.
Conclusions
Co-administration of gemcitabine with oxaliplatin significantly affected the pharmacokinetics of dFdU. The clinical significance of this observation in the context of gemcitabine safety and efficacy is worthy of further investigation.
What is already known about this subject Gemcitabine is an anticancer drug which is metabolized to a number of metabolites, administered using different dosing regimens and increasingly used in combination with oxaliplatin.The impact of dosing strategies and combination therapy on the pharmacokinetics of gemcitabine and its main metabolite is not clearly understood.
What this study adds This study has characterized the pharmacokinetics of gemcitabine and its main metabolite in people with cancer, including the variability between patients and on different occasions.Gemcitabine metabolite (but not gemcitabine) pharmacokinetics were significantly affected by co-administration with oxaliplatin and were dependent on the order of administration.The clinical implications of this observation remain to be established.
doi:10.1111/j.1365-2125.2007.03040.x
PMCID: PMC2291243  PMID: 17961191
chemotherapy; dFdU; gemcitabine; metabolism; oxaliplatin; pharmacokinetics
11.  Adverse Selection? A Multi-Dimensional Profile of People Dispensed Opioid Analgesics for Persistent Non-Cancer Pain 
PLoS ONE  2013;8(12):e80095.
Objectives
This study investigates utilisation patterns for prescription opioid analgesics in the Australian community and how these are associated with a framework of individual-level factors related to healthcare use.
Methods
Self-reported demographic and health information from participants in the 45 and Up Study cohort were linked to pharmaceutical claims from 2006–2009. Participants comprised 19,816 people with ≥1 opioid analgesic dispensing in the 12-months after recruitment to the cohort and 79,882 people not dispensed opioid analgesics. All participants were aged ≥45 years, were social security pharmaceutical beneficiaries, with no history of cancer. People dispensed opioid analgesics were classified as having acute (dispensing period <90 days), episodic (≥90 days and <3 ‘authority’ prescriptions for increased quantity supply) or long-term treatment (≥90 days and ≥3 authority prescriptions).
Results
Of participants dispensed opioid analgesic 52% received acute treatment, 25% episodic treatment and 23% long-term treatment. People dispensed opioid analgesics long-term had an average of 14.9 opioid analgesic prescriptions/year from 2.0 doctors compared with 1.5 prescriptions from 1.1 doctors for people receiving acute treatment. People dispensed opioid analgesics reported more need-related factors such as poorer physical functioning and higher psychological distress. Long-term users were more likely to have access-related factors such as low-income and living outside major cities. After simultaneous adjustment, association with predisposing health factors and access diminished, but indicators of need such as osteoarthritis treatment, paracetamol use, and poor physical function were the strongest predictors for all opioid analgesic users.
Conclusions
People dispensed opioid analgesics were in poorer health, reported higher levels of distress and poorer functioning than people not receiving opioid analgesics. Varying dispensing profiles were evident among people dispensed opioid analgesics for persistent pain, with those receiving episodic and long-term treatment dispensed the strongest opioid analgesics. The findings highlight the broad range of factors associated with longer term opioid analgesics use.
doi:10.1371/journal.pone.0080095
PMCID: PMC3846564  PMID: 24312456
12.  The pharmacokinetics of oxypurinol in people with gout 
AIMS
Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations.
METHODS
Non-linear mixed effects modelling was applied to concentration–time data from 155 gouty patients with demographic, medical history and renal transporter genotype information.
RESULTS
A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration–time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/Fm) from 65% to 29%. CL/Fm for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h−1, respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines.
CONCLUSIONS
In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment.
doi:10.1111/j.1365-2125.2012.04207.x
PMCID: PMC3477349  PMID: 22300439
allopurinol; gout; oxypurinol; pharmacogenetics; pharmacokinetics; urate
13.  PACE – the first placebo controlled trial of paracetamol for acute low back pain: statistical analysis plan 
Trials  2013;14:248.
Background
Paracetamol (acetaminophen) is recommended in most clinical practice guidelines as the first choice of treatment for low back pain, however there is limited evidence to support this recommendation. The PACE trial is the first placebo controlled trial of paracetamol for acute low back pain. This article describes the statistical analysis plan.
Results
PACE is a randomized double dummy placebo controlled trial that investigates and compares the effect of paracetamol taken in two regimens for the treatment of low back pain. The protocol has been published. The analysis plan was completed blind to study group and finalized prior to initiation of analyses. All data collected as part of the trial were reviewed, without stratification by group, and classified by baseline characteristics, process of care and trial outcomes. Trial outcomes were classified as primary and secondary outcomes. Appropriate descriptive statistics and statistical testing of between-group differences, where relevant, have been planned and described.
Conclusions
A standard analysis plan was developed for the results of the PACE study. This plan comprehensively describes the data captured and pre-determined statistical tests of relevant outcome measures. The plan demonstrates transparent and verifiable use of the data collected. This a priori plan will be followed to ensure rigorous standards of data analysis are strictly adhered to.
Trial registration
Australia and New Zealand Clinical Trials Registry ACTRN12609000966291
doi:10.1186/1745-6215-14-248
PMCID: PMC3750911  PMID: 23937999
Acetaminophen; Back pain; Paracetamol; Statistical analysis plan; Randomised controlled trial
14.  PRECISE - pregabalin in addition to usual care for sciatica: study protocol for a randomised controlled trial 
Trials  2013;14:213.
Background
Sciatica is a type of neuropathic pain that is characterised by pain radiating into the leg. It is often accompanied by low back pain and neurological deficits in the lower limb. While this condition may cause significant suffering for the individual, the lack of evidence supporting effective treatments for sciatica makes clinical management difficult. Our objectives are to determine the efficacy of pregabalin on reducing leg pain intensity and its cost-effectiveness in patients with sciatica.
Methods/Design
PRECISE is a prospectively registered, double-blind, randomised placebo-controlled trial of pregabalin compared to placebo, in addition to usual care. Inclusion criteria include moderate to severe leg pain below the knee with evidence of nerve root/spinal nerve involvement. Participants will be randomised to receive either pregabalin with usual care (n = 102) or placebo with usual care (n = 102) for 8 weeks. The medicine dosage will be titrated up to the participant’s optimal dose, to a maximum 600 mg per day. Follow up consultations will monitor individual progress, tolerability and adverse events. Usual care, if deemed appropriate by the study doctor, may include a referral for physical or manual therapy and/or prescription of analgesic medication. Participants, doctors and researchers collecting participant data will be blinded to treatment allocation. Participants will be assessed at baseline and at weeks 2, 4, 8, 12, 26 and 52. The primary outcome will determine the efficacy of pregabalin in reducing leg pain intensity. Secondary outcomes will include back pain intensity, disability and quality of life. Data analysis will be blinded and by intention-to-treat. A parallel economic evaluation will be conducted from health sector and societal perspectives.
Discussion
This study will establish the efficacy of pregabalin in reducing leg pain intensity in patients with sciatica and provide important information regarding the effect of pregabalin treatment on disability and quality of life. The impact of this research may allow the future development of a cost-effective conservative treatment strategy for patients with sciatica.
Trial registration
ClinicalTrial.gov, ACTRN 12613000530729
doi:10.1186/1745-6215-14-213
PMCID: PMC3711833  PMID: 23845078
Sciatica; Pregabalin; Neuropathic pain; Randomised control trial
15.  Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects 
Aim
The aim of this study was to investigate the effect of two common herbal medicines, ginkgo and ginger, on the pharmacokinetics and pharmacodynamics of warfarin and the independent effect of these herbs on clotting status.
Methods
This was an open label, three-way crossover randomized study in 12 healthy male subjects, who received a single 25 mg dose of warfarin alone or after 7 days pretreatment with recommended doses of ginkgo or ginger from herbal medicine products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and the 90% confidence intervals (CIs) of the ratio of log transformed parameters are reported.
Results
INR and platelet aggregation were not affected by administration of ginkgo or ginger alone. The mean (95% CI) apparent clearances of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167–210) ml h−1, 200 (173–227) ml h−1 and 201 (171–231) ml h−1, respectively. The respective apparent clearances of R-warfarin were 127 (106–149) ml h−1, 126 (111–141) ml h−1 and 131 (106–156) ml h−1. The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.98–1.21) and for R-warfarin was 1.00 (0.93–1.08) when coadministered with ginkgo. The mean ratio (90% CI) of AUC0−168 of INR was 0.93 (0.81–1.05) when coadministered with ginkgo. The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.97–1.13) and for R-warfarin was 1.02 (0.95–1.10) when coadministered with ginger. The mean ratio (90% CI) of AUC0−168 of INR was 1.01 (0.93–1.15) when coadministered with ginger. The mean ratio (90% CI) for S-7-hydroxywarfarin urinary excretion rate was 1.07 (0.85–1.32) for ginkgo treatment, and 1.00 (0.81–1.23) for ginger coadministration suggesting these herbs did not affect CYP2C9 activity. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin.
Conclusions
Ginkgo and ginger at recommended doses do not significantly affect clotting status, the pharmacokinetics or pharmacodynamics of warfarin in healthy subjects.
doi:10.1111/j.1365-2125.2005.02322.x
PMCID: PMC1884814  PMID: 15801937
anticoagulants; herb–drug interactions; ginkgo; ginger; warfarin
16.  Vincristine Chemotherapy Trials and Pharmacokinetics in Tasmanian Devils with Tasmanian Devil Facial Tumor Disease 
PLoS ONE  2013;8(6):e65133.
Tasmanian Devil Facial Tumor Disease (DFTD) is a transmissible cancer threatening to cause the extinction of Tasmanian Devils in the wild. The aim of this study was to determine the susceptibility of the DFTD to vincristine. Escalating dosage rates of vincristine (0.05 to 0.136 mg/kg) were given to Tasmanian devils in the early stages of DFTD (n = 8). None of these dosage rates impacted the outcome of the disease. A dosage rate of 0.105 mg/kg, a rate significantly higher than that given in humans or domestic animals, was found to the highest dosage rate that could be administered safely. Signs of toxicity included anorexia, vomiting, diarrhea and neutropenia. Pharmacokinetic studies showed that, as with other species, there was a rapid drop in blood concentration following a rapid intravenous infusion with a high volume of distribution (1.96 L/kg) and a relatively long elimination half life (11 h). Plasma clearance (1.8 ml/min/kg) was slower in the Tasmanian devil than in humans, suggesting that pharmacodynamics and not pharmacokinetics explain the Tasmanian devil’s ability to tolerate high dosage rates of vincristine. While providing base-line data for the use of vincristine in Tasmanian devils and possibly other marsupials with vincristine susceptible cancers, these findings strongly suggest that vincristine will not be effective in the treatment of DFTD.
doi:10.1371/journal.pone.0065133
PMCID: PMC3675106  PMID: 23762298
17.  Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects 
Aim
The aim of this study was to investigate the effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin.
Methods
This was an open-label, three-way crossover randomized study in 12 healthy male subjects, who received a single 25-mg dose of warfarin alone or after 14 days' pretreatment with St John's wort, or 7 days' pretreatment with ginseng. Dosing with St John's wort or ginseng was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and 90% confidence intervals are reported.
Results
INR and platelet aggregation were not affected by treatment with St John's wort or ginseng. The apparent clearances of S-warfarin after warfarin alone or with St John's wort or ginseng were, respectively, 198 ± 38 ml min−1, 270 ± 44 ml min−1 and 220 ± 29 ml min−1. The respective apparent clearances of R-warfarin were 110 ± 25 ml min−1, 142 ± 29 ml min−1 and 119 ± 20 ml min−1. The mean ratio and 90% confidence interval (CI) of apparent clearance for S-warfarin was 1.29 (1.16, 1.46) and for R-warfarin it was 1.23 (1.11, 1.37) when St John's wort was coadministered. The mean ratio and 90% CI of AUC0−168 of INR was 0.79 (0.70, 0.95) when St John's wort was coadministered. St John's wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers.
Conclusions
St John's wort significantly induced the apparent clearance of both S-warfarin and R-warfarin, which in turn resulted in a significant reduction in the pharmacological effect of rac-warfarin. Coadministration of warfarin with ginseng did not affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin.
doi:10.1111/j.1365-2125.2003.02051.x
PMCID: PMC1884493  PMID: 15089812
anticoagulants; ginseng; herb–drug interactions; St John's wort; warfarin
18.  Population pharmacokinetics of raltitrexed in patients with advanced solid tumours 
Aims
To investigate the population pharmacokinetics of raltitrexed in patients with advanced solid tumours and to identify patient covariates contributing to the interpatient variability in the pharmacokinetics of raltitrexed.
Methods
Patient covariate and concentration–time data were collected from patients receiving 0.1–4.5 mg m−2 raltitrexed during the early clinical trials of raltitrexed. Data were fitted using nonlinear mixed effects modelling to generate population mean estimates for clearance (CL) and central volume of distribution (V). The relationship between individual estimates of the pharmacokinetic parameters and patient covariates was examined and the influence of significant covariates on the population parameter estimates and their variance was investigated using stepwise multiple linear regression. The performance of the developed model was tested using an independent validation dataset. All patient data were pooled in the total cohort to refine the population pharmacokinetic model for raltitrexed.
Results
A three-compartment pharmacokinetic model was used to fit the concentration–time data of raltitrexed. Estimated creatinine clearance (CLCR) was found to influence significantly the CL of raltitrexed and explained 35% of variability in this parameter, whilst body weight (WT) and serum albumin concentrations (ALB) accounted for 56% of the variability in V. Satisfactory prediction (mean prediction error 0.17 µg l−1 and root mean square prediction error 4.99 µg l−1) of the observed raltitrexed concentrations was obtained in the model validation step. The final population mean estimates were 2.17 l h−1[95% confidence interval (CI) 2.06, 2.28] and 6.36 l (95% CI 6.02, 6.70) for CL and V, respectively. Interpatient variability in the pharmacokinetic parameters was reduced (CL 28%, V 25%) when influential covariates were included in the final model. The following covariate relationships with raltitrexed parameters were described by the final population model: CL (l h−1) = 0.54 + 0.02 CLCR(ml min−1) and V (l) = 6.64 + 0.08 WT (kg) − 0.16 ALB (g l−1).
Conclusions
A population pharmacokinetic model has been developed for raltitrexed in patients with advanced cancer. Pharmacokinetic parameters of raltitrexed are markedly influenced by the patient's renal function, body weight and serum albumin levels, which may be taken into account in dose individualization. The use of influential covariates to guide anticancer dosage selection may result in less variability in drug exposure and potentially a better clinical outcome.
doi:10.1111/j.1365-2125.2003.02050.x
PMCID: PMC1884470  PMID: 15025739
raltitrexed; cancer; population pharmacokinetics
19.  Human subcutaneous tissue distribution of fluconazole: comparison of microdialysis and suction blister techniques 
Aims
To investigate uptake of fluconazole into the interstitial fluid of human subcutaneous tissue using the microdialysis and suction blister techniques.
Methods
A sterile microdialysis probe (CMA/60) was inserted subcutaneously into the upper arm of five healthy volunteers following an overnight fast. Blisters were induced on the lower arm using gentle suction prior to ingestion of a single oral dose of fluconazole (200 mg). Microdialysate, blister fluid and blood were sampled over 8 h. Fluconazole concentrations were determined in each sample using a validated HPLC assay. In vivo recovery of fluconazole from the microdialysis probe was determined in each subject by perfusing the probe with fluconazole solution at the end of the 8 h sampling period. Individual in vivo recovery was used to calculate fluconazole concentrations in subcutaneous interstitial fluid. A physiologically based pharmacokinetic (PBPK) model was used to predict fluconazole concentrations in human subcutaneous interstitial fluid.
Results
There was a lag-time (approximately 0.5 h) between detection of fluconazole in microdialysate compared with plasma in each subject. The in vivo recovery of fluconazole from the microdialysis probe ranged from 57.0 to 67.2%. The subcutaneous interstitial fluid concentrations obtained by microdialysis were very similar to the unbound concentrations of fluconazole in plasma with maximum concentration of 4.29 ± 1.19 µg ml−1 in subcutaneous interstitial fluid and 3.58 ± 0.14 µg ml−1 in plasma. Subcutaneous interstitial fluid-to-plasma partition coefficient (Kp) of fluconazole was 1.16 ± 0.22 (95% CI 0.96, 1.35). By contrast, fluconazole concentrations in blister fluid were significantly lower (P < 0.05, paired t-test) than unbound plasma concentrations over the first 3 h and maximum concentrations in blister fluid had not been achieved at the end of the sampling period. There was good agreement between fluconazole concentrations derived from microdialysis sampling and those estimated using a blood flow-limited PBPK model.
Conclusions
Microdialysis and suction blister techniques did not yield comparable results. It appears that microdialysis is a more appropriate technique for studying the rate of uptake of fluconazole into subcutaneous tissue. PBPK model simulation suggested that the distribution of fluconazole into subcutaneous interstitial fluid is dependent on tissue blood flow.
doi:10.1046/j.1365-2125.2003.01930.x
PMCID: PMC1884385  PMID: 14651730
fluconazole; human; microdialysis; pharmacokinetics; suction blisters; tissue distribution
20.  Investigation of herb-drug interactions with ginkgo biloba in women receiving hormonal treatment for early breast cancer 
SpringerPlus  2013;2:126.
Women receiving treatment for breast cancer commonly ingest herbal medicines. Little is known about the potential for herb-drug interactions in this population. The aim of this study is to investigate the effect of ginkgo biloba co-administration on the pharmacokinetics of tamoxifen, anastrozole and letrozole. This was a prospective open-label cross-over study in 60 women with early stage breast cancer taking either tamoxifen, anastrozole or letrozole (n=20/group). Participants received ginkgo biloba (EGb 761) for 3 weeks (120 mg twice daily). Trough concentrations of drugs were measured before and after ginkgo biloba treatment using LC-MS/MS. Toxicities were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events. Trough concentrations before and after treatment with ginkgo biloba were not significantly different for tamoxifen (93.5 ± 29.0, 86.5 ± 25.3 ng/mL; p=0.16), letrozole (91.1 ± 50.4, 89.6 ± 52.14 ng/mL; p=0.60) or anastrozole (29.1 ± 8.6, 29.1 ± 7.6 ng/mL; p=0.97). Ginkgo biloba was well tolerated, with no difference in toxicity during ginkgo biloba. Co-administration of ginkgo biloba does not significantly affect the pharmacokinetics of tamoxifen, anastrozole or letrozole. There was no difference in the toxicity profile of hormone therapy with ginkgo biloba use in women with early stage breast cancer.
doi:10.1186/2193-1801-2-126
PMCID: PMC3625417  PMID: 23596562
Anastrozole; Ginkgo biloba; Herb-drug interaction; Letrozole; Tamoxifen
21.  Statin use and clinical outcomes in older men: a prospective population-based study 
BMJ Open  2013;3(3):e002333.
Objective
The aim of this analysis was to investigate the relationship of statins with institutionalisation and death in older men living in the community, accounting for frailty.
Design
Prospective cohort study.
Setting
Community-dwelling men participating in the Concord Health and Ageing in Men Project, Sydney, Australia.
Participants
Men aged ≥70 years (n=1665).
Measurements
Data collected during baseline assessments and follow-up (maximum of 6.79 years) were obtained. Information regarding statin use was captured at baseline, between 2005 and 2007. Proportional hazards regression analysis was conducted to estimate the risk of institutionalisation and death according to statin use (exposure, duration and dose) and frailty status, with adjustment for sociodemographics, medical diagnosis and other clinically relevant factors. A secondary analysis used propensity score matching to replicate covariate adjustment in regression models.
Results
At baseline, 43% of participants reported taking statins. Over 6.79 years of follow-up, 132 (7.9%) participants were institutionalised and 358 (21.5%) participants had died. In the adjusted models, baseline statin use was not statistically associated with increased risk of institutionalisation (HR=1.60; 95% CI 0.98 to 2.63) or death (HR=0.88; 95% CI 0.66 to 1.18). There was no significant association between duration and dose of statins used with either outcome. Propensity scoring yielded similar findings. Compared with non-frail participants not prescribed statins, the adjusted HR for institutionalisation for non-frail participants prescribed statins was 1.43 (95% CI 0.81 to 2.51); for frail participants not prescribed statins, it was 2.07 (95% CI 1.11 to 3.86) and for frail participants prescribed statins, it was 4.34 (95% CI 2.02 to 9.33).
Conclusions
These data suggest a lack of significant association between statin use and institutionalisation or death in older men. These findings call for real-world trials specifically designed for frail older people to examine the impact of statins on clinical outcomes.
doi:10.1136/bmjopen-2012-002333
PMCID: PMC3612783  PMID: 23474793
Clinical Pharmacology; Geriatric Medicine
22.  Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring 
Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of <1.7 mg/liter were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than concentrations of ≥1.7 mg/liter (6/89 patients [7%]) (P < 0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (P < 0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.
doi:10.1128/AAC.00626-12
PMCID: PMC3421881  PMID: 22751544
23.  High risk prescribing in older adults: prevalence, clinical and economic implications and potential for intervention at the population level 
BMC Public Health  2013;13:115.
Background
High risk prescribing can compromise independent wellbeing and quality of life in older adults. The aims of this project are to determine the prevalence, risk factors, clinical consequences, and costs of high risk prescribing, and to assess the impact of interventions on high risk prescribing in older people.
Methods
The proposed project will utilise data from the 45 and Up Study, a large scale cohort of 267,153 men and women aged 45 and over recruited during 2006–2009 from the state of New South Wales, Australia linked to a range of administrative health datasets. High risk prescribing will be assessed using three indicators: polypharmacy (use of five or more medicines); Beers Criteria (an explicit measure of potentially inappropriate medication use); and Drug Burden Index (a pharmacologic dose-dependent measure of cumulative exposure to anticholinergic and sedative medicines). Individual risk factors from the 45 and Up Study questionnaire, and health system characteristics from health datasets that are associated with the likelihood of high risk prescribing will be identified. The main outcome measures will include hospitalisation (first admission to hospital, total days in hospital, cause-specific hospitalisation); admission to institutionalised care; all-cause mortality, and, where possible, cause-specific mortality. Economic costs to the health care system and implications of high risk prescribing will be also investigated. In addition, changes in high risk prescribing will be evaluated in relation to certain routine medicines-related interventions. The statistical analysis will be conducted using standard pharmaco-epidemiological methods including descriptive analysis, univariate and multivariate regression analysis, controlling for relevant confounding factors, using a number of different approaches.
Discussion
The availability of large-scale data is useful to identify opportunities for improving prescribing, and health in older adults. The size of the 45 and Up Study, along with linkage to health databases provides an important opportunity to investigate the relationship between high risk prescribing and adverse outcomes in a real-world population of older adults.
doi:10.1186/1471-2458-13-115
PMCID: PMC3570486  PMID: 23388494
High-risk prescribing; Prevalence; Clinical outcomes; Costs; Older adults
24.  Aging Biology and Novel Targets for Drug Discovery 
Despite remarkable technological advances in genetics and drug screening, the discovery of new pharmacotherapies has slowed and new approaches to drug development are needed. Research into the biology of aging is generating many novel targets for drug development that may delay all age-related diseases and be used long term by the entire population. Drugs that successfully delay the aging process will clearly become “blockbusters.” To date, the most promising leads have come from studies of the cellular pathways mediating the longevity effects of caloric restriction (CR), particularly target of rapamycin and the sirtuins. Similar research into pathways governing other hormetic responses that influence aging is likely to yield even more targets. As aging becomes a more attractive target for drug development, there will be increasing demand to develop biomarkers of aging as surrogate outcomes for the testing of the effects of new agents on the aging process.
doi:10.1093/gerona/glr095
PMCID: PMC4007976  PMID: 21693687
25.  Posaconazole Exposure-Response Relationship: Evaluating the Utility of Therapeutic Drug Monitoring 
Posaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.
doi:10.1128/AAC.05900-11
PMCID: PMC3370770  PMID: 22391534

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