Vidya Perera

The impact of frailty on the utilisation of antithrombotic therapy in older patients with atrial fibrillation

OBJECTIVE to investigate the impact of frailty on the utilisation of antithrombotics and on clinical outcomes in older people with atrial fibrillation (AF). DESIGN prospective study of a cohort of 220 acute inpatients aged > or =70 years with AF, admitted to a teaching hospital in Sydney, Australia (April-July 2007), with 207 followed up over 6 months. RESULTS a total of 140 patients (64%) were identified as frail using a validated tool. Frail patients were less likely to receive warfarin than non-frail on hospital admission (P = 0.002) and discharge (P < 0.001). During hospitalisation, the proportion of frail participants prescribed warfarin decreased by 10.7% and that of non-frail increased by 6.3%. Over the 6-month follow-up, 43 major or severe haemorrhages (20.8%), 20 cardioembolic strokes (9.7%) and 40 deaths (19.2%) were reported. Compared to non-frail, frail participants were significantly more likely to experience embolic stroke (RR 3.5, 95% CI 1.0-12.0, P < 0.05), had a small non-significant increase in risk of major haemorrhage (RR 1.5, 95% CI = 0.7-3.0, P = 0.29) and had greater mortality (RR 2.8, 95% CI 1.2-6.5, P = 0.01). CONCLUSION frail older inpatients with AF are significantly less likely to receive warfarin than non-frail and appear more vulnerable to adverse clinical outcomes, with and without antithrombotic therapy.

Pharmacokinetics of caffeine in plasma and saliva, and the influence of caffeine abstinence on CYP1A2 metrics.

Objectives  To investigate the utility of metrics of CYP1A2 activity using caffeine as a probe, and saliva and plasma sampling with or without a 24‐h caffeine abstinence.

Measurement of CYP1A2 Activity: A Focus on Caffeine as a Probe

The drug metabolising enzyme CYP1A2 contributes to the metabolism of a number of medicines including clozapine, olanzapine and theophylline. These medicines display a high degree of inter-individual variability in pharmacokinetics and response. Measuring CYP1A2 activity in vivo can be an important tool to identify the factors that influence variability in drug pharmacokinetics and inform dose selection. Caffeine is the only currently accepted probe to conduct in vivo phenotyping of CYP1A2. Despite the number of proposed matrices (biological fluid containing the drug and/or metabolite/s of interest) and metrics (mathematical formula relating the drug and/or metabolite/s to enzyme activity) proposed to measure CYP1A2 activity using caffeine, many of these are compromised by factors related to the specific metabolic pathway studied or pharmacokinetic characteristics of caffeine and its metabolites. Furthermore, questions regarding the appropriate study design and methodology to conduct studies to evaluate CYP1A2 activity have often been overlooked. These issues include the potential influence of a methylxanthine abstinence period prior to caffeine CYP1A2 phenotyping and the impact of caffeine formulation on determining CYP1A2 activity. This review aims to discuss the various CYP1A2 matrices and metrics with a particular focus on unresolved methodological issues.

Influence of Environmental and Genetic Factors on CYP1A2 Activity in Individuals of South Asian and European Ancestry

The drug‐metabolizing enzyme CYP1A2 contributes to the metabolism of a number of commonly used medicines and displays wide interindividual variability. The aim of this study was to investigate CYP1A2 activity in a population of South Asian ancestry and compare it with a population of European ancestry. CYP1A2 activity was determined using the 4 h paraxanthine/caffeine saliva concentration ratio following a 100‐mg oral dose of caffeine in healthy individuals of South Asian (n = 166) and European (n = 166) ancestry. Participants were surveyed for extrinsic ethnic factors and genotyped for polymorphisms in CYP1A2 and related genes. Significantly lower CYP1A2 activity was observed in South Asian participants (median: 0.42; range: 0.10–1.06) as compared with European participants (0.54; 0.12–1.64) (P < 0.01). Multiple linear regression indicated that 41% of the variability in CYP1A2 activity could be explained by the diet, lifestyle, and genetic factors studied.

Caffeine and paraxanthine HPLC assay for CYP1A2 phenotype assessment using saliva and plasma

Caffeine has been extensively used as a probe to measure CYP1A2 activity in humans with caffeine clearance or the paraxanthine (major metabolite of caffeine) to caffeine concentration ratio being regarded as the preferred metric. A simple reverse-phased C(18) HPLC assay using ethyl acetate liquid-liquid extraction was developed to quantitate caffeine and paraxanthine concentrations in saliva and plasma. The mobile phase consisted of acetonitrile-acetic acid-H(2)O (100:1:899) and analytes were quantitated with UV detection at 280 nm. The extraction recovery for paraxanthine and caffeine was approximately 70% in both saliva and plasma. The assay was linear over the concentration ranges 0.05-2.50 and 0.05-5.00 µg/mL, for paraxanthine and caffeine, respectively, in saliva. In plasma the assay was linear over the ranges 0.025-2.50 and 0.025-5.00 µg/mL for paraxanthine and caffeine, respectively. Intra- and inter-assay precision and accuracy were less than 15%. Detection limits were 0.015 µg/mL for paraxanthine and caffeine in saliva, while it was 0.005 µg/mL for paraxanthine and caffeine in plasma. Utility was established in samples collected from two healthy volunteers who abstained from caffeine for 24 h and received a single 100 mg oral dose of caffeine. The assay developed is a robust, simple and precise technique to measure caffeine and paraxanthine in saliva and plasma of healthy volunteers after a single oral dose of caffeine.

Diurnal variation in CYP1A2 enzyme activity in South Asians and Europeans.

Response to some medications can depend on time of administration throughout the day. This study investigated diurnal variation in cytochrome P450 1A2 (CYP1A2) activity in people of South Asian and European ancestry.

Murine pharmacokinetics of rifapentine delivered as an inhalable dry powder

A novel inhalable rifapentine dry powder formulation could improve pulmonary rifapentine concentrations resulting in a significantly shorter time to treat tuberculosis infection. The pharmacokinetics of rifapentine (20mg/kg) in healthy mice was compared following intratracheal (IT) and intraperitoneal (IP) administration. Plasma, bronchoalveolar lavage (BAL) and tissue samples were collected and drug levels were quantified at time points up to 24h. Concentration-time data were analysed using a mixed-effects modelling approach to provide model-based estimates of area under the concentration-time curve from time 0 to infinity (AUC0-∞). IT delivery had considerably higher peak rifapentine lung and BAL concentrations and associated AUC0-∞ compared with IP delivery. The plasma AUC0-∞ following IT dry powder delivery was ca. four-fold smaller than the value for IP delivery. Inhaled delivery of rifapentine has the potential to selectively enhance therapeutic efficacy at the pulmonary site of infection whilst minimising systemic exposure and related toxicity.

Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model

ABSTRACT 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.

A Pharmacometric Approach to Investigate the Impact of Methylxanthine Abstinence and Caffeine Consumption on CYP1A2 Activity

This study aimed to investigate the impact of methylxanthine abstinence (MA) periods on CYP1A2 activity in individuals with varying levels of caffeine consumption through development of a population pharmacokinetic model of caffeine and its major metabolite paraxanthine. This study developed and evaluated a mixed-effects pharmacokinetic model for caffeine and paraxanthine concentration-time data derived from a sequential single-dose cross-over study in healthy male volunteers (n = 30) who received oral 100 mg caffeine doses. Participants received caffeine with and without a MA period. Participants were classified as low (0–100 mg/d), medium (100–200 mg/d), or high (>200 mg/d) caffeine consumers (LCCs, MCCs, or HCCs, respectively). All caffeine and paraxanthine concentration-time data were simultaneously modeled. Caffeine pharmacokinetics was described by a two-compartment model with first-order absorption and two first-order elimination pathways. Paraxanthine was described by a one-compartment model with first-order absorption and elimination. Among LCCs (n = 16) and MCCs (n = 9), there was no difference in the mean (95% confidence interval) total apparent caffeine clearance (CL) between the MA period [LCCs: 6.88 (5.61–8.16 l/h); MCCs: 10.09 (7.57–12.60 l/h)] versus the no MA period [LCCs: 6.22 (4.97–7.46 l/h); MCCs: 9.68 (7.12–12.24 l/h)]. The mean CL among HCCs (n = 5) was considerably higher in the MA period [10.48 (5.62–15.33 l/h)] compared with the no MA period [6.30 (3.40–9.20 l/h)] (P < 0.05). The decrease in CL in the no MA period among HCC appears to be due to alternative caffeine elimination pathways, rather than CYP1A2.

Prediction of plasma caffeine concentrations in young adolescents following ingestion of caffeinated energy drinks: a Monte Carlo simulation.

AbstractThe fast-growing consumption of caffeinated energy drinks (CEDs) is linked to increasing reports of caffeine intoxication in adolescents. There is limited data available regarding plasma caffeine concentrations in this population after CED intake and the potential implications for caffeine-related toxicity. This study was an in silico population pharmacokinetic analysis of caffeine. Population pharmacokinetic model of oral caffeine was derived from a previous study of healthy male volunteers. Maximal plasma caffeine concentration (Cmax) profiles following ingestion of one or two servings of popular CEDs were predicted using Monte Carlo simulation and available population body weight data of 10–15-year-old Korean adolescents. Caffeine Cmax values were positively correlated with the amount of caffeine ingested in CEDs and negatively correlated with body weight. The median (range) Cmax profiles varied from a low of 1.2 (0.5–2.6) mg/L to a concentration that is potentially associated with harmful caffeine-related effects of 25.4 (8.1–55.6) mg/L. A subgroup of female 10–11-year-old subjects exhibited the highest caffeine exposure profiles. Conclusion: These data indicate that CED ingestion can increase the risk of serious caffeine intoxication in young adolescents, particularly those with low body mass.What is Known:• Excessive consumption of caffeine can lead to serious caffeine intoxication.• The risk of potential harmful caffeine intoxication after ingestion of caffeinated energy drinks (CED) has not been adequately evaluated in adolescents.What is New:• Predicted maximal plasma caffeine concentration profiles of adolescents with lower body weights showed an overlap with the ingested caffeine concentrations obtained from documented fatalities.• The present simulation-based pharmacokinetic analysis demonstrates that CED ingestion could lead to potentially serious caffeine intoxication in this cohort.