Bruce Green

The global epidemic of obesity has led to an increased prevalence of chronic diseases and need for pharmacological intervention. However, little is known about the influence of obesity on the drug exposure profile, resulting in few clear dosing guidelines for the obese. Here we present a semi-mechanistic model for lean body weight (LBW) that we believe is sufficiently robust to quantify the influence of body composition on drug clearance, and is therefore an ideal metric for adjusting chronic dosing in the obese.

The aim of this study was to compare an individualized dosing regimen for enoxaparin to conventional dosing. Patients in the individualized arm were initially dosed according to weight: patients /=100 kg using lean body weight. Doses were adjusted at 48 h according to renal function. Patients in the conventional arm received enoxaparin according to current practice. Dose-individualized patients had fewer bleeding events (primary end point; relative risk (RR)=0.12, 95% confidence interval (CI)=0.01-0.89, P=0.03) and composite bleeding and bruising events (secondary end point; RR=0.30, 95% CI=0.12-0.71, P=0.003) than those who received conventional dosing. In both arms of the study, there were no recurrent thromboembolic events during treatment and no deaths had occurred at 30 days. Dose individualization of enoxaparin significantly reduces the prevalence of bleeding and bruising events, without apparent loss in effectiveness.

Background: Intravenous (IV) fluid administration is an integral component of clinical care. Errors in administration can cause detrimental patient outcomes and increase healthcare costs, although little is known about medication administration errors associated with continuous IV infusions. Objectives: (1) To ascertain the prevalence of medication administration errors for continuous IV infusions and identify the variables that caused them. (2) To quantify the probability of errors by fitting a logistic regression model to the data. Methods: A prospective study was conducted on three surgical wards at a teaching hospital in Australia. All study participants received continuous infusions of IV fluids. Parenteral nutrition and non-electrolyte containing intermittent drug infusions (such as antibiotics) were excluded. Medication administration errors and contributing variables were documented using a direct observational approach. Results: Six hundred and eighty seven observations were made, with 124 (18.0%) having at least one medication administration error. The most common error observed was wrong administration rate. The median deviation from the prescribed rate was −47 ml/h (interquartile range −75 to +33.8 ml/h). Errors were more likely to occur if an IV infusion control device was not used and as the duration of the infusion increased. Conclusions: Administration errors involving continuous IV infusions occur frequently. They could be reduced by more common use of IV infusion control devices and regular checking of administration rates.

Background: Phase III clinical studies have confirmed that enoxaparin is superior to standard heparin in reducing the rate of recurrent ischaemic events in patients with non‐ST elevation acute coronary syndromes. Patients with moderate to severe renal impairment were, however, excluded from these studies. Due to the hydrophilic disposition of enoxaparin, accumulation is likely in patients with renal dysfunction, thereby increasing the risk of haemorrhagic complications if standard weight adjusted treatment doses are used. Arbitrary dose reduction has been reported to increase the risk of ischaemic events, presumably due to inadequate enoxaparin concentrations.Aim: The aims of this study were to investigate the influence of glomerular filtration rate (GFR) on the pharmacokinetics of subcutaneously administered enoxaparin, and to develop a practical dosing algorithm in renal impairment that can easily be used at the bedside.Methods: Thirty‐eight patients, median age 78 years (range 44–87), mean GFR 32 ml min⁻¹ (range 16–117) and mean weight 69 kg (range 32–95), presenting with acute coronary syndrome were recruited into the study. Approximately 10 anti‐Xa concentrations were taken per patient over their period of therapy. A population pharmacokinetic model was developed using non linear mixed effects modelling techniques, utilizing the software NONMEM. Stochastic simulations were performed to identify the most suitable dosing regimen.Results: Three hundred and thirteen anti‐Xa concentrations were collected. A two compartment, first order input model was identified as the best baseline model. Covariates found to improve model fitting were GFR as a linear function on clearance (CL) and weight as a linear function on the central volume compartment (V_c). The fraction of drug excreted unchanged (F_u) was estimated at 71%. CL and V_c from the final covariate model were estimated as;CL (l h⁻¹) = 0.681 per 4.8 l hr⁻¹ (GFR) + 0.229V_c (l) = 5.22 per 80 kg (total body weight)Conclusions: Clearance of enoxaparin was predictably related to GFR estimated using the Cockroft and Gault equation, with ideal body weight used as the size descriptor. According to our model no dosage adjustment from the standard 1.0 mg kg⁻¹ 12 hourly is required for the first 48 h of treatment. Maintenance doses thereafter can be calculated using standard proportional adjustments based on F_u equal to 0.71.

The prevalence of obesity in the western world is dramatically rising, with many of these individuals requiring therapeutic intervention for a variety of disease states. Despite the growing prevalence of obesity there is a paucity of information describing how doses should be adjusted, or indeed whether they need to be adjusted, in the clinical setting. This review is aimed at identifying which descriptors of body size provide the most information about the relationship between dose and concentration in the obese. The size descriptors, weight, lean body weight, ideal body weight, body surface area, body mass index, fat‐free mass, percent ideal body weight, adjusted body weight and predicted normal body weight were considered as potential size descriptors. We conducted an extensive review of the literature to identify studies that have assessed the quantitative relationship between the parameters clearance (CL) and volume of distribution (V) and these descriptors of body size. Surprisingly few studies have addressed the relationship between obesity and CL or V in a quantitative manner. Despite the lack of studies there were consistent findings: (i) most studies found total body weight to be the best descriptor of V. A further analysis of the studies that have addressed V found that total body weight or another descriptor that incorporated fat mass was the preferred descriptor for drugs that have high lipophilicity; (ii) in contrast, CL was best described by lean body mass and no apparent relationship between lipophilicity or clearance mechanism and preference for body size descriptor was found. In conclusion, no single descriptor described the influence of body size on both CL and V equally well. For drugs that are dosed chronically, and therefore CL is of primary concern, dosing for obese patients should not be based on their total weight. If a weight‐based dose individualization is required then we would suggest that chronic drug dosing in the obese subject should be based on lean body weight, at least until a more robust size descriptor becomes available.

Aims  Enoxaparin dosing is currently based on total body weight. It is not known how to dose adjust for patients who are overweight or obese. This population pharmacokinetic pharmacodynamic (PKPD) study was undertaken to determine a suitable dosing strategy for such patients.Methods  Patients admitted to the Royal Brisbane Hospital and prescribed enoxaparin as part of their normal care were eligible for inclusion into the study. Approximately three blood samples were taken per patient to determine anti‐Xa concentrations. The occurrence of bruising was also recorded. A population pharmacokinetic–pharmacodynamic analysis using NONMEM was undertaken. Simulations were performed using MATLAB.Results  Ninety‐six patients were recruited in a prospective study. One‐third of patients had a body mass index < 24.9 kg m⁻², one‐third from 25 to 29.9 kg m⁻², and one‐third> 30 kg m⁻². A two‐compartment linear model with additive error was fitted to the data. A covariate analysis showed clearance was best described by lean body weight and the central volume compartment by total body weight. The probability of bruising using a logistic regression model was best described by C_max and age. Simulations suggest that patients over 50 years of age whose total body weight is> 90 kg, or under 50 years of age whose total body weight is> 120 kg are likely to have a smoother concentration–time profile and less bruising if a dose of 100 IU kg⁻¹ (1 mg kg⁻¹) based on lean body weight is administered every 8 h.Conclusions  Dose adjustments of enoxaparin in obese patients are likely to reduce the prevalence of bruising, although prospective validation of this is required.

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...

Objectives: To compare variability of blood glucose concentration in patients with type II diabetes with (cases) and without (controls) myocardial infarction. A secondary objective was identification of predictive factors for higher blood glucose on discharge from hospital. Design: A retrospective matched case–control study. Participants: Medical notes of 101 type II diabetic patients admitted with a myocardial infarction (MI) and 101 type II diabetic patients (controls) matched on gender and age with no MI were reviewed. Blood glucose concentrations over two consecutive 48‐h periods were collected. Demographic data and therapy on admission/discharge were also collected. Results: Patient characteristics were comparable on recruitment excluding family history of cardiovascular disease (P=0·003), dyslipidaemia (P=0·004) and previous history of MI (P=0·007). Variability of blood glucose in cases was greater over the first 48 h compared with the second 48 h (P=0·03), and greater when compared with controls over the first 48 h (P=0·01). Cases with blood glucose on discharge >8·2 mmol / L (n=45) were less likely to have a history of previous MI (P=0·04), ischaemic heart disease (P=0·03) or hypertension (P=0·02). Conclusions: Type II diabetics with an MI have higher and more variable blood glucose concentrations during the first 48 h of admission. Only cardiovascular ‘high risk‘ patients had target blood glucose set on discharge. The desirability of all MI patients with diabetes, having standardized‐glucose infusions to reduce variability of blood glucose, should be evaluated in a randomized controlled trial.