Paul K. L. Chin

High TPMT enzyme activity does not explain drug resistance due to preferential 6-methylmercaptopurine production in patients on thiopurine treatment

Up to 20% of patients on thiopurine therapy fail to achieve adequate drug response. Many of these patients preferentially produce the toxic 6‐methylmercaptopurine metabolites (6‐MMP) rather than the active 6‐thioguanine nucleotides (6‐TGN) resulting in a high 6‐MMP/6‐TGN ratio (>20) and increased risk of hepatotoxicity.

A proposal for dose‐adjustment of dabigatran etexilate in atrial fibrillation guided by thrombin time

Dabigatran is an oral anticoagulant that is increasingly used for atrial fibrillation (AF). Presently, many authorities state that routine laboratory coagulation monitoring is not required. However, data have recently been published demonstrating that higher trough plasma dabigatran concentrations are associated with lower thromboembolic and higher haemorrhagic event rates. Using these data, we simulate a range of AF patients with varying risks for these events and derive a target range of trough plasma dabigatran concentrations (30-130 μg l(-1) ). Finally, we propose that a conventional screening coagulation assay, the thrombin time (TT), can be used to discern whether or not patients are within this range of dabigatran concentrations.

Coagulation assays and plasma fibrinogen concentrations in real-world patients with atrial fibrillation treated with dabigatran.

AIMS In patients with atrial fibrillation prescribed dabigatran, the aim was to examine the correlation between plasma dabigatran concentrations and the three screening coagulation assays [international normalized ratio (INR), activated partial thromboplastin time (aPTT) and thrombin time (TT)] as well as the dilute thrombin time (dTT) and to examine the contribution of plasma fibrinogen concentrations to the variability in TT results. METHODS Plasma from patients with atrial fibrillation on dabigatran were analysed for clotting times and concentrations of fibrinogen and dabigatran. Correlation plots (and associated r(2) values) were generated using these data. The variability in TT results explained by fibrinogen concentrations was quantified using linear regression. RESULTS Fifty-two patients (38-94 years old) contributed 120 samples, with plasma dabigatran concentrations ranging from 9 to 408 μg l(-1) . The r(2) values of INR, aPTT, TT and dTT against plasma dabigatran concentrations were 0.49, 0.54, 0.70 and 0.95, respectively. Plasma fibrinogen concentrations explained some of the residual variability in TT values after taking plasma dabigatran concentrations into account (r(2) = 0.12, P = 0.02). CONCLUSIONS Of the screening coagulation assays, the TT correlated best with plasma dabigatran concentrations. Variability in fibrinogen concentrations accounts for some of the variability in the TT.

Perspective on dabigatran etexilate dosing: why not follow standard pharmacological principles?

Individualized drug dosing is a major pursuit in clinical pharmacology. The principal covariates that determine drug maintenance dose rates are the renal and hepatic function of the individual [1]. The process of dose individualization is most clear for drugs that are renally cleared as there are established indices that can be employed to gauge renal function and thus guide dosing. Pharmaceutical companies tend to promote a ‘one size fits all’ approach in the interests of simplicity. In the following commentary, we review the approach to dabigatran etexilate, a renally eliminated drug that was initially promoted by its manufacturer as having ‘one dose for all’. We aim to show that although guidelines have evolved that take renal function into account to some extent, these are applied insufficiently, not always logically and without consistency between indications. Guidelines have also eschewed monitoring of clotting function. This has happened despite the excellent pharmacokinetic and pharmacodynamic data (mostly from the manufacturer) that supports individualized dosing in relation to renal function using standard pharmacological principles, and anticoagulant monitoring in selected patients.

Dosing of dabigatran etexilate in relation to renal function and drug interactions at a tertiary hospital

Plasma concentrations of the anticoagulant dabigatran are correlated with clinical outcomes, and are affected by renal function, intestinal P‐glycoprotein (P‐gp) activity and stomach acidity.

Comparing dose prediction software used to manage gentamicin dosing

Current Australian guidelines recommend initiating directed therapy of gentamicin if administration exceeds 48 h. Directed doses of gentamicin require the monitoring of plasma concentrations of gentamicin to determine the 24‐h area under the time course of plasma gentamicin concentrations (AUC) and a dosage prediction program, for example TCIWorks or Aladdin. However, doses calculated by such programs have not been compared with an established program.

Thirteen years' experience of pharmacokinetic monitoring and dosing of busulfan: can the strategy be improved?

Background: A busulfan concentration monitoring and dosing service has been provided by Christchurch Hospital since 1998. This study aimed to see (1) the percentage of patients with an area under the concentration time curve (AUC) outside the target range and had dose adjustment, (2) how busulfan clearance (CL) relates to body weight, and (3) if fewer samples could be used to predict doses. Methods: Blood samples were taken from patients after oral administration, usually at 0.5, 1, 1.5, and 6 hours, and after the start of a 2-hour intravenous (IV) infusion of busulfan, at 1, 2, 2.5, 3, 6, and 8 hours. Dose adjustment was made based on the AUC compared with the target range. The relationship of CL and body weight for the IV group was used to develop a revised IV dosing schedule. The bias and imprecision of AUCs estimated using fewer sampling points were examined to see if sampling could be economized. Results: Data were available for 150 patients but for 6 patients, data were incomplete and excluded. Of the remaining 144 patients (256 sample sets, 209 oral, 47 IV, 62% with repeats), 38% (IV) and 35% (oral) of patients had AUCs within the target range after the first dose. Dose adjustment was made in 47% and 34% of patients dosed IV and orally, respectively, after which there was a trend to more patients achieving the target AUC. A nonlinear relationship was found between CL and body weight. The initial IV dosing schedule was revised to take this into account. Sampling for busulfan concentration measurement at 3 points (2.5, 4, 8 hours) or 2 points (2.5, 8 hours) after the start of the infusion enabled accurate and precise estimates of AUC0–24. Conclusions: Around two thirds of patients treated with busulfan were outside the target AUC range after the first dose. Dose adjustment was made in 37% of patients. The relationship between CL and body weight was used to revise the initial IV dosing schedule. Sampling for AUC estimation could be reduced to 2 time points after IV dosing.

A unified pharmacokinetic approach to individualized drug dosing

The ideal in drug therapy is to achieve the right dose, of the right drug, for the right time, in the right patient. Choice of drug dosage regimen in order to achieve optimal drug concentrations in an individual patient is based on the likely pharmacokinetics in that individual. In the case of loading doses it is the volume of distribution (Vd) that is the major determinant, while for maintenance dosing the most important determinant is clearance (CL). The half-life is important for choice of dose interval, time to steady-state and time for drug removal from the body. While the broad approach is well defined, adoption of the principles in clinical practice is far from universal. This is exacerbated by the fact that the details of how Vd and CL are affected by different covariates are often not well defined. A logical approach would assist clinical practice and help direct further research. The initial doses chosen for an individual are based on an estimate of that individuals likely pharmacokinetic characteristics, usually by utilizing all known information about others in the population who resemble this individual. The population pharmacokinetic values are then adjusted for covariates such as age, weight, gender and any other characteristics that might make the individual different from the mean member of the population. Underlying this process are simple equations for loading dose (LD), which is based on Vd, and maintenance dose-rate, which is based on CL for drugs with first order elimination. The aim of the LD is to achieve an initial target concentration (Cinitial), whereas for the dose-rate it is to achieve a target steady state concentration (Css). (1) (2) Both Vd and CL are usually estimated after intravenous administration. If calculated after oral administration then the oral availability needs to be considered. For simplicity in this paper we will ignore oral availability. These equations can be adjusted to accommodate any factor known to explain some of the variance in Vd or CL. The main covariates of CL are shown in Table 1 and are similar for Vd. Some of these covariates may be interdependent and should not be accounted for twice. It would be useful if the effect of covariates could be incorporated into universal equations for dose-individualization. Table 1 Examples of covariates of clearance As loading dose is often a single dose only, Vd matters less clinically than CL. The discussion is therefore focussed on CL and maintenance dosing.

Anticoagulation Use and Clinical Outcomes After Major Bleeding on Dabigatran or Warfarin in Atrial Fibrillation

Background and Purpose— Little is known about the clinical outcomes associated with posthemorrhage anticoagulation resumption for atrial fibrillation. This study had 2 objectives: first, to evaluate anticoagulation use after a first major bleed on warfarin or dabigatran and, second, to compare effectiveness and safety outcomes between patients discontinuing anticoagulation after a major bleed and patients restarting warfarin or dabigatran. Methods— Using 2010 to 2012 Medicare Part D data, we identified atrial fibrillation patients who experienced a major bleeding event while using warfarin (n=1135) or dabigatran (n=404) and categorized them by their posthemorrhage use of anticoagulation. We followed them until an ischemic stroke, recurrent hemorrhage, or death through December 31, 2012. We constructed logistic regression models to evaluate factors affecting anticoagulation resumption and Cox proportional hazard models to compare the combined risk of ischemic stroke and all-cause mortality and the risk of recurrent bleeding between treatment groups. Results— Resumption of anticoagulation with warfarin (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.59–0.97) or dabigatran (HR 0.66; 95% CI 0.44–0.99) was associated with lower combined risk of ischemic stroke and all-cause mortality than anticoagulation discontinuation. The incidence of recurrent major bleeding was higher for patients prescribed warfarin after the event than for those prescribed dabigatran (HR 2.31; 95% CI 1.19–4.76) or whose anticoagulation ceased (HR 1.56; 95% CI 1.10–2.22), but did not differ between patients restarting dabigatran and those discontinuing anticoagulation (HR 0.65; 95% CI 0.32–1.33). Conclusions— Dabigatran was associated with a superior benefit/risk ratio than warfarin and anticoagulation discontinuation in the treatment of atrial fibrillation patients who have survived a major bleed.

Gentamicin and renal function: lessons from 15 years' experience of a pharmacokinetic service for extended interval dosing of gentamicin.

Background: Extended interval dosing (EID) of gentamicin most commonly involves dosing every 24 hours, but patients with impaired renal function may require a longer dose interval. This study examines a large database of patients treated with gentamicin from 1996 to 2010 to see how many patients with renal impairment would have benefited from dose intervals >24 hours and to define the incidence of nephrotoxicity. Methods: All patients aged ≥16 years who had received gentamicin by EID over the 14-year period and had concentration data available were examined. End points included the numbers (%) achieving the target peak concentration [predicted maximum gentamicin concentration (Cmax)] >10 mg/L, the target trough concentration at 24 hours [predicted minimum gentamicin concentration (Cmin24)] <0.5 mg/L, and the target area under the curve over 24 hours of 70–100 mg/L·h. How these related to various creatinine clearance (CLcr) groupings was also examined, as was the number who developed nephrotoxicity (increase in creatinine of ≥0.04 mmol/L). Results: After exclusions, information was available on 4523 patients. Of these, 96% achieved the target Cmax, 83% the target Cmin24, and 54% the target area under the curve over 24 hours. Of the 73% of patients with CLcr ≥60 mL/min, 98% and 97% achieved the target Cmax and Cmin24, respectively. Of the 19% of patients with CLcr of 40–59 mL/min, 94% and 61% achieved the target Cmax and Cmin24, respectively. Of the 8% of patients with CLcr of 20–39 mL/min, 83% and 15% achieved the target Cmax and Cmin24, respectively. Nephrotoxicity, “probably” because of gentamicin, was observed in approximately 4% of the patients studied, which was irreversible in 25% of these (ie, 1% overall). Conclusions: Extending the dose interval of gentamicin to >24 hours is useful in patients with renal impairment to achieve the aims of EID. These results support initial dose intervals for gentamicin of 24, 36, and 48 hours for patients with CLcr ≥60, 40–59, and 20–39 mL/min, respectively. Irreversible nephrotoxicity was observed in approximately 1% of the patients studied.