Atholl Johnston

Therapeutic drug monitoring of immunosuppressant drugs in clinical practice

BACKGROUND Therapeutic drug monitoring (TDM) is essential to maintain the efficacy of many immunosuppressant drugs while minimizing their toxicity. TDM has become more refined with the development of new monitoring techniques and more specific assays. OBJECTIVE This article summarizes current data on TDM of the following immunosuppressant drugs used in organ transplantation: cyclosporine, tacrolimus, sirolimus, everolimus, and mycophenolate mofetil. METHODS Published data were identified by a MEDLINE search of the English-language literature through March 2001 using the terms therapeutic drug monitoring, cyclosporine, tacrolimus, sirolimus, everolimus, and mycophenolate mofetil. Relevant conference abstracts were also included. RESULTS TDM of cyclosporine has been well studied, and recent findings indicate that monitoring of drug levels 2 hours after dosing is a more sensitive predictor of outcome than trough (C0) monitoring. C0 levels are being used more widely in TDM of tacrolimus; however, the relationship between C0 and area under the curve has varied widely in clinical trials, with correlations ranging from 0.11 to 0.92. The use of TDM of sirolimus, everolimus, and mycophenolate mofetil is evolving rapidly. CONCLUSIONS TDM of immunosuppressant drugs that have a narrow therapeutic index is an increasingly useful tool for minimizing drug toxicity while maximizing prevention of graft loss and organ rejection.

STRIPE: An interactive computer program for the analysis of drug pharmacokinetics

A computer program for the analysis of drug pharmacokinetics is described. The program is written in BASIC for use with a Hewlett Packard HP85 microcomputer. The pharmacokinetic parameters are estimated by linear regression of the log concentrations against time and the exponentials are separated by curve stripping.

Optimization of cyclosporine therapy with new therapeutic drug monitoring strategies : Report from the International Neoral® TDM advisory consensus meeting (Vancouver, November 1997)

CYCLOSPORINE (CsA) has a very narrow therapeutic range because of the fine line between adequate immunosuppression and the risk of drug-induced side effects. Therapeutic drug monitoring (TDM) of CsA is an essential component of the patient’s long-term management plan and involves the use of blood concentrations of the drug to individualize dosing regimens based on pharmacokinetic principles. The traditional method of optimizing a CsA dose regimen in a patient is by titrating the predose blood concentration of CsA (“trough” level) to a designated range that is considered therapeutic and nontoxic. The designated range of CsA blood concentrations has evolved from previous TDM consensus discussions that have contributed to a standardized CsA monitoring strategy that has been adopted by the majority of transplantation programs. Although CsA trough-level monitoring has developed as the standard of practice for patient management, more accurate pharmacokinetic predictors of clinical outcomes for patients receiving CsA have been identified. The area under the time-blood CsA concentration curve (AUC) was found to be the most sensitive predictor of outcomes such as acute rejection episodes and graft loss at 1 year posttransplant in adult renal transplant recipients in two independent studies. A subsequent re-evaluation of the CsA pharmacokinetic database from University of Texas identified intrapatient variability in AUCs as a significant risk factor in development of chronic rejection. There has been little movement toward the adoption of full AUC monitoring because of the impracticality, cost of multiple samples for analysis, and possibly by a resistance in the transplant community to change their standards of practice without clear evidence of benefit. The introduction of Neoralt as a superior formulation of CsA has provided us with the stimulus to reevaluate the traditional approach to therapeutic monitoring of the drug. The improved and more consistent AUCs from the Neoralt formulation compared with Sandimmunet have been demonstrated in several studies in stable and de novo renal transplant patients. Superior CsA pharmacokinetics with the Neoralt formulation compared to Sandimmunet have also been documented in liver, lung, and cardiac transplant patients. Several studies have documented a significant reduction in the incidence of acute rejection rates in Neoralt-treated versus Sandimmunet-treated de novo renal and liver transplant recipients which confirms the important influence of consistent and enhanced bioavailability of CsA on clinical outcomes in the transplant recipient. The focus on CsA pharmacokinetics and clinical outcomes has resulted in a much more extensive pharmacokinetic database from Neoralt clinical trials than all the Sandimmunet data combined over the past 15 years. This wealth of pharmacokinetic data on Neoralt has re-awakened interest in the utility of monitoring blood concentrations of cyclosporine, and subsequently has stimulated exploration of other therapeutic monitoring strategies. Examples of TDM strategies for Neoralt are listed in Table 1. The goals of this meeting were to discuss, explore, and re-evaluate therapeutic monitoring standards for Neoralt with a focus on sparse-sampling-derived AUCs and singlepoint sampling methods and to provide the transplant community with suggestions concerning first steps on a pathway toward optimizing clinical outcomes with Neoralt.

Variable bioavailability following repeated oral doses of etoposide

Following oral administration considerable variation in the bioavailability of etoposide has been reported between patients and with different formulations of the drug. The variation within patients following repeated doses is unknown and has therefore been studied in seven patients receiving therapy on three successive days for relapsed small cell lung carcinoma. Etoposide was administered at a dose of 400 mg orally and plasma concentrations were measured using high-performance liquid chromatography. Within-patient coefficients of variation over three successive days ranged over 19-45% for peak plasma concentrations and 16-53% for the area under the plasma concentration-time curve. There was no evidence of a trend to suggest improving or worsening absorption and accumulation did not occur. Urinary excretion was less than 25% and showed no increase over the 3 days. These data indicate that etoposide bioavailability is not constant and oral therapy may lead to unsuspected underdosing or unexpected toxicity in schedules extending over several days. Monitoring blood concentrations for a single day following oral therapy may give a misleading idea of the total bioavailability of etoposide during a course of therapy. Studies of the relationship between the pharmacokinetics of prolonged schedules of etoposide and disease outcome may lead to unreliable conclusions unless intravenous etoposide is used.

The effect of dose on the bioavailability of oral etoposide

SummaryThe bioavailability of orally administered etoposide varies considerably. The effect of dose on bioavailability has not previously been investigated. In this study six patients were each treated with oral etoposide at doses of 200, 400, and 600 mg, and the pharmacokinetics determined. Each patient acted as his own control. The area under the plasma concentration-time curve (AUC) was proportionately greatest at the lowest dose. Doubling the dose from 200 mg to 400 mg increased AUC by only 50%, and a further increase of only 2.2% occurred at a dose of 600 mg. These data show nonlinear bioavailability of etoposide within the range in clinical use and may explain the variable results of reported studies. The data may have important implications for chemotherapy regimens with oral etoposide.

THE DIGOXIN-AMIODARONE INTERACTION

SummaryTo assess the cause of the digoxin-amiodarone interaction, the systemic availability and renal excretion of digoxin were examined in 10 patients. Patients were studied before and after 1 week and 6 weeks of concurrent amiodarone therapy, and four were also studied after 4–8 months.Mean (±SD) peak plasma digoxin concentration rose from 1.55±0.6 μg/l prior to amiodarone therapy to 2.85±1.3 μg/l after 1 week of combined therapy (p<0.01). Mean AUC also rose from 7.2±2.1 μg/l.h to 12.1±6.4 μg/l.h (p<0.01) during this period. Mean peak plasma digoxin concentration and AUC remained elevated after 6 weeks and, in the patients studied, at 4–8 months. Mean urinary digoxin clearance remained unchanged. Plasma amiodarone and desethylamiodarone concentrations were consistent with the prescribed doses.This study confirmed previous findings of raised plasma digoxin concentrations following the addition of amiodarone. It has also shown that this interaction is sustained for at least several months. The cause has not been fully elucidated but does not appear to be due to a change in the renal clearance of digoxin.

simp: A computer program in basic for nonlinear curve fitting

A computer program for nonlinear regression analysis is described. The program, SIMP, is written in BASIC for use with a wide range of microcomputers. The simplex algorithm is used to minimize the sum of the squared residuals around the fitted line, and the data can be weighted if required. The program is applicable to a wide range of pharmacological procedures requiring curve fitting, and the analysis of protein-binding data is given as an example.

The efficiency of protective gloves used in the handling of cytotoxic drugs

SummaryA range of clinical and industrial gloves have been evaluated to determine their ability to exclude penetration by cytotoxic drugs.Radiolabelled cyclophosphamide, methotrexate, daunomycin, cytosine arabinoside, and vincristine sulphate were studied in an equilibrium dialysis system in which the glove material was used as the dialysis membrane.The thicker gloves were the most effective, but very little drug crossed any of the gloves tested under laboratory conditions. Further studies to evaluate gloves in conditions of clinical use are now needed.

Concentration-controlled trials : what does the future hold ?

ConclusionsThere can be no doubt that the introduction of measures to control the drug concentration in clinical trials results in additional complexity and increases cost. However, these disadvantages may be balanced by increased study power, a possible reduction in patient numbers and the gain of additional information relating drug concentrations to pharmacodynamics during drug development. Also, the measurement of drug concentrations rationalises the sometimes criticised intention-to-treat analysis,[39] by eliminating the non- or poorly compliant patient from the evaluated study data. There is a need to integrate pharmacokinetics and pharmacodynamics during drug development.[40] Concentration-controlled studies may be one of the ways to do this, but the few, non phase I studies, which have been completed and published, have involved only compliance checking,[41] relatively straight-forward therapeutic drug monitoring[19,42,43] or have been undertaken in single centres.[16,17,21,44–47] Before the potential benefits of concentration-controlled trials can be realised in a wider arena, the practical problems, such as those discussed in section 3, must be addressed.

The relationship between theophylline clearance and age in adult life.

SummaryFifty three subjects (31 normal volunteers and 22 patients with asthma) between the ages of 20 and 87 years had their theophylline clearance measured. Volume of distribution (V) and terminal elimination half-life (t1/2) were also calculated in the volunteers who received i.v. theophylline.Although patients tended to have higher clearance values than volunteers, in both groups the oldest third had the lowest clearances. For the combined group (corrected for the patient effect) the oldest third (mean age 70 years) had a mean clearance of 0.53 versus 0.72 for the middle third (mean age 47 years) and 0.73 ml/min/kg CBW for the youngest third (mean age 26 years). There was no statistically significant age related change in V/kg CBW but t1/2 did rise with increasing age.Thus, although clearance does not fall with increasing age during younger adult life, there is a fall during late adult life becoming apparent in the seventh, eighth and ninth decades.