Individualising aminoglycoside dosage regimens after therapeutic drug monitoring: simple or complex pharmacokinetic methods?

Measurements of aminoglycoside concentration in serum are used to individualise dosage regimens (dose per administration and/or administration interval) with the goal of attaining the desired therapeutic range as quickly as possible. Therapeutic range is defined in terms of peak concentration (to monitor effectiveness) and trough concentration (to avoid toxicity). This article focuses on methods to individualise aminoglycoside dosage regimens in the context of extended dosage intervals. Simple pharmacokinetic methods involve linear dosage adjustment based on peak or trough concentrations or area under the concentration-time curve, or nomograms. The once daily aminoglycoside nomogram determines the dosage interval for aminoglycosides given as a fixed dose per administration, based on a single concentration measurement drawn 6 to 14 hours after the start of the first infusion. This is a preferred method because of its simplicity, strong pharmacodynamic rationale and prospective validation in a large population. However, it does not work when the fixed dose assumed is not relevant, for example for patients with burns, cystic fibrosis, ascites or pregnancy. Furthermore, it has not been validated in children. In these cases, a more sophisticated method is required. Complex pharmacokinetic methods require dedicated software. Non-Bayesian least-squares methods allow the optimisation of both the dose and the dosage interval, but require aminoglycoside concentrations from two or more samples taken in the post-distributive phase during a single dosage interval. With Bayesian least-squares methods, only one concentration measurement is required, although any number of samples can be taken into account. In the Bayesian maximum a posteriori (MAP) method, the parameter estimates are taken as the values corresponding to the maximum of the posterior density. In 'full' Bayesian approaches (also called stochastic control), all the information about the parameters revealed by the posterior distribution is taken into account, and the optimal regimen is found by minimising the expected value of the weighted sum of squared deviations between predicted and target concentrations. If the population model is reasonably well known, Bayesian methods (MAP or stochastic control) should be used because of their good predictive performance. Although only one concentration measurement is required, better precision is afforded by a two-sample strategy, preferably drawn 1 and 6 hours after the start of the first infusion. If the population model is not known, then the non-Bayesian least-squares method is the method of choice, because of its robustness and lack of requirement for prior information about the distribution of parameters in the population.     

A review of current anti-HCV treatment regimens and possible future strategies

Background: Hepatitis C virus (HCV) infection remains a serious health problem worldwide. The current standard treatment of HCV infection is pegylated interferon-α plus ribavirin, but this is clearly not sufficiently effective and tolerable. Objective: To review current HCV treatment strategies and future options. Methods: Review of major clinical trials or observational studies when no trial is available. Results/conclusion: Rates of sustained virologic response are widely variable, approximately 40 – 80%, depending on genotype, and even lower when HIV coinfection occurs. New agents, like small molecules that specifically target the HCV life cycle, may improve response rates; but safety is a concern.     

In vitro-in vivo extrapolation of quantitative hepatic biotransformation data for fish. I. A review of methods, and strategies for incorporating intrinsic clearance estimates into chemical kinetic models

Scientists studying mammals have developed a stepwise approach to predict in vivo hepatic clearance from measurements of in vitro hepatic biotransformation. The resulting clearance estimates have been used to screen drug candidates, investigate idiosyncratic drug responses, and support chemical risk assessments. In this report, we review these methods, discuss their potential application to studies with fish, and describe how extrapolated values could be incorporated into well-known compartmental kinetic models. Empirical equations that relate extrapolation factors to chemical log K(ow) are given to facilitate the incorporation of metabolism data into bioconcentration and bioaccumulation models. Because they explicitly incorporate the concept of clearance, compartmental clearance-volume models are particularly well suited for incorporating hepatic clearance estimates. The manner in which these clearance values are incorporated into a given model depends, however, on the measurement frame of reference. Procedures for the incorporation of in vitro biotransformation data into physiologically based toxicokinetic (PBTK) models are also described. Unlike most compartmental models, PBTK models are developed to describe the effects of metabolism in the tissue where it occurs. In addition, PBTK models are well suited to modeling metabolism in more than one tissue.     

Implementation and evaluation of control strategies for individualizing dosage regimens,with application to the aminoglycoside antibiotics

Three strategies are implemented for controlling serum concentrations by determining individualized dosage regimens. The methods incorporate, respectively, nonlinear least squares parameter estimation, Bayesian maximum a posterioriprobability estimation, and a stochastic control procedure that minimizes the expected value of an appropriate therapeutic cost. The performance of the three dose regimen calculation strategies was evaluated using Monte Carlo simulations of a typical therapeutic protocol for tobramycin.This work was supported in part by NIH grant RR01629.     

Implementation and evaluation of control strategies for individualizing dosage regimens, with application to the aminoglycoside antibiotics

Three strategies are implemented for controlling serum concentrations by determining individualized dosage regimens. The methods incorporate, respectively, nonlinear least squares parameter estimation, Bayesian maximum a posteriori probability estimation, and a stochastic control procedure that minimizes the expected value of an appropriate therapeutic cost. The performance of the three dose regimen calculation strategies was evaluated using Monte Carlo simulations of a typical therapeutic protocol for tobramycin.     

庆大霉素不同给药方案的药代动力学和肾功能损害的实验研究

目的研究庆大霉素(GTM)不同时辰给药方案对大鼠肾功能损害、血药浓度和药动学参数的影响。方法①大鼠分6组:对照组、时辰每日单次给药组[N(活动期给药)100组、D(休息期给药)100组,分别于1:00和13:00给药100mg·kg-1,im]、时辰每日2次不等量给药组和传统每日2次等量给药组(N90+D10组、N70+D30组、N50+D50组,每日1∶00和13∶00分2次im90mg·kg-1+10mg·kg-1、70mg·kg-1+30mg·kg-1、50mg·kg-1+50mg·kg-1)。各组分别于给药d1、10和20测定血清肌酐(Cr)、血清尿素氮(BUN)。②给药后0.25、0.5、1、2、5和8h分别于眼眶取血,测定血药浓度,给药d10、20重复上述采血过程。绘制药时曲线,计算药动学参数。结果①肾功能损害:给药d10,N50+D50组Cr和BUN水平最高,与给药d1和同期对照组相比差异有显著性(P<0.05);N100组最低,与同期对照组相比差异有显著性(P<0.05)。血药浓度:给药d10,N100组和D100组峰浓度差异有显著性(P<0.05)。给药d20,N50+D50组峰浓度高于两次不等剂量组峰浓度,但差异无显著性。③药动学参数:给药d20,N50+D50组CLs最小,N100组最大,给药d1、10、20,N100组T12最短,N50+D50组T12最长(P<0.05)。结论在时辰给药方案中,GTM以活动期单次给药肾功能损害最小,血药峰浓度低,T12最短,CLs最大。     

Hepatocellular neoplasia in fish, rats and man: a selected comparative review.

Liver cancer is a common neoplasm of man that is especially frequent in parts of the world where hepatitis B virus is endemic and high aflatoxin ingestion is experienced. Hepatocellular carcinoma (HCC) has a very aggressive behavior, is quite resistant to radiotherapy and chemotherapy and is often inoperable, all of which lead to a five-year patient survival of less than 5 percent. Studies in lower animals (e.g. fish, rats) lend themselves to preplanned manipulations aimed at answering specific questions which are intended to elucidate the biology of HCC. Information derived from these studies can be applied to the human condition with the hope of earlier diagnosis, improved treatment and possibly prevention. This review touches on selected areas of similarity and dissimilarity in the histology, histochemistry, metastasis, etiology and molecular biology of HCC in fish, rats and man.     

Pharmacokinetics of antimalarials and proposals for dosage regimens.

Blood level data for the antimalarials amodiaquine, chloroguanide, chloroquine, pyrimethamine, quinine and sulphadoxine have been retrieved from the literature and pharmacokinetically analyzed. Minimum, average and maximum blood level concentrations at steady state in suppressive treatment and peak concentrations in therapeutic treatment were predicted and blood level-time curves simulated. Based on the computer-predicted data, changes in dosage regimens are proposed to reduce the fluctuations between maximum and minimum levels in suppressive treatment, and for obtaining maximum peak levels in therapeutic treatment already with the loading dose.     

Pharmacokinetics and comparative nephrotoxicity of fixed-dose versus fixed-interval reduction of gentamicin dosage in subtotal nephrectomized dogs

There is presently no consensus as to the relative safety of fixed-interval/reduced dose (FI) vs fixed-dose/increased interval (FD) dosage adjustment regiments for use in renal insufficiency. This study compared their nephrotoxic potential using gentamicin in beagle dogs with renal insufficiency secondary to subtotal surgical nephrectomy. Pharmacokinetic analysis in six dogs showed that this surgical procedure resulted in a decreased total body clearance of drug and a marginally contracted volume of the central compartment. An allometric analysis of gentamicin disposition in different species was used to derive a human-equivalent maximum canine nontoxic dose of 9 mg kg^?1 day^?1. Nephrotoxicity was detected by histopathologic analysis and changes in the pre- and post-drug treatment, creatinine clearance, and daily drug elimination rate constants. This allometric dose did not produce clinical toxicity in a control group of six dogs with intact kidneys given drug for 14 days. Dosage adjustments within the FI and FD groups were based on serum creatinine concentrations 10 days after surgery. Statistical analysis of morphological and functional parameters indicated that the FD method was significantly less toxic than the FI regimen.     

The comparability of dosage regimens of Lanoxin tablets and Lanoxicaps.

1 Twice daily administration of 0.25 mg digoxin tablets (Lanoxin) or of 0.2 mg digoxin in solution in soft gelatin capsules (Lanoxicaps) produced similar mean steady state plasma digoxin concentrations in ten healthy volunteers. Respective values were 1.07 +/- 0.075 and 0.95 +/- 0.048 ng ml-1. 2 During continued administration, peak plasma concentrations occurred earlier after capsules with a tendency to higher peak levels. However, area under curve determinations over 7 h were similar. 3 Approximately 10% less digoxin was recovered in urine collected in a 12 h dosage interval during the lower dosage administration of capsules. Mean percentage urinary recovery of administered dose was 57% for tablets and 65% for capsules. 4 The enhanced bioavailability of Lanoxicaps was associated with reduced between-subject variability in plasma concentration. 5 Lanoxicaps (0.2 mg) should be approximately equivalent in effect to digoxin tablets (0.25 mg) currently available in the United Kingdom, though improved consistency would be anticipated.     

Design,data monitoring,and analysis of clinical trials with co-primary endpoints: A review

ABSTRACT

We review the design, data monitoring, and analyses of clinical trials with co-primary endpoints. Recently developed methods for fixed-sample and group-sequential settings are described. Practical considerations are discussed, and guidance for the application of these methods is provided.     

A review of selected herbicides and their toxicities.

Since 2500 BC man has strived to develop methods of orderly pest control (1). These methods included prayer, physical labor, mechanical devices and chemicals. Through chemistry many new pesticides have been developed. Pesticides are "chemicals used to kill a species or a group of species that causes trouble, annoyance or destruction" (2) and include insecticides, rodenticides, fungicides and herbicides. This review focuses on the fastest growing group of pest control agents agents--herbicides. Arsenicals, chlorates, chlorophenoxy acids, biprydyl and substituted phenols are discussed as to their physical and chemical properties, sources, environmental fates, absorption/distribution/elimination, modes of action, toxic effects and recommended treatments.     

A comparative review of the efficacy and tolerability of retinoid-containing combination regimens for the treatment of acne vulgaris

Many physicians regularly prescribe combination therapy involving a retinoid for their acne patients. The most common retinoid-containing regimens include either oral antibiotics or topical benzoyl peroxide and antibiotic products. A fair number of studies have been conducted to evaluate the efficacy of these combination therapies, but there is a lack of comparative studies examining different regimens head-to-head. Also, many of the noncomparative studies have very similar trial designs. A review of these studies was conducted in order to organize the available data side by side from the different regimens. Although not derived from comparative studies, this presentation of data is expected to provide dermatologists with valuable information from which they can easily make their own comparisons among similarly designed trials.     

Drug use in pregnancy: A comparative appraisal of data collecting methods

Summary We have compared the reliability of the information about drug therapy and pregnancy retrieved by interviewing patients with that distilled from pharmacy records. In the initial phase of each interview we used the internationally accepted open-ended technique, and extended this with an indication-oriented set of questions and then a set of specific drug-oriented questions. These data were then compared with those from pharmacy records on dispensing for the same patients during their pregnancy.The results suggest that if drug consumption during pregnancy is evaluated by interview, one should not restrict oneself to open-ended questions but should include indication-oriented and, when appropriate, drug-oriented questions. Such specific questions offer the opportunity of detecting the use of over-the-counter medication and of constructing drug use/complaint profiles. By contrast, pharmacy records will give better information in case of long recall periods and in patients with multiple and/or repeated drug use. Investigators should use the complementary elements of both techniques where appropriate.     

Immunosuppressive drugs in renal transplantation. A review of the regimens.

Currently, expected 10-year first graft survival rates for kidneys from HLA-identical sibling, 1-haplotype-matched relative, and cadaver donors are 74, 51, and 40%, respectively. Histocompatibility, immunological conditioning with blood products, and immunosuppression with glucocorticoids, azathioprine, cyclosporin, and the antithymocyte (antilymphocyte) antibody preparations have been significant factors in the gradual improvement of kidney graft survival rates. Nearly all immunosuppression regimens are cyclosporin-based. Antithymocyte antibody induction therapy with delayed administration of cyclosporin is widely practised to avoid cyclosporin nephrotoxicity while the kidney graft is recovering from preservation injury. Late cyclosporin withdrawal results in inferior cadaver kidney transplant survival rates. Rejection crises usually respond to high dose glucocorticoid therapy. Glucocorticoid-resistant rejection usually responds to treatment with antithymocyte antibody. FK-506 is a promising new immunosuppressant that has properties similar to cyclosporin. Prophylaxis against viral, bacterial and fungal infections is necessary to reduce the morbidity of immunosuppression. The incidence of malignant conditions associated with viral infections is significantly increased with immunosuppression. New immunopharmacological agents and advances in genetic procedures may allow the induction of specific transplantation tolerance and successful xenotransplantation within the next decade.     

A review of methods used to compare dissolution profile data

In a number of recent guidance documents, the FDA has placed more emphasis on the meaningful comparison of dissolution profile data. For example, the FDA scale-up and post-approval changes–modified release (SUPAC–MR) guidance indicates that similar dissolution profiles for approved and modified formulations is acceptable justification for certain levels of change without prior FDA approval or the need to perform bioequivalence studies. As a result, interest among pharmaceutical scientists has focused on the methodology that is available for the comparison of dissolution profile data. The authors review the literature on the methods that are currently available.