Adjustment Of Dosage Regimens Research Articles

Evaluation of Dose Adjustment in Patients With Renal Impairment at Muhimbili National Hospital in Tanzania.

Background: The burden of renal diseases is increasing in developing countries like Tanzania. Drug accumulation exposes patients with renal impairment to drug toxicity that may lead to adverse drug reactions, poor adherence to treatment, and increased healthcare costs. There is limited information on the appropriateness of dosage regimen adjustment for patients with renal impairment, particularly in developing countries such as Tanzania. This study aimed to investigate the appropriateness of drug dosing in hospitalized patients with renal impairment in Tanzania. Methods: This was a retrospective cross-sectional study. It was conducted between November 2019 and April 2020 amongst hospitalized patients at Muhimbili National Hospital. All enrolled patients had serum creatinine levels ≥1.2 mg/dL and taking at least one drug requiring dosage regimen adjustment. Creatinine clearance was calculated from patient serum creatinine using the Cockcroft-Gault equation. Drug dosing appropriateness was determined by comparing the current practice with tertiary references. The relationship between the patient's baseline characteristics and the rate of dosage regimen adjustment was determined using the X2 test. Univariate and multivariate logistic regression analysis evaluated the predictors of dosing adjustment. Results: Most of the enrolled patients, 269 (98.9%) had comorbidities. Of the medication orders included in the final analysis, 372 (27%) needed dosage regimen adjustment. Out of the 372 medication orders, not adjusted were 168 (45.2%), inappropriately adjusted 105 (28.2%), and appropriately adjusted were only 99 (26.6%). In this study, 212 (77.9%) patients received at least one drug with an incorrect dosage regimen. Females and those with level 4 renal impairment patients were more likely to have their doses appropriately adjusted compared to their counterparts. Conclusions: In this study, about three-quarters of the patients received at least one drug with an incorrect dosage regimen. Thus, appropriate measures such as the availability of national guidelines and clinical decision support systems for drug dosing adjustment in patients' renal impairment should be in place.

Pharmacokinetics of Marbofloxacin Following Oral Administration in Lactic Acid Pretreated Broiler Chickens

Background: It is hypothesized that feeding lactic acid as a feed additive has the potential to alter the pharmacokinetics of many antimicrobial drugs being used for the treatment of infectious disease in general and marbofloxacin in particular; leading to either increased or decreased efficiency. Hence, the present study was planned to explore the effects of lactic acid pre-treatment on the pharmacokinetics of marbofloxacin after oral administration in broiler chickens. Methods: The pharmacokinetics of marbofloxacin was investigated following single dose oral administration (5 mg/kg) in lactic acid pre-treated (8 gm/l each, oral, 10 days) broiler chickens. The plasma concentration of marbofloxacin was determined by ultra-high-performance liquid chromatography to workout pharmacokinetic profile of marbofloxacin using non compartment model. Result: The AUC (area under curve) of marbofloxacin declined from 14.70 ìg·h/mL to 6.16 ìg·h/mL after pre-treatment of lactic acid. Similarly, the average values of maximum plasma concentration (Cmax) of drug decreased from 2.11 ìg/mL to 0.98 ìg/mL and mean body clearance (ClB) increased from 0.47 L/h/kg to 1.03 L/h/kg. The average elimination half-lives (t½â) of marbofloxacin before and after pre-treatment with lactic acid were 4.89 h and 2.81 h, respectively. Furthermore, the investigation revealed alteration of pharmacokinetic parameters evident in lactic acid pre-treated broiler chickens (as compared to non pre-treated birds) requiring adjustment of dosage regimens.

A retrospective analysis to estimate trough concentrations of teicoplanin in patients with suspected or documented Gram-positive infections

Teicoplanin is a glycopeptide antibiotic commonly used to treat Gram-positive bacterial infections in the clinic. The aim of this study was to provide a therapeutic reference for the clinical application and dosage regimen adjustment of teicoplanin by identifying factors associated with its plasma trough concentration (Ctrough). A retrospective study was performed on patients with suspected or documented Gram-positive infections who were hospitalized from November 2017 to January 2020 and treated with teicoplanin while undergoing routine therapeutic drug monitoring (TDM). A total of 112 Ctrough trough measurements were obtained from 72 patients were included in this study. SPSS software was used for correlation analysis and receiver operator characteristic curve (ROC) analysis. The Ctrough for teicoplanin showed statistically significant relationships (P<0.05) with PLT, Scr, CLcr, eGFR, BUN and Cys-C. ROC curve analysis revealed that CLcr and eGFR were more sensitive and specific for Ctrough compared to the other factors. These findings should be considered in the clinical application of teicoplanin and for its dosage adjustment.

Heart failure as a risk factor of adverse drug reactions. Part 1: potential changes in pharmacokinetics

The use of many drugs is associated with the risk of adverse drug reactions (ADRs), including those that increase mortality and / or morbidity and / or seek medical help or hospitalization, so called «drug-induced diseases» (DID). There is a number of factors that increase the risk of DID (risk factors) including comorbid diseases (for example, chronic kidney disease, hepatic impairment, obesity etc.). These pathologic conditions induce changes in pharmacokinetics (PK) and pharmacodynamics of drugs, thereby increasing the risk of ADRs. One of these diseases is heart failure (HF). Most studies of PK changes were conducted among patients with LVEF from 40 to 45 %, and excluded patients with concomitant diseases that could affect the PK of drugs (for example, serious liver and / or kidney diseases), therefore in polymorbid patients, trial findings may not be applicable. HF may be associated with a decrease in bioavailability, a decrease in volume of distribution, a change in the activity of cytochrome P450 isoenzymes, etc. Individual dose and dosage regimen adjustment can significantly reduce risks, improve the quality of medical care and improve the prognosis in patients with heart failure.

Development of Physiologically Based Pharmacokinetic Model for Pregabalin to Predict the Pharmacokinetics in Pediatric Patients with Renal Impairment and Adjust Dosage Regimens: PBPK Model of Pregabalin in Pediatric Patients with Renal Impairment

Pregabalin (PGB) is widely used clinically; however, its pharmacokinetics (PK) has not been studied in pediatric patients with renal impairment (RI). To design optimized PGB regimens for pediatric patients with varying degrees of RI and predict exposure to PGB, physiologically based pharmacokinetic (PBPK) models of PGB were developed and verified, and its disposition was simulated in the healthy population and adults with RI. The simulated results from the PBPK models after single-dose and multi-dose administrations of PGB were consistent with the corresponding observed data based on the fold error values of less than 2. The area under curve ratios were 1.23 ± 0.06, 2.02 ± 0.10, 3.86 ± 0.21, and 9.92 ± 0.79 in pediatric patients with mild, moderate, severe, and end-stage RI, respectively. Based on the predictions for pediatric patients with moderate, severe, and end-stage RI, the maximum dose should not exceed 7, 3.5, and 1.4 mg/kg/day, respectively, among those weighing < 30 kg, and it should not exceed 5, 2.5, and 1 mg/kg/day, respectively, among those weighing > 30 kg. In conclusion, the developed PBPK model is a valuable tool for predicting PGB dosage for pediatric patients with RI.

Predicting budesonide performance in healthy subjects and patients with Crohn's disease using biorelevant in vitro dissolution testing and PBPK modeling

Objectives: Drug product performance might be affected in Crohn's disease (CD) patients compared to healthy subjects due to pathophysiological changes. Since a low number of clinical studies is performed in this patient population, physiologically-based pharmacokinetic (PBPK) models with integrated results from biorelevant in vitro dissolution studies could be used to assess differences in the bioavailability of drugs. Using this approach, budesonide was used as model drug and its performance in healthy subjects and CD patients was predicted and compared against observed pharmacokinetic data.The in vitro release tests, under healthy versus CD conditions, revealed a similar extent of drug release from a controlled-release budesonide formulation in the fasted state, whereas in the fed state a lower extent was observed with CD. Differences in the physiology of CD patients were identified in literature and their impact on budesonide performance was investigated with a PBPK model, revealing the highest impact on the simulated bioavailability for the reduced hepatic CYP3A4 enzyme abundance and lower human serum albumin concentration. For CD patients, a higher budesonide exposure compared to healthy subjects was predicted with a PBPK population adapted to CD physiology and in agreement with observed pharmacokinetic data.Budesonide performance in the fasted and fed state was successfully predicted in healthy subjects and CD patients using PBPK modeling and in vitro release testing. Following this approach, predictions of the direction and magnitude of changes in bioavailability due to CD could be made for other drugs and guide prescribers to adjust dosage regimens for CD patients accordingly.

Is gentamicin administered to individual patients in optimal doses already at the beginning of therapy?

Abstract Introduction A gentamicin dose, which the physicians select, frequently does not take any pharmacokinetic parameters into consideration. Aim To analyse the results of therapeutic drug monitoring (TDM) of gentamicin for those patients who have not had the gentamicin dose adjusted at the beginning of therapy (first group) and for those patients who had the gentamicin dose adjusted at the beginning of therapy (second group). Methods We acquired the basic data about patients from the requests for laboratory examination of levels of gentamicin. We measured all the gentamicin concentrations mentioned in this work using the FPIA method. Results The monitored set included 379 hospitalized patients during a 4-year period. We divided the monitored set into 2 groups. First group was composed of patients without dose adjustment of gentamicin at the beginning of therapy, and the second group was composed of patients with dose adjustment of gentamicin by the clinical pharmacist at the beginning of therapy. In addition, the patients in each group were divided according to the body mass index (BMI). In the first group of patients, a low percentage of patients had both optimal levels (trough, peak levels). As for patients with BMI &gt; 25 m2/kg, there were only 17 % such cases, and the patients with BMI ≤ 25 m2/kg were only 18.8 %. In the second group, the patients had all trough and peak levels in optimal therapeutic range at obese patients, overweight patients and also at patients with normal weight (p &lt; 0.001). Conclusion Adjustment of dosage regimens immediately at the beginning of therapy will provide for administering sufficient doses of antibiotics at the beginning of therapy, which is a pre-condition for a successful anti-infective therapy. Therapeutic monitoring of levels allows for administration of sufficient dose of gentamicin without fear of any undesirable effects.

Colistin Use in Patients with Chronic Kidney Disease: Are We Underdosing Patients?

Colistin is administered as its inactive prodrug colistimethate (CMS). Selection of an individualized CMS dose for each patient is difficult due to its narrow therapeutic window, especially in patients with chronic kidney disease (CKD). Our aim was to analyze CMS use in patients with CKD. Secondary objectives were to assess the safety and efficacy of CMS in this special population. In this prospective observational cohort study of CMS-treated CKD patients, CKD was defined as the presence of a glomerular filtration rate (GFR) < 60 mL/min/m2 for more than 3 months. The administered doses of CMS were compared with those recently published in the literature. Worsened CKD at the end of treatment (EOT) was evaluated with the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. Colistin plasma concentrations (Css) were measured using high-performance liquid chromatography. Fifty-nine patients were included. Thirty-six (61.2%) were male. The median age was 76 (45–95) years and baseline GFR was 36.6 ± 13.6. The daily mean CMS dosage used was compared with recently recommended doses (3.36 vs. 6.07; p < 0.001). Mean Css was 0.9 (0.2–2.9) mg/L, and Css was <2 mg/L in 50 patients (83.3%). Clinical cure was achieved in 43 (72.9%) patients. Worsened renal function at EOT was present in 20 (33.9%) patients and was reversible in 10 (52.6%). The CMS dosages used in this cohort were almost half those currently recommended. The mean achieved Css were under the recommended target of 2 mg/dL. Despite this, clinical cure rate was high. In this patient cohort, the incidence of nephrotoxicity was similar to those found in other recent studies performed in the general population and was reversible in 52.6%. These results suggest that CMS is safe and effective in patients with CKD and may encourage physicians to adjust dosage regimens to recent recommendations in order to optimize CMS treatments.

The problem of low peak concentration of gentamicin in clinical practice

The problem of low peak concentration of gentamicin in clinical practice Aminoglycoside antibiotics have particular importance in the treatment of Gram-negative infections. Toxicity of gentamicin is well-known, but patients often receive insufficient dosage in clinical practice. The purpose of this study was to refer to the problem of insufficient dosages that were confirmed by low peak concentration and to determine relationship between low peak levels and pharmacokinetic parameters, renal function and body weight. We studied 68 patients who were treated with gentamicin for one year (August 2010 - August 2011). Therapeutic drug monitoring (TDM) was applied for all the patients. Gentamicin peak and trough concentrations were measured by the FPIA (Fluorescence Polarization Immunoassay) method with an analyser, AxSYM of ABBOTT company. We divided the patients into 3 groups according to peak and trough levels. Together 13 (19%) patients had high trough concentrations and optimal peak concentrations. Only 6 (9%) patients had optimal trough and peak levels in the first measurement of plasma concentrations. The third group included 49 patients (72%). These patients had optimal trough levels and low peak levels in the first measurement. 34 patients of the third group (28 males, 6 females) had optimal peak levels after adjustment of dosage in the second measurement. 15 patients, only males did not reach optimal peak levels even after adjustment of dosage in the second measurement. The patients with low peak levels of gentamicin are more frequent than patients with toxic adverse effects in clinical practice. Especially, these are the patients with higher value of body weight and following increased pharmacokinetic parameters: creatinine clearance, total volume of distribution, total clearance and elimination rate constant. The clinical pharmacists have to adjust dosage regimens, especially according to Therapeutic drug monitoring (TDM) and clinical experience. The results of the study have confirmed that the clinical pharmacists must adjust dose regimen not only for patients who require reduced doses but more often for patients who require higher doses than are commonly used in clinical practice. These patients are at risk of underdosing of aminoglycoside antibiotics.

Failure of liver function tests in predicting drug clearance of chemotherapeutic agents in a patient who had recovered from hepatic congestion

Failure of liver function tests in predicting drug clearance of chemotherapeutic agents in a patient who had recovered from hepatic congestion

PROMOTION OF AN APPLIED PHARMACOKINETIC SOFTWARE, NAMED PHARMONITOR, DEVELOPED TO OPTIMIZE INDIVIDUAL DOSAGE REGIMEN THROUGH A NATIONAL QUALITY CONTROL PROGRAM

To improve the practice of therapeutic drug monitoring, the Belgian Health Authorities have decided to support the development of an upgraded version of a pharmacokinetic program, so-called PharMonitor 1.0.0. Based on the Sawchuk-Zaske method, this software is a valuable and user-friendly tool for individually adjusting dosage regimens of aminoglycosides. It allows maximal speed, flexibility, reliability and optimal traceability. Moreover, the software is easily customized according to the user’s selection (language, concentration units, drug target ranges, creatinine clearance, …). Reports can be generated in PDF format after appropriate validation. The software can be connected to most laboratory information systems. Additional applications should be developed on PharMonitor 1.0.0. (other classes of drugs, Bayesian approach, …). Once freely distributed to all Belgian laboratories, this software is expected to reduce the variability observed through external quality assessment schemes (EQAS), in the interpretation of drug concentrations.

Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction

The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with beta-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.

Dosage adjustment of quinolone antibiotics and angiotensin-converting enzyme inhibitors in patients with renal dysfunction

The aim of this study was to verify an approach for calculating pharmacokinetic parameters suitable for adjusting dosage regimens in patients with renal dysfunction. We carried out a retrospective analysis of the pharmacokinetic profiles of 12 new quinolone antibiotics and 11 angiotensin-converting enzyme inhibitors (ACEIs) in patients with normal and impaired renal function to obtain the renal excretion ratio (R(renal)) of each drug. We demonstrated that the pharmacokinetics of each drug in a patient with renal dysfunction can be adequately estimated using the R(renaI) value of each drug together with the creatinine clearance as an index of the individual's renal function. Using the R(renaI) value obtained, we could successfully simulate pharmacokinetic profiles of the drugs in publications other than that used to obtain the R(renal) values. On the other hand, age-related changes in the pharmacokinetics of new quinolone antibiotics are not always adequately predicted using the R(renal) value compared to using creatinine clearance alone as an index, and the reasons for this are not fully understood. These results demonstrate that dosage regimens of quinolone antibiotics and ACEIs in patients with renal dysfunction can be adequately optimized using the R(renal) value for each drug using the present approach.

Effect of severe renal impairment on the pharmacokinetics of azimilide following single dose oral administration.

To assess the influence of severe renal impairment on azimilide pharmacokinetics. A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22-28 and 10 days, respectively. Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h-1 kg-1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h-1 kg-1, 95% confidence interval on the ratio 0.67, 1.36) was observed. Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment.

Effects of altered plasma alpha-1-acid glycoprotein levels on pharmacokinetics of some basic antibiotics in pigs: simulation analysis.

Effects of altered plasma alpha-1-acid glycoprotein (AGP) levels on pharmacokinetic parameters of basic antimicrobials, erythromycin (EM), lincomycin (LM) and clindamycin (CM) were evaluated in pigs by simulation analysis. Intravenous (i.v.) injections of EM, LM and CM were performed to obtain pharmacokinetic parameters in healthy conditions. Binding parameters were obtained from an in vitro study using ultrafiltration. Simulation studies indicated that an increase of plasma AGP levels resulted in a decrease of both volume of distribution at steady state (Vdss) and total body clearance (Cltot) for all the drugs. Elimination rate constant for LM was almost unchanged by an increase of plasma AGP levels, whereas those for EM and CM were increased. Plasma concentration-time profiles at a high AGP level (often observed in pathophysiological conditions) were also simulated. All of the total plasma concentration-time profiles were different from those at normal AGP level. The differences were characterized by a higher initial concentration with faster or similar elimination. Unbound plasma concentration-time profile of LM was unaffected by AGP levels, whereas EM and CM were eliminated from plasma more rapidly at high AGP level. These results suggested that adjustment of dosage regimen of EM and CM is required in pathophysiological conditions, but that of LM is not required.

Plasma concentrations of an angiotensin-converting enzyme inhibitor, benazepril, and its active metabolite, benazeprilat, after repeated administrations of benazepril in dogs with experimental kidney impairment.

In order to examine the safety of an angiotensin-converting enzyme (ACE) inhibitor in dogs with impaired renal excretion route, benazepril was administered orally, and plasma concentrations of benazeprilat, the active metabolite of benazepril, were determined in dogs with renal mass reduction (1/4th kidney) created by right-side nephrectomy and ligation of branches of the left renal arteries. Five dogs were administered benazepril orally at a given dose (0.5 mg/kg body weight) and 4 other dogs received 20 times that dose (10 mg/kg body weight) once daily for 15 consecutive days before (intact kidney period) and after (1/4th kidney period) creation of kidney impairment. Six control dogs received surgical treatment, but no drug. After creating a 1/4th kidney, plasma urea nitrogen and creatinine concentrations increased to approximately 30 mg/dl and 2.0 mg/dl, respectively, and renal plasma flow and glomerular filtration rate decreased to 37% and 30% of pre-treatment values, respectively. However, these parameters did not change significantly during the 1/4th kidney period both in the 0.5 mg/kg and 10 mg/kg groups. In the 0.5 mg/kg group, plasma benazeprilat concentrations increased to approximately 20 ng/ml to 340 ng/ml 2 hr after each administration, and there were no significant differences between the plasma benazeprilat concentrations during the intact and 1/4th kidney periods. In the 10 mg/kg group, plasma benazeprilat concentrations varied in the individual dog, but did not increase with the days of administration, and were not significantly different on each administration day between the intact and 1/4th kidney periods in either dose group. The AUCs(0-24) of plasma benazeprilat concentrations determined on the 15th administration day were not different between the intact and 1/4th kidney periods in dogs of either dose group. Plasma ACE activities decreased after drug administration in dogs of both groups. Benazepril seemed to have a high safety, and the adjustment of dosage regimen might not be needed in dogs with mild to moderate renal function impairment because the drug was excreted both from the kidneys and liver.

Oral Delivery of HIV-Protease Inhibitors

Strategies for optimizing the oral delivery of HIV-protease inhibitors draw from drug discovery efforts in molecular design, drug development tools in dosage formulation, and dosage regimen considerations in clinical medicine. This review outlines the evolution of these strategies for drugs that have been approved for human use, drug candidates still in development, and molecules that are no longer in development but from which valuable delivery information was obtained. Molecular design for obtaining desirable pharmacokinetics following oral administration primarily involved maximizing aqueous solubility and minimizing first-pass metabolism. Optimization of molecular design for oral drug delivery purposes is tempered by additional considerations for drug potency, toxicity, potential for interactions, and development of viral resistance. Strategies for improving oral bioavailability through dosage formulation use information from the effects of coadministered meals on drug plasma levels. Patient adherence to dosage regimens remains a major issue in assuring effective oral drug treatment and in preventing the development of resistance. Progress has been made in clinical studies where improved oral bioavailability and reductions in drug plasma level variability have been achieved with appropriate dosage regimen adjustment.

Population pharmacokinetics of gentamicin in patients with cancer.

The purpose of this study was to describe the population pharmacokinetics of gentamicin in patients with cancer, to identify possible relationships between clinical covariates and population pharmacokinetic parameter estimates and to examine the relevance of existing dosage nomograms in light of the population model developed in these patients. Data were collected prospectively from 210 patients with cancer and were analysed with package NONMEM. Data were split into two sets: a population data set and an evaluation set. Creatinine clearance was estimated using measured creatinine concentrations and using 'low' creatinines set to a minimum of 60 micromol l(-1), 70 micromol l(-1) or 88.4 micromol l(-1) A two compartment model was fitted to the concentration-time curve. Two best models were obtained, one that related clearance to estimated creatinine clearance (minimum creatinine value 60 micromol l(-1)) and the other that related clearance to age, creatinine concentration and body surface area. Volume of the central compartment was influenced by body surface area and albumin concentration. For both models 90% of measured concentrations lay within the 95% confidence interval of the simulated concentrations and the mean prediction errors were -7.2% and -6.6%, respectively. A final analysis performed in all patients identified the following relationship CL (1 h(-1))=0.88 x (1 + 0.043 x creatinine clearance) and central volume of distribution V1 (1)=8.59 x body surface area x (albumin/34)(-0.39). The mean population estimate of intercompartmental clearance (Q) was 1.301 h(-1) and peripheral volume of distribution (V2) was 9.801. Coefficient of variation was 18.5% on clearance and 28.2% on Q. Residual error expressed as a standard deviation was 0.36 mg l(-1) at 1.0 mg l(-1) and 1.32 mg l(-1) at 8.0 mg l(-1). The mean population estimate of clearance was 4.21 h(-1) and volume of distribution (Vss) was 24.61 (0.381 kg(-1)). The mean population estimates of half-lives were 1.8 h and 8.0 h. In the context of published nomograms this analysis indicated that both the traditional approach and the new, 'once daily' approach should achieve satisfactory concentrations in cancer patients although serum concentration monitoring is required to confirm optimal dosing in individual patients.

Behavioural toxicity of medicinal drugs. Practical consequences, incidence, management and avoidance.

Behavioural toxicity is relatively common among medicinal drug users and evidence shows that drugs frequently produce adverse effects that prevent their users from performing everyday operations in a normal manner. Epidemiological research generally indicates that the use of sedative drugs is associated with an increased risk of becoming involved in injurious accidents. Empirical studies have also demonstrated adverse effects of sedative drugs on the performance of healthy volunteers and patients in laboratory tests designed to measure psychomotor and cognitive function, and in real life-tests measuring on-the-road driving performance. Empirical studies also indicate that behavioural toxicity can vary widely between individual drugs depending on differences in dose, dosing regimen, duration of treatment, pharmacokinetics or mechanisms of actions. Besides sedation, other CNS adverse effects such as aggression, paranoia, social withdrawal or lack of motivation may disrupt or prevent the initiation of normal performance, thus imposing a burden on the ability of the patients to function in a normal manner. Emotional disturbances are rare as indicated by the small number of case reports that mention their existence. Yet theses disturbances sometimes involve severe reactions that are more debilitating than sedation. Behavioural toxicity can be minimised by avoidance of pharmacodynamic and pharmacokinetic drug interactions, adjustment of dosage regimens to a patient's individual response to a drug, nocturnal administration of drugs that are expected to produce sedation and patient education on the potential risks of the drugs they receive. Much of this information can be gained from experimental literature comparing the effect of individual drugs on performance. Unfortunately this is presently incomplete, since most research on behavioural toxicity has been confined to psychiatric drugs. Yet, in the interest of the patient, it should be the responsibility of drug manufacturers and regulators to always identify problematic drugs.

Pharmacokinetics of Newer Drugs in Patients with Renal Impairment (Part II)

Cardiovascular diseases occur frequently in patients with renal failure. Any pharmacokinetic impairment in these diseases should be considered when individualizing drug therapy. The pharmacokinetics of new cardiovascular drugs in uraemic patients are reviewed: alpha- and beta-blocking agents, ACE inhibitors, centrally acting antihypertensive agents, calcium antagonists, antiarrhythmic agents and inotropic agents. Guidelines are proposed for adjustment of dosage regimens as a function of renal impairment. Renal or extrarenal elimination of drugs and their metabolites, and the activity of the latter, are taken into account. The disposition of new drugs such as flestolol, alacepril, delapril, propafenone, milrinone or enoximone, is not well documented in patients with renal failure. Further characterizations of the elimination of these compounds are needed and the potential therapeutic or toxic effects of the metabolites require evaluation to determine whether the dosage needs to be adjusted. Until such investigations are performed, those drugs should not be used in uraemic patients; if no therapeutic alternative is available, clinical controls are necessary at regular intervals. Relationships between pharmacological or therapeutic effects and drug plasma concentrations should be evaluated for such long term use drugs. The knowledge of a plasma concentration therapeutic window is important to provide information which will be useful in determining appropriate drug dosage in renal failure.