Drug Dosing Regimens Research Articles

Anticancer drug pharmacodynamics.

A considerable amount of information is available on the pharmacokinetics of anticancer drugs, but much less is known of their pharmacodynamics, that is of the relationship between therapeutic or toxic response and drug concentration. Drug dosage regimens which are to achieve defined therapeutic objectives can only be designed when both the pharmacokinetic and the pharmacodynamic characteristics of a drug are known. There are a few reports in the literature of relationships in man between toxic response and pharmacokinetic parameters of anticancer drugs, and an even smaller number of reports of relationships between therapeutic response and pharmacokinetic parameters. It is suggested that the lack of pharmacodynamic information is currently limiting the application of pharmacokinetic information to cancer therapy. Ways of improving knowledge of the pharmacodynamics of anticancer drugs are suggested.

Practical problems of therapeutic drug monitoring of anticonvulsants

Therapeutic drug monitoring (TDM) of anticonvulsants can be used to improve seizure control while minimizing toxicity. In order to maximize the efficacy of anticonvulsant TDM the clinician must evaluate all of the variables which influence the interpretation of a given level. Variables include sample collection and storage, drug analysis, dosage regimens and preparations, drug pharmacokinetics and pharmacodynamics as well as medical diagnoses and family dynamics. The theoretical basis of TDM is well established. However, many practical aspects of TDM limit its usefulness. The practical aspects of TDM which may be overlooked when applying the theoretical basis of TDM to the clinical situation are reviewed. Therapeutic drug monitoring (TDM) of anticonvulsants can be used to improve seizure control while minimizing toxicity. In order to maximize the efficacy of anticonvulsant TDM the clinician must evaluate all of the variables which influence the interpretation of a given level. Variables include sample collection and storage, drug analysis, dosage regimens and preparations, drug pharmacokinetics and pharmacodynamics as well as medical diagnoses and family dynamics. The theoretical basis of TDM is well established. However, many practical aspects of TDM limit its usefulness. The practical aspects of TDM which may be overlooked when applying the theoretical basis of TDM to the clinical situation are reviewed.

Drug therapy in patients undergoing peritoneal dialysis. Clinical pharmacokinetic considerations.

Peritoneal dialysis has become an accepted treatment modality for end-stage renal disease. The introduction of continuous ambulatory peritoneal dialysis (CAPD) has further popularised this technique. The need for adjustment of drug dosage in patients with endstage renal disease and the need for supplemental dosages following haemodialysis are well recognised. Little documentation exists concerning the need for supplemental drug dosage in patients on peritoneal dialysis. Knowledge of the influence of peritoneal dialysis on the elimination of specific drugs is essential to the rational design of dosage regimens in patients undergoing this dialysis technique. This review addresses the clinical pharmacokinetic aspects of drug therapy in patients undergoing peritoneal dialysis and considers: the efficiency of the peritoneal membrane as a dialysing membrane; the effects of peritoneal dialysis on the pharmacokinetics of drugs; the pharmacokinetic models and estimation methods for peritoneal dialysis clearance and the effects of peritoneal dialysis on drug elimination; the influence of the pharmacokinetic parameters of drugs on drug dialysability; and the application of pharmacokinetic principles to the adjustment of drug dosage regimens in peritoneal dialysis patients. Data on drugs which have been studied in peritoneal dialysis are tabulated with inclusion of pharmacokinetic and dialysability information.

A calculator program for clinical application of the Bayesian method of predicting plasma drug levels

A pharmacokinetic program that allows individualization of drug dosage regimens through the Bayesian method is described. The program, which is designed for the Hewlett-Packard HP-41 CV calculator, is based upon the one-compartment open model with either instantaneous or zero-order absorption. Individualized estimation of the patient's kinetic parameters (clearance and volume of distribution) is performed by analyzing the plasma levels measured in the patient as well as considering the population data of the drug. After estimating the individual kinetic parameters by the Bayesian method, the program predicts the dosage regimen that will elicit the desired peak and trough plasma levels at steady state. For comparison purposes, the least-squares estimates for clearance and volume of distribution are calculated, and dosage prediction can also be made on the basis of the least-squares estimates. The least-squares estimates can be used to calculate population pharmacokinetic parameters according to the Standard Two-Stage method. Several examples of clinical use of the program are presented. The examples refer to patients with classic hemophilia who were treated with Factor VIII concentrates. In these patients, the Bayesian kinetic parameters of Factor VIII have been estimated through the calculator program. The Bayesian parameter estimates generated by the HP-41 have been compared with those determined by a Bayesian program (ADVISE) designed for microcomputers.

A pocket calculator program for pharmacokinetic dosing of drugs exhibiting single compartment first-order elimination and zero-order or first-order absorption

A pocket computer program has been designed to assist clinicians in the appropriate administration of most drugs exhibiting single compartment first-order elimination and either zero-order (intravenous infusions) or first-order (intramuscular and oral) absorption. The program utilizes well-established pharmacokinetic parameters to calculate an optimal drug dose and dosing interval based upon a patient's demographic characteristics and the drug half-life, volume of distribution, and absorption rate constant or infusion time. It also allows the user to estimate peak and trough drug serum concentrations. When measured serum concentrations are available during steady state, it is possible to determine individual patient drug half-life and volume of distribution for more accurate adjustments in dose and/or dosing interval. Usage of this program should enable clinicians to better select effective but safe drug dosing regimens based on individual patient needs and characteristics.

Serum level monitoring of antibacterial drugs. A review.

Serum concentration measurements of antibacterial agents are increasingly used to optimise drug dosage regimens. However, this approach is only justified for drugs with a low therapeutic index and poor predictability of serum concentrations, such as the aminoglycosides, chloramphenicol and vancomycin, whereas the penicillins and cephalosporins can safely be applied well above their minimum inhibitory concentrations. Wide interpatient variation in distribution and elimination are the main reasons for the unpredictability of aminoglycoside serum concentrations. It has been shown that in patients with normal creatinine clearance, the apparent elimination half-life of gentamicin varies from 0.4 to 7.6 hours. The pharmacokinetics of the aminoglycosides are most adequately described by a 3-compartment open model where the slow terminal half-life reflects elimination from the deep tissue compartment. The accumulation of the aminoglycosides in this compartment, which includes the kidneys and inner ear, is probably an important factor in their potential toxicity in these organs. Careful serum level monitoring may reduce, but cannot totally avoid, the risk of side effects. However, maintenance of effective drug levels appears to be at least an equally important goal of aminoglycoside serum level monitoring. Chloramphenicol is also a potentially toxic antibacterial agent. Its therapeutic range is usually considered to be 15 to 25 mg/L. The most important side effects are the 'grey baby syndrome' and bone marrow toxicity. Chloramphenicol is metabolised to several microbiologically inactive products. It also shows wide interpatient variability of its pharmacokinetics, especially in young children, and serum levels should therefore be followed in these patients. Vancomycin, a highly effective agent for staphylococcal and enterococcal infections, may also exhibit nephrotoxic and ototoxic side effects. A well-defined therapeutic range has not yet been established but in view of its minimum inhibitory concentrations it seems reasonable to maintain vancomycin serum concentrations between 15 and 50 mg/L. Since this drug is excreted unchanged in the urine, serum levels should particularly be monitored in patients with impaired renal function. The advances in routine therapeutic drug monitoring are directly related to rapid developments in technologies associated with the quantification of these agents. Microbiological plate diffusion assays are now often replaced by more specific immunoassays (radioimmunoassay, enzyme immunoassay, and fluorescence immunoassay) and chromatographic techniques.

Plasmodium berghei: Diet and drug dosage regimens influencing selection of drug-resistant parasites in mice

Two different diets for the host and three drug dosage regimens were used to select lines resistant to sulfadoxine and pyrimethamine from the parent strain of the rodent malaria parasite Plasmodium berghei [the N (K173) strain]. A higher yield of resistance was obtained when a high parasitemia was present at the beginning of the drug pressure schedule. The development of resistance to the association of sulfadoxine plus pyrimethamine was accelerated by a relatively high para-aminobenzoic acid (PABA) content diet. Reproducibility was satisfactory when one of the dosage regimens was applied independently by two different technicians at different times.

Some consequences of drug choice and dosage regimen for patients with impaired kidney function.

The object of this article is to discuss difficulties in extrapolating the performances of a drug for which the kinetic parameters are derived in healthy volunteers, to patients with severely impaired kidney function. The theoretical background of some actual or probable background is given, and a possible solution for these problems is offered, that is, choosing another drug from the same drug group. In patients without kidney function, metabolism is the only pathway of elimination. When the elimination of the metabolite formed occurs by means of renal excretion only, this metabolite accumulates in patients with impaired or absent kidney function. When a metabolic pathway of the parent drug is part of a metabolic equilibrium, the metabolic return reaction results in an "apparent parent compound," with a half-life identical to that of the accumulated metabolite. In this way, the concentration of the "apparent" parent compound increases and the half-life of the sum of parent and "apparent" parent drug will change. Examples of this drug behavior are given for sulfamethoxazole, sulfametrole, sulfamethizole, procainamide, and N4-acetylprocainamide.

Estimating Ideal body Mass in children

An equation and nomogram to estimate ideal body mass (IBM) for establishing dosage regimens of certain drugs in children was derived from a large pediatric data base. The data were from more than 20,000 U.S. children (ages 1-17 years) included in two major surveys published by the National Center for Health Statistics. The IBM was defined as the 50th percentile weight for a given height (ht). The equation derived was IBM(kg) = 2.396e0.01863(ht), where height is in cm. The IBMs estimated from this equation were compared with estimates from three other methods, two of which were derived from an adult population. The adult methods were unsuitable for pediatric use. This equation and nomogram for estimating IBM in children should be useful in determining dosage regimens of aminoglycosides and other drugs for obese pediatric patients.

Modern drug analysis in biological fluids suitable for clinical pharmacokinetics

Therapeutic drug monitoring can provide valuable information to guide clinicians in achieving optimal treatment with selected therapeutic agents. Large intersubject variations in drug response are common. There are many factors that may cause variability in drug disposition and drug plasma levels using standard dosage regimens: (1) Biometric factors: age, height, weight; (2) Absorption and patient compliance; (3) Distribution, cardiac failure; (4) Elimination: hepatic and/or renal failure; (5) Individual capacity in metabolizing drugs; (6) Drug-drug interactions. All these factors demand dosage adjustments for the individual patient and contribute to the observation that the correlation between drug plasma level and response is much better than that between the total dose and response among a given patient population. Pharmacokinetic-pharmacodynamic studies yield information on the therapeutic plasma concentration range of a drug that should be maintained during therapy to achieve maximum benefits. This leads to the concept of the ‘target level’ of a particular drug in plasma, which is important for the application of clinical pharmacokinetics in drug therapy. There are two ways by which ‘target levels’ can be utilized to optimize the individual drug dosage regimen: first, calculation of the dose based on predictive pharmacokinetic models for the individual patient; and second, inclusion of drug level monitoring to correct the predictive model for unaccountable intersubject variation. Predictive pharmacokinetic models are particularly useful for drugs that are mainly eliminated by renal excretion, since good correlations between clinical kidney function tests and drug clearance have been established. Thus dosage adjustments, based on individual kidney functions, are an integral part of modern drug therapy with drugs like

Formal theory of discrete drug dosing regimen adjustments.

A formal theory of discrete drug dosing regimen adjustments has been developed, based on the recognition that in practical drug administration the possibilities for partition of a drug formulation are limited, and that only definite dosing intervals are acceptable in clinical practice. Normalization of the treatment regimen variables was used to reduce the innumerable cases of dosing regimens subject to adjustment to a limited number of categories. By replacing the dosing interval by the corresponding daily dosing frequency it was possible to associate with each treatment regimen a characteristic variable — the daily dose. The definition of the minimal normalized maintenance dose and the minimal normalized dosing frequency then permitted establishment for each case of a complete set of normalized dosing regimen adjustments, which consisted of all acceptable adjustments of both the variables of the regimen. This could be subdivided into several equivalency classes according to the value of the associated daily dose. The adjustment procedure of a dosing regimen can be regarded in general as a two stage process. In the first stage the normalized daily dose is selected according to the relative reduction in the total body clearance of the drug. This is followed, if necessary, by choice of which ever of the equivalent dosing regimens is more appropriate in the given situation. The theory also allows simultaneous change in both dosing regimen variables, thus enhancing the limited possibilities for adjustment. Its practical employment can be facilitated by use of a series of decision tables, although the formal character of the theory permits its implementation on mini- or desk-top computers.

Estimating Steady State Desipramine Levels in Noninstitutionalized Elderly Patients Using Single Dose Disposition Parameters

Clearances calculated from single oral dose data have been utilized to predict steady state levels of desipramine in 12 noninstitutionalized depressed elderly patients. Observed steady state plasma levels correlated very well (r = 0.967, p less than 0.0005) with those predicted from single dose clearances, but not with plasma levels obtained 20 hours after a single oral dose (r = 0.24, p greater than 0.2). The mean half-life of desipramine (20.9 hours) in this group of elderly (mean age, 72 years) was considerably less than values of "apparent disappearance" half-life previously reported for elderly patients receiving imipramine. The single dose clearance technique yielded a precise criterion for quantitating early compliance with and adjusting drug dosing regimens.

Integrated calculator programs for pharmacokinetic calculations

A package of integrated programs for calculating pharmacokinetic variables and drug-dosing regimens using a hand-held programmable calculator is described. Twelve pharmacokinetic programs, which were based on previously published pharmacokinetic equations, were developed for use in a HP-41C hand-held calculator (Hewlett-Packard). The programs perform, pharmacokinetic calculations for many drugs, including digoxin, theophylline, phenytoin, nd the aminoglycosides. Also programs for ideal body weight, body surface area, and creatinine clearance calculations are included. Eleven of the 12 programs can be stored in the calculator at any time. Values generated in one program are stored in memory registers and can be recalled directly for use in other programs. The calculator has a continuous memory; therefore, all stored data, programs, and functions are maintained when the calculator is turned off. The integrated calculator programs provide a quick and reliable means of applying pharmacokinetic principles to everyday hospital pharmacy practice.

Prediction of steady-state plasma concentrations and individual dosage regimens of tricyclic antidepressants from a single test dose.

Inappropriate plasma drug concentrations may be one major reason why many patients fail to show a satisfactory clinical response or experience side-effects to treatment with tricyclic antidepressants. One way of improving the situation is to try to reduce the variability in plasma concentrations by individualising drug dosage regimens as early as possible in treatment. This could be done if it were possible to predict the steady-state plasma concentrations that would be achieved by patients on any given dosage regimen. Our own studies, as well as those of other groups, have demonstrated that it is possible to make such predictions from simple measurements of drug plasma concentrations after administration of a single test dose of antidepressant. The test is best carried out in addition to therapeutic monitoring and is a simple means of selecting the optimum starting dose. The clinical advantages of a simple tolerance test are (1) ensuring that an appropriate dosage is prescribed, (2) reducing the number of dosage alterations, (3) reducing the risk of toxicity, and (4) checking patient compliance when used in combination with routine therapeutic monitoring.

The method of separate exponentials: a simple aid to devising intravenous drug-loading regimens.

Stimulation of complex dosage regimens for drugs with multicompartmental kinetics is described using the method of separate exponentials. This approach requires that alpha- and beta-phases are treated separately throughout and summed only at the end of the stimulation. The method was used to devise a loading regimen for pirmenol, comprising a priming injection, and a rapid loading infusion, followed by a maintenance infusion. The regimen was tested in a patient with excellent agreement. The method of separate exponentials is mathematically simple and of informational value in that it demonstrates when the early distribution phase is important. Its use can avoid the potentially dangerous assumption of one-compartmental kinetics in the design of intravenous loading regimens.

Collaborative clinical pharmacokinetic services

A program for routine pharmacokinetic interpretation of serum analyses of gentamicin, tobramycin, amikacin, phenytoin, phenobarbital, theophylline, lidocaine, digoxin, quinidine, and procainamide at the Medical University of South Carolina Hospital is described. Results of all analyses of serum for the drugs listed are evaluated by a pharmacist trained in clinical pharmacokinetics. Patient variables relevant to the determination of drug serum concentrations, drug elimination, distribution, and dosage are given appropriate consideration in each evaluation. A summary of the pharmacokinetic interpretation and any necessary modification of drug dosage regimens are then written into the progress notes of the patients' medical records. Approximately 12 patients and 20 drug concentrations are evaluated each day. The average charge for te service is +35. This service, which is reimbursed by third-party carriers, has resulted in improved use of laboratory personnel, equipment, and time and has provided a framework for education and research as well as a mechanism for direct contributions to patient care by the pharmacist.

Automated pharmaceutical assistance systems. I. Clinical pharmacokinetics. II. Drug interference with laboratory tests results.

The function of the clinical pharmacokinetic service (CPS) in University Hospital is described. A methodological procedure was developed for routine interpretation of specified drug serum levels. Work lists that identify analytical procedures to be included for clinical pharmacokinetic evaluation are prepared daily. The results of all analyses of serum drug levels are evaluated by a pharmacist who is trained in clinical pharmacokinetics. Patient variables that influence serum levels of drugs are mathematically manipulated by program logic. Projections of expected drug levels as a result of dosing regimens are made and compared to measured laboratory results. Iterative programming that modifies projections on the basis of actual measurements is employed to determine individual drug dosing regimens that provide therapeutic/nontoxic serum levels of drugs. The drug/test interference system, which accesses the CPS data base, provides information concerning the potential physiologic, therapeutic, or toxic effect of drugs on biochemical substances. The system allows display of data concerning each drug before it is administered. Information concerning the date and time of initiation and termination of drug therapy allows for a warning comment to be attached automatically to the appropriate laboratory test result if interference is indicated.

Computer-assisted Customized Antimicrobial Dosages

The use of a computer-based consultation program to customize dosage regimens of antimicrobials for patients with meningitis or bacteremia is described. Using clinical and laboratory information entered by the user, the program determines causative organisms, recommends therapeutic regimens, and generates a graph depicting the expected blood level of each drug as a function of time. During therapy selection, the program considers the site of infection, the susceptibility of the organism to antibiotics, and the patient's clinical status and drug history. Individualized pharmacokinetic values allow for dosage adjustments in renal failure and estimation of blood levels. If renal impairment is present, dosage regimens for drugs excreted by the kidneys are adjusted to assure the desired steady-state blood levels. To help in selection of the optimal regimen, estimated blood levels for each regimen are graphed along with the minimum inhibitory concentration for the organism and the toxic level of the drug. A bulit-in knowledge base in conjunction with patient-specific information enables the computer program to determine appropriate treatment specific to a patient's age, renal function, and prior drug reactions.

Using Pharmacokinetics in Drug Therapy. VI: Comparing Methods for Dealing with Nonlinear Drugs Like Phenytoin

Four methods for estimating dosage regimens for drugs exhibiting non-linear pharmacokinetic behavior (e.g., phenytoin) are described and compared. Estimations of phenytoin Vmax (maximum rate of drug metabolism) and Km (dissociation constant of drug-enzyme complex), and resulting dosage estimates arrived at by four methods were compared with values in six cases. All four methods provided pharmacokinetic estimates that shorten the period of dose titration and improve estimates of phentoin levels. Given a minimum amount of dose-versus-plasma-level data, all four methods provided reliable and comparable estimates of dosage regimens, although one method based on a nomogram sometimes estimated a narrower range of dosage regimens and plasma levels. When there is a potential for inaccuracy in the plasma-level-data, however, the estimated dosage regimens may be too unreliable for practical application.

Factors affecting theophylline clearances: Age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol

Pharmacokinetic, pathophysiologic, and historic data were systematically collected while monitoring theophylline therapy in adult pulmonary patients and from special studies in pediatric patients, normal volunteers, and patients with other diseases. Total body clearances (ClT) were estimated by nonlinear computer analysis after infusion dosage or from area under the curve data following single oral or intravenous theophylline doses. The ClT values, primarily reflecting the theophylline biotransformation rate, averaged 58 (±30) ml/hr/kg and ranged from 4 to 143 ml/hr/kg. Factors examined for their effect on theophylline ClT included age; sex; liver disease; congestive heart failure; obesity; renal function; history of drug, tobacco, marijuana, caffeine, or alcohol use; and pregnancy. The NYBAID (automatic interaction detector) computer program for analysis of variance was employed to determine the order, priority, and combinations of independent variables correlating with ClT. The major factors that affected theophylline ClT in this population included age, liver disease, smoking status, and congestive heart failure. Age showed strong correlation (r = −0.49) with ClT. Much additional variability was accounted for in specific subgroups. For example, young adult (20-40 years) marijuana users exhibited highest ClT vales (83 ± 29 ml/hr/kg) while older patients (>40 years) with liver disease had the lowest metabolism rates (22 ± 10 ml/hr/kg). In particular subject types, sex (in teenagers), oral contraceptives (in smokers), obesity (in young nonsmokers), and barbiturates also affected theophylline disposition. In contrast, several common factors such as chronic theophylline, chronic corticosteroids, caffeine, sex (in adults), and pregnancy did not alter theophylline ClT.- This unique clinical pharmacokinetic monitoring and statistical approach to drug clearance characterization in patients permits identification of criteria in a format that may be useful for the prediction of drug disposition rates and dosage regimens.