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P Veng-Pedersen

Publications and source records attributed to P Veng-Pedersen.

At least 91 records · Page 5Linked to original sources
PubMed1986

A note on appropriate constraints on the initial input response when applying deconvolution.

When deconvolution is employed to estimate cumulative input profiles, nonzero initial values may result unless certain constraints are imposed on the function used to approximate the input response c(t). It is shown that the initial value of the response to a nonimpulse input is zero, i.e., c(t0) = 0, where t0 is the input lag time. If, in addition, the initial value of the impulse response is zero, i.e., c delta (0) = 0, then c'(t0) = 0. Therefore, it is appropriate to impose the constraint c(t0) = 0 in general and c'(t0) = 0 when c delta (0) = 0 if c(t) is the response to a nonimpulse input. The use of such constraints is demonstrated in an example where the cumulative in vivo dissolution profile is estimated by deconvolution.

Animals↗
PubMed1986

Linear systems approach to the analysis of an induced drug removal process. Phenobarbital removal by oral activated charcoal.

The theory of linear systems analysis is applied to the evaluation of induced drug removal processes. The rate and extent of removal are determined by deconvolution for the case of phenobarbital removal from the systemic circulation by orally administered activated charcoal. The proposed method is model independent in the sense that no specific models of intrinsic or induced pharmacokinetic processes are required, and it is readily adapted to the analysis of most types of induced removal processes (hemodialysis, peritoneal dialysis, etc.). Application of the approach indicates that phenobarbital was removed from the systemic circulation to an extent of 25-53% following multiple oral doses of activated charcoal in healthy human subjects.

Charcoal↗
PubMed1985

Novel method of calculating absolute bioavailability in nonlinear pharmacokinetics.

Current methods of evaluating the bioavailability of drugs with nonlinear disposition kinetics are based on specific pharmacokinetic models in contrast to the more rational model independent (structureless) area under the curve (AUC) and deconvolution methods used in linear pharmacokinetics. A novel method of evaluating bioavailability is presented which applies to any nonlinear type of drug elimination, but is limited to drugs with a distribution phase which is short relative to the elimination phase. The method applies to drugs with autonomic disposition characterized by a rate of decline in the systemic drug level in the absence of drug input which depends only on the drug level, i.e., dC/dt = -q(C), where q can be any function dependent only on C and constant kinetic parameters. It is shown that the disposition function q(C) can be evaluated in an empirical fashion from elimination-phase data and that this function can be used to calculate the absolute bioavailability of autonomic, nonlinear drugs. Some preliminary results are presented to demonstrate the procedures involved in applying the method.

Biological Availability↗
PubMed1985

Deconvolution applied to the kinetics of extracorporal drug removal. Haemodialysis of cefsulodin.

A novel approach to the evaluation of the kinetics of drug removal by an extracorporal device (ECD), e.g., haemodialysis, haemofiltration, and haemoperfusion, is presented. The rate and extent of extracorporal drug removal (ECR) are determined by deconvolution. The proposed method is model independent in the sense that no specific models of corporal or extracorporal disposition are required. The estimation of various derived functions and parameters useful for describing ECR such as clearance and fractional drug removal are facilitated by the technique. The kinetics of cefsulodin elimination by haemodialysis in 3 patients were evaluated using the deconvolution approach. The results indicated that cefsulodin was dialyzable with approximately 50% of the drug in the body removed by haemodialysis over 3-4 h.

Cefsulodin↗
PubMed1985

The determination of mean residence time using statistical moments: it is correct.

The present communication seeks to end a controversy created by a recent publication regarding the applicability of statistical moment principles for determination of mean residence time of drug in the body tb. It is shown that the equation tb = AUMC/AUC is correct when applied to pharmacokinetic systems in which the total drug elimination rate is directly proportional to the drug concentration in the systemic circulation, i.e., first-order central elimination. More general equations for tb in terms of elimination rate, amount eliminated, and amount in the body are presented along with demonstrations of their utility.

Body Burden↗
PubMed1985

Theorems and implications of a model-independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. II. Clearance concepts applied to the evaluation of distribution kinetics.

The disposition decomposition approach is employed to derive clearance parameters descriptive of drug distribution kinetics. The name distribution clearance, CLd, is given to a characteristic constant of linear and some nonlinear pharmacokinetic systems. CLd is the clearance associated with the steady-state rate of drug transfer from the peripheral tissues to the systemic circulation. Also introduced is the elimination clearance, CLe, which is associated with the total drug transfer rate from the systemic circulation in linear systems. Estimates of CLd and CLe are presented for several drugs.

Animals↗
PubMed1985

A polyexponential deconvolution method. Evaluation of the "gastrointestinal bioavailability" and mean in vivo dissolution time of some ibuprofen dosage forms.

A new deconvolution algorithm (DCON) suitable for pharmacokinetic applications is presented. It requires that both the impulse and input responses, typically systemic drug levels, be well described by polyexponential equations. DCON has a wider range of applications than an earlier method (DECONV) from which it is derived. A FORTRAN program is provided, making implementation of the technique a simple matter. DCON is demonstrated to evaluate the "GI bioavailability," defined as the rate and the extent of gastrointestinal drug release, of various ibuprofen dosage forms. The GI drug release kinetics exemplifies a pharmacokinetic system which cannot be evaluated using the previous deconvolution algorithm (DECONV) because of an initial zero drug level response. This limitation is not found in DCON. It is also demonstrated how the mean in vivo dissolution time MDT can be evaluated by deconvolution.

Biological Availability↗
PubMed1984

Model-independent steady-state plasma level predictions in autonomic nonlinear pharmacokinetics I: Derivation and theoretical analysis.

Current drug level predictions in nonlinear pharmacokinetics are based on specific pharmacokinetic models in contrast to the model-independent (structureless), dose-linearity, and superposition principles used in linear pharmacokinetics. Such model-dependent methods may not provide reliable predictions due to their inherent nonuniqueness, computational complexity, and often unrealistic kinetic assumptions. Some novel model-independent methods for predicting the steady-state drug levels of extravascular, intravenous bolus, and intravenous infusion administrations are presented that should overcome such disadvantages. The methods only assume an autonomic nonlinear kinetic behavior, which implies that following an intravenous bolus administration the derivatives of the drug concentration-time profile at arbitrary drug levels are independent of the dose given. Such a kinetic behavior is found for any nonlinear pharmacokinetic system when the rate of change of the drug level following an intravenous bolus administrations depends only on the drug level, i.e., dC/dt = -q(C), where q can be any function dependent only on C and time-invariant kinetic parameters. The basic approach presented represents a novel alternative which avoids the very difficult and often impractical task of identifying and incorporating the numerous kinetic parameters and processes responsible for the observed drug concentration data into a useful pharmacokinetic model. The focus in the kinetic analysis is instead on two much simpler processes: (a) fitting empirical functions to estimate the mean drug disposition behavior of the subject or population and (b) testing the validity of the assumptions involved.

Infusions, Parenteral↗
PubMed1984

Pulmonary absorption and excretion of compounds in the gas phase: theoretical pharmacokinetic and toxicokinetic analysis.

Kinetic equations were derived that describe the plasma concentration of an inhaled compound during and following single or repeated regular and irregular pulmonary exposures. The equations are based on a diffusional type of input function and assume a linear disposition with a biexponential unit-impulse response. The use of linear system analysis avoids the complexity of modeling the disposition processes; yet, the effect of these processes is still accounted for mathematically. The approach, therefore, appears to be more general and rational than approaches based on linear compartmental modeling. The ways in which the kinetic equations can be readily applied in pharmacokinetic or toxicokinetic analyses to obtain valuable parameters that enable kinetic predictions of the cumulation during prolonged exposure are discussed. The toxicokinetic problem of comparing the effect of different work schedules in occupational environments with air contaminants is discussed. Formulas derived from considerations of the blood plasma kinetics are presented for the calculation of an adjustment factor for the adjustment of the contaminant threshold limit value for abnormal work weeks. The use of these formulas appears to be more rational than that of similar formulas that have been proposed.

Absorption↗
PubMed1984

Theorems and implications of a model independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. I. Derivations and theoretical analysis.

The approach presented enables a model independent representation of the pharmacokinetics of drugs with a liner disposition and some drugs with a nonlinear disposition. The approach is based on a decomposition of the drug disposition into an elimination function q(c) and a distribution function h(t). The q function represents the net effect of all disposition processes which work toward a reduction in the systemic drug level. The h function represents the net effect of all disposition processes which slow down the rate of decline of the systemic drug level by returning drug from the peripheral environment to the systemic circulation. Several theorems relating q and h to the drug disposition are presented which uniquely define these functions mathematically. The disposition decomposition is of particular significance in three main areas of pharmacokinetics: (1) evaluation of drug absorption, (2) drug level predictions including steady state predictions, (3) and elucidation of drug disposition kinetics. The practical significance of the decomposition method in these three areas is discussed, and various procedures for the application of the method are proposed. The decomposition method represents a model independent alternative to pharmacokinetic models such as linear compartmental models, the recirculation model, and some physiologic models. This also includes nonlinear forms of such models, as long as the nonlinearity is due to a central nonlinear elimination. The greatest promise and significance of the disposition decomposition approach appears to be its application to nonlinear pharmacokinetics. In contrast to linear pharmacokinetics the kinetic analysis in such cases has been limited to model dependent methods employing specific pharmacokinetic models, due to the lack of model independent alternatives. The novel development presented offers such alternatives. For some applications these alternatives appear more rational in the sense that the analysis becomes more general and objective and may be based on fewer assumptions.

Intestinal Absorption↗
PubMed1983

Theophylline blood-brain barrier transfer kinetics in dogs.

A simple diffusion-based pharmacokinetic model is proposed relating blood-brain barrier transfer kinetics of theophylline to the difference in the free concentrations of the drug in serum and cerebrospinal fluid (CSF). The model predicts that the CSF drug level is proportional to the serum drug level convoluted by exp(-kt), where k is the blood-brain barrier diffusion rate constant. An excellent agreement was found by nonlinear regression analysis between serum and CSF theophylline data in eight dogs and the proposed model for the blood-brain barrier transfer kinetics of theophylline. The ratio of the free fractions of theophylline in serum and CSF predicted from the model also agrees with the value determined experimentally.

Animals↗
PubMed1983

Diffusion and flow transfer of theophylline across the blood-brain barrier: pharmacokinetic analysis.

Two possible schemes describing the transfer of theophylline across the blood-brain barrier are investigated. The first, the "diffusion only model," assumes that the rate of transfer is proportional to the difference in free drug concentration in the serum and cerebrospinal fluid. The second, the "diffusion and flow model," has the added feature that drug may be transferred from the CSF to the blood by the continuous secretion of CSF into the blood. Comparison of the results of nonlinear regression for the two proposed schemes indicated that the "diffusion and flow" model best describes the transfer process. The analysis indicates that the parameters obtained for the "diffusion and flow" model are physiologically meaningful.

Animals↗
PubMed1982

Theophylline elimination in the pregnant and fetal rabbit.

Aminophylline and theophylline are commonly used to treat asthma. We studied theophylline pharmacokinetics in the pregnant and nonpregnant rabbit as well as in the intrauterine and extrauterine fetus. The t1/2 was increased (p less than 0.05) and the clearance was decreased (p less than 0.05) in the pregnant compared to the nonpregnant rabbit. The t1/2 of theophylline in the newborn rabbit was 43.5 +/- 12.0 hr, approximately 15 times longer than in the nonpregnant rabbit. Twenty-four hours after a 20 min maternal aminophylline infusion, both the intrauterine fetus and maternal serum theophylline concentrations were very similar. The transplacental transfer from the maternal to fetal circulation occurred in less than 1 hr. The maternal to fetal serum ratios for theophylline were similar after a 5-day maternal aminophylline infusion (ratio 1.22 +/- 0.20) or after a 20 min infusion (ratio 1.24 +/- 0.20). Our findings indicate that the newborn rabbit eliminates theophylline very slowly, and maternal aminophylline or theophylline therapy that would result in high peak serum concentrations in the fetus, particularly just before birth, should be avoided.

Aminophylline↗