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P Veng-Pedersen

Publications and source records attributed to P Veng-Pedersen.

At least 19 recordsLinked to original sources
PubMed1992

An algorithm for constrained deconvolution based on reparameterization.

The method of deconvolution is the most general method of evaluating drug absorption. Deconvolution does not normally subscribe to a particular structured model for the input function that would ensure non-negativity of the calculated input rate. Unfortunately, the increased flexibility gained by this "model independence" sometimes results in a calculated input rate that becomes negative in the late absorption phase. A method for constrained deconvolution is proposed to overcome this deficiency. The method is based on a reparameterization of the input function in a "model-free" context. The reparameterization schemes proposed are optimal in the sense that they give the input function its maximum flexibility possible while at the same time ensuring non-negativity. The method makes use of "deconvolution through convolution." The basic procedure of this technique is, during the curve fitting, to iteratively adjust the input function so that when it is convolved with the unit impulse response function it results in a curve that best fits the data from the extravascular administration. Cimetidine data from oral and iv administrations are deconvolved by the proposed method to demonstrate the basic procedures involved. The proposed method is easy to implement since it relies on simple curve-fitting procedures as routinely performed in pharmacokinetics. The procedure can be carried out using any of the many curve-fitting programs available that allow the user to supply the function to be fitted and allow simple bounds to be specified for the fitted parameters. The convolution required by the method can be done analytically using a previously published computer program.

Algorithms↗
PubMed1992

Pharmacodynamic system analysis of the biophase level predictor and the transduction function.

This work deals with the pharmacodynamic problem of relating a drug effect E(t) to an observable pharmacokinetic (PK) predictor variable r(t), which may be a venous and/or arterial drug level, some other PK variable, or a drug infusion scheme. It is proposed that the relationship between E(t) and r(t) may, in many cases, be appropriately modeled as E(t) = N(F(r(t))) [for practical analysis reasons, F(r(t)) is denoted the biophase level, cb(t), the operator F() is accordingly denoted the biophase level predictor (BLP), and N() is denoted the transduction function (TF)]. This work proposes a method for determining the two fundamental components, BLP and TF, that define the E(t)-r(t) relationship. The BLP is determined by a hysteresis minimization (HM) technique with the following features: (1) the method considers errors in both HM variables; (2) the method is suitable for dealing with the important case in which the predictor variable is a drug infusion scheme; (3) the approach is noncompartmental in contrast to the effect-compartment approaches and it does not require a specific structured modeling of the cb(t)-r(t) relationship when dealing with drugs with linear PKs in a general operational sense; and (4) the method makes use of a dimensionless transformation of the hysteresis variable that eliminates numerical scaling problems so that a complex penalty function optimization approach can be avoided. The TF is determined by a cross validation procedure in conjunction with the BLP determined by HM. The method is demonstrated using pharmacodynamic data for several drugs, considering both concentration-based and drug input-based r(t) values. The significance of the information obtained from the determined BLP and TF is discussed, including the concepts of equilibration dynamics and overloading. The limitations and potential problems of the methodology are discussed.

Alfentanil↗
PubMed1992

Neural networks in pharmacodynamic modeling. Is current modeling practice of complex kinetic systems at a dead end?

Neural networks (NN) are computational systems implemented in software or hardware that attempt to simulate the neurological processing abilities of biological systems, in particular the brain. Computational NN are classified as parallel distributed processing systems that for many tasks are recognized to have superior processing capability to the classical sequential Von Neuman computer model. NN are recognized mainly in terms of their adaptive learning and self-organization features and their nonlinear processing capability and are considered most suitable to deal with complex multivariate systems that are poorly understood and difficult to model by classical inductive, logically structured modeling techniques. A NN is applied to demonstrate one of the potentially many applications of NN for modeling complex kinetic systems. The NN was used to predict the effect of alfentanil on the heart rate resulting from a complex infusion scheme applied to six rabbits. Drug input-drug effect data resulting from a repeated, triple infusion rate scheme lasting from 30 to 180 min was used to train the NN to recognize and emulate the input-effect behavior of the system. With the NN memory fixed from the 30- to 180-min learning phase the NN was then tested for its ability to predict the effect resulting from a multiple infusion rate scheme applied in the subsequent 180 to 300 min of the experiment. The NN's ability to emulate the system (30-180 min) was excellent and its predictive extrapolation capability (180-300 min) was very good (mean relative prediction accuracy of 78%). The NN was best in predicting the higher intensity effect and was able to identify and predict an overshoot phenomenon likely caused by a withdrawal effect from acute tolerance. Current modeling philosophy and practice is discussed on the basis of the alternative offered by NN in the modeling of complex kinetic systems. In modeling such systems it is questioned whether traditional modeling practice that insists on structure relevance and conceptually pleasing structures has any practical advantages over the empirical NN approach that largely ignores structure relevance but concentrates on the emulation of the behavior of the kinetic system. The traditional searching for appropriate models of complex kinetic systems is a painstakingly slow process. In contrast, the search for empirical models using NN will continue to improve, limited only by technological advances supporting the very promising NN developments.

Alfentanil↗
PubMed1992

Pharmacokinetics and pharmacodynamics of erythropoietin during therapy in an infant with renal failure.

We treated an infant with anemia and chronic renal failure with recombinant human erythropoietin (300 to 750 U/kg subcutaneously per week) and iron (6 mg/kg enterally) from 1 to 4 months of age. A suboptimal pharmacodynamic response was seen at the lower dose. This may have been due to developmental erythropoietin pharmacokinetic differences, that is, relatively greater neonatal plasma clearance and steady-state volume of distribution compared with those in adults.

Anemia↗
PubMed1992

Surface characterization of activated charcoal by X-ray photoelectron spectroscopy (XPS): correlation with phenobarbital adsorption data.

X-ray photoelectron spectroscopy (XPS) was used to identify the functional states of carbon existing on the surfaces of various activated charcoals. The relative percentages of carbon, oxygen, and detectable trace elements comprising the activated charcoal surfaces were determined. Analysis of the carbon core-electron binding energy region revealed the existence of one hydrocarbon state (C-H, C-C are indistinguishable) and three oxygen-containing functional states. These states were hydroxyls or ethers (C-O), carbonyls (C = O), and carboxylic acids or esters (O-C = O). The C-O functional state contributed approximately 60-70% to the total percentage of oxygen-containing states. A very good correlation existed between the apparent areas occupied on the adsorbent surface per phenobarbital molecule and the relative percentages of the C-O functional state. Previously reported heat of displacement results for phenobarbital adsorption are now explained since the C-O state appears to be the primary site involved in the binding of phenobarbital by the activated charcoals.

Adsorption↗
PubMed1992

A sensitive and specific erythropoietin immunoprecipitation assay: application to pharmacokinetic studies.

Previous pharmacokinetic studies with radiolabeled erythropoietin have relied on results of nonspecific methods to derive pharmacokinetic parameters. Dependence on nonspecific protein precipitation or total radioactivity may result in falsely high determinations of plasma radiolabeled erythropoietin and erroneous determinations of pharmacokinetic elimination and distribution parameters. In the present study pharmacokinetic parameters were derived by using a specific, sensitive, and reproducible immunoprecipitation assay for biologically active iodine 125-labeled recombinant human erythropoietin (125I-rhEp) and compared with those obtained by using nonspecific protein precipitation with trichloroacetic acid (TCA). Tracer amounts of 125I-rhEp were administered by bolus injection to six newborn lambs. Plasma-precipitable radioactivity assayed by the immunoprecipitation method became progressively lower with time relative to those observed with the TCA method. Pharmacokinetic parameters derived from the immunoprecipitation assay demonstrated significantly more rapid plasma and elimination clearances, shorter terminal half-life, shorter mean body residence time, and shorter distribution time when compared with the TCA assay (p less than 0.01). Volume of distribution was not different. Comparison of immunoprecipitation and TCA assay results from gel permeation fractions of iodinated erythropoietin demonstrated that immunoprecipitation assay results provide a better evaluation of biologically active hormone as determined by comparisons with SDS-PAGE and erythropoietin radioreceptor data. We conclude that 125I-rhEp pharmacokinetic parameters derived by using the immunoprecipitation assay more accurately reflect physiologic conditions than do those derived by using TCA precipitation.

Animals↗
PubMed1992

Developmental differences in erythropoietin pharmacokinetics: increased clearance and distribution in fetal and neonatal sheep.

Although erythropoietin (Ep) is considered the primary hormone responsible for erythrocyte production throughout development, the administration of recombinant human Ep (rhEp) to premature human neonates has, thus far, been ineffective in the prevention and treatment of their anemia. To determine if developmental pharmacokinetic differences might in part be responsible for this lack of efficacy, Ep pharmacokinetic studies were carried out in four groups of sheep: late gestation fetal, neonatal, adult and pregnant. After i.v. bolus injection of tracer amounts of the biologically active [125I]rhEp, plasma [125I]rhEp was measured using a sensitive and specific Ep immunoprecipitation assay. Pharmacokinetic parameters were derived using noncompartmental system analysis. Significantly greater clearances, shorter half-lives, shorter residence times, greater distribution volumes and greater Ep production rates were found in the fetal and neonatal groups compared to pregnant and nonpregnant adults (P less than .01). These developmental differences likely reflect more rapid metabolism and greater distribution of Ep in less mature individuals. As such, they could result in a reduction in Ep's erythropoietic effect similar to that reported in premature infants. We speculate that treatment of anemic premature neonates using rhEp doses shown to be effective in adults may be inadequate.

Animals↗
PubMed1991

A system approach to pharmacodynamics. III: An algorithm and computer program, COLAPS, for pharmacodynamic modeling.

Many pharmacodynamic (PD) models may be generalized in the form E(t) = N(L[c(t)]), where E(t) is a recorded effect response, c(t) is a sampled drug level, N is a nonlinear autonomic function, and L is a linear operator that commonly is a convolution operation. The NL class of PD models includes the traditional effect compartment PD models as a subclass, but is not limited to such models. An algorithm and computer program named COLAPS, based on system analysis principles and hysteresis minimization, that enable N and L to be empirically determined for the NL class of models without addressing specific kinetic structure aspects ("model independence") are presented. The kinetic concepts of biophase conduction and transduction functions are used by COLAPS. Such an approach is more general than the effect compartment approaches because it does not assume first-order transport principles. The pitfalls of hysteresis minimization in PD modeling are discussed and the procedures taken by COLAPS to avoid these pitfalls are outlined. A transformation technique prevents improper convergence to a point. A novel reparameterization scheme is introduced that maximizes the flexibility of the kinetic functions and extends the generality of the analysis. Inequality function constraints are maintained without the need for troublesome constrained nonlinear optimization procedures. Usage of the COLAPS program is illustrated in the analysis of the PD of amobarbital. The COLAPS program resulted in an excellent minimization of the effect versus biophase level hysteresis. The biophase conduction function, the biophase drug level (normalized), and the transduction curve were determined. The transduction curve showed clear biphasic behavior.

Algorithms↗
PubMed1991

Stochastic interpretation of linear pharmacokinetics: a linear system analysis approach.

Linear drug disposition is most generally defined in terms of the superposition principle. This principle is explained on the molecular level by probability principles involving stochastic, independent kinetic behavior of drug molecules. A stochastic modeling approach is presented that is more general than pharmacokinetic models typically employed in stochastic approaches. First-order microscopic transfer rate constants (Kij) are not employed or assumed in the analysis. The approach is a linear system analysis approach that makes use of the simplest possible kinetic structure that enables a differentiation of the drug disposition into elimination and distribution components. This is done by applying stochastic principles in the context of the disposition decomposition analysis (DDA). The DDA approach in its linear form is a generalization of linear pharmacokinetic systems that assume a homogeneous sampling space. Disposition kinetics is partitioned into two kinetic spaces, a homogeneous sampling space, and a heterogeneous peripheral kinetic space. A structure differentiation beyond this is difficult to justify in common situations when only the parent drug is determined from a single iv sampling site. A stochastic independent molecule (SIM) model is formulated in the structure context of DDA. The model is employed to identify core relationships by isolating elementary stochastic building blocks of the disposition kinetics and absorption kinetics. It is shown how the stochastic building blocks of the SIM-DDA model are related to various mean time parameters. Residence probability functions and drug delivery probability functions provided by the approach appear useful for extending kinetic bioavailability concepts into a purely stochastic realm. The emphasis on transit time concepts enables a kinetic differentiation and a more intrinsic characterization than possible by the use of common residence time principles. Relationships are presented that link stochastic and kinetic elements. Formulas are presented for the practical calculations of the mean time parameters and stochastic functions presented. Practical examples are given of the concepts presented using data from several drugs.

Biological Availability↗
PubMed1991

Exact dosing times calculations in linear pharmacokinetics.

The problem of determining the particular dosing time, tau, that results in a certain ratio between peak and trough drug levels at steady state (ss) is addressed. Calculation of tau in combination with simple dose linearity principles ensures constraint on the drug level variations at ss, contrary to calculations based on only clearance principles. It is shown that the dosing time problem is solved using a nested, single-variable rootsolving. Using a derivative-free, robust, single-variable rootsolver enables automatic, reliable calculations of tau. An algorithm and computer program, SSTATE, for the automatic calculation of tau in intra- and extravascular dosings are presented. Contrary to various approximation formulae proposed in the past, SSTATE provides solutions that are exact. SSTATE provides additional ss parameters such as time to peak, and maximum, minimum, and mean levels, and can also be executed in a simulation mode to explore various practical dosage regimen schemes. Dosage regimen calculations for quinidine are presented to demonstrate the practical utility of the proposed approach. It is also demonstrated by simulation studies that some approximation formulae previously proposed may produce excessive errors, especially when applied to extravascular dosings.

Algorithms↗
PubMed1991

Biophase equilibration times.

Various methods for describing how quickly a drug equilibrates at the biophase are proposed. The biophase equilibration time (BET) is the time it takes the biophase drug level to reach a given percentage (p) of its predicted steady state in a drug administration that leads to a steady-state condition. The time to reach biophase equilibrium may be defined as the BET value for p = 95, and the 50% biophase equilibration time is obtained when p = 50. Biophase equilibration profiles (BEPs), obtained by plotting p versus BET, give a dynamic representation of the approach to equilibrium and may serve as an indicator of the rate of drug delivery to the biophase. A pharmacodynamic system analysis method is proposed to determine BETs and BEPs from the biophase conduction function. The approach is demonstrated using pharmacodynamic data from the CNS effect of amobarbital evaluated by an aperiodic analysis of EEG recordings. The relevance of the BET and/or BEP principles in optimal computer-controlled drug infusion, drug design, and evaluation of targeted drug delivery is discussed. Both vascular and extravascular drug administrations are considered in the analysis.

Amobarbital↗
PubMed1991

Reparameterization to implementing kinetic constraints in pharmacokinetics.

Polyexponential expressions are widely used in pharmacokinetic system analysis to represent various functions and pharmacokinetic responses. It is often necessary to impose simple constraints (e.g., non-negativity, monotonicity, etc.) to make such expressions agree with obvious kinetic conditions or general assumptions made. Enforcement of such constraints is typically obtained by specifying upper and/or lower limits for the polyexponential parameters in the curve fitting procedure. However, this method often limits the search to only a subset of all possible polyexponentials expressions which satisfy the specified constraints. A less restricted search may be performed by not specifying a lower or upper limit on some polyexponential parameters, but this may occasionally result in violations of the constraints. A reparameterization approach is presented to overcome the above problems. Various schemes are presented that allow a completely unrestricted search to be done among all possible polyexponential expressions which satisfy various constraint configurations. The practical significance of this approach is discussed and demonstrated with some examples. It is pointed out that evaluation of various pharmacokinetic processes in the context of specific models or families of models may intrinsically impose certain constraints that may not be justified when the kinetics is analyzed in a more general system analysis context. The application of system analysis principles in conjuction with an enforcement of functional constraints in a "model-free" context by reparameterization appears to be a rational alternative to current methods.

Half-Life↗
PubMed1991

Optimal extravascular dosing intervals.

An explicit formula is presented for simple calculations of the dosing time, tau, that results in a steady-state peak-to-trough ratio of 2 in extravascular dosings. Contrary to other formulae presented, the calculations are guaranteed to be well bound in the percentage error (less than 1%) for any parameter value combination. It is shown that the biexponential dosing interval problem can be transformed into a general, dimensionless problem enabling a global error analysis in the approximation. The proposed formula is demonstrated in the calculation of an "optimal" dosing interval for quinidine. An algorithm and FORTRAN computer program OPTAU for exact calculation of tau and dosing simulations is also demonstrated in the quinidine example.

Algorithms↗
PubMed1991

Estimation of amobarbital plasma-effect site equilibration kinetics. Relevance of polyexponential conductance functions.

The time delay between drug plasma concentrations and effect has been modeled most commonly by the effect compartment approach, assuming first-order monoexponential equilibrium kinetics between plasma and effect site. So far this assumption has not been rigorously probed. The purpose of the present investigation was to model the delay between amobarbital plasma concentrations and EEG effect using a new approach based on system analysis principles. This approach models the equilibrium between plasma and effect site without assuming a specific kinetic structure. Assuming linear distribution kinetics between plasma and effect site, the relationship between the two variables may be described by a convolution type of linear operation, involving a conductance function phi(t), which is approximated by a sum of exponentials. Six male Wistar-derived rats received an iv infusion of amobarbital at a rate of 10 mg/kg per min until isoelectric periods of 5 sec or longer appeared on the EEG. Frequent arterial blood samples were obtained and EEG was continuously quantified using aperiodic analysis. The amplitudes in the 2.5-30 Hz frequency band were used as EEG effect measure. The delay between plasma concentrations and EEG effect was best modeled by a biexponential conductance function. The use of a biexponential conductance function resulted in a significant further reduction (41 +/- 10%) in hysteresis when compared to a monoexponential function, indicating that the assumption of simple first-order monoexponential equilibration kinetics is inadequate. The use of a biexponential conductance function also resulted in a significantly different shape of the effect site concentration-EEG effect relationship and hence the estimated pharmacodynamic parameters, when compared with a monoexponential function. This relationship showed a biphasic behavior, with EEG effects being maximal at amobarbital concentrations of 29.6 +/- 1.3 mg/L. At 80.2 +/- 2.0 mg/L the EEG effect was reduced 50% below baseline values. A comparison was made with the equilibration between amobarbital plasma and cerebrospinal fluid (CSF) concentrations. Six male Wistar-derived rats received an iv infusion of amobarbital, 10 mg per min for 15 min. Arterial blood and CSF samples were taken simultaneously at regular intervals. The equilibration between plasma and CSF concentrations was best fitted by a monoexponential conductance function. Significant differences in equilibration profiles of CSF and effect site with the plasma site were observed. To reach 50% equilibrium the effect site requires 2.5 +/- 0.3 min and the CSF 3.5 +/- 0.2 min, to reach 95% the values were, respectively, 90 +/- 27 and 15 +/- 1 min. This suggests that CSF is kinetically distinguishable from the effect site.

Amobarbital↗
PubMed1991

Model selection for the adsorption of phenobarbital by activated charcoal.

Activated charcoal is known to adsorb a wide variety of substances from solution, and several equations have been used to fit the resulting adsorption data. The determination of the correct model to fit phenobarbital adsorption onto activated charcoal was made using a calorimetric method. The differential heats of displacement of water by phenobarbital for four activated charcoals were determined and found to be linearly related to the amount of phenobarbital adsorbed. The activated charcoals studied had statistically similar heats of displacement. The linear relationship between heat evolved and the amount of phenobarbital adsorbed is consistent with the assumptions implicit in the Langmuir model.

Adsorption↗
PubMed1990

Effect of aspirin and sulindac on methotrexate clearance.

The pharmacokinetics of low dose methotrexate (MTX) were evaluated in 12 rheumatoid arthritis patients in the presence and absence of steady-state levels of salicylic acid (ASA) and sulindac (SU). Using a Latin square design, patients were given MTX plus ASA (mean 3.4 g/day), MTX plus SU (mean 400 mg/day), or MTX alone. On a background of at least one year of regular MTX therapy, patients received 10 mg/m2 MTX iv (mean 17.8 mg) given after at least 2 weeks of treatment with each of the above regimens. Plasma concentrations of MTX and 7-hydroxymethotrexate (7-OH-MTX) were measured using HPLC. No differences in MTX clearance (Cl) were found comparing MTX alone, MTX + ASA, and MTX + SU. However, if one particular subject that had a very low clearance when receiving MTX alone was excluded, there was a statistically significant decrease in MTX clearance when either ASA or SUL were present. It is also noteworthy that ASA significantly increased the exposure of the subject to 7-OH-MTX and, to a lesser extent, so did sulindac. Since 7-OH-MTX has been shown to be an active metabolite when given for cytotoxic effects at higher doses and because it has been show to be nephrotoxic at doses a thousand-fold greater than used in rheumatoid arthritis, nonsteroidal anti-inflammatory drugs should be used cautiously with MTX until further large scale safety studies are conducted. The data indicate that if a clinically significant interaction were to occur, ASA is more likely than SU to interact with MTX.

Arthritis, Rheumatoid↗
PubMed1989

Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients.

The pharmacokinetics and bioavailability of low-dose methotrexate (MTX) (10 mg/m2) were evaluated in 41 subjects who had definite or classical rheumatoid arthritis as defined by the American Rheumatism Association criteria. Subjects received 10 mg/m2 (to the nearest 2.5 mg) of MTX in a single oral dose and a single intravenous (iv) dose one week apart. Serum concentrations for this low-dose regimen were monitored using a radiochemical ligand binding assay. The results indicate the MTX is cleared from the plasma at a rate of 84.6 mL/min/m2. The terminal half-life was approximately 6 h. The volumes of distribution at steady state and for the central compartment were 22.2 and 13.5 L/m2, respectively. The mean residence time in the body, in the systemic circulation, and in the periphery were estimated to be 4.7, 3.0, and 1.7 h, respectively, with a peripheral single-pass mean transit time of 6.0 h and an intrinsic mean residence time in the periphery of 7.9 h. The mean absorption time was 1.2 h and the oral bioavailability was 0.70. The ratio of synovial fluid concentration to serum concentration 4 and 24 h after a dose was found to be approximately 1.0, indicating that at least within that time range serum and synovial fluid concentrations are approximately equal. Because of conflicting results and insufficient data from previous high-dose pharmacokinetic studies, it is difficult to say whether or not low-dose MTX pharmacokinetics differs from those of high-dose MTX.

Administration, Oral↗