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D Verotta

Publications and source records attributed to D Verotta.

At least 19 recordsLinked to original sources
PubMed2005

Mechanistic pharmacokinetic modelling of ephedrine, norephedrine and caffeine in healthy subjects.

AIM: The combination of ephedrine and caffeine has been used in herbal products for weight loss and athletic performance-enhancement, but the pharmacokinetic profiles of these compounds have not been well characterized. This study aimed to develop a mechanistic model describing ephedrine, norephedrine, and caffeine pharmacokinetics and their interactions in healthy subjects. METHODS: The pharmacokinetic model was developed based on the simultaneous modelling using plasma samples gathered from two clinical trials. The treatments consisted of single-doses of pharmaceutical caffeine and ephedrine, given alone or together, and an herbal formulation containing both caffeine and ephedrine. We used a mixed-effect statistical model and the program NONMEM to take account of intersubject variability. RESULTS: Three hundred and seventy-nine ephedrine, 352 norephedrine, 417 caffeine plasma concentrations and 40 ephedrine urine concentrations were obtained from 24 subjects. A one-compartment model with first-order absorption described the caffeine data. Caffeine clearance was 0.083 l min(-1) (CV 38%) and decreased to 0.038 l min(-1) in presence of oral contraceptive therapy, its volume of distribution was 38.6 l (CV 20%) and its absorption rate constant was 0.064 l min(-1) (CV 50%). A four-compartment model described the pharmocokinetics of ephedrine and norephedrine. Ephedrine was eliminated mostly renally, with a clearance of 0.34 l min(-1) (CV 11%), and a volume of distribution of 181 l (CV 19%). Nonlinearity in the conversion of ephedrine to norephedrine was observed. Different models showed that the simultaneous administration of caffeine, or the amount of caffeine in the absorption compartment, was associated with a slower rate of absorption of ephedrine. A 32% greater relative bioavailability of herbal compared with pharmaceutical ephedrine administration was observed. CONCLUSIONS: We describe a mechanistic model for ephedrine, norephedrine and caffeine pharmacokinetics and their interactions. The relative bioavailability of ephedrine differed between the herbal supplement compared with the pharmaceutical formulation. Concomitant ingestion of caffeine slowed the absorption rate of ephedrine, which is mainly related to the amount of the former in the absorption compartment. A saturable process appears to be involved in the metabolism of ephedrine to norephedrine.

Administration, Oral↗
PubMed2001

A semiparametric deconvolution model to establish in vivo-in vitro correlation applied to OROS oxybutynin.

In vitro-in vivo correlation (IVIVC) models may be used to predict in vivo drug concentration-time profiles given in vitro release characteristics of a drug. This prediction is accomplished by incorporating in vitro release characteristics as an input function (A(vitro)) to a pharmacokinetics model. This simple approach often results in biased predictions of observed in vivo drug concentrations, and it can result in rejecting IVIVC. To solve this problem we propose a population IVIVC model that incorporates the in vitro information and allows one to quantify possibly changed in vivo release characteristic. The model assumes linear kinetics and describes the in vivo release as a sum of A(vitro) and a nonparametric function (A(d), a spline) representing the difference in release due to in vivo conditions. The function A(vitro) and its variability enter the model as a prior distribution. The function A(d) is estimated together with its intersubject variability. The number of parameters associated with A(d) defines the model: no parameters indicates perfect IVIVC, a large number of parameters indicates poor IVIVC. The number of parameters is determined using statistical model selection criteria. We demonstrate the approach to solve the IVIVC problem of an oral extended release oxybutynin form (OROS), administered in three pharmacokinetic studies. These studies present a particular challenging case; that is, the relative bioavailability for the OROS administration is >100% compared with that of the immediate-release form. The result of our modeling shows that the apparent lack of IVIVC can be overcome: in vivo concentration can be predicted (within or across data sets) based on in vitro release rate together with a simple form of systematic deviation from the in vitro release.

Biological Availability↗
PubMed2001

Selecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncompliance.

For single-dose concentration-time data collected in clinical trials to be useful for explanatory pharmacokinetic (PK) or pharmacokinetic-pharmacodynamic (PK-PD) analyses, the following two assumptions on the data must hold: (i) the times of the concentration (PK) observations are known, and (ii) the patient's recent past dosing history (times and amounts) is known. If either (or both) of these assumptions does not hold, and data analysis proceeds as if it did, biased estimates may result. Assumption (i) usually does hold as study personnel observe and record PK sampling times. Assumption (ii) is a problem when, as is often the case of outpatient studies, one must rely on patient recall for past dosing history. This paper presents a technique to avoid assumption (ii) by identifying for deletion those PK observation occasions likely exhibiting unreliable preceding dose histories. To so identify occasions, a Bayes objective function (posterior density) for the data is maximized in its parameters for each individual. The likelihood factor of this function is a mixture pharmacostatistical model expressing the likelihood of the observed concentration(s) under three mutually exclusive events: the prescribed dose preceding the occasion was not taken at all (NT), the prescribed dose was taken at the specified time (T), or the prescribed dose was taken at an unspecified time (U). Suspect observations are identified as those whose maximum corresponding likelihood component is other than T. The approach as defined here relies on the following assumptions in addition to (i): (ii) population PK (i.e., the distribution of PK parameters in the population being sampled) is known, at least approximately. (iii) PK samples (at least 1 or 2 per occasion) are available, (iv) doses taken are of the stated magnitude, and (v) the drug has a short half-life. Simulations reveal that especially when more than one PK sample is available per study occasion, the methodology chooses a set of PK observations that should perform better in subsequent explanatory analyses, or as a basis for estimating individual PK parameters, than do other simpler methods.

Clinical Trials as Topic↗
PubMed2000

Nasal mucosal versus gastrointestinal absorption of nasally administered cocaine.

OBJECTIVE: Several xenobiotics, including cocaine, are dosed by the nasal route for systemic effects. The aim of this study was to estimate and compare cocaine input into the systemic circulation after oral and nasal dosing, and to determine the relevance of local absorption through the nasal mucosa. METHODS: Cocaine was administered to healthy volunteers through the intravenous, oral, and nasal routes. Cocaine serum concentrations were measured at frequent intervals. From these data, the gastrointestinal, nasal, and nasal mucosa input rate functions were determined using nonparametric, subject-specific population deconvolution. RESULTS: After oral dosing, cocaine input into systemic circulation increased slowly and peaked around 45 min after ingestion. The median systemic bioavailability after oral dosing was 33%. After nasal dosing, drug input was substantial even during the first minute and showed two peaks at 10 min and 45 min after ingestion. Since the second peak after nasal dosing closely resembled drug input after oral administration, we hypothesized that, after nasal administration, a part of the dose is swallowed and thereafter absorbed gastrointestinally. The data from the sessions with nasal cocaine administration were reanalyzed assuming the same shape for gastrointestinal drug input as after oral dosing. The fraction absorbed through the nasal mucosa was estimated to be 19% (95% CI: 11-26%). The fraction absorbed through the nasal mucosa contributed 31% (95% CI: 23-37%) of total systemic cocaine exposure. CONCLUSIONS: Our data suggest that the main reason addicts prefer nasal to oral cocaine dosing is faster absorption, enhancing the subjective effects rather than higher bioavailability.

Administration, Inhalation↗
PubMed2000

Linear mixed-effect multivariate adaptive regression splines applied to nonlinear pharmacokinetics data.

In a frequently performed pharmacokinetics study, different subjects are given different doses of a drug. After each dose is given, drug concentrations are observed according to the same sampling design. The goal of the experiment is to obtain a representation for the pharmacokinetics of the drug, and to determine if drug concentrations observed at different times after a dose are linear in respect to dose. The goal of this paper is to obtain a representation for concentration as a function of time and dose, which (a) makes no assumptions on the underlying pharmacokinetics of the drug; (b) takes into account the repeated measure structure of the data; and (c) detects nonlinearities in respect to dose. To address (a) we use a multivariate adaptive regression splines representation (MARS), which we recast into a linear mixed-effects model, addressing (b). To detect nonlinearity we describe a general algorithm that obtains nested (mixed-effect) MARS representations. In the pharmacokinetics application, the algorithm obtains representations containing time, and time and dose, respectively, with the property that the bases functions of the first representation are a subset of the second. Standard statistical model selection criteria are used to select representations linear or nonlinear in respect to dose. The method can be applied to a variety of pharmacokinetics (and pharmacodynamic) preclinical and phase I-III trials. Examples of applications of the methodology to real and simulated data are reported.

Algorithms↗
PubMed2000

Additive inhibition of nicotinic acetylcholine receptors by corticosteroids and the neuromuscular blocking drug vecuronium.

BACKGROUND: Neuromuscular disorders associated with muscular weakness and prolonged paralysis are common in critically ill patients. Acute myopathy has been described in patients receiving a combination therapy of corticosteroids and nondepolarizing neuromuscular blocking drugs for treatment of acute bronchospasm. The cause of this myopathy is not fully established and may involve drug interactions that perturb neuromuscular transmission. To investigate the interaction of corticosteroids with neuromuscular blocking drugs, the authors determined the effects of methylprednisolone and hydrocortisone alone and in combination with vecuronium on fetal (gamma-subunit containing) and adult (epsilon-subunit containing) subtypes of the muscle-type nicotinic acetylcholine receptor. METHODS: Functional channels were expressed in Xenopus laevis oocytes and activated with 1 microM acetylcholine. The resulting currents were recorded using a whole cell two-electrode voltage clamp technique. RESULTS: Both forms of the muscle-type acetylcholine receptor were potently inhibited by methylprednisolone and hydrocortisone, with concentrations producing 50% inhibition in the range of 400-600 microM and 1-2 mM, respectively. The corticosteroids produced noncompetitive antagonism of the muscle-type nicotinic acetylcholine receptor at clinical concentrations. Both receptor forms were also inhibited, even more potently, by vecuronium, with a concentration producing 50% inhibition in the range of 1-2 nM. Combined application of vecuronium and methylprednisolone showed additive effects on both receptor forms, which were best described by a two-site model, with each site independent. CONCLUSIONS: The enhanced neuromuscular blockade produced when corticosteroids are combined with vecuronium may augment pharmacologic denervation and contribute to the pathophysiology of prolonged weakness observed in some critically ill patients.

Adrenal Cortex Hormones↗
PubMed1999

A general solution for nonparametric control of a linear system using computer-controlled infusion pumps.

Investigators have developed algorithms for use in computer-controlled infusion pumps (CCIP's) which dose intravenous drugs assuming multiexponential unit impulse response (UIR) function. However for many UIR multiexponential functions are at best an approximation. For almost all substances the early times after an impulse administration show complex profiles hardly described by multiexponential functions. For many later times also show departures from exponential decline. We derive a general approach for a CCIP which can be used with an arbitrary UIR function. A particular instance of the approach is based on a nonparametric representation of an UIR which uses spline functions. The approach is computationally simple, it can take into account desired constraints (for example no overshoot to avoid toxicity) and presents a solution to control concentrations of substances in a site different from the input site. Examples based on real lodocaine, veralipride, and thiopental data demonstrate the approach.

Algorithms↗
PubMed1999

Down-regulation models and modeling of testosterone production induced by recombinant human choriogonadotropin.

Chorionic gonadotropin (CG) is a glycoprotein hormone, whose action is mediated by the luteinizing hormone/CG receptor. Testosterone concentrations from six pituitary-desensitized, healthy male volunteers were obtained after four different administrations of recombinant-human CG (rhCG). We present a modeling study to provide a possible explanation for the observations that increased exposure to rhCG induces higher and then lower testosterone concentrations and that marked rebound effects are observed at the end of repeated administration of rhCG. We used semimechanistic models (in which flexible functions represent unknown parts of the models) to identify the relationship of rhCG concentrations to the testosterone levels. Based on the results obtained with the semimechanistic models, different mechanistic down-regulation models were devised and tested. The final model uses a one-compartment model to describe the endogenous production rate of testosterone; rhCG affects the production rate with a mechanism consistent with a two-site binding site, with effect proportional to one-site bound concentration. The modeling results indicate that when rhCG concentration increases, the testosterone production rate increases to 45 times the baseline value. However, at an rhCG concentration of more than about 30 IU/liter, the production rate decreases. Simulations showed that both dose and dosing interval profoundly influence testosterone response to rhCG.

Adult↗
PubMed1998

Passive versus electrotransport-facilitated transdermal absorption of ketorolac.

OBJECTIVE: To investigate the bioavailability (extent and rate of absorption) of ketorolac from two cutaneous absorption sources, active electrotransport and passive transdermal, and to examine the enantiomeric selectivity of bioavailability for each source. METHODS: Based on a crossover study in 12 healthy volunteers, the extent and rate of absorption of ketorolac, delivered by a patch, were found by estimating the input rate function of the drug. For that purpose, deconvolution was used in two steps. First, intravenous data were analyzed to estimate the ketorolac disposition function, and second, postpatch data were deconvolved to estimate the unknown patch input profile given the disposition function estimated in the first step. Because the input rate function curves to be estimated for the patches may be of arbitrary shape, a spline was used to model the patch input function, whereas intravenous data were modeled with use of a sum of exponentials. Differences in the extent of absorption (F) for the four treatment-enantiomer combinations were further examined with a mixed-effect regression model, based on the sets of four individual estimates of bioavailability. RESULTS: On average, the F value for the active electrotransport treatment, which exhibited the faster absorption rate, was four times greater than the F for the passive transdermal treatment. Further, during the passive treatment, R-ketorolac yielded an average F that is 42% greater than that for S-ketorolac and also exhibited a smaller absorption lag-time. During the active treatment, there was no important enantiomeric difference in either extent or rate of absorption.

Administration, Cutaneous↗
PubMed1998

Use of a pharmacokinetic/pharmacodynamic model to design an optimal dose input profile.

A model for the pharmacodynamic effect of a drug (designated only X), and the use of the model to explore optimal input is described. The data analyzed here are from a crossover comparison study of the effect of 4 active treatments, yielding distinct concentration vs. time curves, plus placebo in 32 subjects. The model expresses total effect as the sum of placebo effect and (pure) drug effect. The latter allows for possible tolerance (found) and time effects (not found). Random effects allow interindividual differences to be expressed. Conditioning on the fitted model, a population optimal input profile is designed that obeys certain protocol constraints. The profile minimizes the expectation of a sum of squared differences between target effect and the resulting response over a given time interval. The target is a fixed constant, chosen to be either the individuals' maximum effect level in response to a baseline input regimen used in the study or the maximum effect level for the typical individual in the population in response to this regimen, as predicted from the model. The expectation is taken over the estimated nonparametric distribution of the 32 subjects' random effects. As one goal of early clinical studies of drugs may be to provide a basis for designing an optimal delivery profile (with respect to a specified loss function), we suggest this report as an example of a reasonable way to go about finding such a profile.

Analgesics↗
PubMed1998

Importance of chronopharmacokinetics in design and evaluation of transdermal drug delivery systems.

Circadian and meal effects on nicotine kinetics determine in part blood nicotine concentrations and in doing so may influence cigarette smoking behavior throughout the day. We have shown previously that nicotine clearance varies by approximately 17% (from peak to through) due to diurnal factors throughout the day and that meals increase nicotine clearance by about 42%. Until now pharmacokinetic analyses of nicotine absorption from patches have assumed a constant clearance of nicotine over 24 hr. Using 11 individual kinetic estimates from a previous study, we analyzed plasma nicotine concentrations vs. time data of two nicotine patch studies, and conducted a set of simulations to determine the extent to which time-varying kinetics would influence the design of transdermal drug delivery systems, intented to maintain a constant plasma nicotine concentration over 24 hr. Not incorporating time-varying kinetics leads to biased estimates of the delivery rate of the nicotine patches, and increases the variability in the delivery rates estimates. The hypothetical transdermal drug delivery systems designed assuming constant nicotine clearance results in a systematical underdosing during the first 12 hr after beginning therapy. The transdermal drug delivery systems obtained assuming the correct time-varying clearance shows three components: 1) an early high delivery rate, followed by 2) a rather constant, but slightly decreasing at night, release rate and 3) transient increases in delivery rate for 2 hr after each meal. The effect of circadian variations in clearance could be compensated for in patch design by decreasing the delivery rate during the night. Transient variations in clearance due to meals would require the corresponding use of rapid drug delivery dosage forms. The methods we devise to predict optimal dosing regimens in presence of chronopharmacokinetics might be useful for other medications in which blood levels need to be precisely controlled.

Administration, Cutaneous↗
PubMed1997

A pooled analysis of CD4 response to zidovudine and zalcitabine treatment in patients with AIDS and AIDS-related complex.

INTRODUCTION: This article reports a meta-analysis focused on the efficacy of zalcitabine and zidovudine alone or in combination as reported by three AIDS Clinical Trial Group trials. We analyzed the log CD4 count (LCD4) response to therapy up to 1 year after the beginning of therapy. One of the purposes of this article was to illustrate a meta-analysis method that permits pooling of original data from trials with different designs. METHODS: To effectively eliminate obvious differences due to design, we first estimated complete (1 year) individual LCD4 versus time curves using a sophisticated smoothing technique. Then several summary descriptors were computed from the completed LCD4 curves. Those descriptors were corrected for baseline covariate differences, and the corrected values were then related to measures of drug exposure. RESULTS: Significant baseline covariates were LCD4 baseline count and AIDS-related complex or AIDS diagnosis. The predictor, corrected for baseline covariates, that correlated best with drug exposure was intensity, the initial rate of rise of LCD4, estimated as the slope of LCD4 between pretreatment and peak LCD4. CONCLUSION: Using intensity as a single response measure, we found weak evidence for synergism of zalcitabine and zidovudine: combination therapy increased response by 20% over that expected from a purely additive interaction.

AIDS-Related Complex↗
PubMed1997

A semiparametric method for describing noisy population pharmacokinetic data.

We propose a semiparametric method to estimate model-independent pharmacokinetic (PK) measures such as area under concentration-time, peak concentration and time to peak concentration (Tpeak), for noisy population PK data from a sparsely sampled prospectively designed trial. The method is developed within the mixed-effect model framework, for the single-dose and steady-state case. We describe individual concentration vs. time using a longitudinal spline, consisting of a template spline, common to all individuals, and an individual-specific distortion spline accounting for individual differences. We impose a number of constraints on the longitudinal spline, including (i) it has a decreasing tail, (ii) its typical Tpeak is near the modal Tpeak observed in the population data, and (iii) its value is zero at time zero (single dose), or the same nonzero value at the beginning and end of a dosing interval (steady state). We test our method using simulated data and compare its performance to that of a parametric and a nonparametric method. An actual data example is also shown. The performance of the method is as good or better than that of a standard nonparametric method, and when the analysis model is misspecified, the method is superior to a standard parametric one. Since it is often not apparent that an analysis model is correct, we propose this approach as a general method for analysis.

Anti-HIV Agents↗
PubMed1997

Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in combination therapy.

We investigated the pharmacokinetics of zidovudine, zalcitabine, and saquinavir in AIDS Clinical Trial Group protocol 229. Patients received either saquinavir, zalcitabine, or a combination of both, together with zidovudine three times a day. Approximately 100 patients were enrolled in each treatment arm, and intensive pharmacokinetic studies were performed on about 25 patients per arm at weeks 1 and 12. We estimated the pharmacokinetic parameters of all three drugs by using parametric and nonparametric methods. The mean values of the pharmacokinetic parameters of zidovudine (clearance [CL]/bioavailability [F], 168 liters/h; volume of distribution [V]/F, 185 liters; half-life, 0.76 h) and zalcitabine (CL/F, 25 liters/h; V/F, 92.2 liters; half-life, 2.7 h) were similar to those reported previously. For saquinavir, the mean pharmacokinetic parameter estimates using parametric methods were as follows: maximum concentration of drug in serum [Cmax], 70.8 ng/ml; time to Cmax, 3.11 h; area under the curve, 809 ng x h/ml; CL/F, 989 liters/h; V/F, 1,503 liters; half-life, 1.38 h. For all three drugs, clearance decreased with age. Weight did not influence the clearance of zidovudine, but the clearance of zalcitabine and saquinavir increased with weight. There were no differences in pharmacokinetic parameters between study weeks and arms, suggesting that there is no change in kinetics with chronic administration and that there are no significant pharmacokinetic interactions among these three drugs.

Adult↗
PubMed1997

Exposure-response relationships for saquinavir, zidovudine, and zalcitabine in combination therapy.

The relationship of CD4+ cell response, level of RNA in plasma, and quantitative peripheral blood mononuclear cell (PBMC) titer to apparent drug exposure was investigated by using data from AIDS Clinical Trial Group protocol 229, a multicenter randomized study. Patients received either saquinavir, zalcitabine, or a combination of both, along with open-label zidovudine. Approximately 100 patients were enrolled in each arm, and the primary study duration was 24 weeks. Individual drug exposure, the area under the concentration-time curve, was estimated by using population-based pharmacokinetic methods. Response was defined as the maximum increase in CD4+ cell count or the maximum decrease in RNA in plasma or PBMC titer adjusted for baseline CD4+ cell count, RNA in plasma, and PBMC titer, respectively. Regression of responses on exposure demonstrated an exposure effect for saquinavir which was significant for the maximum increase in CD4+ cell count and the decrease in RNA in plasma. For the PBMC titer, no significant relationship could be demonstrated but the results suggested a trend similar to that of the other response variables. For all three response variables, the slope of the saquinavir exposure response was greater with the triple combination (saquinavir, zidovudine, and zalcitabine) than with the combination of saquinavir and zidovudine, suggesting possible synergism between saquinavir and zalcitabine.

Adult↗
PubMed1997

Age effects on interrelationships between lung volume and heart rate during standing.

To determine the effects of aging and posture on the relationship between respiration and heart rate (HR), we collected 5 min of lung volume and R-R interval data from 7 young (27 +/- 3 yr, mean +/- SD) and 10 old (69 +/- 6 yr) healthy humans during spontaneous breathing while they were supine (SU) and standing (ST). Lung volume and HR power spectra and transfer functions between lung volume and HR were estimated. Age and position effects and age-position interactions were determined by analysis of variance for repeated measures. Older subjects had a lower and more variable respiration rate (P < 0.03, P < 0.04), but both age groups exhibited decreased rate of respiration and increased tidal volume with ST (P < 0.05, P < 0.005). ST decreased lung volume-to-HR transfer function magnitude in both groups (P < 0.07). The more marked age-related differences were in phase angle. Both SU and ST phase angles were greater in older subjects (P < 0.003). ST decreased phase angle in young but increased phase angle in older subjects (P < 0.001). In conclusion, respiration, and respiration-HR interrelationships are altered by aging, with increased time delays between lung volume and HR and altered relationships with ST.

Adult↗
PubMed1997

Pharmacodynamics of acute tolerance to multiple nicotinic effects in humans.

Tolerance is an important determinant of addiction as well as therapeutic and/or toxic effects of drugs. The development of acute tolerance to various effects of nicotine was studied in nine healthy smokers who were abstaining from tobacco. Nicotine was infused rapidly to reach a concentration of about 25 ng/ml, followed by a computer-controlled infusion to maintain that concentration. A novel semiparametric model of nicotine effects and tolerance was developed. Tolerance to various effects of nicotine (increases in heart rate, blood pressure, plasma epinephrine and energy expenditure) occurred within the range of nicotine levels found in smokers. However, the rate of tolerance development varied considerably. The half-lives of tolerance ranged from 3.5 min for the increase in energy expenditure to 70 min for systolic blood pressure. There was no apparent tolerance to the effects on free fatty acid concentrations, which reflects lipolysis. Differences in the pharmacodynamics of tolerance may reflect differences in rate of desensitization of various subtypes of nicotinic receptors and/or differences in mechanisms of tolerance for various nicotinic effects.

Adult↗