Pharmacokinetic/pharmacodynamic relationships: basic concepts.
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Models, Biological↗
Biomedical subjects
I F Trocóniz
Publications and source records attributed to I F Trocóniz.
Pharmacokinetic/pharmacodynamic modeling of antipyretic and anti-inflammatory effects of naproxen in the rat.
Pharmacokinetic/pharmacodynamic modeling was used to characterize the antipyretic and anti-inflammatory effects of naproxen in rats. An indirect response model was used to describe the antipyretic effects of naproxen after short intravenous infusions. The model assumes that basal temperature (T(a)) is maintained by the balance of fever mediators given by a constant (zero order) rate of synthesis (K(syn)), and a first order rate of degradation (K(out)). After an intraperitoneal injection of lipopolysaccharide, the change in T(a) was modeled assuming an increase in fever mediators described as an input rate function [IR(t)] estimated nonparametrically. An inhibitory E(max) model adequately described the inhibition of IR(t) by naproxen. A more complex model was used to describe the anti-inflammatory response of oral naproxen in the carrageenin-induced edema model. Before carrageenin injection, physiological conditions are maintained by a balance of inflammation mediators given by K(syn) and K(out) (see above). After carrageenin injection, the additional synthesis of mediators is described by IR(t) (see above). Such mediators induced an inflammatory process, which is governed by a first order rate constant (K(IN)) that can be inhibited by the presence of naproxen in plasma. The sigmoidal E(max) model also well described the inhibition of K(IN) by naproxen. Estimates for IC(50) [concentration of naproxen in plasma eliciting half of maximum inhibition of IR(t) or K(IN)] were 4.24 and 4.13 microg/ml, for the antipyretic and anti-inflammatory effects, respectively.
Analgesics, Non-Narcotic↗
Comparison of manual versus ambulatory blood pressure measurements with pharmacokinetic-pharmacodynamic modeling of antihypertensive compounds: application to moxonidine.
OBJECTIVES: To compare the results of the pharmacokinetic-pharmacodynamic analyses of 24-hour ambulatory blood pressure measurements and manual blood pressure data in patients receiving moxonidine. METHODS: 32 patients with borderline to mild-to-moderate hypertension were enrolled in a double-blind, placebo-controlled phase II study. After receiving placebo for 1 week (run-in phase), the patients were randomly allocated to the placebo or the 0.6-, 0.9-, or 1.2-mg dose groups. Placebo and moxonidine were administered once daily for 1 week (drug-treatment phase). Four 24-hour ambulatory blood pressure measurement profiles were obtained for each individual. Plasma samples (n = 9) and four measurements of manual blood pressure were taken at the start and end of the drug-treatment phase. Two additional manual blood pressure measurements were taken during the run-in and drug-treatment phases. RESULTS: Pharmacokinetics was described by a one-compartment model. For the 24-hour ambulatory blood pressure measurements, baseline circadian patterns were described with a two-cosine function model that included interindividual and interoccasion variability. Pharmacodynamics was described with use of an effect-compartment model [k(e0) = 0.37 (1/h)] and an Emax model. For diastolic blood pressure the maximum drug-induced decrease (Emax) was 30.9 mm Hg and the steady-state plasma drug concentration eliciting half of maximum effect (C50) was 1.33 microg/L. Interindividual variability was estimated for ke0 (24.8%) and Emax (33.3%). For the manual blood pressure measurements, data was described by a time-invariant baseline model combined with an effect-compartment model and an Emax model. Mean population estimates were in agreement with those obtained during the analysis of 24-hour ambulatory blood pressure measurements. However, interindividual variability could be estimated for the baseline parameter only. CONCLUSIONS: Although similar typical population estimates for the drug action-related parameters were obtained with use of manual blood pressure data and 24-hour ambulatory blood pressure measurements, the latter allowed for a more detailed description of the individual pharmacodynamic profiles because interindividual variability in pharmacodynamic parameters could be estimated together with increased precision in parameter estimates.
Adult↗
Comparative pharmacokinetics, tissue distributions, and effects on renal function of novel polymeric formulations of amphotericin B and amphotericin B-deoxycholate in rats.
The pharmacokinetic profiles of a traditional formulation of amphotericin B (Fungizone) and novel nanosphere and mixed micelle delivery systems developed for amphotericin B were compared and described. Six groups of male Wistar rats received intravenous injections of the different formulations. Plasma and tissue samples were obtained at 11 different times after dosing, with three animals used each time. The amphotericin B concentrations in plasma and tissues were analyzed by high-performance liquid chromatography. The plasma drug concentration-time profiles were best described by a two-compartment model. Models that described the observed single or double peak disposition kinetics in kidney, liver, and spleen were also developed. Parameter estimates from those models show that components of the formulation such as poloxamer 188, which is present in all new formulations, seem to play an important role in the rate of drug uptake by the tissues; in general, the levels of amphotericin B in tissues were increased after the administration of the new formulations compared with those after the administration of Fungizone. The increment in the baseline plasma creatinine level was used as an index of renal function. All formulations increased this baseline value, but the novel formulations exhibited fewer renal effects than Fungizone did. However, a direct relationship between drug exposure in the kidneys and development of renal damage could not be found.
Amphotericin B↗
Pharmacokinetic-Pharmacodynamic Modelling of the antipyretic effect of two oral formulations of ibuprofen.
OBJECTIVE: To analyse the population pharmacokinetic-pharmacodynamic relationships of racemic ibuprofen administered in suspension or as effervescent granules with the aim of exploring the effect of formulation on the relevant pharmacodynamic parameters. DESIGN: The pharmacokinetic model was developed from a randomised, cross-over bioequivalence study of the 2 formulations in healthy adults. The pharmacodynamic model was developed from a randomised, multicentre, single dose efficacy and safety study of the 2 formulations in febrile children. PATIENTS AND PARTICIPANTS: Pharmacokinetics were studied in 18 healthy volunteers aged 18 to 45 years, and pharmacodynamics were studied in 103 febrile children aged between 4 and 16 years with bodyweight 225kg. METHODS: The pharmacokinetic study consisted of two 1-day study occasions, each separated by a 1-week washout period. On each occasion ibuprofen 400mg was administered orally as suspension or granules. The time course of the antipyretic effect was evaluated in febrile children receiving a single oral dose of 7 mg/kg in suspension or 200 or 400mg as effervescent granules. During the pharmacodynamic analysis, the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used. RESULTS: The disposition of ibuprofen was described by a 2-compartment model. No statistical differences (p > 0.05) were found between the 2 formulations in the distribution and elimination parameters. Absorption of ibuprofen from suspension was adequately described by a first-order process; however, a model with 2 parallel first-order input sites was used for the drug given as effervescent granules, leading to time to reach maximum drug concentration (tmax) values of 0.9 and 1.9 hours for suspension and granules, respectively. The time course of the antipyretic effect was best described using an indirect response model. The estimates (with percentage coefficients of variation in parentheses) of Emax (maximum inhibition of the zero-order synthesis rate of the factor causing fever), EC50 (plasma concentration eliciting half of Emax), n (slope parameter) and k(out) (first order rate constant of degradation) were 0.055 (10), 6.16 (14) mg/L, 2.71 (18) and 1.17 (23) h(-1), respectively, where To is the estimate of the basal temperature, 38.8 (1) degrees C. No significant (p > 0.05) covariate effects (including pharmaceutical formulation) were detected in any of the pharmacodynamic parameters. CONCLUSIONS: Because of the indirect nature of the effect exerted by ibuprofen, the implications of differences found in the plasma drug concentration profiles between suspension and effervescent granules are less apparent in the therapeutic response.
Adolescent↗
Alpha 1-acid glycoprotein (AAG) and serum protein binding of methadone in heroin addicts with abstinence syndrome.
OBJECTIVE: To quantify serum protein levels and protein-binding of methadone in vitro in heroin-addicted patients showing objective signs of heroin abstinence. SUBJECTS AND METHODS: Serum samples were obtained from patients (n = 27) hospitalized to participate in a methadone detoxification program and from healthy volunteers (n = 21). The severity of the abstinence syndrome was assessed before blood sampling using a standardized scale. Concentrations of both albumin and alpha1-acid glycoprotein (AAG) were measured in all serum samples. The protein-binding of alpha1-methadone was determined by the ultrafiltration technique and the unbound concentration was measured by liquid scintillation counting. RESULTS: The mean of the AAG concentrations was significantly increased in patients showing signs of withdrawal while the albumin concentrations did not change. Also, the unbound methadone was significantly decreased in this group when compared to the control. A positive correlation (Pearson r = 0.48; p < 0.005) indicates that AAG levels rise during abstinence as the score of withdrawal symptoms increases. Additionally, pooled data from all individuals show the binding of methadone to be related to AAG (r = 0.46; p < 0.05) levels and not to albumin. CONCLUSIONS: The observed changes in protein-binding in abstinence individuals suggest the need for increased dosages of methadone when such patients are treated. Levels of AAG or protein-binding appear to be components of the interindividual variance observed in the response to methadone treatment, hence these variables could be included in future kinetic and dynamic studies.
Adult↗
Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effects of main active metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, in rats.
The pharmacokinetics and pharmacodynamics of the two main metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, were studied in rats. Pharmacodynamic endpoints evaluated were respiratory depression, measured as the change in arterial blood pCO(2), pO(2), and pH levels; and antinociception, measured by the tail-flick technique. The administration of 10 mg/kg (+)-O-desmethyltramadol in a 10-min i.v. infusion significantly altered pCO(2), pO(2), and pH values in comparison with baseline and lower-dose groups (P <.05). However, 2 mg/kg administered in a 10-min i.v. infusion was enough to achieve 100% antinociception without respiratory depression. Moreover, the beta-funaltrexamine pretreatment completely eliminated the antinociception of the 2-mg/kg dose, suggesting that such an effect is due to mu-opioid receptor activation. To describe and adequately characterize the in vivo antinociceptive effect of the drug, (+)-O-desmethyltramadol was given at different infusion rates of varying lengths (10-300 min). Pharmacokinetics was best described by a two-compartmental model. The time course of response was described using an effect compartment associated with a linear pharmacodynamic model. The estimates of the slope of the effect versus concentration relationship were significantly decreased (P <. 05) as the length of infusion was increased, suggesting the development of tolerance. Doses of up to 8 mg/kg (-)-O-desmethyltramadol given in 10-min i.v. infusion did not elicit either antinociception in the tail-flick test or respiratory effects. These in vivo results are in accordance with the opiate and nonopiate properties reported for these compounds in several in vitro studies.
Algorithms↗
Modeling of the in vivo antinociceptive interaction between an opioid agonist, (+)-O-desmethyltramadol, and a monoamine reuptake inhibitor, (-)-O-desmethyltramadol, in rats.
The pharmacokinetic-pharmacodynamic (pk-pd) characterization of the in vivo antinociceptive interaction between (+)-O-desmethyltramadol [(+)-M1] and (-)-O-desmethyltramadol [(-)-M1], main metabolites of tramadol, was studied in three groups of rats. (+)-M1 and (-)-M1, both with different pd properties, were studied under steady-state and nonsteady-state conditions, depending on the group. Plasma drug concentration and antinociception were simultaneously measured in each animal by using an enantioselective analytical assay and the tail-flick test, respectively. Respiratory depression also was evaluated in another series of experiments according to the same experimental conditions. The pk behavior was similar for both enantiomers and no significant (P >.05) interaction between two compounds was found at this level. However, a significant (P <.01) potentiation in the antinociceptive effect elicited by (+)-M1 was found during and after (-)-M1 administration. The pd model used to describe the time course of the antinociception in the presence of (+)-M1, (-)-M1, or both is based on previous knowledge of the compounds and includes the following: 1) an effect compartment model to account for the opioid effect of (+)-M1, and 2) an indirect response model accounting for the release of noradrenaline (NA) caused by (+)-M1, and the inhibition of the NA reuptake due to the action of (-)-M1. The model predicts a positive contribution to antinociception of the predicted increasing levels of NA. No significant (P >.05) respiratory effects were seen during or after (+)-M1 and (-)-M1 administration.
Analgesics, Opioid↗
Simultaneous determination of tramadol and its major active metabolite O-demethyltramadol by high-performance liquid chromatography with electrochemical detection.
A novel, highly sensitive method was developed for simultaneous determination of tramadol and its main active metabolite O-demethyltramadol (ODMT) in rat plasma. The method involves a single-step extraction procedure and a specific determination by high-performance liquid chromatography with electrochemical detection, using an ethoxy analogue of tramadol (L-233) as internal standard. The dual-electrode detector was operated in the oxidation-screening mode. Absolute recoveries of tramadol and ODMT were about 80%. Calibration curves were linear over a concentration range of 10-1000 ng/ml for ODMT and 10-10000 ng/ml for tramadol with intra- and inter-day coefficients of variation not exceeding 10% and 15%, respectively. The limit of quantification for tramadol and ODMT was lower than 15 ng/ml and 10 ng/ml using 100 microl of plasma, respectively. The described method allows an adequate characterization of the plasma vs. time profiles for both compounds.
Analgesics, Opioid↗
Methadone: a review of its pharmacokinetic/pharmacodynamic properties.
During the past decades the use of methadone has been increased as a result of the interest of optimizing its therapeutics in opioid addicts, one of the groups with higher risk for AIDS infection. However standard dose of methadone are far from being the appropriate for relief pain or prevent withdrawal signs in maintenance programs in many patients. To achieve an optimal dose regimen for an individual, the knowledge of the relationship between the pharmacokinetics/pharmacodynamics (pk/pd) drug properties and the demographic and physiopathological characteristics of the subject is required. Unfortunately, there is a lack of studies dealing with the population pk/pd properties of methadone. In the current study, a review of the pk/pd properties of methadone is presented with the aim of understanding the sources of variability in response. This will help in the design of prospective pk/pd studies; in particular, individual data including sex, weight, alpha(1)-acid glycoprotein levels in plasma, concomitant medications, time after starting treatment with methadone and previous exposure to other opioids should be requested. In addition, designs for drug administration should allow the characterization of the plasma-versus-biophase distribution and the development of tolerance processes. Because methadone is usually administered as a racemic mixture, the use of enantioselective techniques to determine both enantiomers in plasma is also highly recommended.
Animals↗
Altered plasma and brain disposition and pharmacodynamics of methadone in abstinent rats.
The pharmacokinetics and pharmacodynamics of methadone were investigated in control and abstinent rats. Minipumps filled with saline (control group) or saline-morphine (abstinent group) solutions were used to induce physical dependence. Solutions were delivered continuously by minipumps for 6 days. The physical dependence was evaluated 12 h after minipump removal by measuring specific withdrawal signs. Animals from the abstinent group showed clear withdrawal signs such as hostility on handling and weight loss. Plasma and brain disposition and pharmacodynamics of methadone were evaluated after a 0.35 mg/kg i.v. bolus dose administered 12 h after minipump removal. Plasma clearance, distribution clearance, and volume of distribution at steady-state were significantly decreased (P < 0.05) in the abstinent group. Plasma levels of alpha1-acid glycoprotein and plasma protein binding were significantly increased (P < 0.05) in the abstinent group. The estimates of pharmacokinetic parameters based on unbound plasma concentrations did not differ between groups, with the sole exception of the unbound apparent volume of distribution. The access of methadone to the brain was significantly faster (P < 0.05) in the abstinent group, although the extent of distribution in the brain was diminished in comparison with the control group. Analgesia recorded with tail-flick was used as the pharmacodynamic endpoint. Analgesic response and effect compartment concentrations of methadone were related by the sigmoidal Emax model. Estimates of C50 [steady-state plasma concentrations eliciting half of maximum effect (Emax)]] based on unbound concentrations did not differ between groups. On the other hand, the estimate of Emax had decreased by 65% in the abstinent group.
Analgesics, Opioid↗
Serum protein binding of lerisetron, a novel specific 5HT3 antagonist, in patients with cancer.
The aim of this study was, (1) to characterize the serum protein binding of lerisetron, a new 5-hydroxytryptamine (5-HT3) receptor antagonist under investigation as an antiemetic agent, and (2) to measure the percentage of unbound lerisetron in cancer patients. The binding parameters were determined in human serum albumin (HSA), alpha1-acid glycoprotein (AAG) and in pooled serum from six healthy volunteers. Concentrations of lerisetron ranging from 50 ng/ml to 2 microg/ml were used. The serum protein binding of 14C-lerisetron (2 microg/ml) was determined by ultrafiltration in three groups of individuals. Group I comprised healthy subjects (n = 11), group II comprised cancer patients undergoing radiotherapy (n = 9), and group III comprised cancer patients receiving chemotherapy (n = 18). The unbound concentration of lerisetron was measured in all samples by liquid scintillation counting. Concentrations of both AAG and HSA were also measured in all serum samples. The drug was extensively bound in pooled serum, involving a nonsaturated process. In HSA, lerisetron was also highly bound (4.04+/-0.8% unbound) and the protein binding was essentially unchanged within the studied concentration range of lerisetron. The extent of binding to AAG was high but significantly lower than in serum and in HSA and was also independent of lerisetron concentration. The unbound lerisetron was significantly decreased in group II cancer patients when compared with group I subjects (2.38+/-0.64% vs 3.70+/-0.70%; P < 0.001). No significant changes in lerisetron binding were observed in group III patients. HSA was diminished in both groups of patients and AAG was only significantly increased in group II. Unbound lerisetron was correlated with AAG in group II and with HSA in group III.
Adult↗
Population pharmacodynamic modeling of levodopa in patients with Parkinson's disease receiving entacapone.
OBJECTIVE: To assess the pharmacodynamics of levodopa among patients with Parkinson's disease showing end-of-dose fluctuations at different doses of entacapone. METHODS: Nineteen patients participated in a randomized, double-blind phase II study with a crossover design. Doses of 50, 100, 200, or 400 mg entacapone or placebo were given with the patient's individual levodopa-dopa decarboxylase inhibitor dose. Blood samples were withdrawn for pharmacokinetic analysis, and the clinical response was measured using the motor part of the Unified Parkinson's Disease Rating Scale. A population pharmacodynamic model was developed with the NONMEM program. RESULTS: A sigmoidal Emax model with an effect compartment was used to relate plasma concentrations of levodopa with clinical response. In the population analysis two covariate relationships were found. The first was E0 = 55.2, [1 + 0.012. (Dur-13)], where E0 is the initial motor Unified Parkinson's Disease Rating Scale score, and Dur is the duration of disease in years. The second was C50(carbidopa) = 951 ng/ml; C50(benserazide) = 1238 ng/ml, where C50 is the steady-state plasma concentration of levodopa eliciting half of maximum attainable effect, and carbidopa and benserazide are the dopa decarboxylase inhibitors given in the study. No effect of entacapone on clinical response beyond its influence on levodopa pharmacokinetics was found. Interindividual and interoccasion variabilities were estimated. CONCLUSIONS: A population pharmacodynamic model for levodopa was built that took into account interindividual and intraindividual variability. The main finding was that entacapone does not alter the concentration-effect curve of levodopa, suggesting that entacapone acts at the level of peripheral pharmacokinetics of levodopa and that plasma levels of 3-O-methyldopa have a negligible role in the pharmacodynamics of levodopa.
Aged↗
Pharmacokinetic-pharmacodynamic modeling of mivacurium in rats.
The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the neuromuscular blocking agent mivacurium were evaluated separately in two groups of rats receiving 0.6 mg kg-1 of mivacurium in a 2.5-min intravenous continuous (iv) infusion. The PK parameters for mivacurium were determined in the first group. A two-compartment model describes the kinetics of mivacurium in plasma. The estimates of the apparent volume of distribution at steady-state and plasma clearance [mean(SE)] were 650 (123) mL kg-1 and 9.9 (0.75) mL min-1 kg-1, respectively. In the second group, the evoked tibialis anterior muscle tension was monitored. The PK parameters derived from the first group were used to compute mivacurium plasma concentrations (C) at the times the PD measurements were recorded in the second group. The concentration-neuromuscular effect [% depression of initial twitch tension (E)] relationship was analyzed by two approaches. (1) The relationship of estimated effect site concentrations versus E; a sigmoidal Emax model described the effect compartment concentrations versus E relationship. The estimate [mean(SE)] of Cess50 (steady-state plasma concentration eliciting half of maximum E) was 0.65 (0.01) microgram mL-1. The value [mean-(SE)] of Keo (rate constant of equilibration between plasma and effect site) was estimated at 0.32 (0.03) min-1. (2) The relationship of descending limb C versus E; a sigmoidal Emax model described such relationship. The estimate [mean(SE)] of C50 (post-infusion C eliciting half of maximum E) was 0.57(0.03) microgram mL-1. The PD properties of mivacurium were also evaluated in another two groups of animals receiving either 5- or 10-min continuous iv infusion; PK and PD parameters obtained from the 2.5-min infusion experiments were used to predict the time course of E in the groups receiving 0.6 mg kg-1 of mivacurium in 5- and 10-min infusions; simulations using the estimated parameters adequately describe the time course of E in those groups. The effect of mivacurium on the mean arterial blood pressure (MAP) was also investigated; a 10% nonsignificant decrease (p > 0.05) in MAP was found in all groups.
Animals↗
Pharmacokinetics and pharmacodynamics of penbutolol in healthy and cancer subjects: role of altered protein binding.
The pharmacokinetic and pharmacodynamic profiles of penbutolol were examined in healthy volunteers and in cancer patients using a pharmacokinetic/pharmacodynamic (pk/pd) model. After receiving a 40 mg single oral dose of penbutolol, the absorption rate constant, apparent volume of distribution and serum clearance of penbutolol were found to be reduced in the cancer group. Changes in the disposition of the conjugate metabolite were also observed in the cancer patients. Penbutolol unbound fraction in serum was statistically decreased (p < 0.005) in the cancer group, according to the increase in the serum levels of alpha 1-acid glycoprotein seen in that group (p < 0.05). The pharmacodynamic effect of penbutolol was measured as the reduction in heart rate (HR); in healthy volunteers, a linear relationship (p < 0.01) between effect and penbutolol serum concentrations (total or unbound) was found. In contrast, in cancer patients, values of HR did not vary statistically in respect to baseline values. These results show that in cancer patients, a change in the pharmacokinetics of penbutolol occurs (associated with changes in drug protein binding), together with an alteration in the pharmacodynamics.
Adult↗
Population-based approach to the assessment of pharmacokinetic-pharmacodynamic data.
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Analysis of Variance↗
Resistance to atracurium in rats with experimental inflammation: role of protein binding.
The influence of altered protein binding on the neuromuscular effect of atracurium has been studied in rats with experimental inflammation induced by subcutaneous injection of turpentine oil. Doses of atracurium ranging from 0.45 to 1.5 mg.kg-1 were administered to control (n = 30) and to experimental inflammation induced rats (n = 30). Neuromuscular transmission was monitored by recording the twitch tension of the tibialis-anterior muscle elicited by stimulation of the sciatic nerve. Three effect parameters were recorded: (i) intensity of the effect, measured as percentage depression of baseline twitch tension, (ii) duration of drug action (min) and (iii) recovery time (min). The dose-intensity of the effect relationship was modelled using a sigmoid Emax model. The ED50 (effective dose eliciting 50% of the maximum effect) was significantly increased (P < 0.01) in the inflammation group as compared to the control group (0.94 vs. 0.68 mg.kg-1). This change was reflected in a shift of the dose-response curve to the right in the pretreated rats. For equipotent doses ED95 (defined as the effective dose eliciting 95% of maximum effect), no differences were found in recovery time and duration of action between the two groups of rats. Mucoproteins levels (index of alpha 1-acid glycoprotein (AAG) and protein binding were significantly increased in rats with experimental inflammation as compared to control rats. Based on these results, altered serum protein binding of atracurium appears to be responsible, at least in part, for the resistance to atracurium.
Animals↗