Pharmacokinetic and pharmacodynamic comparison of conventional and controlled release formulations of motoprolol in healthy chinese subjects

Summary A double-blind, crossover comparison of the pharmacokinetics and pharmacodynamics of controlled- release metoprolol (CR) 100 mg and 200 mg, metoprolol plain tablet 100 mg, metoprolol Durules 200 mg, and placebo was carried out in 10 healthy Chinese subjects. Standardized treadmill exercise tests according to the Bruce protocol were performed at a steady state of medication, before and 2, 6, 12 and 24 hours after the dose, and multiple blood samples were collected for determination of the metoprolol concentration. The plasma metoprolol levels over 24 hours were more uniform after metoprolol CR than Durules and the plain tablet. The mean peak concentrations for CR 100 mg, 200 mg, Durules, and the plain tablets were 231, 426, 790, and 1105 nmol/l, respectively. The corresponding fluctuation incides were 1.1, 1.5, 2.2, and 5.0. The effects on exercise heart rate (EHR) were investigated at steady state. Metoprolol CR produced more even reduction in EHR over 24 hours than Durules and plain tablets. All four treatments gave similar maximal reduction in EHR of about 20% at 2 hours after the dose. In conclusion, once daily metoprolol CR showed almost even blood levels and provided relatively constant levels of beta¹ blockade over 24 hours in healthy Chinese subjects.     

Pharmacokinetic and pharmacodynamic concepts for an interpretative reading of the antibiogram

Both microbiological and epidemiological reading of the antibiogram can be performed without additional pharmacokinetic or pharmacodynamic concepts. However, when the aim is a clinical reading of the antibiogram, knowledge of the pharmacokinetics of antimicrobial agents and of all phenomena occurring between antimicrobial agents and microorganisms is imperative. Pharmacokinetics includes the study of absorption, distribution, metabolism and elimination of drugs. These data provide information on the active concentrations of antimicrobial agents in blood and other fluids as well as in the tissues where infection may develop. Knowledge of metabolism and of elimination pathways complete the main pharmacokinetic parameters of antimicrobial agents. The bactericidal effect of antimicrobial agents can be either concentration- or time-dependent. In the former, high concentrations of antimicrobial agents, much higher than their corresponding MICs, are needed, while in the latter, maintaining the concentration of antimicrobial agents at levels slightly higher than their MICs over time is more important. With these concepts, a microbiological-pharmacological reading of the antibiogram, taking into account dosage, administration pathway and location of the infectious process among other factors, can be achieved. Most working groups, either national or from abroad, have considered both pharmacokinetics and pharmacodynamics in interpretative reading of the antibiogram. In all cases, breakpoints for susceptibility and resistance should be corrected on the basis of data from well designed and performed clinical trials. Clinically oriented breakpoints do not necessarily have to be the same as those based on microbiological or epidemiological concepts, but clinical microbiologists should be able to give an appropriate response to the question and to the application based on that response.     

Pharmacokinetics of sustained release and conventional tablets of theophylline plus hydroxyethyltheophylline and its comparison with tablet aminophylline.

Pharmacokinetics of a sustained release (SR) and conventional formulations of theophylline plus hydroxyethyltheophylline was compared with tablet aminophylline. Time concentration curve of serum theophylline with the three formulations after single and multiple dosage schedules revealed significantly retarded absorption with the SR preparation. SR tablet was also seen to produce uniform steady state levels with fluctuation of serum concentrations within the therapeutic range for a duration of over 12 hours. In comparison, aminophylline and conventional theophylline hydroxyethyltheophylline tablets produced sharp swings in steady state levels with trough levels dipping to subtherapeutic concentrations within 4-6 hours. SR formulation, therefore, is likely provide consistent serum levels and better therapeutic control in comparison to the other two conventional tablets.     

Pharmacokinetic and pharmacodynamic effects of diltiazem

The pharmacokinetic and pharmacodynamic effects of diltiazem were studied in 8 patients after a short intravenous infusion (20 mg over 10 minutes), a single oral dose (60 or 90 mg), and repeated oral administration (60 or 90 mg every 6 hours for 16 doses). Diltiazem levels decreased in a triexponential manner after intravenous infusion. Terminal half-lives after intravenous, single oral, and repeated oral administration were not significantly different (4.5 ± 1.3, 3.7 ± 0.6, and 4.9 ± 0.4 hours, respectively). The kinetic effects of oral diltiazem were nonlinear. With repeated oral administration, there was accumulation of both diltiazem and its metabolite, deacetyldiltiazem. The diltiazem area under the time versus concentration curve increased by a factor of 2.39 ± 0.42 (p = 0.00002). Most patients showed a double peaked time versus concentration curve after oral administration, indicating possible enterohepatic recirculation.After intravenous administration, there was a substantial increase in the P-R interval (14.3 ± 5.4%). Although only small changes in P-R interval were seen with a single oral dose, with chronic administration there was persistent P-R interval prolongation, peaking at 17.3 ± 5.6% over control. Counterclockwise hysteresis was present in the P-R interval versus plasma diltiazem concentration curve after intravenous administration. Only small changes were seen in heart rate and blood pressure.     

Pharmacokinetic and pharmacodynamic characterization of a medium-molecular-weight heparin in comparison with UFH and LMWH

Despite the well-established medical use of heparins, the question arises whether the efficacy-safety ratio of the available heparins can still be improved. Therefore, a medium-molecular-weight heparin (MMWH), a new heparin with an average molecular weight of 10.5 kDa and a narrow molecular weight range (9.5 to 11.5 kDa) was developed. Its in vitro activities amount to 174.9 anti-factor Xa (aXa) U/mg and 170.0 antithrombin (aIIa) U/mg. In the presented randomized, double-blind, cross-over study in healthy volunteers, the pharmacokinetics and pharmacodynamics of MMWH are compared with those of an unfractionated heparin (UFH) and a low-molecular-weight heparin (LWMH; enoxaparin). After subcutaneous administration of 9000 aXa-U of either heparin in 16 volunteers, the prolongation of the activated partial thromboplastin time (aPTT), the aXa activity, and the aIIa activities were determined at 11 time points spread over 24 hours after injection. The ex vivo analysis revealed striking pharmacodynamic and pharmacokinetic differences between the three heparins. UFH had the lowest bioavailability regarding the aPTT, aXa, and aIIa activities. Enoxaparin exhibited only low aIIa activity but the highest aXa activity. Unlike UFH and enoxaparin, MMWH showed a high recovery of aIIa activity, which suggests that it combines the high potency to inhibit thrombin that characterizes UFH with the high bioavailability of the LMWHs. Consequently, substantially lower doses are needed to bring about effects comparable to those of UFH and LMWH.     

Pharmacokinetic and pharmacodynamic modelling of antibiotic therapy

Despite the advances in pharmacokinetic and pharmacodynamic modelling, there is still much more to gain from this concept. The use of pharmacokinetic and pharmacodynamic modelling in vitro, in animal and in human models has confirmed that an index, such as peak concentration divided by the minimum inhibitory concentration (Cmax/MIC), the area under the curve divided by the minimum inhibitory concentration (AUC/MIC) and time above the minimum inhibitory concentration (T>MIC), may be used as an aid to understanding better the variability between patients who receive similar antibiotic dosage regimens but have dissimilar outcomes. Efforts to find the optimal pharmacokinetic or pharmacodynamic index predictive of response is crucial to identify targets that will ensure efficacy and for the prediction of failure.     

Pharmacokinetic/pharmacodynamic antimicrobial individualization and optimization strategies

Effective antimicrobial chemotherapy integrates pharmacology and microbiology to achieve the most favorable clinical and microbiologic outcomes. Understanding such relationships allows us to select the optimal drug dose in a rational manner. The difficulty lies in translating the research findings to clinicians at the bedside. Current clinical practices have not embraced fully many advances in pharmacokinetic/pharmacodynamic research. This article summarizes what we have learned over the past decades and highlights some of the barriers to translating these results into clinical practice. Reducing these barriers would help to bring clinically relevant laboratory work to the bedside and would emphasize evidence-based medicine. It may also improve patient outcomes and minimize the emergence of resistance.     

Evolution of oral drug forms of metoprolol: advantages of long acting modified release forms with modified release

Review oral modified release drug forms of beta-adrenoblocker metoprolol which is used in arterial hypertension and ischemic heart disease is presented. Metoprolol has salts such as tartrate which is used for production of immediate release (IR) and sustained release (SR) forms and succinate used for production of controlled release form (CR/XL). Metoprolol SR has monolith matrix type, metoprolol CR/XL-system of multiple pellets. Effect of metoprolol tartrate (IR) on mortality was demonstrated in a number of studies in patients with arterial hypertension (AH) (MAPHY), myocardial infarction (SMT, GMT, MIAMI), dilated cardiomyopathy and heart failure (MDC). Studies of efficacy of metoprolol SR are scarce. Antihypertensive efficacy of metoprolol SR in patients with AH did not exceed that of a metoprolol IR or CR/XL. First retrospective analysis of efficacy of metoprolol tartrate and succinate (CR/XL) in patients after myocardial infarction allowed to obtain comparable results of 34% mortality lowering. In a prospective study in patients with chronic heart failure (COMET) metoprolol tartrate IR was not superior to carvedilol when mortality lowering was concerned. At the same time administration of controlled release metoprolol (CR/XL) in 2 large clinical trials (RESOLVD, MERITAHF) was advantageous in patients with chronic heart failure relative to lowering of mortality and rate of hospitalizations. A novel controlled release form of metoprolol has been created as a tartrate salt on the basis of pellet technology (CD/ERT) and its bioequivalence to metoprolol CR/XL has been proved.     

Pharmacokinetic comparison of intranasal, oral, and intramuscular metoclopramide in healthy volunteers

This was a randomized, crossover study of the bioavailability and pharmacokinetics of metoclopramide given by intranasal (IN), oral (PO), and intramuscular (IM) routes. The formulations tested were 5 and 10 mg of IN gel, 10 mg PO, and 5 mg IM. The findings showed that metoclopramide follows similar absorption and elimination characteristics when given via these three extravascular routes. There were no statistically significant differences in the area under the drug concentration versus time curve (AUC) or peak metoclopramide plasma concentration (Cmax) data following PO, IM, or 10-mg IN administration. However, the 5-mg IN doses achieved an AUC that was 39.5% the AUC of the 10-mg IN dose. These data show consistent and relatively predictable metoclopramide plasma concentrations following IN administration. Further, 10-mg doses of IN and PO metoclopramide appear to be bioequivalent.     

Pharmacokinetic and pharmacodynamic aspects of antibiotic use in high-risk populations

The study of pharmacokinetics includes the absorption, distribution, metabolism, and elimination of drugs. The pharmacologic effect that a medication has on the body is known as pharmacodynamics. With antimicrobials, pharmacokinetic and pharmacodynamic parameters become especially important because of the association between host drug concentrations, microorganism eradication, and resistance. This article focuses on the pharmacokinetic changes that can occur with antimicrobials when they are used in patients at high risk of infections and how they influence pharmacodynamic effects. The populations described here include patients with obesity and diabetes mellitus, renal or hepatic failure, chronic lung disease, severe burns, and long-term prosthetic devices and the elderly.     

Pharmacokinetic and pharmacodynamic properties of long-acting insulin analogue NN304 in comparison to NPH insulin in humans.

NN304 is a long-acting insulin analogue that is acylated with a 14-C-fatty acid chain. Protraction of action of this novel insulin analogue is due not to slow absorption after subcutaneous administration but to reversible binding to albumin. We investigated the pharmacokinetic and pharmacodynamic properties of insulin analogue NN304 (0.3 and 0.6 U/kg) in comparison to NPH insulin (0.3 and 0.6 IU/kg) in 10 healthy volunteers performing a randomised, double-blind, cross-over, placebo-controlled glucose clamp study. During the observation period of 24 hours the areas under the insulin curve for NPH[0.3 IU/kg] vs. NPH[0.6 IU/kg] were 60 vs. 102 nmol min l(-1) (p<0.01) and for insulin analogue NN304[0.3 U/kg] vs. NN304[0.6 U/kg] 490 vs. 932 nmol min l(-1) (p <0.001), suggesting a clear dose-response relationship for both NPH insulin and NN304. The amount of disposed glucose (area under the curve of glucose infusion) differed with statistical significance between the five treatments and was highest with NPH[0.6 IU/kg] (2671 mg/kg) and lowest with placebo (265 mg/kg). However, area under the curve of glucose infusion after treatment with NN304 was only 36% (dose of 0.3 U/kg) and 24% (dose of 0.6 U/kg) of that observed with corresponding doses of NPH insulin. Moreover, increasing dosages of NN304 failed to demonstrate a significant dose-response with regard to the area under the curve of glucose infusion. This study demonstrates that the principle of protracted insulin action of NN304 by reversible binding to albumin is effective in humans albeit at a much lower rate of glucose utilisation when compared to NPH insulin. Thus, in contrast to animal studies NN304 and NPH insulin can not be considered equipotent in humans.     

Pharmacokinetics and pharmacodynamic effects of an oral ghrelin agonist in healthy subjects

CONTEXT: An oral formulation of EP01572, a peptidomimetic growth hormone secretagogue, was studied. An oral delivery system would be preferable in many of the possible therapeutic indications of ghrelin agonists such as EP01572. OBJECTIVES: Our objective was to establish the pharmacological profile and the GH-releasing activity of increasing oral doses of EP01572 in healthy volunteers. In addition, the pharmacokinetics and pharmacological effects of EP01572 were investigated after intraduodenal (ID) administration. SETTING: This study was a single-center escalating dose study with oral and ID applications. SUBJECTS AND METHODS: In the first part, EP01572 was given orally to 36 male subjects; the treatment consisted of one oral dose of either EP01572 or placebo (0.005, 0.05, and 0.5 mg/kg body weight). Six subjects received two additional oral doses of EP01572: 0.125 and 0.25 mg/kg body weight. In the second part, the following treatments were performed in a randomized order: 1) administration of a bolus of saline (placebo) to the small intestine; 2) ID administration of a bolus of EP01572 at 0.2 mg/kg body weight; 3) ID perfusion of a bolus of EP01572 at 0.35 mg/kg body weight; and 4) ID perfusion of a bolus of EP01572 at 0.5 mg/kg body weight. RESULTS: The oral and ID administration of EP01572 induced a rapid and dose-dependent increase in plasma drug concentrations and a potent GH release in healthy male volunteers. CONCLUSIONS: This study showed that EP01572 was active with regard to stimulation of GH release in humans after oral and ID administration.     

Pharmacokinetic and pharmacodynamic properties of antimicrobials in the therapy of respiratory tract infections

Antimicrobial pharmacodynamics examines the relationship between the pharmacokinetics of a drug over time and its treatment effect. Pharmacokinetic/pharmacodynamic parameters have been shown to be predictors of the antimicrobial activity of a variety of drugs. The pharmacodynamic parameter linked to efficacy has been demonstrated to vary for different antimicrobial classes. Within an antimicrobial class, the magnitude of the pharmacodynamic parameter predictive of efficacy has been shown to be similar, as long as free-drug levels in serum are considered. Treatment outcome predictions based upon parameter magnitudes have correlated well and have been useful for assessing the future course of both susceptible and resistant pathogens of the respiratory tract. This has been useful for the development of susceptibility breakpoints and antimicrobial treatment guidelines. Recent studies have begun to investigate the relationship between antimicrobial pharmacodynamics and the prevention of drug resistance.     

Pharmacokinetic and pharmacodynamic evaluation of intramuscular artesunate in healthy beagle dogs

Pharmacokinetic and pharmacodynamic responses were evaluated after intramuscular (i.m.) injection of artesunate (AS). Twelve dogs were injected with i.m. AS at 2.5, 5, or 10 mg/kg into the left gluteal muscle. A second injection of only diluent was given in the right gluteal muscle. At 24 hours post-injection, plasma creatine kinase (CK) concentrations were elevated above normal. Muscle biopsies showed myocyte necrosis and acute inflammation, which was worse on the treated side. At 7 days after injection, CK concentrations were normal. Muscle biopsies showed mineralization, fibrosis, and chronic inflammation with less difference between sides. Compared with intravenous administration, i.m. AS resulted in a prolonged half-life for both AS and DHA. Intramuscular AS also had a lower mean dose-adjusted C(max) and a higher mean dose-adjusted area under the curve; but produced similar concentrations of dihydroartemisinin. These findings suggest that adverse reactions to i.m. artesunate are minor and temporary which justify further study of this route in treating severe malaria.