Pharmacokinetics and pharmacodynamics of low-dose methotrexate in the treatment of psoriasis

AIMS: The aim of this 13 week, randomized, parallel-group study was to evaluate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of low-dose intermittent oral methotrexate (LDMTX) in patients with psoriasis. METHODS: Twenty-four psoriatic patients (15 male and 9 female, aged 31-73 years) were given weekly doses of MTX doses of either 7.5 mg or 15 mg with each dose divided into three aliquots given at 12 h intervals. The pharmacokinetics of MTX were evaluated at weeks 1 and 13. Skin impairment was assessed using the PASI-scoring system (The Psoriasis Area and Severity Index) at baseline and at weeks 5, 9 and 13 of therapy. Haematological and biochemistry tests were also performed at these times. RESULTS: The comparison of the areas under the plasma concentration-time curve (AUC(MTX)) after the first and third weekly doses showed that the extent of MTX accumulation in plasma was only about 12%. Two-way anova (factors: subject and the week of therapy) on the log-transformed AUC(MTX) showed no effect of the week of therapy (P>0.8). Moreover, the intraindividual variability in the AUC(MTX) was at least 4-fold less than the interindividual variability (F-test; P<0.01). The steady-state total plasma clearance of MTX ranged from 5.0 to 18.2 l h(-1) and was proportional to the renal clearance (r2=0.45, P<0.001) which accounted for 65+/-20% of the former. The renal clearance of 7-OHMTX was approximately 4-8% of that of the parent compound. PK/PD analysis revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady-state AUC(MTX) (rs=-0.65, P<0.001). Seventeen subjects (8 from the 7.5 mg group and 9 from the 15 mg group MTX, P=0.67) achieved a greater than 50% decrease in the initial PASI score and were classified as responders. Thirteen of 14 subjects with AUC(24,36 h)> or =700 nmol l(-1) h responded to pharmacotherapy. Conversely, only 4 out of 10 subjects with AUC(24,36 h)<700 nmol l-1 h were responders (P<0.01, Fisher's exact test). CONCLUSIONS: A strong correlation was observed between the pharmacokinetics (AUC(MTX) at the steady state) and antipsoriatic effect (PASI-score) of LDMTX. The considerable interindividual variability and low intraindividual variability in MTX pharmacokinetics support a role for therapeutic monitoring and dose individualization at the start of pharmacotherapy. The results of this study suggest that a steady state AUC(MTX) values of 700 nmol l(-1)h and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values.     

Pharmacokinetics,pharmacodynamics and toxicities of methotrexate in healthy and collagen‐induced arthritic rats

Methotrexate (MTX) is an anchor drug used to treat rheumatoid arthritis (RA), but responsiveness is variable in effectiveness and toxicity. Methotrexate and its polyglutamate conjugates (MTXPG_n) in red blood cells (RBC) have been associated with patient response. In the current study, 13 collagen‐induced arthritic (CIA) rats and 12 healthy rats were given subcutaneous doses of either saline or 0.3 or 1.5 mg/kg per 2 days of MTX from day 21 to 43 post‐induction. Blood samples were obtained at various times to measure MTX in plasma, and MTX and MTXPG_n in RBC. Effects on disease progression were indicated by body weight and paw size. After multiple‐doses, RBC MTX reached steady‐state (82.4 nm ) within 4 days. The MTXPG₂ and MTXPG₃ in RBC kept increasing until the end of the study, attaining 12.5 and 17.7 nm . Significant weight loss was observed after dosing with 1.5 mg/kg/2 days, whereas moderate effectiveness was observed after dosing with 0.3 mg/kg/2 days. A pharmacokinetic/pharmacodynamic/disease (PK/PD/DIS) model with indirect mechanisms and transduction components incorporating plasma MTX, RBC MTX and RBC MTXPG_n concentrations, and paw size was developed using naïve data pooling and ADAPT 5. The PK/PD in CIA rats dosed at 0.3 mg/kg/2 days were captured well by our proposed model. Methotrexate showed modest (I_maxd = 0.16) but sensitive (IC_50d = 0.712 nm ) effectiveness on paw edema. The higher dose produced toxicity. The proposed model offers improved understanding of the effects of methotrexate on rheumatoid arthritis. Copyright © 2013 John Wiley & Sons, Ltd.     

Pharmacokinetics and pharmacodynamics in toxicology

1. Pharmacokinetics aids interpretation of the dose-response relationship in individual toxicology studies. 2. When used to compare across studies, even in a single species other factors, including variation in pharmacodynamic response, must be taken into account. Variation in pharmacodynamic response becomes more profound when one compares across species. 3. Examples do occur where plasma concentration-response relationships are constant across species, particularly when corrected for unbound drug. These examples should not be taken as support, however, of a general universal principle. 4. Owing to multiple factors such as species differences in receptors, enzymes and ion channels,dose or plasma concentration-response relationships can vary enormously across species. In the light of this, the results of toxicology studies should be viewed as qualitative rather than quantitative. Once sufficient clinical experience is gained the human database is the overriding measure of drug safety.     

Pharmacokinetics and pharmacodynamics of diprophylline

Diprophylline is used in many countries as a bronchodilator. It is an N-substituted theophylline derivative which does not release theophyllinein vitro orin vivo. It therefore has its own pharmacokinetic and pharmacodynamic properties. In a cross-over study in ten healthy volunteers serum concentrations and urinary excretion were studied after administration of diprophylline.Its serum decay after intravenous administration shows two-compartment kinetics with a rapid distribution. The-phase lasted on average 0.75 h and was 0.427±0.118 h^–1, corresponding with a-phase half-life of 1.7±0.4 h. The mean volume of distribution was 0.70±0.20 l/kg, total body clearance 0.29±0.09 l.kg^–1.h^–1. About 84% of the drug is excreted unchanged in the urine. A comparison of the area under the curve suggests that the drug was almost completely absorbed from the gastro-intestinal tract. Its bioavailability is about 90%. Mean renal clearance values are higher than paired creatinine clearance values, which is an indication for active renal transport.Peak levels of diprophylline were 7.4±2.2 mg/l at about 30 min after oral administration. The normal dose advocated is 200–400 mg three times a day. Inin vitro studies and in pharmacological animal studies diprophylline appears to be much less active than theophylline. Consequently estimated effective dosages are irrationally high.In honour of ProfessorHuizinga on the occasion of his retirement.     

Pharmacokinetics and pharmacodynamics of isothiocyanates

Isothiocyanates from Brassica vegetables are of great interest for use in the cure of bacterial infections, as is their potential application in the prevention and treatment of cancer. Although much information is available on their mode of action within the cell, when it comes to the question of whether the necessary pharmacologic concentration has been reached at the target organ, detailed knowledge is still lacking. However, a basic prerequisite for clinical application to humans is knowledge of isothiocyanate pharmacokinetic and dynamic behavior in the human body (e.g., to define intake intervals or to ascertain constant levels of the active compound). In this context, we, therefore, reviewed the available literature on in vitro studies, as well as animal and human intervention trials conducted with isothiocyanate and isothiocyanate-containing food preparations.     

Pharmacokinetics and pharmacodynamics of pegfilgrastim

Pegfilgrastim is a sustained-duration form of filgrastim, a recombinant methionyl form of human granulocyte colony-stimulating factor (G-CSF), to which a 20 kDa polyethylene glycol molecule is covalently bound to the N-terminal methionine residue. Similar to filgrastim, pegfilgrastim increases the proliferation and differentiation of neutrophils from committed progenitor cells, induces maturation, and enhances the survival and function of mature neutrophils, resulting in dose-dependent increases in neutrophils. After subcutaneous administration, pegfilgrastim exhibits nonlinear pharmacokinetics and exposure to pegfilgrastim increases in more than a dose-proportional manner, suggesting that the clearance of pegfilgrastim decreases with increased dosing. Filgrastim is primarily eliminated by the kidney and neutrophils/neutrophil precursors; the latter presumably involves binding of the growth factor to the G-CSF receptor on the cell surface, internalization of the growth factor-receptor complexes via endocytosis, and subsequent degradation inside the cells. Pegylation of filgrastim renders renal clearance insignificant, which was demonstrated in bilaterally nephrectomized rats and confirmed in subjects with renal impairment. As a result, the neutrophil-mediated clearance is the predominant elimination pathway for pegfilgrastim. During chemotherapy-induced neutropenia, the clearance of pegfilgrastim is significantly reduced and the concentration of pegfilgrastim is sustained until onset of neutrophil recovery. Pegfilgrastim concentrations are sustained longer in patients with profound neutropenia. Evidence supports the use of a postnadir absolute neutrophil count (ANC) of ≥ 1?×?109/L as a surrogate marker threshold for the clearance of pegfilgrastim to subtherapeutic levels. After repeated administration of pegfilgrastim, the peak concentrations of pegfilgrastim decrease, likely due to increased neutrophil and neutrophil precursor mass. A pharmacokinetic-pharmacodynamic model was developed to describe the pharmacokinetic and ANC profiles of pegfilgrastim; the analysis supported that 100 μg/kg was an adequate weight-based dose of pegfilgrastim and predicted that 6 mg would be an optimal fixed dose of pegfilgrastim to simplify treatment. Data from a pivotal study confirmed that a once-per-chemotherapy-cycle injection of pegfilgrastim at 6 mg was as safe and effective as 11 daily injections of filgrastim at 5 μg/kg in reducing neutropenia and its complications in patients with breast cancer receiving four cycles of doxorubicin/docetaxel chemotherapy. Because of the highly efficient regulation of pegfilgrastim clearance via neutrophils and neutrophil precursors, a single fixed dose of pegfilgrastim can be given once per chemotherapy cycle in conjunction with a variety of myelosuppressive chemotherapy regimens.     

氟卡胺的药代动力学与药效动力学

氟卡胺是抑制心脏传导间期AH,HV,QRS,QT的抗心律不齐新药。犬iv 2,4 mg/kg氟卡胺后呈二室型代谢动力学特点,其t_(1/2)为60～70min。健康人po 200 mg/kg与小鼠sc 10 mg/kg氟卡胺后呈一级吸收一室型,t_(1/2)为60～76 min。 以抑制传导间期为药效指标,犬iv 4 mg/kg氟卡胺后测各传导间期变化,计算药效动力学,公式为:△％=(△_(max)％)c~(-kt)。以血药浓度对数对相应时间传导间期变化(△％)作图呈线性相关,计算公式为:C=ae~b(△％)。     

Pharmacokinetics and pharmacodynamics of azosemide

Azosemide is used in the treatment of oedematous states and hypertension. The exact mechanism of action is not fully understood, but it mainly acts on both the medullary and cortical segments of the thick ascending limb of the loop of Henle. Delayed tolerance was demonstrated in humans by homeostatic mechanisms (principally an increase in aldosterone secretion and perhaps also an increase in the reabsorption of solute in the proximal tubule). After oral administration to healthy humans in the fasting state, the plasma concentration of azosemide reached its peak at 3-4 h with an absorption lag time of approximately 1 h and a terminal half-life of 2-3 h. The estimated extent of absolute oral bioavailability in humans was approximately 20.4%. After oral administration of the same dose of azosemide and furosemide, the diuretic effect was similar between the two drugs, but after intravenous administration, the effect of azosemide was 5.5-8 times greater than that in furosemide. This could be due to the considerable first-pass effect of azosemide. The protein binding to 4% human serum albumin was greater than 95% at azosemide concentrations ranging from 10 to 100 microg/ml using an equilibrium dialysis technique. The poor affinity of human tissues to azosemide was supported by the relatively small value of the apparent post-pseudodistribution volume of distribution (Vdbeta), 0.262 l/kg. Eleven metabolites (including degraded products) of azosemide including M1, glucuronide conjugates of both M1 and azosemide, thiophenemethanol, thiophencarboxylic acid and its glycine conjugate were obtained in rats. Only azosemide and its glucuronide were detected in humans. In humans, total body clearance, renal clearance and terminal half-life of azosemide were 112 ml/min, 41.6 ml/min and 2.03 h, respectively. Azosemide is actively secreted in the renal proximal tubule possibly via nonspecific organic acid secretory pathway in humans. Thus, the amount of azosemide that reaches its site of action could be significantly modified by changes in the capacity of this transport system. This capacity, in turn, could be predictably changed in disease states, resulting in decreased delivery of the diuretic to the transport site, as well as in the presence of other organic acids such as nonsteroidal anti-inflammatory drugs which could compete for active transport of azosemide. The urinary excretion rate of azosemide could be correlated well to its diuretic effects since the receptors are located in the loop of Henle. The diuretic effects of azosemide were dependent on the rate and composition of fluid replacement in rabbits; therefore, this factor should be considered in the evaluation of bioequivalence assessment.     

Pharmacokinetics and pharmacodynamics of cannabinoids

Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.     

喹诺酮类抗菌药物的药动学和药效学研究进展

喹诺酮类是目前临床普遍使用的一类抗菌药物.现从体外实验、动物实验和人体试验等方面对其药动学/药效学(PK/PD)研究进行了综述,并对PK/PD与细菌耐药及其在临床上的应用进行了简介.     

Pharmacokinetics and pharmacodynamics of procyclidine in man

The pharmacokinetics and pharmacodynamics of procyclidine (10 mg) after oral and intravenous administration were studied in six healthy volunteers. Treatment order was randomised and the study was placebo-controlled and conducted blind. After oral dosing the mean peak plasma concentration was 116 ng/ml and mean bioavailability was 75%. After both oral and intravenous dosing the mean values for the volume of distribution, total body clearance and plasma elimination half-life of procyclidine were in the order of 1 l/kg, 68 ml/min and 12 h respectively. Autonomic effects were maximal within 0.5 h of intravenous administration and at about 1-2 h after oral dosing. Significant effects on pupil diameter, visual near point, salivary secretion and heart rate occurred after intravenous treatment and similar but less marked effects occurred after the oral dose. Significant autonomic effects were still detectable 12 h after both forms of treatment.     

Pharmacokinetics and pharmacodynamics of famotidine in infants

The pharmacokinetics and pharmacodynamics of intravenous famotidine were evaluated in 10 infants ranging from 5 to 19 days of age who had a therapeutic indication for the prophylactic treatment of stress ulceration. After a 0.5-mg/kg infusion of famotidine, timed serum (n = 6), urine (24-hour collection), and repeated measurements of gastric pH were obtained. The mean +/- standard deviation maximum plasma concentration (Cmax) was 640.66 +/- 250.66 ng/mL, the elimination half-life (t1/2 beta) was 10.51 +/- 5.43 hours, and the apparent volume of distribution at steady state (Vdss) was 0.82 +/- 0.29 L/kg. Plasma clearance (Cl) and renal clearance (ClR) were 0.132 +/- 0.061 L/hr/kg and 0.093 +/- 0.056 L/hr/kg, respectively. No significant correlations were found between t1/2 beta, Vdss, Cl, and ClR and age. Six of the nine infants who had intragastric pH monitoring maintained a gastric pH > 4 until the final 24-hour sampling point. In this study, the t1/2 beta of famotidine was prolonged and the Vdss, Cl, ClR were reduced compared with corresponding parameters in previously reported studies of children older than one year of age and adults.     

Pharmacokinetics and pharmacodynamics of oral nizatidine

Nizatidine was studied in six high-acid-secretor (basal secretion, greater than or equal to 5 mEq/hr) male volunteers in a randomized, double-blind, nonbalanced, cross-over, placebo and standard drug-controlled study. Doses of 75 mg, 150 mg, and 300 mg bid were compared with placebo and cimetidine 300 mg qid. Nocturnal acid output was significantly reduced (P less than .01) by all doses of nizatidine (36 +/- 22, 36 +/- 31, and 26 +/- 20 mEq) with 75 mg, 150 mg and 300 mg, respectively, and also by cimetidine (43 +/- 39 mEq) as compared with placebo (101 +/- 61 mEq). Nizatidine also significantly reduced meal-stimulated acid secretion at breakfast (14 +/- 9, 9 +/- 7, and 5 +/- 6 mEq/2 hours with 75 mg, 150 mg, and 300 mg, respectively, P less than .01), at lunch (50 +/- 22, 57 +/- 22 and 50 +/- 35 mEq/2 hours, P less than .05) but did not have any effect at dinner (65 +/- 16, 78 +/- 24, and 71 +/- 17 mEq/2 hours) whereas cimetidine, given every 6 hours, significantly (P less than .01) reduced meal-stimulated acid secretion (25 +/- 16, 27 +/- 20 and 31 +/- 15 mEq/2 hours, breakfast, lunch, and dinner, respectively) as compared with placebo (81 +/- 30, 76 +/- 25, and 66 +/- 16 mEq/2 hours, breakfast, lunch, and dinner, respectively). Both drugs have a similar pharmacokinetic profile. Nizatidine seems to be a promising H2 antagonist, more potent than cimetidine (on an mg/mg basis), and efficacy studies on gastric acid disorders should be performed.     

Pharmacokinetics and pharmacodynamics of transdermal dexmedetomidine

This study was designed to determine whether both enantiomers of chloroquine inhibit histamine N-methyltransferase. The mean estimates of IC₅₀ for the d- and l-enantiomers of chloroquine were 4.9 and 17.8 M (liver), respectively and 6.9 and 21.6 M (brain), respectively. K_i estimates were significantly lower with d- than with l-chloroquine; hence, d-chloroquine interacts with the enzyme more effectively than l-chloroquine. If the adverse effects of chloroquine are due to the inhibition of histamine N-methyltransferase, therapy with the l-enantiomer might have lower toxicity. The residual activity of histamine N-methyltransferase should reflect both the degree of inhibition by chloroquine and the level of enzyme expression. The rate of histamine methylation was measured in 100 human liver samples and its range and fold of variation were 29% and threefold, respectively.Susceptibility to chloroquine should be greater in subjects with limited expression of histamine N-methyltransferase.     

Pharmacokinetics and pharmacodynamics of ketoprofen plasters

Ketoprofen plasters of 70 cm(2) size using DuroTak acrylic adhesive polymers were developed either containing 30 mg (Ketotop-L) or 60 mg drug (Ketotop-P). The in vitro skin permeation profile was obtained in hairless mouse skin and showed the permeation rate of Ketotop-P to be twice that of Ketotop-L. The plasma concentration profile of ketoprofen was determined in Sprague-Dawley rats after applying a 3 x 3 cm(2) plaster. AUC(0-24h) and C(max) of Ketotop-P were 260.92 microg.h/ml and 25.09 microg/ml, respectively, which were about twice the values of Ketotop-L. The hind paw edema induced by carrageenan injection was measured for 6 h after applying a 2 x 2 cm(2) plaster, and the area under the time-response curve (AUR) value was significantly lower in Ketotop-P attached rats (180.70%.h) than in those with the Ketotop-L (298.65%.h) and the control (407.04%.h) groups, indicating a stronger anti-inflammatory action of Ketotop-P. However, the analgesic effect of the two formulations did not show a statistically significant difference. In conclusion, Ketotop-P was able to achieve higher plasma concentration of ketoprofen, thereby exhibiting higher and more constant anti-inflammatory effect compared with Ketotop-L.     

Pharmacokinetics and pharmacodynamics of rapacuronium bromide

Rapacuronium is an aminosteroidal nondepolarising neuromuscular blocking agent (NMBA). Its neuromuscular blocking effects have a different time course to those of most currently available agents. It also has lower potency than many of the other NMBAs. In doses consistent with short to medium duration of action, rapacuronium has rapid and complete onset. In some doses it gives tracheal intubating conditions that compare favourably with those produced by suxamethonium (succinylcholine) during rapid sequence induction of anaesthesia. Tracheal intubating conditions improve as dose increases, but adverse effects (including potentially severe bronchospasm) become more prominent. Rapacuronium has an active metabolite that is at least as potent as the parent compound and is eliminated much less efficiently. Consequently, the time course of action of rapacuronium is prolonged after multiple doses or an infusion. Its potency is similar across age ranges and its time course after single doses is little altered in patients with hepatic or renal insufficiency. At least in part because of its active metabolite, rapacuronium is highly cumulative in renal failure. In keeping with its rapid onset and short to medium duration of action, rapacuronium has a more rapid clearance than most other NMBAs. Values for clearance are in the range 0.26-0.67 L/h/kg, with most studies giving a value of approximately 0.45 L/h/kg. There is some evidence that clearance declines marginally with advanced age, and it is also reduced in children. A typical value for steady-state volume of distribution is 0.3 L/kg. This is similar to that of many other NMBAs, but is small compared with many other drugs, as expected with a highly polar compound. Pharmacokinetic parameters do not appear to differ markedly in hepatic insufficiency, but clearance is reduced by approximately 30% in renal failure. Rapacuronium equilibrates very rapidly between the plasma and the site of effect. This is the principal explanation behind its unusually rapid onset. It also appears to have a similar potency at the larynx compared with the adductor pollicis; most other NMBAs are less effective at the larynx. Because it gives rapid onset in a dose consistent with brief duration of action, it was hoped that rapacuronium might be a suitable alternative to suxamethonium. It does not have the problems associated with suxamethonium, but its use is associated with bronchospasm, the incidence of which is dose-related. Rapacuronium has been withdrawn from sale because of this adverse effect, and its future availability is uncertain.     

Pharmacokinetics and pharmacodynamics in antibiotic dose optimization

Introduction: Identifying the optimized dosing regimen and algorithm is critical in the development of antibiotics. Suboptimal regimens and inappropriate choice of drug give rise to drug-resistant bacteria which have limited the therapeutic utility of many commercially available antimicrobial agents. Strategies to optimize therapy of antimicrobial candidates to speed up the development process are urgently needed.

Areas covered: We examined pharmacokinetics and pharmacodynamics of antimicrobial agents with modeling and simulation approaches. The approach that is based on minimum inhibitory concentration to evaluate antimicrobial dosing strategy is widely utilized in drug development. The modeling approach utilizing information from time-kill kinetic studies is a tool that can provide more information on the time-course of bacterial response to a particular dosing regimen. Animal studies of dosing regimens that mimic human pharmacokinetics are another option to evaluate antimicrobial efficacy. Empirical, semi-mechanistic and mechanistic models of bacterial dynamics and development of drug resistance in response to drug therapy are discussed.

Expert opinion: Both theories and applications of these approaches provide an overall understanding of how the tools can streamline drug development process and help make crucial decisions. Many opportunities and potentials are presented to incorporate more rigorous integration of PK-PD modeling approaches even at preclinical stage to extrapolate to clinical settings, thus enabling successful trials and optimizing dosing strategies in relevant populations where the drug is mostly used.