Population pharmacokinetics and pharmacodynamics of oral etoposide

AIMS: To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours. METHODS: A prospective, open label, cross-over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P-Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints. RESULTS: Mean clearance was 1.14 l h(-1) (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r(2) = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l(-1) h; CV 64%; range 0.4-9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l(-1) h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l(-1) h) than in patients with stable (2.1 mg l-1 h) or progressive disease (2.3 mg l-1 h) (P = 0.01). CONCLUSIONS: Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.     

Population pharmacokinetics of doxorubicin, etoposide and ifosfamide in small cell lung cancer patients: results of a multicentre study

AIMS: To determine the population pharmacokinetic (PK) parameters of doxorubicin (Dox), etoposide (Eto) and ifosfamide (Ifo) in small cell lung cancer (SCLC) patients, to assess the potential relationship between those parameters and to estimate the impact of individual morphological and biological covariates on patients' PK parameters. METHODS: Twenty-four patients with either SCLC limited to the thorax or extensive SCLC entered the study. All but one received at least two 3 day courses of the standard AVI (Dox 50 mg m-2 day 1, Eto 120 mg m-2 day 1,2,3, Ifo 2000 mg m-2 day 1,2) regimen. Individual blood samples were collected during each course and data on 47 courses were available. Data were analysed with the NONMEM program. Dox, Eto and Ifo plasma concentrations were studied with multicompartment (3, 2 and 2, respectively) models. Inter-individual and interoccasion (course-to-course) variabilities were estimated. The influence of individual covariates (age, sex, stage of the disease, weight, height, body-surface area, serum creatinine, total protein, LDH, ASAT, ALAT, alkaline phosphatase, gamma-GT, bilirubin) on PK parameters was also assessed. Correlations between individual PK parameters of Dox, Eto and Ifo were explored by using Pearson's correlation coefficient. RESULTS: Multiple data were available for each patient. Dox clearance (CL) and volume of distribution (Vd) were 32.0 l h-1 and 9.3 l (Inter-individual variability: 17.2% and 19.2%). Eto CL (l h-1) and Vd were, respectively, 3.34-0.0083* serum creatinine (micromol l-1) and 6.38 l (interindividual variability: 15.6% and 18.7%). Ifo CL and Vd at day 1 were 5.6 l h-1 and 26.0 l (interindividual variability: 10.1% and 17.2%, respectively). Estimation of course-to-course variability improved the precision of PK models in some cases. No correlation was observed between the respective PK parameters of each drug. Of individual covariates tested, only serum creatinine correlated with Eto CL (r = -0.37, P < 0.001). Self-induction of the metabolism of Ifo was apparent (mean CL increase from day 1 to day 2 : 42%) and individually correlated with the CL value at day 1 (r = -0.61, P < 0.001). CONCLUSIONS: Assessment of potential relationships between individual systemic exposure of chemotherapy and therapeutic endpoints (tumour response, toxicity and survival) will be required to adjust drugs dosages based on individual PK parameters rather than questionable body-surface area. However, all three drugs in the AVI regimen should be monitored simultaneously.     

Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes

AIMS

The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS.

METHODS

A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated.

RESULTS

The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h⁻¹ (interindividual variability, 139%), 6.48 l h⁻¹ (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients.

CONCLUSIONS

The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure–prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied.     

Potential pitfalls of propofol target controlled infusion delivery related to its pharmacokinetics and pharmacodynamics

Target controlled infusion (TCI) devices are increasingly used in clinical practice. These devices unquestionably aid optimization of drug dosage. However, it still remains to be determined if they sufficiently address differences in pharmacological make up of individual patients. The algorithms guiding TCI pumps are based on pharmacological data obtained from a relatively small number of healthy volunteers, which are then extrapolated, on the basis of sophisticated pharmacokinetic and pharmacodynamic modeling, to predict plasma concentrations of the drug and its effect on general population. One has to realize the limitation of this approach: these models may be less accurate when applied to patients in extreme clinical conditions: in intensive care units, with a considerable loss of blood, severe hypothermia or temporary changes in the composition of plasma, e.g., hypoalbuminemia. In the future, data obtained under these “extreme” clinical circumstances, may be used to modify the dosage algorithms of propofol TCI systems to match the clinical scenario.     

Population pharmacokinetics and exploratory pharmacodynamics of ifosfamide and metabolites after a 72-h continuous infusion in patients with soft tissue sarcoma

OBJECTIVE: The population pharmacokinetics and pharmacodynamics of the cytostatic agent ifosfamide and its main metabolites 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide were assessed in patients with soft tissue sarcoma. METHODS: Twenty patients received 9 or 12 g/m2 ifosfamide administered as a 72-h continuous intravenous infusion. The population pharmacokinetic model was built in a sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalised additive modelling. RESULTS: The addition of the covariates weight, body surface area, albumin, serum creatinine, serum urea, alkaline phosphatase and lactate dehydrogenase improved the prediction errors of the model. Typical pretreatment (mean +/- SEM) initial clearance of ifosfamide was 3.03 +/- 0.18 l/h with a volume of distribution of 44.0 +/- 1.8 l. Autoinduction, dependent on ifosfamide levels, was characterised by an induction half-life of 11.5 +/- 1.0 h with 50% maximum induction at 33.0 +/- 3.6 microM ifosfamide. Significant pharmacokinetic-pharmacodynamic relationships (P = 0.019) were observed between the exposure to 2- and 3-dechloroethylifosfamide and orientational disorder, a neurotoxic side-effect. No pharmacokinetic-pharmacodynamic relationships between exposure to 4-hydroxyifosfamide and haematological toxicities could be observed in this population.     

Baicalin,an emerging multi-therapeutic agent: pharmacodynamics,pharmacokinetics, and considerations from drug development perspectives

1. Baicalin was extensively researched for utility in a number of therapeutic areas owing to its anti-inflammatory, anti-oxidant, anti-bacterial, and anti-cancer properties.

2. A number of preclinical studies, in vitro work, and mechanistic studies were performed to understand the absorption, distribution, metabolism, and excretion profiles of baicalin.

3. The absorption of baicalin involved several complexities: the restriction to two distant sites; the conversion of baicalin to baicalein; the possible role of transporter(s); and enhanced absorption due to breakdown of conjugates by beta-glucuronidase.

4. Limited distribution data suggest that baicalin reached several sites such as the brain, eye lens, thymus, etc. Hepatobiliary recycling also served as a distribution phase for sustained delivery of baicalin.

5. Metabolism data suggest the rapid conversion of baicalin to baicalein, which was extensively subjected to Phase 2 metabolism, conjugates baicalein glucuronide/sulfate have been identified.

6. Limited excretion data suggest involvement of renal and faecal routes—glucuronide and sulfate conjugates were excreted in urine and faeces (via biliary excretion).

7. The published data on baicalin suggest imminent challenges for developing baicalin and/or during co-administration with other agents. These challenges are absorption related (transporter or changes in the microenvironment), metabolism related (CYP2B6 induction and/or CYP2E1 inhibition), and excretion/efflux related (competitive biliary pathway and/or OATP1B1 transport).

     

Population pharmacokinetics and pharmacodynamics of bivalirudin in young healthy Chinese volunteers

Aim:

To investigate the population pharmacokinetics (PK) and pharmacodynamics (PD) of bivalirudin, a synthetic bivalent direct thrombin inhibitor, in young healthy Chinese subjects.

Methods:

Thirty-six young healthy volunteers were randomly assigned into 4 groups received bivalirudin 0.5 mg/kg, 0.75 mg/kg, and 1.05 mg/kg intravenous bolus, 0.75 mg/kg intravenous bolus followed by 1.75 mg/kg intravenous infusion per hour for 4 h. Blood samples were collected to measure bivalirudin plasma concentration and activated clotting time (ACT). Population PK-PD analysis was performed using the nonlinear mixed-effects model software NONMEM. The final models were validated with bootstrap and prediction-corrected visual predictive check (pcVPC) approaches.

Results:

The final PK model was a two-compartment model without covariates. The typical PK population values of clearance (CL), apparent distribution volume of the central-compartment (V₁), inter-compartmental clearance (Q) and apparent distribution volume of the peripheral compartment (V₂) were 0.323 L·h^-1·kg^-1, 0.086 L/kg, 0.0957 L·h^-1·kg^-1, and 0.0554 L/kg, respectively. The inter-individual variabilities of these parameters were 14.8%, 24.2%, fixed to 0% and 15.6%, respectively. The final PK-PD model was a sigmoid E_max model without the Hill coefficient. In this model, a covariate, red blood cell count (RBC^*), had a significant effect on the EC₅₀ value. The typical PD population values of maximum effect (E_max), EC₅₀, baseline ACT value (E₀) and the coefficient of RBC^* on EC₅₀ were 318 s, 2.44 mg/L, 134 s and 1.70, respectively. The inter-individual variabilities of E_max, EC₅₀, and E₀ were 6.80%, 46.4%, and 4.10%, respectively.

Conclusion:

Population PK-PD models of bivalirudin in healthy young Chinese subjects have been developed, which may provide a reference for future use of bivalirudin in China.     

Population analysis to assess the influence of age and body weight on pharmacokinetics and pharmacodynamics of dexmedetomidine in New Zealand White rabbits

The purpose of this work was i) to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model of dexmedetomidine (DEX) in New Zealand White rabbits, ii) to investigate the influence of the age and weight of the animals on the model parameters, and iii) to assess the linearity of DEX PKs in the examined dose range. This was a prospective, crossover study, using a total of 18 New Zealand White rabbits. DEX was administered as a single intravenous bolus injection in the doses from 25 to 300 μg kg⁻¹. Each New Zealand White rabbit was given the same dose of drug in its three developmental stages. To determine the DEX PK, seven blood samples were taken from each animal. The pedal withdrawal reflex was the PD response used to assess the degree of sedation. Nonlinear mixed effects modelling was used for the population PK/PD analysis. The typical value of elimination clearance was 0.061 L min⁻¹ and was 35% higher in younger New Zealand White rabbits compared with older animals. The PK of DEX was linear in the examined concentration range. Age-related changes in sensitivity to DEX were not detected. The results suggest that due to the pharmacokinetics, younger animals will have lower DEX concentrations and a shorter duration of sedation than older animals given the same doses of DEX per kg of body weight.     

Double-blind,randomized, placebo-controlled study of safety,tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men

Aims

Two randomized, double-blind, placebo-controlled studies were performed to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the investigational metastin analogue, TAK-683, in healthy men.

Methods

We first investigated a single subcutaneous (s.c.) dose of TAK-683 (0.01–2.0 mg) in 60 subjects (TAK-683, n = 42; placebo, n = 18). We then assessed a single s.c. bolus of 0.03–1.0 mg TAK-683 on day 1, followed by a 0.01–2.0 mg day⁻¹ continuous infusion on days 2–13, to simulate a depot formulation, in 30 subjects (TAK-683, n = 25; placebo, n = 5) for 14 days.

Results

TAK-683 was well tolerated up to a dose of 2.0 mg day⁻¹ by continuous s.c. infusion for 14 days. Adverse events were similar between TAK-683 and placebo subjects at all dose levels. TAK-683 plasma concentrations generally increased in proportion to dose with single and continuous dosing, with steady-state concentrations achieved by day 2 of continuous dosing. TAK-683 at 2.0 mg day⁻¹ suppressed testosterone below castration level (<50 ng dl⁻¹) in four of five subjects by day 7 of continuous dosing. Luteinizing hormone and follicle stimulating hormone concentrations were suppressed with TAK-683 continuous dosing compared with placebo by up to 70 and 43%, respectively, but this was not consistently dose-dependent.

Conclusions

In healthy men, s.c. administration of TAK-683 was well tolerated at all dose levels. The PK profile of TAK-683 was favourable, and TAK-683 suppressed testosterone profoundly during continuous dosing. Further investigation of metastin analogues is warranted for the treatment of castration-resistant prostate cancer.     

Population pharmacokinetics of total and unbound plasma cisplatin in adult patients

AIMS: To investigate the pharmacokinetics of unbound (ultrafilterable) and total plasma platinum using a population approach and to identify patient characteristics that may influence the disposition of the drug. METHODS: Pharmacokinetic and demographic data were collected from adult patients treated with 30-min daily infusions of cisplatin for various malignancies. Unbound and total platinum concentration-time data were analysed using a nonlinear mixed effects model. RESULTS: Data from 43 patients were available for analysis. A linear two-compartment model best described total and unbound platinum plasma concentration-time data. The mean population estimates for total and unbound drug were, respectively, 0.68 and 35.5 l h(-1) for clearance and 21.1 and 23.4 l for central distribution volume (V(1)). Unbound clearance (CL) was dependent on body surface area (BSA) and creatinine clearance, and V(1) was dependent on BSA. The elimination rate constant for plasma-bound platinum (modelled as metabolite formation) was 0.014 h(-1). The pharmacokinetic parameter, f(m)/V(m), a measure of the clearance of unbound platinum due to irreversible plasma binding, was related to serum protein concentration and to the inverse of dose per m(2). The covariate modelling of CL, V(1) and f(m)/V(m) improved the intersubject variabilities associated with these parameters. The final pharmacokinetic models were validated using 200 bootstrap samples from the original datasets. CONCLUSIONS: The results support the conventional dose adjustment of cisplatin based on BSA. They also support the need for a dose reduction in case of renal insufficiency.     

A randomized trial of the safety,pharmacokinetics and pharmacodynamics of edoxaban,an oral factor Xa inhibitor,following a switch from warfarin

Aims

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of edoxaban, an oral direct factor Xa inhibitor, in healthy subjects switching from warfarin.

Methods

Seventy-two subjects were randomized to edoxaban 60 mg once daily (n = 48) or matching placebo (n = 24) for 5 days at 24 h after the last dose of warfarin treatment (INR 2.0 to 3.0). Safety/tolerability was the primary outcome measure. Pharmacokinetics, INR, aPTT, anti-FXa, thrombin generation and other coagulation assays were assessed.

Results

Seventy-two subjects were randomized and 64 subjects received at least one dose of edoxaban (n = 43) or placebo (n = 21) after achieving a target INR of 2.0 to 3.0 on warfarin treatment. Edoxaban 60 mg administered 24 h post-warfarin appeared to be safe and well tolerated. Adverse events were similar across treatments. For bleeding-related adverse events, eight subjects tested positive for faecal occult blood, five subjects during warfarin treatment and three subjects during edoxaban treatment. The mean (SD) baseline (post-dose of warfarin) INR was 2.31 (0.193) which increased to 3.84 (0.744) over 2 h during the edoxaban treatment (P < 0.0001 vs. placebo), returning to post-warfarin baseline within 12 h. A similar time course of effects for the other coagulation assays was observed in accordance with the drugs'' mechanisms of action.

Conclusion

In this study of healthy subjects, edoxaban administered 24 h after the last dose of warfarin was safe and well tolerated with transient increases across the various coagulation assays above post-warfarin baseline levels.     

Binding of propofol to blood components: implications for pharmacokinetics and for pharmacodynamics

AIMS: Propofol is a widely used i.v. anaesthetic agent. However, its binding properties to blood components have not been fully studied. METHODS: We studied the binding of propofol to erythrocytes, to human serum and to isolated serum proteins. Because propofol bound to ultrafiltration and equilibrium dialysis membranes, we used a co-binding technique with dextran coated charcoal and with erythrocytes. RESULTS: Propofol free fraction in blood was 1.2-1.7% at total concentrations ranging from 2.80 to 179 microM (0.5 to 32 microg ml(-1)). Fifty percent was bound to erythrocytes and 48% to serum proteins, almost exclusively to human serum albumin. In the clinical range of concentrations (0.5-16 microg ml(-1)) 40% of the molecules bound to erythrocytes are on the red blood cells membranes. No binding to lipoproteins occurred and binding to alpha1-acid glycoprotein was less than 1.5% CONCLUSIONS: We conclude that hypoalbuminaemia may increase propofol free fraction particularly during prolonged administration. Since propofol is non-restrictively cleared, no change in clearance is expected to occur, and the increase in free fraction will not be compensated by a parallel increase in clearance. It is also noted that many in vitro studies used concentrations 50 to 500 times the concentration expected to be encountered in the immediate cellular environment.     

Pharmacodynamics and pharmacokinetics of urapidil in hypertensive patients: A crossover study comparing infusion with an infusion-capsule combination

Summary The pharmacokinetics and haemodynamic effects of infused urapidil and an infusion-capsule combination were followed to study the correlation between the serum urapidil level and the blood pressure. Prior to urapidil administration, basal blood pressure and heart rate were measured for 16 h in 12 male hypertensive patients. Six patients received infusions lasting for 4 h of urapidil 10, 2.5 and 5 mg/h. Six patients were infused with urapidil 10 mg/h for 4 h and 2 h after the end of the infusion each took a 60-mg capsule. After a 5 day washout period the procedures were crossed over. A maximum serum urapidil level of 625±232 ng/ml was achieved at the end of the 10 mg/h infusion, when the fall in blood pressure was 37/21 mmHg. During the 2.5 and 5 mg/h infusions the serum urapidil level was 330 and 420 ng/ml, respectively, and the corresponding decreases in blood pressure were 28/16 mmHg and 31/8 mmHg. Although the urapidil concentration 1 hour after beginning the infusion was only 184±89 ng/ml a near maximal blood pressure decrease had already occurred 33±9/20±8 mmHg, whereas, 1 h after the end of the infusion the reduction in blood pressure was only 10±12/3±8 mm, with a urapidil concentration of 358±120 ng/ml. During the plateau phases of both the infusion and infusion-capsule treatments the falls in blood pressure followed the serum urapidil levels. Only in the initial rising and final falling phases of the treatments were the pharmacodynamics and pharmacokinetics of urapidil not correlated.     

Population Pharmacokinetics of Fast Release Oral Diclofenac in Healthy Volunteers: Relation to Pharmacodynamics in an Experimental Pain Model

Purpose. Population pharmacokinetics of a fast release diclofenac wereassessed with special focus on pharmacodynamic implications. Methods In a double blind four-way crossover study, 20 healthyvolunteers received orally 50 and 100 mg diclofenac-Na effervescent(fast-release NSAID), 50 mg diclofenac tablets (control), or placebo.Population pharmacokinetics of the fast release diclofenac wereassessed using a nonlinear mixed effects modeling approach(NON-MEM). Analgesic effects were investigated by means of anexperimental pain model based on both pain-ratings and cortical evoked potentialsafter specific stimulation of nasal nociceptors with short pulses ofgaseous CO₂. Results. Pharmacokinetics of fast release diclofenac were bestdescribed by a two-compartment population model, with an estimatedterminal half-life of 1.2 hours. Pharmacokinetics of diclofenac tabletswere highly variable and a population pharmacokinetic model couldnot be obtained. As an indication of an early onset of analgesic effects,100 mg fast release diclofenac but not the tablets significantly reducedthe amplitudes of pain-related evoked potentials at 30 min afteradministration. Conclusions. Earlier drug absorption and lower pharmacokineticvariability of the fast-release formulation are likely to be preserved ina population.     

Population pharmacokinetics of gemcitabine and its metabolite in patients with cancer: effect of oxaliplatin and infusion rate

Aims

To characterize the population pharmacokinetics of gemcitabine and its metabolite (dFdU) in patients with cancer and identify factors that are influential in gemcitabine dose regimen design.

Methods

Gemcitabine and dFdU plasma concentration–time and clinical data from 94 patients with cancer and nonlinear mixed effect modelling were used to characterize gemcitabine and metabolite pharmacokinetic variability and identify influential covariates.

Results

Gemcitabine and dFdU pharmacokinetics were described by a two-compartment model with first-order elimination. The population mean (and between-subject variability, CV%) for clearance and volume of distribution of the central compartment (V_C) for gemcitabine were 2.7 l min⁻¹ (31%) and 15 l (39%), respectively, and 0.04 l min⁻¹ (35%) and 46 l (15%), respectively, for dFdU. Oxaliplatin co-administration significantly decreased dFdU V_C by 35% when gemcitabine was administered first and by 46% when oxaliplatin was administered first compared with patients who received gemcitabine alone.

Conclusions

Co-administration of gemcitabine with oxaliplatin significantly affected the pharmacokinetics of dFdU. The clinical significance of this observation in the context of gemcitabine safety and efficacy is worthy of further investigation.

What is already known about this subject

• Gemcitabine is an anticancer drug which is metabolized to a number of metabolites, administered using different dosing regimens and increasingly used in combination with oxaliplatin.
• The impact of dosing strategies and combination therapy on the pharmacokinetics of gemcitabine and its main metabolite is not clearly understood.

What this study adds

• This study has characterized the pharmacokinetics of gemcitabine and its main metabolite in people with cancer, including the variability between patients and on different occasions.
• Gemcitabine metabolite (but not gemcitabine) pharmacokinetics were significantly affected by co-administration with oxaliplatin and were dependent on the order of administration.
• The clinical implications of this observation remain to be established.

     

口服及静注乙醇后血中乙醇与β-羟丁酸,乙酰乙酸,乳酸及丙酮酸浓度关系的探讨:一项群体药效动力学的研究

目的 :应用群体药理学方法探讨血浆中乙醇浓度对 β 羟丁酸 ,乙酰乙酸 ,乳酸 ,丙酮酸 ,β 羟丁酸 乙酰乙酸 (H A)比值及乳酸 丙酮酸 (L P)比值变化的效应。方法 :给 14名健康成人口服剂量相当于1.0 2g·L-1总身体水的乙醇。在另一项实验中 ,给 8名健康成人静脉注射剂量相当于 0 .83g·L-1总身体水的乙醇。在服用乙醇后 380min采取静脉血测定乙醇 ,β 羟丁酸 ,乙酰乙酸 ,乳酸及丙酮酸的血浆浓度。在静注乙醇后 340min采血测定上述 5种物质的血浆浓度。结果 :在口服乙醇实验中 ,C0 为 6 6 .6±8.1mg·dl-1,显著低于 10 2mg·dl-1,(t检验 ,P <0 .0 0 1)。清除相斜率 β为 0 .2 2 9± 0 .0 5mg·dl-1·min-1。在静注实验中 ,C0 为 75 .6± 10 .9mg·dl-1,与 83mg·dl-1比较无显著性差异 ,β为0 .2 4 5± 0 .0 5mg·dl-1·min-1。在两项实验中 ,我们应用群体间接生理反应模型来拟合乙醇浓度对 β 羟丁酸 ,乙酰乙酸 ,乳酸 ,丙酮酸 ,β 羟丁酸 乙酰乙酸比值及乳酸 丙酮酸比值变化的效应 ,并得出各项参数。同时 ,我们发现 ,当乙醇的清除相结束时 ,H A比值尚未达最大值 ,说明在乙醇的零级代谢相时肝脏仍在产生NADH。乳酸和乙醇的关系曲线显示乳酸的变化呈现一种逆时钟方向的滞后。结论 :血L P比值不适合用作实     

Relating Observed Psychoactive Effects to the Plasma Concentrations of Delta-9-Tetrahydrocannabinol and Its Active Metabolite: An Effect-Compartment Modeling Approach

The medical use of marijuana is increasing, yet little is known about the exposure-response relationship for its psychoactive effects. It is well known that the plasma concentrations of the principal psychoactive component of marijuana, Δ⁹-tetrahydrocannabinol (THC), do not directly correlate to the observed psychoactive effects. The purpose of this research was to use an effect-compartment modeling approach to predict and relate the concentrations of the psychoactive components (THC and its active metabolite) in the “hypothetical” effect-site compartment to the observed psychoactive effects. A “hypothetical” effect-compartment model was developed using literature data to characterize the observed delay in peak “highness” ratings compared with plasma concentrations of the psychoactive agents following intravenous administration of THC. A direct relationship was established between the reported psychoactive effects (“highness” or intoxication) and the predicted effect-site concentrations of THC. The differences between estimated equilibration half-lives for THC and THC-OH in the effect-compartment model indicated the differential equilibration of parent drug and the active metabolite between plasma and the effect-site. These models contribute to the understanding of the pharmacokinetic-pharmacodynamic relationships associated with marijuana use and are important steps in the prediction of pharmacodynamic effects related to the psychoactive components in marijuana.     

Fifth-generation model for corticosteroid pharmacodynamics: application to steady-state receptor down-regulation and enzyme induction patterns during seven-day continuous infusion of methylprednisolone in rats

A fifth-generation model for receptor/gene-mediated corticosteroid effects was proposed based on results from a 50 mg/kg IV bolus dose of methylprednisolone (MPL) in male adrenalectomized rats, and confirmed using data from other acute dosage regimens. Steady-state equations for receptor down-regulation and tyrosine aminotransferase (TAT) enzyme induction patterns were derived. Five groups of male Wistar rats (n=5/group) were subcutaneously implanted with Alzet mini-pumps primed to release saline or 0.05, 0.1, 0.2, and 0.3 mg/kg/hr of MPL for 7 days. Rats were sacrificed at the end of the infusion. Plasma MPL concentrations, blood lymphocyte counts, and hepatic cytosolic free receptor density, receptor mRNA, TAT mRNA, and TAT enzyme levels were quantitated. The pronounced steroid effects were evidenced by marked losses in body weights and changes in organ weights. All four treatments caused a dose-dependent reduction in hepatic receptor levels, which correlated with the induction of TAT mRNA and TAT enzyme levels. The 7 day receptor mRNA and free receptor density correlated well with the model predicted steady-state levels. However, the extent of enzyme induction was markedly higher than that predicted by the model suggesting that the usual receptor/gene-mediated effects observed upon single/intermittent dosing of MPL may be countered by alterations in other aspects of the system. A mean IC₅₀ of 6.1 ng/mL was estimated for the immunosuppressive effects of methylprednisolone on blood lymphocytes. The extent and duration of steroid exposure play a critical role in mediating steroid effects and advanced PK/PD models provide unique insights into controlling factors.