Role of oxycodone and oxycodone/naloxone in cancer pain management

Oxycodone is a valued opioid analgesic, which may be administered either as the first strong opioid or when other strong opioids are ineffective. In case of insufficient analgesia and/or intense adverse effects such as sedation, hallucinations and nausea/vomiting a switch from another opioid to oxycodone might be beneficial. Oxycodone is administered to opioid-naive patients with severe pain and to patients who were unsuccessfully treated with weak opioids, namely tramadol, codeine and dihydrocodeine. Oxycodone effective analgesia may be attributed to its affinity to μ and possibly κ opioid receptors, rapid penetration through the blood-brain barrier and higher concentrations in brain than in plasma. Oxycodone displays high bioavailability after oral administration and may be better than morphine in patients with renal impairment due to the decreased production of active metabolites. Recently an oral controlled-release oxycodone formulation was introduced in Poland. Another new product that was launched recently is a combination of prolonged-release oxycodone with prolonged-release naloxone (oxycodone/naloxone tablets). The aim of this review is to outline the pharmacodynamic and pharmacokinetic properties, drug interactions, dosing rules, adverse effects, equianalgesic dose ratio with other opioids and clinical studies of oxycodone in patients with cancer pain. The potential role of oxycodone/naloxone in chronic pain management and its impact on the bowel function is also discussed.     

Morphine and oxycodone in the management of cancer pain: plasma levels determined by chemical and radioreceptor assays

Morphine and oxycodone were administered to ten patients suffering from severe cancer pain in a double-blind cross-over study. The patients titrated themselves pain-free, first intravenously, using a patient-controlled analgesia device, and then orally. Each titration phase lasted for 48 hours. Blood samples were drawn after 36 hr of each administration phase. The plasma levels of morphine, morphine-6- and morphine-3 glucoronides were determined with high performance liquid chromatography (HPLC), whereas the oxycodone samples were assayed with gas chromatography (GC). Twin samples were analyzed for plasma opioid activity with a radioreceptor assay (RRA) using 3H-dihydromorphine and 3H-naloxone as radioligands. Adequate analgesia was achieved with both morphine and oxycodone. About 30% more oxycodone was needed intravenously, whereas 25% less oxycodone than morphine was consumed orally. There was a good linear correlation between the morphine concentrations measured with HPLC and RRA. The mean morphine-6-glucuronide to morphine concentration ratio was 2.3 after intravenous and 4.6 after oral administration. Results from RRA indicate that oxycodone in vivo is a potent mu-agonist and that at least part of its analgesic action is mediated by active metabolites. In vitro morphine glucuronides enhanced morphine in displacing radioligands from the opioid receptors, thus suggesting their complex interactions in vivo.     

Pharmacokinetic-pharmacodynamic modelling of opioids in healthy human volunteers. a minireview

Abstract: Pain is characterized by its multi‐dimensional nature, explaining in part why the pharmacokinetic/pharmacodynamic (PK/PD) relationships are not straightforward for analgesics. The first part of this MiniReview gives an overview of PK, PD and PK/PD models, as well as of population approach used in analgesic studies. The second part updates the state‐of‐the‐art in the PK/PD relationship of opioids, focusing on data obtained on experimental human pain models, a useful tool to characterize the PD of analgesics. For the so‐called weak opioids such as codeine, experimental human studies showed that analgesia relies mainly upon biotransformation into morphine. However, the time‐course of plasma concentrations of morphine did not always reflect the time‐course of effects, the major site of action being the central nervous system. For tramadol, a correlation has been observed between the analgesic response and the PK of the (+)R‐O‐demethyl‐tramadol metabolite. For ‘stronger’ opioids such as oxycodone, studies assessing the PK/PD of oxycodone suggested that active metabolite oxymorphone also strongly contributes to the analgesia and that analgesia may also be partially related through an action to peripherally located κ‐opioid receptors. Different models have been proposed to describe the time‐course of buprenorphine. An effect‐compartment model was adopted to describe the PK/PD of morphine and its active metabolite, morphine‐6‐glucuronide (M6G). A longer blood‐effect site equilibration half‐life t_1/2k_e0 was observed for M6G, suggesting a longer onset of action. The studies assessing the PK/PD of fentanyl and its derivatives showed a short t_1/2k_e0 for analgesia, between 0.2 and 9 min., reflecting a short onset of effect. In conclusion, depending on the speed of transfer between the plasma and the effect site as well as the participation of active metabolites, the time‐course of the analgesic effects can be close to the plasma concentrations (alfentanil and derivates) or observed with a prolonged delay (codeine, buprenorphine, morphine). These PK/PD data can be used to better characterize the differences between opioids, and partly explain the important observed variability among opioids in experimental conditions and should be systematically evaluated during drug development to better predict their selection in specific clinical conditions.     

Avinza - 24-h sustained-release oral morphine therapy

Avinza is a once-daily, extended-release oral morphine preparation. It has a pharmacokinetic profile that exhibits less peak-to-trough fluctuations in plasma concentration whilst providing analgesia statistically identical to that produced by MS Contin (controlled-release morphine sulfate), Oxycontin (oxycodone HCl controlled-release) and six doses of oral morphine sulfate administered every 4 h. Avinza improves quality of sleep by several measures but interestingly gives the best sleep improvement when given in the morning rather than at night. It causes the same side effects of other opioids: constipation, nausea, vomiting, somnolence and mood swings. Doses of 30 - 60 mg/day have been shown to be well tolerated by patients with osteoarthritis (even in the elderly), who have failed other medications.     

Cerebral kinetics of oxycodone in conscious sheep

Oxycodone is an opioid analgesic that is administered orally or parenterally. The time-course of opioid action is a function of the systemic kinetics of the opioid, and the rate and extent of its entry into the brain and central nervous system. The latter is incompletely understood for oxycodone. Therefore, the cerebral kinetics of oxycodone was quantified using a conscious chronically instrumented sheep preparation. Five sheep were administered oxycodone as intravenous infusions (30 mg over 4 min). Using hybrid physiologically based kinetic models, cerebral kinetics was estimated from arterio-sagittal sinus concentration gradients and cerebral blood flow (CBF). A two-compartment membrane-limited model best described the data. The volume of the first brain compartment was 35.4 mL with a half-life of equilibrium of 0.6 min. The brain:blood equilibration of oxycodone was relatively slow (half-life of 7.2 min), with a large deep cerebral distribution volume (222.8 mL) for the second compartment and a moderate membrane permeability of 54.8 mL/min, which exceeded the nominal CBF (40 mL/min). Drug retention in the brain was 1.3% after 45 min. In conclusion, pharmacokinetic modelling of oxycodone showed a delayed equilibration between brain and blood of a nature that would be affected by changes in both CBF and blood brain barrier permeability.     

7-(4-氯苄基)-7,8,13,13a-四氢小檗碱氯化物在犬体内的药代动力学和药效学

以 QT校正 ( QTc)延长百分率为效应指标 ,用药代动力学 -药效学 ( PK- PD)结合模型对家犬 iv1 .0 ,2 .0 mg· kg-1的 7- ( 4 -氯苄基 ) - 7,8,1 3,1 3a-四氢小檗碱氯化物 ( CPU860 1 7)后在体内的处置和效应作定量分析 .给家犬 iv CPU860 1 7后的血药浓度经时过程符合二房室模型 ,药物的效应与效应室浓度之间的关系符合 S形 Emax模型 .CPU860 1 7的 PK- PD性质在所用剂量范围内均为非剂量依赖性 .     

Population pharmacokinetics of oxycodone in children 6 months to 7 years old

Young children are often undertreated for pain. One barrier to effective pain treatment is understanding the pharmacokinetic behavior of analgesics in this age group. Oxycodone is a commonly prescribed opioid for severe pain, yet little is known about its pharmacokinetics in young children. This article used population pharmacokinetic modeling to synthesize pharmacokinetic data from several studies into a model. A single population model that described the observed pharmacokinetics was developed. The combined data were best described with a 2-compartment linear model with different first-order absorption rates depending on route of administration. Weight was found to significantly influence both clearance (CL) and volume of distribution (Vd). The following model adequately describes the population pharmacokinetic profile of oxycodone where absolute bioavailability (F) is estimated for each administration route: CL/F=55x(body weight/70)0.87; V/F=86x(body weight/70)1.16. The interindividual coefficients of variation in CL and Vd were 20.2 and 19.7%, respectively. This finding confirms that the allometric scaling using the above model explained most of the variability in exposure observed among children. This model confirms using a weight-based dose for oxycodone without adjustment for age between 6 months and 7 years and is valuable for evaluating dosing schedules and dosing routes.     

In vivo profiling of seven common opioids for antinociception,constipation and respiratory depression: no two opioids have the same profile

BACKGROUND AND PURPOSE

For patients experiencing inadequate analgesia and intolerable opioid-related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles.

EXPERIMENTAL APPROACH

Male Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine-6-glucuronide (M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D-penicillamine^2,5]-enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail-flick test, the castor oil-induced diarrhoea test and whole body plethysmography respectively.

KEY RESULTS

These opioid agonists produced dose-dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell-shaped dose–response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression.

CONCLUSION AND IMPLICATIONS

For the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of ‘opioid rotation’.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Population Pharmacokinetic Modelling of Morphine,Gabapentin and their Combination in the Rat

Purpose

The combination of morphine and gabapentin seems promising for the treatment of postoperative and neuropathic pain. Despite the well characterised pharmacodynamic interaction, little is known about possible pharmacokinetic interactions. The aim of this study was to evaluate whether co-administration of the two drugs leads to modifications of their pharmacokinetic profiles.

Methods

The pharmacokinetics of morphine, morphine-3-glucuronide and gabapentin were characterised in rats following subcutaneous injections of morphine, gabapentin or their combination. Non-linear mixed effects modelling was applied to describe the pharmacokinetics of the compounds and possible interactions.

Results

The plasma-concentration-time profiles of morphine and gabapentin were best described using a three- and a one-compartment disposition model respectively. Dose dependencies were found for morphine absorption rate and gabapentin bioavailability. Enterohepatic circulation of morphine-3-glucuronide was modelled using an oscillatory model. The combination did not lead to pharmacokinetic interactions for morphine or gabapentin but resulted in an estimated ~33% diminished morphine-3-glucuronide formation.

Conclusions

The finding of a lack of pharmacokinetic interaction strengthens the notion that the combination of the two drugs leads to better efficacy in pain treatment due to interaction at the pharmacodynamic level. The interaction found between gabapentin and morphine-3-glucuronide, the latter being inactive, might not have any clinical relevance.

     

Avinza® – 24-h sustained-release oral morphine therapy

Avinza^® is a once-daily, extended-release oral morphine preparation. It has a pharmacokinetic profile that exhibits less peak-to-trough fluctuations in plasma concentration whilst providing analgesia statistically identical to that produced by MS Contin^® (controlled-release morphine sulfate), Oxycontin^® (oxycodone HCl controlled-release) and six doses of oral morphine sulfate administered every 4 h. Avinza improves quality of sleep by several measures but interestingly gives the best sleep improvement when given in the morning rather than at night. It causes the same side effects of other opioids: constipation, nausea, vomiting, somnolence and mood swings. Doses of 30 – 60 mg/day have been shown to be well tolerated by patients with osteoarthritis (even in the elderly), who have failed other medications.     

口服氨酚羟考酮和盐酸曲马多治疗妇科腹腔镜手术后早期疼痛的研究

目的 :观察妇科腹腔镜手术病人术后早期单次口服氨酚羟考酮 (泰勒宁 )和盐酸曲马多 (奇曼丁 )进行镇痛的有效性和安全性。方法 :12 0例VAS评分 >3分的妇科腹腔镜手术病人 ,随机分 3组 ,分别口服泰勒宁、奇曼丁或安慰剂 1片 ,3组病人均给予吗啡静脉自控止痛泵作为补救镇痛用药。观察并记录服药即刻、服药后 0 .2 5、0 .5、0 .75、1、2、4、6、8、12、2 4h的VAS评分、PCA用量以及不良反应 ,根据VAS评分计算疼痛缓解度 ,2 4h进行总体镇痛满意度评估。结果 :泰勒宁组和奇曼丁组VAS评分低于安慰剂组 (P <0 .0 5 ) ,泰勒宁组和奇曼丁组之间VAS评分相近 (P >0 .0 5 )。泰勒宁组和奇曼丁组补救PCA吗啡用量明显低于安慰剂组 (P <0 .0 5 ) ,泰勒宁组和奇曼丁组补救PCA吗啡用量相当 (P >0 .0 5 )。泰勒宁组和奇曼丁组总体镇痛满意度评估优于安慰剂组 (P <0 .0 5 )。 2 4h恶心呕吐率方面 ,奇曼丁组明显高于其他两组 (P <0 .0 5 )。结论 :口服泰勒宁和奇曼丁能有效地缓解妇科腹腔镜病人手术后的中至重度疼痛 ,早期口服给药镇痛的方式安全、有效。与奇曼丁组相比 ,泰勒宁组的不良反应发生率更低。     

Determination of α(2)-adrenoceptor and imidazoline receptor involvement in augmentation of morphine and oxycodone analgesia by agmatine and BMS182874

Studies have demonstrated that clonidine (α(2)-adrenoceptor and imidazoline receptor agonist) and BMS182874 (endothelin ET(A) receptor antagonist) potentiate morphine and oxycodone analgesia. Agmatine, an endogenous clonidine-like substance, enhances morphine analgesia. However, its effect on oxycodone analgesia and its interaction with endothelin ET(A) receptor antagonists are not known. The present study was performed to determine the effect of agmatine on morphine and oxycodone analgesia and the involvement of α(2)-adrenoceptors, imidazoline receptors, opioid receptors, and endothelin receptors. Antinociception at various time intervals was determined by the tail-flick latency method in mice. Agmatine produced dose-dependent increase in tail-flick latency, while BMS182874 did not produce any change over the 360-min observation period. Agmatine significantly potentiated morphine as well as oxycodone analgesia which was not altered by BMS182874. BMS182874 pretreatment did not increase the analgesic effect produced by agmatine alone. Agmatine-induced potentiation of morphine and oxycodone analgesia was blocked by idazoxan (imidazoline receptor/α(2)-adrenoceptor antagonist) and yohimbine (α(2)-adrenoceptor antagonist). BMS182874-induced potentiation of morphine or oxycodone analgesia was not affected by yohimbine. However, idazoxan blocked BMS182874-induced potentiation of oxycodone but not morphine analgesia. This is the first report demonstrating that agmatine potentiates not only morphine but also oxycodone analgesia in mice. Potentiation of morphine and oxycodone analgesia by agmatine appears to involve α(2)-adrenoceptors, imidazoline receptors, and opioid receptors. In addition, imidazoline receptors may be involved in BMS182874-induced potentiation of oxycodone but not morphine analgesia. It is concluded that agmatine may be used as an adjuvant in opiate analgesia.     

Kinetics of drug action in disease states. XXI. Relationship between drug infusion rate and dose required to produce a pharmacologic effect

Computer simulations were performed to determine if the threshold dose of an infused drug (rather than the drug concentration in the biophase at onset of action) can be a suitable index for pharmacodynamic investigations as proposed by others. A two-compartment pharmacokinetic model with drug elimination from the central compartment was used for the simulations. Drug was administered into the central compartment by a constant-rate infusion, and concentrations in the central and peripheral compartments were calculated as a function of time. The pharmacologic effect was assumed to be reversible and to occur at a defined concentration (the effective concentration) in one or the other compartment. The dose required to produce an effective concentration (threshold dose) was determined as a function of infusion rate. The relationship between infusion rate and the dose required to produce an effective concentration in the peripheral compartment was found to be affected by drug distribution and elimination kinetics and by the effective concentration. The infusion rate-dose relationship showed a dose minimum at an infusion rate which others have designated as the "optimal dose rate" and have used for pharmacodynamic studies. No such minimum occurred for pharmacologic effects associated directly with drug concentrations in the central compartment. Since optimum dose rate and threshold dose are affected by both pharmacokinetic and pharmacodynamic alterations, it is concluded that this method (which avoids determination of drug concentrations) is not generally suitable for quantitative pharmacodynamic investigations.     

Characterization and validation of a pharmacokinetic model for controlled-release oxycodone

1Oxycodone is a strong opioid agonist that is currently available in immediate-release (IR) formulations for the treatment of moderate to severe pain. Recently, controlled-release (CR) oxycodone tablets were developed to provide the benefits of twice-a-day dosing to patients treated with oxycodone. The purpose of this investigation was to develop and validate a pharmacokinetic model for CR oxycodone tablets in comparison with IR oxycodone solution. 2Twenty-four normal male volunteers were enrolled in a single-dose, randomized, analytically blinded, two-way crossover study designed to compare the pharmacokinetics of two 10 mg CR oxycodone tablets with 20 mg IR oxycodone oral solution. Pharmacokinetic models describing the oxycodone plasma concentration vs time profiles of CR tablets and IR solution were derived using NONMEM version IV. The predictive performance of the models was assessed by comparison of predicted oxycodone plasma concentrations with actual oxycodone plasma concentrations observed in a separate group of 21 volunteers who received repeated doses of IR and CR oxycodone for 4 days. 3The unit impulse disposition function of oxycodone was best described by a one-compartment model. Absorption rate of the IR solution was best described by a mono-exponential model with a lag time, whereas absorption rate of the CR tablet was best described using a bi-exponential model. The absorption profile of the CR tablets was characterized by a rapid absorption component ( t_1/2abs=37 min) accounting for 38% of the available dose and a slow absorption phase ( t_1/2abs=6.2 h) accounting for 62% of the available dose. Two 10 mg tablets of oral CR oxycodone hydrochloride were 102.7% bioavailable relative to 20 mg of IR oxycodone hydrochloride oral solution. The population model derived after administration of a single dose accurately predicted both the mean and range of oxycodone concentrations observed during 4 days of repeated dosing. The mean prediction error was 2.7% with a coefficient of variation of 54%. 4The absorption characteristics of CR oxycodone tablets should allow effective plasma concentrations of oxycodone to be reached quickly and for effective concentrations to be maintained for a longer period after dosing compared with the IR oral solution. The CR dosage form has pharmacokinetic characteristics that permit 12 hourly dosing.     

Pharmacokinetic-pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats.

1. The purpose of this investigation was to examine in vivo drug-concentration anticonvulsant effect relationships of oxazepam in individual rats following administration of a single dose. 2. Whole blood concentration vs time profiles of oxazepam were determined following administration of doses of 4, 8 and 12 mg kg-1. The pharmacokinetics could be described by an open 2-compartment pharmacokinetic model. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of clearance and volume of distribution were 28 +/- 2 ml min-1 kg-1 and 2.6 +/- 0.31 kg-1, respectively, and were not significantly different from the values obtained at the other doses. 3. The anticonvulsant effect was quantitated by a new technique which allows repetitive determination of the convulsive threshold by direct cortical stimulation within one rat. Significant dose-dependent elevations of the seizure threshold were observed. 4. By pharmacokinetic-pharmacodynamic modelling, a log-linear relationship was found between concentration and anticonvulsant effect. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of the pharmacodynamic parameters slope and minimal effective concentration (Cmin) were 243 +/- 27 microA and 0.11 +/- 0.02 mg l-1, respectively and not significantly different from the values obtained at the other doses. 5. In a repeatability study the pharmacodynamic parameters were determined twice on two different occasions with an interval of two weeks in the same group of 11 rats. The inter-animal variability in the pharmacodynamic parameter slope was 46%, whereas the intra-animal variability was 24 +/- 18%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Population pharmacokinetic analysis and dosing regimen optimization of meropenem in adult patients

The objectives of this study were to develop a meropenem population pharmacokinetic model using patient data and use it to explore alternative dosage regimens that could optimize the currently used dosing regimen to achieve higher likelihood of pharmacodynamic exposure against pathogenic bacteria. We gathered concentration data from 79 patients (ages 18-93 years) who received meropenem 0.5, 1, or 2 g over 0.5- or 3-hour infusion every 8 hours. Meropenem population pharmacokinetic analysis was performed using the NONMEM program. A 2-compartment model fit the data best. Creatinine clearance, age, and body weight were the most significant covariates to affect meropenem pharmacokinetics. Monte Carlo simulation was applied to mimic the concentration-time profiles while 1 g meropenem was administrated via infusion over 0.5, 1, 2, and 3 hours. The 3-hour prolonged infusion improved the likelihood of obtaining both bacteriostatic and bactericidal exposures most notably at the current susceptibility breakpoints.     

盐酸羟考酮缓释片与硫酸吗啡缓释片直肠给药控制重度癌性疼痛的疗效比较

目的:比较盐酸羟考酮缓释片与硫酸吗啡缓释片经直肠给药治疗重度癌性疼痛的疗效和不良反应。方法:将102例伴有中、重度疼痛的癌症患者随机分为A组(50例)与B组(52例),分别经直肠给予盐酸羟考酮缓释片和硫酸吗啡缓释片,比较2组药物起效时间、癌痛类型和药品不良反应的差异。结果:A组患者治疗1、3h时的疼痛与B组同期比较,差异有统计学意义(P<0.05),2组内脏痛和躯体痛比较差异分别有统计学意义(P<0.05),2组的不良反应如恶心、呕吐、便秘比较分别有显著性差异(P<0.05),A组均优于B组。结论:盐酸羟考酮缓释片经直肠给药控制重度癌性疼痛,安全、有效、简便。     

Do Diuretics have Antinociceptive Actions: Studies of Spironolactone,Eplerenone, Furosemide and Chlorothiazide,Individually and with Oxycodone and Morphine

Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid receptor antagonism. In co‐administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.)‐ and morphine (3 mg/kg, s.c.)‐induced antinociception using tail‐flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system.     

家兔体内呋喃苯胺酸的药动学和药效学结合模型

用药动学-药效学结合模型对呋喃苯胺酸在家兔体内的处置和效应动力学作定量分析。呋喃苯胺酸的k_(eo),S,E_(max),EC_(50)分别为0.131±0.029min~(-1),2.21±0.61,6.5±0.6ml/min,3.49±0.77μg/ml。结果表明血浆与作用部位属于不同的房室,两者之间存在着一个平衡过程。     

Population pharmacokinetic-pharmacodynamic modelling of angiotensin receptor blockade in healthy volunteers

OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic characteristics of angiotensin II receptor antagonists as a therapeutic class. DESIGN: Population pharmacokinetic-pharmacodynamic modelling study. METHODS: The data of 14 phase I studies with 10 different drugs were analysed. A common population pharmacokinetic model (two compartments, mixed zero- and first-order absorption, two metabolite compartments) was applied to the 2685 drug and 900 metabolite concentration measurements. A standard nonlinear mixed effect modelling approach was used to estimate the drug-specific parameters and their variabilities. Similarly, a pharmacodynamic model was applied to the 7360 effect measurements, i.e. the decrease of peak blood pressure response to intravenous angiotensin challenge recorded by finger photoplethysmography. The concentration of drug and metabolite in an effect compartment was assumed to translate into receptor blockade [maximum effect (Emax) model with first-order link]. RESULTS: A general pharmacokinetic-pharmacodynamic (PK-PD) model for angiotensin antagonism in healthy individuals was successfully built up for the 10 drugs studied. Representatives of this class share different pharmacokinetic and pharmacodynamic profiles. Their effects on blood pressure are dose-dependent, but the time course of the effect varies between the drugs. CONCLUSIONS: The characterisation of PK-PD relationships for these drugs gives the opportunity to optimise therapeutic regimens and to suggest dosage adjustments in specific conditions. Such a model can be used to further refine the use of this class of drugs.