Prediction of steady-state bioequivalence relationships using single dose data I-linear kinetics

Simulated data using a linear one- and two-compartment body model with different absorption characteristics were used to evaluate the ability of single dose bioavailability data to predict the relationships that exist at steady state. This was done by comparing the confidence intervals obtained from single and multiple dose data sets for the parameters of Tmax, Cmax, and area under the curve from time zero to infinity (AUC0-infinity). As a consequence of Tmax and Cmax decreasing and increasing from single to multiple dosing regimens, the confidence intervals for these parameters reflected these changes. The 90 per cent confidence interval expressed as a percentage of the reference mean increased or decreased for Tmax dependent upon the ratio of Ka test/Ka reference, and decreased for Cmax while the interval for AUC0-infinity exhibited no predictable pattern and appeared to be influenced by the amount of error in the data set. Alteration of either the dosing interval or the fraction absorbed did not affect the pattern of change in the confidence intervals for Tmax and Cmax, but the latter did result in a decrease in the interval for AUC0-infinity. Analysis of the confidence intervals for Tmax, Cmax and AUC0-infinity in bioequivalency studies for quinidine gluconate and procainamide hydrochloride following administration of single and multiple doses to different subjects appeared to be consistent with the patterns observed for the simulated data sets.     

Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products

In the European Union multiple dose bioequivalence studies are required for the approval of generic prolonged-release products, but they are not required by the US-FDA. In order to investigate if the multiple dose bioequivalence studies are necessary, the bioequivalence studies assessed in the Spanish Agency for Medicines and Health Care Products in the last 10 years were searched to find all reasons for rejection and identify those cases where the multiple dose study had failed to show bioequivalence and the single dose study had shown bioequivalence. In these latter cases, the plasma concentration at the end of the dosing interval (C_τ) in the single dose study was assessed to investigate its sensitivity to predict non-bioequivalence in the steady state.The search identified six cases where the non-equivalence in the multiple dose study was not detected by the corresponding single dose study. C_τ was not able to detect the difference in five cases and in general it was more variable than conventional metrics. In conclusion, the multiple dose bioequivalence study is necessary to ensure therapeutic equivalence and the use of C_τ would be counterproductive, increasing the sample size of the studies without enough sensitivity to detect differences in the steady state.     

Prediction of steady state plasma and saliva levels of desmethylimipramine using a single dose,single time point procedure

In normal volunteer study (20 subjects) where each ingested 75 mg desmethylimipramine (DMI), blood and saliva samples were collected at 1, 2, 3, 4, 5, 7, 12, 24, and 32 h post dose. Each subject then was given DMI 25 mg b.i.d. for 15 days. Blood and saliva samples were collected on days 3, 4, 12, 13, 14, and 15. All samples were analyzed for total DMI content. Strong correlations were found between the blood samples collected 12, 24, and 32 h post dose (r=0.93, 0.96, 0.95) and saliva samples collected 24 and 32 h post single dose (r=0.91, 0.84) and the subjects' respective steady states. Although the correlation between blood and saliva levels was weaker (r=0.7) because of considerable interindividual variation in the saliva/plasma DMI ratio (16-fold variation), this ratio in individual subjects was stable. These data suggest that, as has been shown for other psychotropic drugs, single blood measures at 24 h post ingestion of 75 mg DMI can be used to predict optimal dosage in individual patients. Acceptable predictions of steady state plasma levels were obtained when this technique was applied to patient data available in the literature. It is also suggested that if the saliva/plasma ratio is established for each individual patient, their drug level monitoring may be possible using this noninvasive approach.     

辛伐他汀片的人体相对生物利用度及生物等效性研究

目的建立人体血浆中辛伐他汀片的LC-MS/MS测定方法,通过研究辛伐他汀片在健康男性志愿者体内的药代动力学行为,评价其相对生物利用度及生物等效性。方法对20名健康男性志愿者采用开放、随机、交叉、单剂量给药方式,单剂量口服辛伐他汀片40mg后,用LC-MS/MS测定血浆中的药物浓度。结果口服含辛伐他汀40mg的受试制剂(规格:10mg)和参比制剂(规格:20mg)后,血中药代动力学参数:Tmax分别为(1.95±0.43)、(1.90±0.45)h;Cmax分别为(8.42±2.13)、(8.40±1.89)ng/mL;t1/2分别为(5.02±1.72)、(6.51±2.62)h;AUC0-t分别为(41.6±11.1)、(40.5±9.75)ng/mL;AUC0-∞分别为(43.3±11.6)、(43.6±10.1)ng/mL。辛伐他汀的相对生物利用度平均为(102.6±13.3)%。进一步采用双单侧检验和(1-2α)置信区间法分析,受试制剂AUC0-t的90%置信区间为参比制剂相应参数的96.7%～107.1%。结论本方法简便、快速。辛伐他汀片的相对生物制度高,与参比制剂相比在体内具有生物等效性。     

Child and adolescent nortriptyline single dose kinetics predict steady state plasma levels and suggested dose: preliminary data

The use of nortriptyline single dose kinetics to predict steady state plasma levels and suggested dose was investigated in 33 pediatric subjects who were diagnosed as having major depressive disorder. The data were analyzed separately for the 11 subjects 5 to 9 years old who received a single dose of 25 mg and a fixed daily dose of 20 mg of nortriptyline, and for the 22 subjects 10 to 16 years old who received a single dose of 50 mg and a fixed daily dose of 50 mg of nortriptyline (N = 17) or a fixed daily dose of 20 mg (N = 5) because of a very slow rate of metabolism of the drug. Correlations within the group of 5 to 9 years olds between the steady state plasma levels and the five sampling points after the single dose were all highly significant. Correlations between the steady state plasma levels within the group of 10 to 16 year olds and the five sampling points after the single dose and a fixed daily dose of 50 mg (N = 17) were also highly significant. Similar correlations for the total group of 10 to 16 year olds (N = 22) were performed (prorating the steady state plasma levels of the slow metabolizers), and these too were highly significant. Suggested dose schedules for each age group were developed from the regression equations of nortriptyline steady state plasma levels versus 24-hour nortriptyline plasma levels after the single dose. The regression equation for the group of 5 to 9 year olds was highly significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

吲哚美辛缓释胶囊单剂量与多剂量达稳态时的相对生物利用度

采用反相高效液相色谱法测定１１名健康志愿受试者单剂量口服７５ｍｇ和多剂量口服吲哚美辛缓释胶囊和吲哚美辛片后，吲哚美辛血药浓度变化情况。测得单剂量口服７５ｍｇ吲哚美辛缓释胶囊与吲哚美辛片的达峰时间分别是４．０ｈ与１．５ｈ，峰浓度分别是１．０２μｇ·ｍｌ－１与３．７μｇ·ｍｌ－１，吲哚美辛缓释胶囊的相对生物利用度为１０２％。测得多剂量口服吲哚美辛缓释胶囊与吲哚美辛片达稳态后的Ｃｍｉｎ分别是０．２０８μｇ·ｍｌ－１与０．２６３μｇ·ｍｌ－１，Ｃｍａｘ分别是１．２６μｇ·ｍｌ－１与１．２２６μｇ·ｍｌ－１，Ｔｍａｘ分别为２．７７ｈ与１．８２ｈ，ＦＩ分别是１４０．８１％与１２８．２１％。以ＡＵＣ为指标，经统计分析，吲哚美辛缓释胶囊与吲哚美辛片在单剂量和多剂量达稳态时是生物等效制剂。     

A combined single and multiple dose pharmacokinetic study of oral isosorbide-5-mononitrate in healthy volunteers.

Pharmacokinetics of 20 mg isosorbide-5-mononitrate (IS-5-MN) after single and multiple administration of two different tablet formulations were investigated in twelve healthy human subjects using an open, randomized, two-way crossover experimental design. Pentacard 20 mg tablets were compared with Ismo 20 mg tablets. After single-dose administration, both preparations caused a rapid increase in IS-5-MN plasma levels with the peak plasma concentration occurring between 0.5 and 1.5 h. For both formulations, the mean plasma half-life was found to be approximately 5 h after a single dose. In steady state during multiple dosing (t.i.d. at 8 h dosing intervals), a reduced elimination rate was observed. In line with this observation, the area under the plasma concentration-time curve (AUC) for one 8 h dosing interval during multiple dosing was higher than the extrapolated AUC after a single dose. Based on statistical evaluation of the various relevant pharmacokinetic parameters calculated from the plasma concentrations occurring after single and multiple dosing, the tablet formulations are judged to be bioequivalent.     

Bioequivalency and dose proportionality of three tableted promethazine products

Data from a five-way crossover study in human subjects using four talented promethazine products and a promethazine solution are presented. All products were administered as a single oral dose. The five objectives of the study were to investigate bioequivalency, to estimate dose proportionality at two dose levels, to establish validity of a reference production solution for future bioequivalency studies, to estimate intersubject variation, and to compare bioavailability/tablet dissolution data. Blood samples were collected at given intervals over a 24-hour period and analysed for promethazine using an HPLC technique. Pharmacokinetic parameters were calculated using standard procedures and a two-way analysis of variance (ANOVAR) was used to assess whether the differences were statistically significant. The AUC0----infinity data from the ANOVAR analysis showed that the 50 mg innovator and generic products and the 50 mg solution were not significantly different. However, the innovator product had a significantly lower Cmax and longer tmax than the solution. The generic product did not differ significantly from the solution. Promethazine was found to exhibit linear dose proportionality in the range and product studied. Intersubject variation was high for all parameters (23 to 63 per cent) and the in vivo and in vitro data showed a positive relationship.     

The effect of piperacillin dose on elimination kinetics in renal impairment

Summary The effect of drug dose on piperacillin elimination kinetics was examined in 27 adult subjects with varying renal function. Piperacillin, 15 mg/kg or 60 mg/kg, was given by bolus intravenous injection. The elimination half-life (t_1/2) increased five-fold and plasma clearance (Cl_p) decreased by 80% in patients with renal failure. Both parameters were dose dependent in patients with normal renal function, but not in patients with renal insufficiency. Piperacillin dose dependent elimination is due primarily to capacity limited renal excretion.     

Evaluation of the bioequivalence of two transdermal fentanyl systems following single and repeat applications

ABSTRACT

Objective: Transdermal delivery of fentanyl has potential benefits over slow-release morphine, being largely preferred by patients owing to the combination of effective pain relief, a good safety profile and easy, pain-free dosing. The new drug-in-adhesive Durogesic D-TRANS fentanyl Matrix Delivery System (DDTDF) has improved pharmaceutical characteristics and patient acceptability compared to the original Durogesic transdermal reservoir system (fentanyl transdermal reservoir), whilst still providing reliable and consistent delivery of fentanyl. The bioequivalence of these two systems was evaluated in two studies.

Research designs and methods: Eighty healthy volunteers received single (72?h) or multiple (288?h) applications of DDTDF and the transdermal reservoir system (100?µg/h) in two separate randomised, crossover bioequivalence studies. Bioequivalence was assessed by calculating the ratio of least squares means based on log-transformed data following single system application and at steady-state during the fourth application.

Results: Both transdermal systems were bioequivalent with respect to all tested pharmacokinetic parameters. Inter-subject variability was comparable between the two systems and was greater than intra-subject variability. Transdermal delivery was well tolerated in both groups.

Conclusions: The pharmacokinetic results demonstrate that DDTDF is bioequivalent to the original fentanyl transdermal reservoir system after single and multiple applications.     

两种布洛芬缓释制剂的药物动力学与相对生物利用度

目的：考察两种布洛芬缓释剂芬尼康止痛消炎片与芬必得胶囊达稳态后，血清中布洛芬的药物动力学与相对生物利用度。方法：采用反相高效液相色谱法分别测定１８名健康志愿受试者一日两次分别口服芬尼康６００ｍｇ与芬必得６００ｍｇ达稳态后，布洛芬的血药浓度变化情况，计算药物动力学参数与相对生物利用度，并以配对ｔ检验与双单侧ｔ检验进行统计分析。结果：两种制剂达稳态后Ｃｓｓｍａｘ分别为２６．６±５．６与２６．８±６．２ｍｇ·Ｌ－１，Ｔｍａｘ分别为２．８±０．５与２．７±０．６ｈ，ＡＵＣ０→∞分别为２９８．８±６５．７和２９８．８±７１．１（ｍｇ·Ｌ－１·ｈ），ＦＩ分别是１２３．７％±１９．５％与１２２．３％±２６．０％；以配对ｔ检验与双单侧ｔ检验对上述参数进行统计分析，两种制剂的Ｃｓｓｍａｘ、ＡＵＣ０→∞、Ｔｍａｘ、ＦＩ差异均无显著性（Ｐ＞０．０５）。结论：两者具生物等效性；以芬必得为标准参比制剂，芬尼康相对生物利用度为１０１．７％±１６．８％。     

Estimation of steady state antibiotic concentration in cerebrospinal fluid from single-dose kinetics

Objective: Assuming linear kinetics, the mean CSF concentrations of an antibacterial in steady state (C_ssCSF) can be estimated, when the area under the concentration-time curve in CSF after the first dose is known. For this purpose we propose the function C_ssCSF=AUC_CSF·Anticipated dose/Dosing Interval·Applied dose. Results: Together with the MIC and MBC of the causative pathogen, the estimate is of value in the choice of antibacterial drug and the dosing regimen in central nervous system infections.     

Plasma kinetics of methaqualone in man after single oral doses

Summary Plasma concentrations of methaqualone were followed for several days after single oral doses in 5 healthy subjects. The analysis of methaqualone was performed by gas chromatography-mass spectrometry (mass fragmentography). The plasma levels of methaqualone were interpreted according to a two compartment model. The elimination rate of methaqualone was found to be much slower than has been reported previously, half lives in the -phase ranging from 19.6 to 41.5 h.     

冷血停跳液单次灌注在心内直视手术中的应用

目的:探讨体外循环(Cardiopulmonary Bypass.CPB)心内直视手术中,单次灌注含钾冷血停跳液的心肌保护效果.方法:50例患者采用4:1血液晶体停搏液灌注.灌注量20 ml/kg,术中心电图不出现活动波形,则不再重复灌注.结果:患者CPB时间(76.78.±18.57)min,主动脉阻断时间(42.08±10.44)min.开放主动脉后心脏自动复跳48例(96%),复跳后除颤2例(4%),术后患者全部康复出院.结论:单次灌注含钾冷血停搏液心肌保护作用明显.     

Anticoagulant effect and plasma kinetics of fluorophenindione after a single dose in man

Summary After administration of a single loading dose (80 mg p.o.) of fluorophenindione, the prothrombin level decreased to 37 % in 24 h, and the effect lasted for 48 h. Accordingly, fluorophenindione can be classified as an anticoagulant with an intermediate effect. Its elimination half-life was 31 h, which is longer than that of phenindione, because of the greater stability of the fluorinated derivate.     

Comparison of single and multiple dose pharmacokinetics of theophylline using stable isotopes

Summary Theophylline, enriched with the stable isotopes¹³C and¹⁵N, was administered intravenously in a dose of 10 mg to 8 healthy men following single (200 mg) and multiple (200 mg 8-hourly for 5 days) oral dose administration of aminophylline.Total plasma clearance, volume of distribution, and half-time determined from the intravenous data were similar, demonstrating that the pharmacokinetics of theophylline after chronic dosing can be predicted from the pharmacokinetics of a single dose.With chronic oral dosing, however, the mean trough concentration was 12% higher at 9 a.m. than at 5 p.m., the end of the dose interval (3.94±0.55 vs. 3.50±0.45 µg·ml^–1). The AUC following oral dosing was 25% higher in the multiple dose study than in the single dose study.Simulation analysis suggested that these results could be explained by diurnal variation in the clearance or absorption rate or a combination of both. Thus, the systemic availability of theophylline measured during a single dosage interval after chronic oral dosing to steady state would be overestimated in comparison with that measured after a single oral dose.     

Bioavailability of propranolol hydrochloride tablet formulations: application of multiple dose crossover studies

Two multiple dose crossover pharmacokinetic studies were carried out to determine the steady-state bioavailability of newly formulated generic propranolol HCl tablets relative to Inderal tablets. In Study I, 24 healthy volunteers were dosed with 4 x 10 mg test tablets, 1 x 40 mg test tablet, 4 x 10 mg Inderal tablets, and 40 mg of propranolol HCl in solution. In Study II, 24 healthy volunteers were dosed with 1 x 80 mg test tablet, 1 x 80 mg Inderal tablet, and 80 mg of propranolol HCl in solution. Both studies were of randomized design with each formulation administered every 8 h for 15 doses. Serial plasma samples were obtained for 8 h after morning doses on Days 4 and 5 of each treatment period and assayed for propranolol using a validated HPLC method. Mean plasma concentration-time data for test tablets and reference tablets were superimposable in both studies. Pharmacokinetic parameters from Days 4 and 5 were combined for statistical analysis since subjects were determined to have reached steady-state. Mean AUC, Cmax, tmax, and Cmin values were not statistically different between test tablets and Inderal tablets in either study. Based on these findings, the test tablets demonstrated the same rate and extent of propranolol absorption as did corresponding Inderal tablets. Therefore, the test tablets and Inderal tablets were determined to be bioequivalent.     

我院口服药单剂量摆药存在的问题及探讨

住院药房口服药单剂量摆药在现有工作模式下存在许多问题,调查、分析摆药过程中影响药品质量的因素,寻找药品质量控制的方法与摆药过程的规范管理,以保证药品质量,提高药学服务水平。     

Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man

Summary Plasma concentrations of orphenadrine were measured by a specific gaschromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2–20.1 h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.     

Pharmacokinetics of single and multiple doses of phenytoin in man

Summary Plasma concentration of phenytoin (diphenylhydantoin, DPH) have been studied in 5 volunteers after single oral and iv doses (5.0 mg sodium DPH/kg), and after multiple oral doses (2.0 mg sodium DPH/kg b.i.d. for 12 days). The data were analysed according to a one compartment model. The plasma half-life was 14.5 h±1.2 S.D. after i.v. administration, its apparent volume of distribution varied little (0.52 l/kg±0.04) and its bioavailability ranged between 0.70 and 1.0 (mean 0.87). After oral administration peak plasma concentrations were reached in 4 to 12 h. Elimination curves were slightly convex, probably due to an effect of slow absorption. Steady-state plasma levels varied twofold between individuals after multiple oral doses and exceeded those predicted from the single i.v. dose by 29 to 77%. The discrepancy was considered to be due to transition to dose-dependent kinetics.This is the last paper written in collaboration with Dr. Balzar Alexanderson before his untimely death on 2nd June 1973. We are grateful for the inspiring and fruitful experience of working with him. To honour his memory as a good friend and brilliant clinical pharmacologist a number of papers from our laboratory will be dedicated to him.