Pharmacokinetics and pharmacodynamics of peldesine (BCX-34), a purine nucleoside phosphorylase inhibitor, following single and multiple oral doses in healthy volunteers

The pharmacokinetic parameters of peldesine (BCX-34) were investigated after single and multiple oral doses in two groups of healthy adult volunteers. The pharmacodynamic elevation of endogenous inosine and 2'-deoxyguanosine was simultaneously monitored. The first group of 8 subjects received an intravenous dose (18 mg/m2) and five oral doses (30, 63, 108, 144, and 192 mg/m2) of drug. A second group of 12 subjects received 160 mg/m2 in four and in six divided doses orally. Serial blood samples and total urine outputs were collected during dosing and for at least 24 hours after the last dose was administered. One set of samples was analyzed using high-pressure liquid chromatography/ultraviolet (LC/UV) methods, validated for intact drug in human plasma and urine samples. Another set of samples was analyzed for the biomarkers, inosine and 2'-deoxyguanosine, using high-pressure LC with either mass spectrometry (MS) or electrochemical detection (EC) methods. The pharmacokinetic parameters of inosine and 2'-deoxyguanosine were calculated using noncompartmental methods and correlated against the pharmacokinetic parameters of BCX-34. For the single-dose study, the results exhibited linear pharmacokinetics over the dose range from 30 to 144 mg/m2. The calculated terminal half-life was 3.5 +/- 1.0 h, and the absolute bioavailability of the oral formulation was approximately 51%. Analysis of urine in the first 24 hours of collection accounted for approximately 82% of the absorbed intact drug. Evaluation of the multiple-dose pharmacokinetics indicated that steady-state blood concentrations were achieved by 24 hours when the drug was administered four or six times a day. A drug dose-related elevation of plasma 2'-deoxyguanosine was observed. This phenomenon was not seen with plasma inosine levels. However, analysis of urine samples showed an increase in inosine output with an increase in the drug dose. The calculated terminal half-life of inosine and 2'-deoxyguanosine was 15.3 +/- 1.8 h and 1.3 +/- 0.1 h, respectively.     

Use of gamma distributed residence times in pharmacokinetics

The multiple dose pharmacokinetics of isotretinoin and its major blood metabolite, 4-oxo-isotretinoin, were studied in 10 patients with cystic acne and 11 patients with various keratinization disorders. Blood samples were obtained at predetermined times following the first dose, interim doses and the final dose. Blood concentrations of isotretinoin and 4-oxo-isotretinoin were measured by a specific and sensitive HPLC method. A lag time was usually observed prior to the onset of absorption following oral administration of the drug in a soft elastic gelatin capsule. Absorption then proceeded rapidly and maximum blood concentrations usually occurred within 4 h of drug administration. The harmonic mean half-life for the elimination of isotretinoin by the cystic acne patients was approximately 10 h after the initial dose and did not change significantly following 25 days of 40 mg b.i.d. dosing. Steady-state blood concentrations remained relatively constant after the fifth day of dosing. The harmonic mean elimination half-life in the patients with various disorders of keratinization was about 16 h. The results of the 2 studies suggest that no significant changes in the pharmacokinetics of isotretinoin occur during multiple dosing and that the multiple dose pharmacokinetic profile is predictable and can be described using a linear pharmacokinetic model. This suggests that the steady-state concentrations of isotretinoin can be predicted from single dose data.     

Blood level studies with viloxazine hydrochloride in man.

1 The pharmacokinetic characteristics of a new antidepressant, viloxazine hydrochloride, (ICI 58,834, Vivalan), have been investigated in four separate studies. 2 In Study 1, blood levels were measured over a period of 24 h after single doses of viloxazine hydrochloride from 10-100 mg (expressed as base). In Study 2, blood levels were measured over 24 h, during which three single doses of viloxazine hydrochloride (80 mg, expressed as base) were given 4 h apart. In Study 3, blood samples and urine and faeces were collected for 96 h after doses of 40 and 100 mg of [14C] viloxazine hydrochloride (40 muCi). In Study 4, 1 h blood levels were measured at weekly intervals during a comparative clinical trial in which viloxazine was given at a dose of 100 mg four times a day. 3 The half-life of the drug is in the range 2-5 h with maximum blood levels occurring in 1-4 h of the oral dose. Maximum blood levels are proportional to the oral dose given over the range studied (0.76(mug/ml)/(mg/kg)). The drug is very well absorbed orally, only 2% being found in faeces. Repeated dosing at 4 hourly intervals leads to slightly higher blood levels after the second, but not subsequent, doses. No accumulation was seen from week to week in depressed patients. No regular sex difference was seen in the pharmacokinetic characteristics of viloxazine hydrochloride but two females in one study did show a markedly higher maximum blood level and apparently longer half-life than the males. 4 It is concluded that viloxazine is rapidly and almost totally absorbed after an oral dose, and has a shorter half-life than the tricyclic antidepressants; therapy with it should be easily controllable.     

Drug dose prediction with flexible test doses

This article presents the first known practical method to apply one-compartment pharmacokinetic modeling to prediction of doses for drugs from one or more blood-drug concentrations, without requiring approximations or a computer. It should be useful for regulating doses of orally administered CNS drugs whose effects develop over a day or more, e.g., lithium, antidepressants, and anticonvulsants. Pharmacokinetic calculations for sequences of one, two, and three test doses are condensed into graphs that can be rapidly applied for clinical purposes. These graphs account for dose division, blood sampling time, and drug elimination rate; they show that the ratio of the steady-state day-mean drug level to the test-drug blood level is independent of the half-life if the test level is about a day after the last test dose. The calculations show the same value as experimental measurements for the ratio between steady-state serum lithium level and serum lithium level measured after a test dose. A rational strategy for drug-loading doses is discussed.     

A comparison of two sparse sampling population pharmacokinetic approaches for the estimation of pharmacokinetic parameters in children

BACKGROUND AND OBJECTIVE: The objectives of this study were to assess pharmacokinetic parameters (clearance, volume and half-life) in children using sparse sampling population as well as Bayesian (post hoc) approach. METHODS: Three drugs were selected for this study. Two sparse sampling methods (variable or fixed) using population and Bayesian approaches were used to assess pharmacokinetic parameters in children following a single oral dose. The initial estimates of the model parameters and inter- and intrasubject variability were obtained from the pharmacokinetic studies conducted in adults. The estimated pharmacokinetic parameters using sparse sampling (3 blood samples) were compared with the pharmacokinetic parameters obtained by extensive sampling (> or = 7 blood samples). RESULTS AND CONCLUSIONS: The results indicated that both variable and fixed sampling approaches could be used to estimate mean population as well as individual pharmacokinetic parameters in children with fair degree of accuracy. The methods described here can be used to assess either population or individual pharmacokinetic parameters in children, provided there is a prior knowledge of the pharmacokinetics of a drug in adult population.     

Pharmacokinetic analysis of concentration-time data obtained following administration of drugs that are recycled in the bile

A pharmacokinetic model for calculating the pharmacokinetic parameters for a compound that is recycled in the bile is presented and tested using theoretical as well as experimental data. The results indicate that this method is stable and only slightly susceptible to sampling and recycling times. It is apparent from the present study that pharmacokinetic terms that have been used in classical situations are not directly applicable to drugs that enter the enterohepatic circulation. Effective half-life and effective clearance are used to describe the intrinsic ability of the eliminating organs to remove drug from the blood, whereas net half-life and net clearance are used to describe the irreversible elimination of the drug from the body.     

The effect of altered physiological states on intravenous anesthetics

This chapter begins with the rationale for the intense interest in how altered physiologic states change the effect seen following administration of similar doses of intravenous anesthetic drugs. It then traces the development of two types of pharmacokinetic models that have been used to understand the relationship between pharmacokinetics and cardiovascular physiology. Physiologic pharmacokinetic models are constructed from detailed knowledge of tissue blood flow, tissue weight, and blood: tissue partitioning characteristics. The invasive methods involved are often destructive of the subjects being studied. Rodent models are developed and scaled to simulate human subjects under a variety of physiologic conditions. Traditional pharmacokinetic models, based on drug concentration versus time data from easily obtained blood samples, can also be plumbed for physiologic information. Whereas the physiologic estimates obtained are less detailed than those from physiologic models, they do represent the actual pharmacokinetics for the subjects studied and give sufficient physiological detail to delineate the basis for the changed pharmacokinetics of intravenous pharmacokinetics.     

In Vivo Microdialysis Sampling for Pharmacokinetic Investigations

In vivo microdialysis sampling coupled to liquid chromatography was used to study acetaminophen disposition in anesthetized rats. The pharmacokinetics of acetaminophen and its sulfate and glucuronide metabolites were determined using both microdialysis sampling and collection of whole blood. For microdialysis, samples were continuously collected for over 5 hr without fluid loss using a single experimental animal. Microdialysis sampling directly assesses the free drug concentration in blood. The pharmacokinetic results obtained with microdialysis sampling were the same as those obtained from blood collection. The administration of heparin, necessary when collecting blood samples, was found to double the elimination half-life of acetaminophen. Microdialysis sampling is a powerful tool for pharmacokinetic studies, providing accurate and precise pharmacokinetic data.     

Choosing optimal sampling times for therapeutic drug monitoring

Recent advances linking pharmacokinetic theory with the selection of optimal sampling times and the influence of sampling times on the interpretation of serum drug concentrations are discussed. For serum drug assay results to be interpreted easily, samples should be obtained during the postdistributive phase (for loading and maintenance doses) or at steady state (for maintenance doses). Beyond this, the choice of sampling times depends on whether peak, trough, or intermediate concentrations are being monitored. When intrapatient and interpatient variation in pharmacokinetic values are considered to be the principal components of variability, the best time for taking a single sample after a test dose in order to predict the average concentration during the steady-state dosage interval is when sample time equals 1.4 times the population half-life of the drug. Optimal sampling times to predict maximum or minimum steady-state concentrations may differ from those used to estimate the average concentration. Efforts to decrease the number of samples needed to estimate accurately steady-state drug concentrations have led investigators to test "single-point" prediction methods following a test dose. However, for drugs administered by continuous infusion, it seems prudent to assay more than one serum sample obtained before steady state is achieved; a single sample obtained too early could contribute to inaccurate predictions. Recommendations are presented for optimal sampling times for commonly monitored drugs.     

Inhaled corticosteroids in asthma: a dose-proportionality study with triamcinolone acetonide aerosol.

The systemic exposure to triamcinolone acetonide (TAA) after inhalation of aerosolized drug has not been examined previously. This study evaluates the plasma concentrations, pharmacokinetics and dose proportionality of TAA after single oral inhalations at doses of 400, 800, and 1600 mcg. Nine moderately asthmatic male patients received each of the doses in a randomized crossover manner using a 1-week washout period between dosing. Serial blood samples were collected for 10 hours postdosing for the determination of plasma TAA concentrations by using a specific radioimmunoassay. The pharmacokinetic profiles that were obtained showed slow and limited absorption over the first 4 hours after dosing followed by rapid elimination with a half-life of approximately 2 hours (range: 1.8-2.3 hr). Comparison of pharmacokinetic parameters from each dose group showed excellent proportionality and consistent absorption for all patients. Mean Cmax values ranged from 0.51 ng/mL after the 400 mcg dose to 1.01 ng/mL and 1.97 ng/mL after the 800 and 1600 mcg doses, respectively. Mean AUC0-10 values for these same doses were 2.6 ng x hr/mL, 5.3 ng x hr/mL and 10.5 ng x hr/mL, respectively. The results suggest that systemic exposure to TAA is minimal after oral inhalation, occurs in a dose proportional fashion, and produces circulating plasma concentrations which are unlikely to have significant adverse systemic effects.     

Pharmacokinetics of diltiazem and propranolol when administered alone and in combination

Multiple oral doses of diltiazem (DTZ) and propranolol (PPL, 60 mg every 8 h daily for 13 doses) were administered to 14 healthy volunteers alone and in combination on three separate occasions. Serial blood samples were collected up to 24 h after dose 13 on day 5 to determine possible pharmacokinetic interactions between the two drugs. When administered alone, DTZ concentration peaked at 161.4 ng ml-1 3 h following the final dose with an elimination half-life of 6.1 h. DTZ oral clearance was 65.1 l h-1. PPL did not affect DTZ oral clearance and half-life during the combination treatment. However, DTZ tmax was extended from 2.9 h to 3.5 h (p less than 0.05) and Cmax was 144.7 ng ml-1. Unlike the parent drug DTZ, desacetyldiltiazem (DAD) plasma profile was elevated during the combination treatment. DAD Cmax and AUC both increased approximately 20 per cent (p less than 0.05). PPL pharmacokinetics were altered as well. Oral clearance of PPL decreased from 80.4 l h-1 to 61.0 l h-1 while the half-life increased from 5.9 h to 8.0 h (p less than 0.05). PPL Cmax increased from 155.1 ng ml-1 to 167.5 ng ml-1.     

Pharmacokinetics of single and multiple ascending doses of the antiallergic agent tiacrilast in man

Five groups of six healthy subjects received single oral doses of 150, 300, 450, 600 or 750 mg tiacrilast 150 mg capsules, followed 24 h later by the same dose given every 6 h for 7 days, in a study designed to assess the pharmacokinetics of single and multiple doses of tiacrilast. Plasma samples were obtained at specified times after the initial dose, after 4 days of multiple dosing and after the last dose of tiacrilast. Samples were assayed for unchanged drug by a specific HPLC method. Wide variability was seen in the plasma concentration-time data. Plasma concentrations and pharmacokinetic parameters were nearly proportional to dose over the 150 to 750 mg dose range studied. Moreover, there was no evidence of unexpected accumulation of the drug in the plasma during multiple dosing and food did not appear to alter the bioavailability of tiacrilast to any clinically significant extent. The apparent elimination half-life was similar after single and multiple doses and ranged from 1 to 3 h.     

Rituximab (IDEC-C2B8): validation of a sensitive enzyme-linked immunoassay applied to a clinical pharmacokinetic study

Rituximab is a chimeric monoclonal antibody (MAb) directed against the B-cell CD20 antigen that has been approved for therapy of relapsed and resistant follicular non-Hodgkin's lymphoma (NHL). This study describes the development and validation of a highly sensitive, rapid, accurate, precise enzyme-linked immunosorbent assay (ELISA) to measure Rituximab serum concentrations. This study also describes the application of the ELISA method to a pharmacokinetic study in a homogeneous group of patients with follicular lymphoma who received 4 weekly doses of MAb at the standard dose of 375 mg/m2 as consolidation of chemotherapy. In the patients in this study, the median Rituximab serum concentrations increased during therapy, and showed a slow decline during the posttreatment period. The Rituximab elimination half-life of approximately 20 days accounts for the demonstrated accumulation of MAb in serum samples. Because previous pharmacokinetic studies showed a correlation between Rituximab serum levels and tumor response, the ELISA method used in this study, which allows a precise control of serum concentrations, could be useful for predicting the final response to the MAb and for selecting patients able to benefit from higher dosage or repeated drug administration.     

单克隆抗体药物药代动力学特征、分析方法以及体内分析方法学研究进展

近年来,单克隆抗体药物发展迅速,在肿瘤、免疫、血液等系统疾病领域应用日益广泛。截至2019年其全球处方药物市场占比已达15.3%(1400亿美元)。单克隆抗体药物作为一种大分子蛋白,因其特殊的结构和生理性质,在体内的吸收、分布、代谢及排泄均与小分子药物存在较大差异,具有靶点介导的药物处置、非线性药动学代谢、时间依赖性、较长的半衰期等独特的药代动力学特征,充分了解这些特征有益于该类药物分析方法的开发。单克隆抗体药物在生物体内的处置具有特殊性和复杂性,极大地增加了生物检测的难度,因此必须建立专属、灵敏、准确、可重复的测定分析方法。本文旨在论述单克隆抗体药物的药代动力学特征、常用分析方法及其优缺点、体内分析方法学验证要求等,并逐点与小分子药物进行对比讨论,以期为单克隆抗体药物的分析技术开发提供部分参考。     

Nonlinear relationship between plasma and red blood cell pharmacokinetics of chlorthalidone in man

Plasma concentrations, red blood cell concentrations, and urinary excretion of chlorthalidone were measured after oral administration of single doses of 100 or 200 mg to ten human subjects. The decay of red blood cell concentrations showed a much longer elimination half-life than the terminal plasma decay curve. The in vitrodistribution of chlorthalidone between plasma and erythrocytes was similar to the in vivodistribution curve obtained from patients who were in a steady-state concentration range. A pharmacokinetic model was developed including nonlinear binding of chlorthalidone by the red blood cells, which in detail accounted for the observed time courses of drug in plasma and erythrocytes simultaneously.This work was supported in part by a grant from the Netherlands Foundation for Medical Research (FUNGO).     

Influence of mode of intravenous administration and blood sample collection on rat pharmacokinetic data

The influence of the mode of intravenous dosing and blood sample collection on the pharmacokinetics of 4-[(3-methoxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2, 6-disilacyclohexane hydrochloride (I) was studied in the rat. Blood samples obtained from the tail and by exsanguination following injection of the 14C-labeled drug into the caudal vein, the jugular vein, and the heart were analyzed for total radioactivity, and the concentration profiles from the different treatments were compared. Dosing and sampling from the tail vein resulted in significantly different blood levels (and related pharmacokinetic parameters) when compared to other methods, probably attributable to a local depot effect. Intracardiac administration tended to cause higher drug levels in the heart than intravenous doses, although no significant differences were found between the respective blood concentrations. The results showed that caudal vein injection is a simple and adequate method of intravenous administration in rats designated for exsanguinated blood and tissue collection. For serial blood sampling in individual animals, the dose may be given via the jugular vein and the blood collected from the cut tail. These methods require little or no surgical preparations and are particularly suitable for prolonged sampling in studies where a relatively large number of animals are involved.     

Simulation for population analysis of Michaelis-Menten elimination kinetics

A simulation study was conducted to compare the cost and performance of various models for population analysis of the steady state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. The usual Michaelis-Menten model (MM) and its variants provide no estimate of the volume of distribution, and generally give poor estimates of the maximal elimination rate and the Michaelis-Menten constant. The exact solution to the Michaelis-Menten differential equation (TRUE) requires a precise analysis method designed for estimation of population pharmacokinetic parameters (the first-order conditional estimation method) and also considerable computational time to estimate population mean parameters accurately. The one-compartment model with dose-dependent clearance (DDCL), in conjunction with the first-order conditional estimation or Laplacian method, ran approximately 20-fold faster than TRUE and gave accurate population mean parameters for a drug having a long biological half-life relative to the dosing interval. These findings suggest that the well-known MM and its variants should be used carefully for the analysis of blood concentrations of a drug with Michaelis-Menten elimination kinetics, and that TRUE, in conjunction with a precise analysis method, should be considered for estimating population pharmacokinetic parameters. In addition, DDCL is a promising alternative to TRUE with respect to computation time, when the dosing interval is short relative to the biological half-life of a drug. This work was supported in part by the Epilepsy Research Foundation, the Nakatomi Foundation, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.     

Determination of plicamycin in plasma by radioimmunoassay.

This article describes a method for the determination of plicamycin in plasma by radioimmunoassay. The anti-plicamycin antibody was produced against a plicamycin-bovine serum albumin conjugate prepared by using diazotized p-aminobenzoic acid as a cross-linker. The radiolabeled ligand, 125I-plicamycin, was prepared by the chloramine-T method. The linear plicamycin concentration range was 7-400 ng/ml. The coefficients of variation for intra- and interday variabilities were 7.5 and 15%, respectively. No interference was observed from either the structurally related chromomycin A or concomitantly used drugs hydroxyurea or allopurinol. With this method of testing, plicamycin levels in plasma could be determined in patients receiving small (0.85-1.0 mg/m2) therapeutic plicamycin doses. Preliminary pharmacokinetic data in humans indicate that the plasma drug disappearance curve was biphasic with a mean elimination half-life of 10.6 +/- 1.7 h, total clearance rate of 11.1 +/- 0.4 ml/min/m2, and area under the plasma drug concentration-time curve of 1,289-1,546 ng-h/ml. This assay method is clinically useful for pharmacokinetic studies of plicamycin and may be helpful in the design of rational therapeutic drug trials.     

Phase I trial of aclacinomycin-A

Aclacinomycin-A is a new anthracycline antibiotic with a broad spectrum of antitumor activity in animals. Compared to doxorubicin, it was found to produce less cardiotoxicity and alopecia. A Phase I trial of aclacinomycin-A given as a weekly 15 min IV infusion was conducted in 20 previously treated patients with advanced solid tumors. Four dose levels ranging from 40 to 100 mg/m2 were studied; myelotoxicity was dose-limiting at 85 and 100 mg/m2. Other toxicities were moderate to severe nausea and vomiting in 9 patients, mild phlebitis in 2 patients, and mild abnormality of liver function tests in 3 patients. No cardiac or renal toxicities were seen, but two partial responses were observed. The pharmacokinetic profile of aclacinomycin-A in plasma and urine was studied in 3 patients given 65 mg/m2 using a high performance liquid chromatography assay. The data obtained were consistent with a two compartment model of drug disposition with initial and terminal half-life values of 6.6 min and 13.3 h, respectively. The major fluorescent metabolite was eliminated with a terminal half-life of 25 h. Two metabolites as well as the parent drug were excreted in the urine as less than 10% of the doses given. This pharmacokinetic profile is similar to that of other anthracyclines, although aclacinomycin-A appears to have lower blood levels than doxorubicin given at equivalent doses. On this weekly schedule, the recommended dose is 65 mg/m2 for Phase II trials.     

Dosage regimen of cimetidine reviewed. Possible drug accumulation after multiple oral doses

Summary The doses of cimetidine recommended differ in children, especially those with cystic fibrosis. These dosage regimens were derived from single-dose pharmacokinetic studies of the drug. Some authors showed, however, that after administration of repeated oral doses of cimetidine in healthy adults and children with cystic fibrosis, the elimination half-life of the drug was markedly prolonged. In view of the ability of cimetidine to inhibit metabolism of other drugs, it is suggested that the parent compound and/or its metabolite(s) may inhibit its own metabolism during a prolonged course of treatment. Enterohepatic recirculation of the drug and/or its metabolite(s) may also contribute to prolongation of its elimination. One should therefore be cautious in using single-dose pharmacokinetic parameters to calculate repeated dose regimens and expected plasma steady-state concentrations.