Evaluation of four once-daily aminoglycoside dosing nomograms

STUDY OBJECTIVE: To evaluate the accuracy of four once-daily aminoglycoside dosing nomograms in producing the desired gentamicin peak concentration (Cmax) target of 20 microg/ml in patients with varying degrees of renal function. DESIGN: Retrospective analysis using prospectively collected pharmacokinetic data. SETTING: Rural teaching hospital. PATIENTS: Ninety patients receiving intravenous gentamicin divided into three groups (30 patients each) determined by estimated renal function: group 1, creatinine clearance (Cl(cr),) 60 ml/minute or greater; group 2, Cl(cr) 40-59 ml/minute; group 3, Cl(cr) 20-39 ml/minute. Intervention. Serum gentamicin concentrations were collected for a 2-point (two consecutive infusions and one predose and one postdose concentration sampled during steady state) or 3-point (single infusion and one predose and two postdose concentrations at least 1.5 estimated half-lives apart) pharmacokinetic study for determination of patient-specific pharmacokinetic parameters (elimination rate constant, volume of distribution at steady state, and clearance) after 30-minute infusions of gentamicin 2.8 +/- 1.6 mg/kg. MEASUREMENTS AND RESULTS: The four nomograms evaluated were from Hartford Hospital, Barnes-Jewish Hospital, University of Rochester, and the Sanford Guide. With a pharmacokinetic analysis program and the patient-specific pharmacokinetic parameters, Cmax and minimum concentration (Cmin) were determined with use of the recommended doses and dosing intervals of the four nomograms. Also, the gentamicin dose and interval needed to achieve a Cmax and Cmin of 20 microg/ml and 0.2 microg/ml, respectively, were determined. Dosing was based on total body weight unless that weight was more than 25% of ideal body weight, in which case, an adjusted body weight was used. In general, the recommended dosages and resultant Cmax produced by the nomograms were significantly less (p < 0.05) than the dosage and Cmax actually needed to achieve a Cmax:minimum inhibitory concentration (MIC) ratio of 10 or greater for bacteria with an MIC of 2 microg/ml. CONCLUSION: Once-daily aminoglycoside dosing using the four nomograms resulted in inaccurate dosing, and because of the large variability in human pharmacokinetics, dosing nomograms such as these should be abandoned in favor of individualizing dosages with therapeutic drug monitoring.     

The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing

AIMS: The pharmacokinetics and pharmacodynamics of oral dofetilide, a novel, class III antiarrhythmic drug, were assessed during administration either twice or three times daily. METHODS: Dofetilide was administered orally to three groups of healthy subjects in daily doses of 1000 microg (n = 8), 1500 microg (n = 8), or 2500 microg (n = 9) as twice daily and three times daily treatment regimens, with the two regimens assigned randomly as a two-way crossover for each subject and separated by at least a 6 day washout period. RESULTS: Pharmacokinetic analysis indicated a rise in plasma dofetilide concentrations until steady state was attained on day 3. Ctrough had a linear dependence on dose for both the twice daily and three times daily dosing regimens. The maximum concentration attained (Cmax) and the area under the concentration vs time curve (AUC(0,tau) increased linearly with dose for each dosing regimen on both days 1 and 5 of dosing. Cmax occurred at 2 h. Pharmacodynamic measurements showed that the QTc interval increased in a dose-dependent manner and that the time to maximum QTc was 2 h after dosing. A linear relationship was determined between plasma dofetilide concentration and the prolongation of the QTc interval. The slope of this line was significantly greater on day 1 (ranging from 12.9 to 14.2 ms/ng ml-1) than on day 5 (ranging from 9.9 to 12. 8 ms/ng ml(-1). CONCLUSIONS: The pharmacokinetics and pharmacodynamics of dofetilide are predictable and based on a linear relationship for both twice daily and three times daily dosing regimens. The QT responsiveness to dofetilide is greater on day 1 than on day 5.     

Importance of oral dosing rate on the hemodynamic and pharmacokinetic profile on nilvadipine

Nilvadipine was administered as an oral solution formulation to 12 normotensive subjects in a three-way randomized crossover study at a dose of 16 mg as three different dosing regimens: 1) as a single 16 mg dose, 2) as a 1.6 mg dose given hourly for 10 doses, and 3) as an initial dose of 4.8 mg, followed by 1.6 mg doses given every hour for seven additional doses. After each dose, clinical effects, hemodynamic changes and the pharmacokinetic profile of the drug were determined. The mean maximum changes in diastolic (DBP) and systolic (SBP) blood pressure and heart rate (HR) after dosing regimens 1, 2, and 3 were: -33, -13 and +46%; -17, -14 and +38%; and -24, -14 and +36%, respectively. There was a relationship between the changes in DBP and HR and plasma concentrations of nilvadipine only after dosing regimen 1. The effect-concentration relationships were fit to a modified Emax model. There was no relationship between the change in SBP and plasma concentration after any of the dosing regimens. While there were no significant differences in the mean area under the plasma concentration-time curve (AUC0----infinity) between dosing regimens 2 (38.7 ng.hr/mL) and 3 (42.1 ng.hr/mL) (P greater than 0.05), the mean AUC0----infinity after regimen 1 (76.3 ng.hr/mL) was significantly greater than after dosing regimens 2 or 3 (P less than 0.05). The mean maximal plasma concentrations (Cmax) were 31.6, 1.3 and 6.3 ng/mL after dosing regimens 1, 2 and 3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Circadian variation in theophylline absorption during chronic dosing with a slow release theophylline preparation and the effect of clock time of dosing.

1. Eight volunteers were given seven doses of 200 mg of slow release theophylline at either 11.00 h and 23.00 h (regimen 1) or 17.00 h and 05.00 h (regimen 2). At the time of the sixth dose (60 h) hourly blood sampling was started and continued for 24 h. After at least 1 week volunteers crossed over to the other regimen. 2. Volunteers retired to bed at 23.00 h and arose after the 07.00 h sample during both regimens. 3. During regimen 1 there was a marked rise in mean tmax from 3.3 h after dosing at 11.00 h to 9.3 h after dosing at 23.00 h (P less than 0.001). There was also a fall in AUC(0,12) from 89.9 mg l-1 h after dosing at 11.00 h to 79.0 mg l-1 h after dosing at 23.00 h. There was no difference in mean Cmax values. 4. During regimen 2 these circadian changes were abolished with mean values after both dosing times lying between those observed during regimen 1. 5. A marked delay in absorption occurs at night and cannot be explained by food intake.     

Relationships among duration of infusion, dose, dosing interval, and steady-state plasma concentrations during intermittent intravenous infusions: studies with metronidazole

Relationships among duration of infusion (T), dose, dosing interval (tau), maximum and minimum plasma drug concentrations at steady state (Cmax,ss and Cmin,ss, respectively), and the duration of effective plasma concentrations (tD) during multidose intermittent infusion regimens were studied by computer simulation using metronidazole as a model drug. Pharmacokinetic parameter values for metronidazole were obtained from the literature and the minimum effective plasma concentration (MEC) was taken as 6.0 micrograms/ml. Increasing the infusion period of the dose reduces Cmax,ss, but increases Cmin,ss. If intermittent bolus injection of a given dose of drug results in effective plasma concentrations for the entire dosage interval (i.e., Cmin,ss,bolus greater than MEC), then infusion of that dose over any period (T less than or equal to tau) will also result in effective concentrations for the entire dosage interval. However, if the dosage is such that Cmin,ss,bolus less than MEC, the relationships among duration of infusion, dose, dosage interval, and duration of effective plasma concentrations are complex. Therefore a nomogram was developed to allow selection of dose, dosing interval, and infusion period such that Cmax,ss and Cmin,ss could be maintained within a desired range.     

Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady state

The pharmacokinetics of cefixime (CL 284,635; FK027), a new orally active broad-spectrum cephalosporin, were determined in 26 healthy volunteers, after multiple 200-mg twice-a-day (group 1; N = 13) or 400-mg once-a-day (group 2; N = 13) dosing for 15 days. On study days 1, 8, and 15, mean peak serum concentrations (Cmax) were 1.67, 1.75, and 1.87 micrograms/mL, respectively, for group 1 and 2.76, 3.04, and 2.67, respectively, for group 2. Over the 15-day period, mean trough serum concentrations were, on average, 0.40 and 0.08 microgram/mL for groups 1 and 2, respectively. Comparison (ANOVA) of serum and urinary excretion pharmacokinetic parameters for cefixime on days 1, 8, and 15 found no significant (P greater than .05) differences for either group except for a small but significantly (P less than .05) earlier time to reach Cmax and higher renal clearance on days 8 and 15 in group 1. These differences, however, are not clinically significant. On study days 1, 8, and 15, mean Cmax and AUC0-tau values for Group 2 were about 1.5 to 2.2 time those for Group 1. Urinary excretion of cefixime accounted for 11.9 to 14.5% and 9.9 to 12.4% of the dose in groups 1 and 2, respectively, over the 15-day study. Overall, there was no accumulation of cefixime in serum or urine nor was there a reduction in serum concentrations of urinary amounts over the 15-day dosing period when the drug was given either as a 200-mg twice-a-day or 400-mg once-a-day dosing regimen.     

Pharmacokinetics of cerivastatin when administered under fasted and fed conditions in the morning or evening

OBJECTIVE: The influence of food and time of drug dosing on the pharmacokinetics of cerivastatin, a potent HMG-CoA reductase inhibitor, was evaluated in 24 healthy male subjects between 21 and 44 years of age. METHODS: A single-dose, four-way crossover design was employed, with each subject receiving cerivastatin 0.8 mg at weekly intervals under each of four conditions: 8 a.m. dosing after an overnight fast (reference), 8 a.m. dosing with a high-fat breakfast (test), 6 p.m. dosing with the evening meal (low-fat; test), and 10 p.m. dosing 4 h after dinner (reference). Plasma concentrations of the parent compound and its active metabolites were measured by high performance liquid chromatography with fluorescence detection subsequent to post-column derivatization. RESULTS: The calculated 90% confidence intervals for cerivastatin AUC and Cmax were completely contained within the range 0.8 to 1.25. Thus, no relevant influence of food could be detected, although the presence of food increased the Cmax of cerivastatin on average by 12% (90% confidence interval: 1.04 - 1.21) under morning, but not evening dosing. With respect to the effect of daytime on cerivastatin pharmacokinetics, AUCs were bioequivalent for all treatment conditions, with Cmax values slightly lower (8 - 19%) following evening dosing, irrespective of food intake. Cerivastatin was well tolerated by the subjects in the study. CONCLUSION: Food effect bioequivalence according to current guidelines could be demonstrated. Cerivastatin can be administered independent of meal intake at dinner or at bedtime, the preferred time of dosing for statins because the rate of hepatic cholesterol synthesis is greatest at night.     

Glipizide pharmacokinetics: effects of age, diabetes, and multiple dosing

Aging and disease may contribute to alterations in drug pharmacokinetics. The purpose of this study was to determine the effects of aging, the presence of NIDDM, and multiple dosing on the pharmacokinetics of glipizide, an oral hypoglycemic drug. Ten healthy young men (under age 25), ten healthy older men (over age 65) and 15 older diabetic men ingested a single 5 mg tablet of glipizide after an overnight fast. Blood samples for measurement of serum glipizide were obtained over the next 24 hours. The study was repeated in the diabetics after 2 weeks of daily therapy. The mean values for Tmax (range 2.0-2.5 hours), Cmax (385-465 micrograms/l), and t1/2 (4.0-4.2 hours) were not significantly different in the three populations after single doses of glipizide. Several subjects in each population had slow absorption, with peak concentrations delayed for up to 12 hours. Only one elderly diabetic subject had evidence of drug accumulation at steady state. AUC, Cl, Vss and V area were not significantly different in the three populations or at steady state, but there was a trend for AUC to be smaller and each of the other parameters to be increased in the older diabetics. The young subjects had a significantly higher fp (0.83%) than either of the two elderly groups (0.55-0.64%), but Cl int did not differ between groups. Age, diabetes, and multiple dosing appear to have little effect on the pharmacokinetics of glipizide and should have little influence on the clinical response to this drug.     

Alternate-day buprenorphine dosing is preferred to daily dosing by opioid-dependent humans

Alternate-day buprenorphine dosing was compared to daily dosing in opioid-dependent outpatients and choice of alternate-day versus daily dosing was assessed. Four dosing schedules were presented in random order under blind and open dosing conditions. Subjects received two exposures to each dosing schedule. During daily dosing, subjects received maintenance doses every 24 h. During blind alternate-day dosing, subjects received double maintenance doses every 48 h; placebo was interposed on intervening days. During open alternate-day dosing, subjects received twice their maintenance dose on Monday, Wednesday and Friday and maintenance doses on Sunday. After completing two exposures to each dosing schedule, subjects chose either daily or alternate-day schedules each week for 1 month. Study participation was contingent on daily attendance and opioid abstinence. Ten subjects were exposed to the four conditions once. Seven subjects repeated these conditions and participated in the choice phase. The effects of daily versus alternate-day dosing were not influenced by blind or open dosing conditions. Subjects’ ratings of withdrawal, “sick” and sedation were lower during daily than during alternate-day dosing, but the difference between treatments was small. Nonetheless, subjects still chose alternate-day dosing on 96% of occasions, suggesting that the subject-rated differences between dosing schedules were not influential. These results extend prior findings to open-dosing conditions, and replicate the safety and acceptability of alternate-day buprenorphine treatment. Choice of alternate-day buprenorphine administration underscores the procedure’s clinical utility and potential use as a positive reinforcer to enhance opioid treatment. Received: 1 August 1996/Final version: 11 September 1997     

Prediction of steady state bioequivalence relationships using single dose data II-nonlinear kinetics

Two nonlinear pharmacokinetic models were simulated to investigate the relationship between single and multiple dose bioequivalency parameters for drugs such as phenytoin and propranolol which exhibit either saturable elimination kinetics or a capacity limited first pass effect. Mean Tmax, Cmax and area under the plasma-concentration time curve values from 0 to infinity (AUC 0-infinity) were compared after a single and multiple dose(s) of a test or reference drug. The aim was to determine if there were systematic changes in the limits of the single dose confidence interval at steady state that would limit the usefulness of confidence intervals following a single dose in accurately predicting bioavailability following multiple dosing. The 90 per cent confidence interval expressed as a percentage of the reference mean for Tmax, Cmax, and AUC 0-infinity showed model dependent changes from single to multiple dosing in response to the level of data error and changes in absorption. Changes in clearance also seemed to have a marked effect on the observed limits of the single and multiple dose confidence intervals especially for Cmax which showed a characteristic change in the intervals as a function of the clearance ratio. The model used to describe phenytoin had confidence intervals for Cmax and AUC 0-infinity from single to multiple dosing that were similar to that seen for the experimental data. However, the model predictions for Tmax confidence intervals following single and multiple dosing was at variance with the experimental data for formulations A and B.     

Effect of time of dosing on the disposition of oral cibenzoline

Single oral doses of cibenzoline were administered to eight healthy volunteers on two different occasions, once at 8.00 am and once at 10.00 pm, in a randomized crossover design with at least one week separating treatments. A fast was maintained for 12 hours prior to and for 2 hours after the morning dose and the subjects did not lie down for at least 12 hours after dosing. A standard dinner was eaten 3 hours prior to the evening dose, and a fast was maintained for 10 hours after dosing; the subjects laid down 2 hours after dosing for at least 6 hours. Blood was collected at specific times for 72 hours and the total volume of urine voided was collected through 72 hours. Cibenzoline concentrations in plasma and urine were measured by HPLC. Cibenzoline absorption was slower in 7 of the 8 volunteers following the evening dose relative to the morning dose. Mean +/- S.D. tmax for the evening dose was 2.6 +/- 0.5 hours compared to 1.7 +/- 0.8 for the morning dose. The corresponding mean +/- S.D. Cmax following the morning dose was 446 +/- 124 ng ml-1 compared to 402 +/- 114 ng ml-1 after the evening dose. The mean +/- S.D. AUC was 3328 +/- 1101 ng . h . ml-1 after the morning dose and 3561 +/- 1430 ng . h . ml-1 after the evening dose. The harmonic mean half-life was 7.4 hours after both treatments. These data indicated that the total amount of drug absorbed and the elimination rate constant of the drug had not varied between treatments.(ABSTRACT TRUNCATED AT 250 WORDS)     

基于群体药动学的儿童奥卡西平给药方案优化和漏服药物补救方案研究

目的:建立奥卡西平在儿童群体中的药动学模型,辅助制定个体化给药方案和漏服药物后的补救方案。方法:收集124例4个月~18岁儿童癫痫患者口服奥卡西平后体内主要活性代谢产物羟基卡马西平(MHD)的药物浓度数据和临床资料,采用非线性混合效应建模法建立群体药动学(PPK)模型。应用自举法、预测值校准的直观预测检验(pc-VPC)、正态化预测分布误差检验(NPDE)评价PPK模型的预测性能。基于最终模型参数,模拟不同特征儿童患者的最佳给药方案和不同漏服场景下的补救给药方案。结果:本研究发现奥卡西平在儿童体内的药动学特征符合一级吸收和消除的一房室模型,按标准体质量70 kg成人校正的群体典型值为:吸收速率常数(K_a)=0.83 h^-1,表观分布容积(V_d/F)=16.70 L,清除率(CL/F)=1.92 L·h^-1。体质量是影响V_d/F和CL/F的显著性协变量。自举法、pc-VPC和NPDE检验显示模型预测准度高,稳定性好。模拟结果显示,按本研究推荐的维持方案和漏服后补救方案给药可提高药物浓度的达标概率,保证治疗的安全性和有效性。结论:本研究通过群体药动学研究,制定了不同体质量分层儿童患者的奥卡西平优化给药方案以及漏服药物后的补救方案,可为临床药物治疗决策提供参考。     

Bioequivalence study of a valsartan tablet and a capsule formulation after single dosing in healthy volunteers using a replicated crossover design

AIM: Two formulations of valsartan (Diovan), 320 mg tablets and marketed 160 mg capsules, were evaluated for bioequivalence after single dosing. METHODS: The study was designed as a single-center, open-label, 2-treatment, 3-period, repeated-measure (replicated), randomized crossover comparison in 40 healthy volunteers, all of whom completed the study successfully. Valsartan was determined in plasma by HPLC with fluorescence detection after solid-phase extraction. RESULTS: Comparing the new 320 mg tablet with 2 x 160 mg of the marketed valsartan capsules taken at the same time, the ratios of the least square means for AUC(0-t), AUC(all), AUC(0-infinity) and Cmax were 1.11, 1.10, 1.10 and 1.09, respectively. The 90% confidence intervals of the AUC and Cmax parameters were within the range of 0.80-1.25. CONCLUSIONS: Bioequivalence of the new 320 mg tablet with 2 marketed 160 mg capsules was demonstrated.     

Single oral dose pharmacokinetics of erythromycin and roxithromycin and the effects of chronic dosing

Roxithromycin is a semisynthetic macrolide antibiotic having similar in vitro antibacterial profile and potency to erythromycin but possibly greater in vivo potency. The single and multiple oral dose pharmacokinetics of roxithromycin and erythromycin were studied in 12 healthy volunteers. Plasma concentrations of the two compounds were measured by a sensitive and specific high-performance liquid chromatographic method using electrochemical detection. After single doses, roxithromycin 150 mg gave a Cmax 3.3-fold higher and an area under the curve (AUC) 16.2-fold higher than erythromycin 250 mg. The half-life for roxithromycin was 12.42 +/- 3.94 h compared with 1.53 +/- 0.42 h for erythromycin. On multiple dosing, the AUC over a dosing interval for erythromycin (250 mg, six hourly doses) was increased 2.3-fold compared with the single dose, whereas that for roxithromycin (150 mg, 12 hourly) was decreased by 25.4%. Because of these opposing changes during chronic dosing, the average plasma roxithromycin concentration over the dosing interval was 2.6-fold higher than that for erythromycin, which was a smaller excess than would have been predicted from the single dose data. The results suggest that roxithromycin exerts less inducing and inhibiting effects on human cytochrome P450 than erythromycin. Roxithromycin has a favorable pharmacokinetic profile suitable for twice daily dosing and may have a lower potential than erythromycin for cytochrome P450-mediated drug interactions.     

Double dummy comparison between once and twice daily dosing with modified-release carbamazepine in epileptic patients.

1. Fourteen patients with refractory epilepsy on a twice daily regimen of modified-release carbamazepine (CBZ-MR. Tegretol Retard. Ciba Pharmaceuticals) completed a balanced, double-blind, double dummy, random order, crossover comparison of 8 weeks treatment with once (o.d.) and twice daily (b.d.) dosing. In order to obtain a profile of serum CBZ concentrations over 24 h on once daily dosing, patients were randomised to taking it in the morning (o.d. a.m.) or evening (o.d. p.m.) for 4 weeks. Each treatment was taken with a placebo of the other and total tablet numbers were matched. Blood sampling was undertaken 0, 2, 4, 6, 8, 10, 12 and 24 h after the morning tablets at the end of each 4 week treatment period. 2. Overall, trough serum drug concentrations (Cmin) were lower with once daily dosing (Cmin: b.d. 7.5 mg l-1, o.d. 6.5 mg l-1, P < 0.05, 95% CI of the difference -1.3 to -0.1), but no significant differences were found in average (Cav) or peak (Cmax) concentrations, AUC values or fluctuations in CBZ concentrations. 3. Pharmacokinetic parameters for CBZ 10.11 epoxide, the active metabolite of CBZ did not differ significantly between the dosage schedules. 4. Seizure control was similar during once and twice daily dosing with CBZ-MR (median seizures/month (range): b.d. 1 (0-14.5), o.d. 0.5 (0-11), NS, 95% CI of the difference -1.8 to + 0.25). 5. There were no differences in psychomotor performance between the treatment periods. 6. More patients (n = 11) preferred treatment (P < 0.05) with once daily than twice daily dosing (n = 3) with CBZ-MR. 7. Once daily dosing with CBZ-MR should be possible in the majority of patients receiving the drug as monotherapy.     

The effect of repeat dosing with cimetidine on the pharmacokinetics of intravenous granisetron in healthy volunteers

The primary route of elimination of granisetron is by oxidative hepatic metabolism, thus its pharmacokinetic profile may be altered by co-administration of other drugs that inhibit or induce hepatic drug metabolizing enzymes. This open-label study investigated the effect of inhibition of cimetidine, a potent inhibitor of CYP1A2, CYP2D6 and CYP3A4, on the pharmacokinetic profile of intravenous granisetron in healthy male volunteers. Subjects (n = 12; 18-60 years) received granisetron (40 microg kg(-1)) infused over 3 min, six days before and on the eighth day of dosing with cimetidine (200 mg, four times a day). Blood samples were taken for pharmacokinetic analysis at intervals over 48 h following the administration of each dose of granisetron. Clinical chemistry, haematology and urinalysis were performed before, and 24 h after, each infusion. Electrocardiogram (ECG), resting blood pressure (BP) and pulse were monitored. There were no significant changes in the ECG, lead II trace or ECG time intervals, pulse or blood pressure on each study day. Minor falls in pulse rate and BP (likely to be related to recumbent posture) were seen during both granisetron dosing days, lasting 2 h after each infusion. No significant changes were apparent in the clinical chemistry, haematology or urinalysis measurements following granisetron dosing. No pharmacokinetic parameters measured after cimetidine administration were significantly different from those taken before. Adverse events were mild-to-moderate in severity and were similar to those reported in other studies with granisetron. The pharmacokinetics of granisetron, when administered as a single dose, appeared to be unaltered by cimetidine, an inhibitor of multiple hepatic enzymes (CYP1A2, CYP2D6 and CYP3A4). Granisetron was equally well tolerated before and after repeated dosing with cimetidine.     

Development of a dosing strategy for enoxaparin in obese patients

AIMS: Enoxaparin dosing is currently based on total body weight. It is not known how to dose adjust for patients who are overweight or obese. This population pharmacokinetic pharmacodynamic (PKPD) study was undertaken to determine a suitable dosing strategy for such patients. METHODS: Patients admitted to the Royal Brisbane Hospital and prescribed enoxaparin as part of their normal care were eligible for inclusion into the study. Approximately three blood samples were taken per patient to determine anti-Xa concentrations. The occurrence of bruising was also recorded. A population pharmacokinetic-pharmacodynamic analysis using NONMEM was undertaken. Simulations were performed using MATLAB. RESULTS: Ninety-six patients were recruited in a prospective study. One-third of patients had a body mass index < 24.9 kg x m(-2), one-third from 25 to 29.9 kg x m(-2), and one-third> 30 kg x m(-2). A two-compartment linear model with additive error was fitted to the data. A covariate analysis showed clearance was best described by lean body weight and the central volume compartment by total body weight. The probability of bruising using a logistic regression model was best described by Cmax and age. Simulations suggest that patients over 50 years of age whose total body weight is> 90 kg, or under 50 years of age whose total body weight is> 120 kg are likely to have a smoother concentration-time profile and less bruising if a dose of 100 IU x kg(-1) (1 mg x kg(-1)) based on lean body weight is administered every 8 h. CONCLUSIONS: Dose adjustments of enoxaparin in obese patients are likely to reduce the prevalence of bruising, although prospective validation of this is required.     

Pharmacokinetics and biochemical efficacy after single and multiple oral administration of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide, a new type of specific competitive inhibitor of testosterone 5 alpha-reductase, in volunteers.

The pharmacokinetics and biochemical efficacy of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (I) were evaluated in healthy male volunteers after single and multiple oral administration. The mean times to reach peak plasma concentrations (Tmax) of (I) at doses of 5, 10, 20, 50 and 100 mg ranged from 1.8 to 2.8 h, and the corresponding mean peak plasma concentrations (Cmax) were 38.1, 81.5, 147.1, 442.0 and 835.5 ng/ml, respectively. The drug disappeared from the systemic circulation with half-lives (t1/2) of 4.7-7.1 h. The mean values of the area under the curve (AUC0-24) and Cmax increased linearly in a dose-dependent manner. After multiple oral administration of (I) (10 mg/d) for 7 days, Cmax and AUC increased slightly during administration, however, there were no significant differences between day 4 and day 7. Although there were large intersubject differences in the 24 h plasma levels after each dosing, no accumulation of (I) occurred after 7 days dosing. Serum 5-alpha-dihydrotestosterone (DHT) was markedly reduced at all dose levels. The mean serum levels of DHT at 24 h post-dosing decreased to 27-42% of that before dosing. On the other hand, the serum testosterone (T) did not change significantly. After multiple administration of (I), serum DHT was significantly reduced and remained suppressed for up to 7 days after the final dosing.     

Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation

Aim

The aim of the present study was to evaluate the pharmacokinetics of bevacizumab and various dosing strategies for this agent in paediatric patients.

Methods

Data were collected from 232 paediatric patients (1971 concentrations) in five studies, with a wide range of age (0.5 – 21 years), body weight (BWT; 5.9 – 125 kg), and regimens (5 – 15 mg kg^–1 biweekly or triweekly). Data from 152 patients (1427 concentrations) and 80 patients (544 concentrations) were used for model building and external validation, respectively. Steady‐state exposure was simulated under BWT‐based, body surface area (BSA)‐based, ideal body weight (IBW)‐based, and tier‐based doses. NONMEM and R were used for analyses.

Results

Typical estimates of clearance, central volume of distribution (V1), and median half‐life were 9.04 ml h^–1, 2851 ml, and 19.6 days, respectively. Clearance decreased with increasing albumin. Clearance and V1 increased with BWT and were higher in male patients. Clearance and V1 were lower in children with primary central nervous system (CNS) tumours than in children with sarcomas, resulting in 49% higher trough (Cmin) and 29% higher peak (Cmax) concentrations. BWT‐adjusted clearance and V1 remained unchanged across ages. Paediatric Cmin was similar to adult Cmin under all dosing strategies. Paediatric Cmax exceeded adult Cmax under tier‐based doses.

Conclusions

BWT‐adjusted pharmacokinetic parameter estimates in paediatric patients were similar to those in adults, and similar across ages. Bevacizumab exposure was higher in children with primary CNS tumours than in children with sarcomas. BSA‐based, IBW‐based, and tier‐based doses offered no substantial advantage over the BWT‐based dose currently used in adults for bevacizumab. Given the similarity in pharmacokinetics among many monoclonal antibodies, this may help to develop practical paediatric dosing guidelines for other therapeutic antibodies.     

The bioavailability and pharmacokinetics of slow release nifedipine during chronic dosing in volunteers.

Eight healthy volunteers received slow release nifedipine 20 mg 12 hourly, for six doses. A nifedipine pharmacokinetic profile was performed after the fifth dosing interval using 12 sampling times over 12 h. A specific high pressure liquid chromatography (h.p.l.c.) nifedipine assay was used. Six of the volunteers subsequently received an i.v. infusion of 3.5 mg of nifedipine after an identical period (five dosing intervals) of chronic oral dosing with slow release nifedipine 20 mg 12 hourly. An identical pharmacokinetic profile was performed after the infusion. Bioavailability, clearance (CL), apparent volume of distribution (V), apparent half life (t1/2) and area under the curve (AUC) were calculated. The geometric mean apparent t1/2 for the slow release preparation was 6.3 +/- 2.0 h. In the six volunteers, the mean bioavailability was 46% (range 29-86%), the mean CL was 588.0 +/- 67.1 ml min-1, the mean apparent V was 160.1 +/- 61.7 l. The pharmacokinetics of slow release nifedipine during chronic dosing appear similar to those derived from single dose studies.