Two-period Crossover Trial Research Articles

The two‐period cross‐over clinical trial

British Journal of Clinical PharmacologyVolume 58, Issue 7 p. S703-S716 Free Access The two-period cross-over clinical trial M. Hills, M. HillsSearch for more papers by this authorP. Armitage, P. ArmitageSearch for more papers by this author M. Hills, M. HillsSearch for more papers by this authorP. Armitage, P. ArmitageSearch for more papers by this author First published: 03 December 2004 https://doi.org/10.1111/j.1365-2125.2004.02275.xCitations: 21AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume58, Issue7December 2004Pages S703-S716 RelatedInformation

Subject–treatment interactions in crossover trials: performance evaluation of subgrouping methods

Ghosh and Fairchild (J. Statist. Plann. Inference 88 (2000) 301; In: Sen and Rao (Eds.), Handbook of Statistics 18: Bioenvironmental and Public Health Statistics, North-Holland, Amsterdam, 2000, p. 547.) proposed a model for drawing inference on the subject–treatment interactions in a two-period crossover trial and presented a method of subgrouping subjects in a group. In this paper we present another method of subgrouping for the same purpose of drawing inference on the subject–treatment interactions. This new method is based on a threshold level, a critical adjacent factor (CAF), and a majority rule. We then compare these two methods of subgrouping. Three performance measures are used for our comparison. The first measure is the probability of identifying the correct number of subgroups. The second measure is the probability that a subject is correctly placed in a subgroup under the condition that the number of subgroups has been correctly identified. The third measure is defined for subjects ordered from lowest to highest differences in their responses for two treatments. For the subjects placed into a subgroup by a method, the third measure determines the number of distinct subgroups beyond a single subgroup that these subjects really belong to. Extensive simulations are used for calculating the estimated numerical values of the performance measures and then for comparing the methods of subgrouping.

The cardiovascular dose–response effects of isoflurane alone and combined with butorphanol in the green iguana (Iguana iguana)

ObjectiveTo assess the cardiovascular effects (arterial blood pressure, heart rate, and metabolic acid–base status) of three doses (MAC multiples) of isoflurane alone and combined with butorphanol in the green iguana (Iguana iguana). Study designProspective randomized double-blind, two-period cross-over trial. AnimalsSix mature healthy green iguanas (Iguana iguana). MethodsThe iguanas received each of two treatments, saline 0.1 mL kg−1 (SAL) and butorphanol 1.0 mg kg−1 (BUT) during isoflurane anesthesia. Treatments were separated by at least 1 week. The iguanas were exposed to each of the three minimum alveolar concentration (MAC) multiples (1.0, 1.5, and 2.0) in random order. Anesthesia was induced with isoflurane and maintained using controlled ventilation. Instrumentation included use of an ECG, airway gas monitor, cloacal thermometer, esophageal pulse oximeter, and the placement of a femoral arterial catheter. Body temperature was stabilized and maintained at 32 °C. The treatment was administered, and the animals were equilibrated for 20 minutes at each MAC multiple. At each concentration, the heart rate, blood pressure (systolic, mean, diastolic), end-tidal CO2, and SpO2 were measured. At 1.0 and 2.0 MAC, simultaneous blood samples were drawn from the tail vein/artery complex and femoral catheter for blood gas analysis. Data were analyzed using a two-way analysis of variance for repeated measures looking for differences between treatments and among MAC multiples. ResultsThere were no significant differences in any of the cardiovascular variables between the treatments. Significant differences among isoflurane MAC multiples were observed for HR, mean, diastolic, and systolic blood pressures. Blood pressure and heart rate decreased with an increasing dose of anesthetic. There were no significant differences between treatments or MAC multiples for any of the blood gas variables. The blood pH, PCO2, HCO3−, and hemoglobin saturation differed significantly between sites. Pulse oximetry values measured from the carotid complex did not correlate with and were significantly different from the calculated hemoglobin saturation values determined using the gas analyzer. Conclusion and clinical relevanceCardiovascular depression associated with isoflurane anesthesia in the green iguana is dose dependent. The degree of cardiovascular depression was not significantly different when isoflurane was combined with butorphanol. This finding suggests that the pre-emptive or intraoperative use of butorphanol is unlikely to be detrimental to cardiovascular function. Butorphanol may be a useful anesthetic adjunct to isoflurane anesthesia in the green iguana.

Analysis of two-treatment, two-period crossover trials in emergency medicine

In an AB/BA crossover trial, patients are randomly assigned to receive either treastment A in the first period followed by treatment B in the second period or treatment B in the first period followed by treatment A in the second period. The crossover trial allows for a within-patient comparison between treatments because each patient serves as his or her own control subject, removes the interpatient variability from the comparison between treatments, and can provide unbiased estimates for the differences between treatments. When applied inappropriately, crossover designs have serious problems that might adversely influence and invalidate their results. The primary concern is the residual carryover effect of a treatment in subsequent treatment periods. Rather than depending on a statistical procedure to eliminate the possibility of the presence of carryover effects, it is more important that the crossover design be used only in those situations in which the likelihood of a carryover effect is exceptionally small. Even though the AB/BA crossover trial appeals to the physician researcher, it is surprisingly difficult to take advantage of this design. The primary objective of this article is to introduce readers and trialists to some of the issues surrounding crossover trials. Researchers who use this design should explicitly examine the assumptions about crossover effects and the adequacy of the lead-in washout period and the between-period washout period and clearly indicate that the results of the study are conditional on the acceptance of those conditions.

A multicenter, randomized, open-label, comparative, two-period crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial/syringe for insulin injection in patients with type 1 or 2 diabetes mellitus

Background: The accuracy and convenience of pen devices for insulin injection have improved quality of life for patients with insulin-treated diabetes mellitus (DM). Prefilled, disposable pens have the advantage of simplicity, with minimal training and attention required and no installation of new cartridges necessary. Objective: The aim of this study was to assess patient preference, efficacy, and safety profiles of a prefilled, disposable pen (FlexPen®) and conventional vial/syringe injection method for insulin injection therapy among patients with DM. Methods: In a multicenter, randomized, open-label, crossover study, patients with type 1 or 2 DM were transferred from previous QD or BID conventional insulin therapy to a mixture of 70% insulin aspart protamine suspension and 30% insulin aspart injection (NovoLog® Mix 70 30 ) for 4 weeks of dose optimization using their usual type of syringe. Patients were then randomly assigned to use either vial/syringe or a prefilled, disposable pen to inject the biphasic insulin aspart 70 30 mixture for the next 4 weeks, followed by 4 weeks of use of the other injection device. Efficacy, safety profiles, and patient preference for the delivery systems were compared. Results: A total of 121 patients (mean [SD] age, 57.0 [12.4] years; age range, 28–81 years; mean [SD] body mass index, 31 [5.5] kg/m 2) were enrolled. One hundred three patients completed the study. Seventy-four percent of patients ( 78 105 ) indicated a preference for the pen over the vial/syringe method (95% CI, 71%–87%), compared with 20% ( 21 105 ) who preferred the vial/syringe. Eighty-five percent ( 88 104 ) considered the pen more discreet for use in public (compared with 9% [ 9 104 ] for the vial/syringe), 74% ( 77 104 ) considered it easier to use overall (compared with 21% [ 22 104 ] for the vial/syringe), and 85% ( 89 105 ) found the insulin dose scale on the pen easier to read (compared with 10% [ 10 105 ] for the vial/syringe). Patients had statistically significant improvement in glycosylated hemoglobin values during the study ( P < 0.05). No statistically significant differences in fasting plasma glucose, mean 4-point blood glucose profiles, or serum fructosamine values were found between groups. Overall, the safety profiles during treatment periods with the pen were comparable to those with the vial/syringe. Conclusions: In this trial, differences in efficacy and safety profiles between the vial/syringe and prefilled, disposable pen appeared negligible. However, more patients expressed a preference to continue use of the pen.

Meta-analysis combining parallel and cross-over clinical trials. III: The issue of carry-over.

In meta-analysis combining results from parallel and cross-over trials, there is a risk of bias originating from the carry-over effect in cross-over trials. When pooling treatment effects estimated from parallel trials and two-period two-treatment cross-over trials, meta-analytic estimators of treatment effect can be obtained from the combination of parallel trial results either with cross-over trial results based on data of the first period only or with cross-over trial results analysed with data from both periods. Taking data from the first cross-over period protects against carry-over but gives less efficient treatment estimators and may lead to selection bias. This study evaluates in terms of variance reduction and mean square error the cost of calculating meta-analysis estimates with data from the first period instead of data from the two cross-over periods. If the information on cross-over sequence is available, we recommend performing two combined design meta-analyses, one using the first cross-over period data and one based on data from both cross-over periods. To investigate simultaneously the statistical significance of these two estimators as well as the carry-over at meta-analysis level, a method based on a multivariate analysis of the meta-analytic treatment effect and carry-over estimates is proposed.

Estimating the difference between differences: measurement of additive scale interaction for proportions

A simple, effective closed-form method to calculate a confidence interval for the difference between two differences of proportions is proposed. The method is based on the Wilson score interval for the single proportion, and may be used to compare either unpaired or paired differences. It is equally applicable whether cell frequencies are large or small; and coverage properties are favourable. It is easily adapted to give a confidence interval for the treatment effect for a binary outcome in a two-period cross-over trial.

Inference on interactions between treatments and subjects within groups in a two-period crossover trial

Abstract In this paper, we consider nine two-period crossover trial data sets. We present a method of forming subgroups of subjects within each group. A new model is proposed for analyzing the crossover trial data. Treatment-by-subgroup within group interactions are tested both parametrically and nonparametrically for the nine data sets. We observe the presence of significant treatment-by-subgroup within group interactions for all data sets. The significance of such interactions shows the importance of the fact that the treatments do act differently on subjects. This fact should not be ignored in the analysis. The assumption of normality in the parametric method of analysis for the nine data sets is checked by graphical as well as standard test procedures.

Serum leptin in children with asthma treated with inhaled budesonide

Leptin, a 167-amino-acid peptide, is a recently discoverd hormone which is believed to play a major role in the regulation of body weight. Systemic administration of exogenous glucocorticoids has been found to increase circulating leptin levels. In this study, we aimed to assess serum leptin in children with asthma treated with inhaled budesonide 800 μg day −1. Ten boys and three girls with asthma, all adolescents aged from 12·9 to 16·6 years, were studied in a randomized double-blind two-period cross-over trial with 4-week treatment periods and a 1-week wash out. Placebo was given during one period and 800 μg budesonide during the other via a 750 ml volume spacer (Nebuhaler ®, Astra Draco, Lund, Sweden). On the last day of the placebo and budesonide periods blood samples were taken and serum leptin was measured by a specific radioimmunoassay. The difference in mean ( sem) leptin concentration between the budesonide and placebo period was 0·2 (0·4) μg 1 −1 ( P=0·71; t=−0·4; df=12, 95% confidence interval −0·9–0·7 μg 1 −1). Inhaled budesonide 800 μg per day from a Nebuhaler ® does not influence circulating leptin levels, suggesting that regulation of body weight is unaffected.

Comparison of the Effects of Cetirizine and Ebastine on the Skin Response to Histamine Iontophoresis Monitored with Laser Doppler Flowmetry

Background: The administration of histamine with iontophoresis is an alternative method to skin prick tests or intradermal injections. Skin reactions obtained with this method can be recorded with laser Doppler flowmetry (LDF) and previous studies with this method have shown histamine-induced laser Doppler changes in the wheal area. Objective: In order to compare the influence of two H₁ receptor antagonists (cetirizine 10 mg vs. ebastine 10 mg) on the skin vascular responses to histamine introduced by iontophoresis, we designed a double-blind, randomized, two-period crossover trial in which 18 volunteers were randomized. Methods: Before and 2, 5 and 7 h after drug administration, iontophoresis (30 s, 1.4 mA/cm²) of histamine 10% was performed and followed by (1) monitoring of skin vascular responses with LDF at the administration site and at 1 cm from it, and (2) wheal and flare area measurements. Results: 2, 5 and 7 h after intake of the antihistaminic drug, there were significant differences between both drugs. Concerning LDF recordings, we noted at the histamine administration site an increase in perfusion unit (PU) values which is an effect known to be in proportion to the degree of inhibition of wheal reaction, and at 1 cm distal to the histamine administration site, there was a decrease in PU values. These changes were more marked under cetirizine. A greater suppressive effect of cetirizine on the wheal and flare reaction was consistently observed at all time points during the study, demonstrating its superior efficacy. Conclusion: We conclude that (1) cetirizine demonstrated a stronger antihistaminic effect compared to ebastine at all time points; (2) iontophoresis appears to be an appropriate method to study specific microvascular changes at the delivery site of histamine and hence to detect the earliest changes occurring at the site of agonist-antagonist competition in the skin.

Metrics comparing simulated early concentration profiles for the determination of bioequivalence.

To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles. Two-period crossover trials were simulated with increasing assumed ratio of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC(AUCP), the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I L/H), and the ratios of intercepts extrapolated from logarithmic C/ time values of the two products (MLOG). For comparison, also properties of CMAX and an ideally evaluated measure (Id) were determined. MLOG showed generally the highest statistical power and KS, and also the largest SE, closely followed by I L/H. Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than CMAX. These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation. The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. MLOG had the highest statistical power, closely followed by I L/H and then by partial AUC.

The Leukotriene Receptor Antagonist Zafirlukast Inhibits Sulfur Dioxide–induced Bronchoconstriction in Patients with Asthma

Inhalation of sulfur dioxide (SO2) causes bronchoconstriction in most people with asthma. To examine the role of leukotrienes in this response, the antagonism of SO2-induced bronchoconstriction by a single oral dose of the leukotriene receptor antagonist zafirlukast was assessed in a double-blind, placebo-controlled, two-period crossover trial in 12 subjects with mild-to-moderate asthma. Subjects had bronchial hyperresponsiveness, an FEV1 < or = 70% of predicted, and a positive response to inhaled SO2 (an 8-unit increase in specific airway resistance on inhaling an SO2 concentration of < or = 4 ppm (PC8SRaw). Subjects were treated with zafirlukast (20 mg) or placebo on two treatment days 5 to 14 d apart. Two and 10 hours after treatment, subjects inhaled SO2 (0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 ppm) during eucapnic hyperventilation at 20 L/min. PC8SRaw was determined after each challenge. Blood samples were collected to assess zafirlukast plasma concentrations versus effect. PC8SRaw was significantly higher 2 h after zafirlukast compared with placebo (3.1 versus 1.5 ppm; p = 0.02) and remained higher 10 h after treatment with zafirlukast (2.7 versus 1.9 ppm; p = 0.09). An association was found between zafirlukast plasma concentrations and increases in PC8SRaw 10 h after treatment (p = 0.001). The safety profile of zafirlukast was not clinically different from placebo. A single 20-mg dose of zafirlukast attenuated SO2-induced bronchoconstriction. We conclude that S02-induced bronchoconstriction involves release of leukotrienes and that treatment with zafirlukast attenuates the bronchoconstrictor response.

Short-term growth and collagen turnover in asthmatic adolescents treated with the inhaled glucocorticoid budesonide

Short term lower leg growth, the insulin-like growth factor axis, and collagen turnover were assessed in 16 adolescents with asthma during treatment with inhaled budesonide, 800 μg/d, from a pressurized metered dose inhaler with a volume spacer. The design was a randomized double blind, placebo-controlled two-period crossover trial with treatment periods of 4 weeks and a 1-week wash-out. Lower leg growth was assessed by knemometry. Serum levels of insulin-like growth factor-I, insulin-like growth factor-binding protein-3, and the following markers of collagen turnover were evaluated: Serum markers of type I collagen formation and degradation; the carboxy-terminal propeptide of type I procollagen and the carboxy terminal pyridinoline cross-linked telopeptide of type I procollagen (ICTP), the serum marker of type III collagen formation; the amino-terminal propeptide of type III procollagen (PIIINP) and the urinary concentrations of the type I collagen degradation products pyridinoline (PYD) and deoxypyridinoline (DPD) cross-links. Mean lower leg growth velocity was suppressed from 0.51 mm/week during placebo to 0.18 mm/week during budesonide treatment ( p < 0.001). No statistically significant effects on insulin-like growth factor-1, insulin-like growth faster-binding protein-3, or carboxy-terminal propeptide of type I procollagen were observed. ICTP and PIIINP were reduced with 2.3 and 2.5 μg/liter ( p < 0.001 and p < 0.001, respectively) during budesonide treatment, urinary concentrations of PYD and DPD with 32.9 nmol/mmol creatinine ( p < 0.005) and 6.8 nmol/mmol creatinine ( p < 0.005), respectively. Significant correlations between lower leg growth velocity and ICTP, PIIINP, PYD, and DPD during placebo ( p < 0.01, p < 0.05, p < 0.01, and p < 0.01) and budesonide ( p < 0.05, p < 0.05, p < 0.05, and p < 0.05) periods were found. Short term lower leg growth suppression in adolescents treated with inhaled budesonide, 800 μg/d, reflects suppression of type I and III collagen turnover.

Use of Two-Stage Test Statistic in the Two-Period Crossover Trials

For two-period crossover trials where the residual carryover can only exist in the presence of treatment effect, Willan (1988, Biometrics 44, 211-218) recommended use of the maximum test statistic that chooses the analysis with the larger test statistic corresponding to the parallel analysis and the crossover analysis. We construct two alternative two-stage test procedures, based on Grizzle's approach, that maintain the actual type I error rate at the desirable level. The power, accuracy, and precision of the analysis based on the modified two-stage procedures are compared to those based on the parallel analysis, crossover analysis, and the maximum test statistic.

Calculation of knemometric growth rates in group studies of children treated with exogenous glucocorticoids

SummaryCalculation of growth rates in short-term knemometry studies is often based on linear regression analysis. The method, however, has not been compared to the conventional method for calculation of growth rates (increase in length divided by the time interval) in glucocorticoid-treated populations. The aim of the present study was to assess whether the conventional method for calculation of growth rates is as sensitive as the linear regression method in the assessment of short-term lower leg growth in group studies of children treated with exogenous glucocorticoids. Three different studies were conducted during which knemometry was performed once or twice weekly. Six boys and six girls aged 5–12 years, with atopic dermatitis, participated in an open longitudinal study with three periods of 2 weeks duration. Ten boys and four girls aged 12–16 years, with asthma, were studied in a randomized double-blind, placebo-controlled two-period crossover trial, with treatment periods of 4 weeks. Thirteen boys and 11 girls aged 5–12 years, with asthma, were enrolled in a randomized double-blind two-period crossover trial with treatment periods of 4 weeks. During active treatment periods topical budesonide was given. Mean lower leg growth rates and the results of significance tests based on the two methods for calculation of growth rates were similar in all studies. Significant correlations between the growth rates based on the two methods were found in the non-glucocorticoid and glucocorticoid treatment periods in all studies (Pearson correlation r coefficient varied from 0·81 to 0·97, p from <0·001 to < 0·0001). The conventional method for calculation of lower leg growth rates is as reliable as linear regression analysis. By using the conventional method the number of visits required for knemometric growth rate assessment in group studies of systemic activity of exogenous glucocorticoids can be reduced.

The Impact of Ibuprofen on the Efficacy of Antihypertensive Treatment With Hydrochlorothiazide in Elderly Persons

Nonsteroidal antiinflammatory drugs (NSAIDs) may alter blood pressure through their inhibitory effects on prostaglandin biosynthesis. Such potential hypertensive effects of NSAIDs have not been adequately examined in the elderly, who are the largest group of NSAID users. We performed a randomized, double-blind, two-period crossover trial of ibuprofen (1800 mg per day) vs placebo treatment in patients older than 60 years of age with hypertension controlled with hydrochlorothiazide. While continuing their usual thiazide dosage, subjects were randomized to a 4-week treatment period (ibuprofen or placebo) followed by a 2-week placebo wash-out period and a second 4-week treatment period with the alternative therapy. Supine and standing systolic and diastolic blood pressures were measured weekly. Of 25 randomized subjects, 22 completed the study protocol (mean age = 73 +/- 6.7 years). Supine systolic blood pressure and standing systolic blood pressure were increased significantly with ibuprofen treatment, compared with placebo. Mean supine systolic blood pressures were 143.8 +/- 21.0 and 139.6 +/- 15.9 mmHg on ibuprofen and placebo, respectively (p = .004). Mean standing systolic blood pressures were 148.1 +/- 19.9 and 143.4 +/- 17.9 mmHg on ibuprofen and placebo, respectively (p = .002). We conclude that 1800 mg per day of ibuprofen does induce a significant increase in systolic blood pressure in older hypertensive patients treated with hydrochlorothiazide. NSAID therapy may negatively impact the control of hypertension in elderly patients.

Crossover Trials with a Binary Response: A Powerful Method Despite the Carryover Effect

The two-period crossover trial has the evident advantage that, by use of within-patient comparisons, the usual large between-patient variability is not used as a measure to compare treatments. A prerequisite, however, is that the order of the treatments does not substantially influence the outcome of the treatment. Crossover studies with a binary response (such as yes/no or present/absent), although widely used for initial screening of new compounds, have not previously been studied for such order effects. This study uses a mathematical model based on standard statistical tests to study to what extent such order effects, here identical to carryover effects, may reduce the power of detecting a treatment effect. It is concluded that, despite large carryover effects, the crossover study with a binary response remains a powerful method and that testing for carryover effects makes sense only if the null hypothesis of no treatment effect cannot be rejected.

Haemodynamic effects of arteriovenous and venovenous haemofiltration in piglets.

The aim of this study was to compare the early haemodynamic effects of continuous arteriovenous haemofiltration (CAVH) with those of continuous venovenous haemofiltration (CVVH) in normal and endotoxic piglets, within the framework of a two-period cross-over trial. Sixteen domestic piglets (weight 6-18 kg) underwent 1 h of CAVH followed by 1 h of CVVH or 1 h of CVVH followed by 1 h of CAVH. Six were pre-treated with a graded endotoxin infusion to simulate clinical sepsis. The main measurements included: heart rate; mean arterial (MAP), pulmonary artery, central venous and pulmonary artery occlusion pressures; thermodilution cardiac output; and calculated systemic (SVRI) and pulmonary vascular resistance indexes. Each measurement was performed immediately before and 30 min after commencement of each technique of filtration. Commencement of haemofiltration in normal piglets caused minimal haemodynamic effects. In endotoxic piglets, commencement of filtration, whether CAVH or CVVH, caused a haemodynamic change which was significantly more pronounced in the first filter (SVRI -39%, MAP -32%) than the second filter (SVRI +22%, MAP +0.9%) (SVRI, P=0.01, first filter vs. second) (MAP, P=0.009 first filter vs. second). In conclusion, there were no significant differences between the early haemodynamic effects of CAVH and CVVH in normal or endotoxic piglets. The haemodynamic effects of either technique may become more significant in the presence of sepsis.

A Two-Step Method for Assessing Bioequivalence

Bioequivalence data arising from a two-period crossover trial are routinely analyzed to establish equivalence of the population means of a characteristic of the blood level curve, for example, AUC, for each formulation. Current methods only address equivalence of the formulation means, and recently, intrasubject variability, while intersubject variability is often neglected and assumed to be equal for each formulation. In this paper, the bioequivalence problem is cast into a linear structural relationship framework and a new two-step decision rule for assessing bioequivalence which takes intersubject variability into consideration is proposed. The two steps consist of 1) applying the current 90% parametric confidence interval method for equivalence of population means and 2) applying a 90% approximate confidence interval method for equivalence of population (intersubject) standard deviations. The ratio of the population standard deviations is shown to be the slope of the linear structural relationship. Bi...

The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin.

The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin was studied in three separate, two-period crossover trials, each involving eight healthy volunteers. After an overnight fast, a single dose of norfloxacin (400 mg), ciprofloxacin (500 mg) or ofloxacin (400 mg) was administered with and without ferrous sulphate (corresponding to 100 mg elemental iron). The absorption of all the fluoroquinolones studied was significantly reduced when they were co-administered with ferrous sulphate. The reduction in the area under the plasma drug concentration-time curve from 0 to 24 h was most marked in the case of norfloxacin, while ofloxacin was least affected by ferrous sulphate. The AUC of norfloxacin was reduced by 73% (P < 0.001) and its peak plasma concentration by 75% (P < 0.01) by concomitant ingestion of ferrous sulphate. The AUC and peak plasma concentration of ciprofloxacin were reduced by 57% (P < 0.001) and 54% (P < 0.01), respectively, by ferrous sulphate. Concomitant ingestion of ferrous sulphate reduced the AUC and peak plasma concentration of ofloxacin by 25% (P < 0.01) and 36% (P < 0.01), respectively. Similar results were obtained with respect to the urinary recoveries of each fluoroquinolone. We recommend that norfloxacin and ciprofloxacin should not be taken together with ferrous sulphate. It would also be advisable not to take ofloxacin with ferrous sulphate, especially if the organism causing infection is only moderately susceptible.