The Statistical Evaluation of a Three-Period Two-Treatment Crossover Pharmacokinetic Drug Interaction Study

Ciminera, Joseph L.; Bolognese, James A.; Gregg, M. Hall

doi:10.2307/2532008

Cited by 9 publications

(9 citation statements)

References 6 publications

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“…To account for this, a classification variable called “pair” was defined to capture the variability due to the different pairs of periods in which two treatments were compared. This variable “pair” is based on a model proposed by Ciminera et al 14 It was of interest to test whether the treatment comparisons varied across the three different pairs (i.e., the treatment‐by‐pair interaction). The interaction was tested using the contrast proposed by Ciminera et al through the use of a modified three‐period ANOVA model on log‐transformed data.…”

Section: Methodsmentioning

confidence: 99%

Indinavir and Rifabutin Drug Interactions in Healthy Volunteers

Kraft

McCrea

Winchell

et al. 2004

The Journal of Clinical Pharma

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Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three‐period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC(0–8h) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC(0–24h) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC(0–8h) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC(0–24h) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin.

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Section: Methodsmentioning

confidence: 99%

Indinavir and Rifabutin Drug Interactions in Healthy Volunteers

Kraft

McCrea

Winchell

et al. 2004

The Journal of Clinical Pharma

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“…The statistical analysis of log transformed (e base) pharmacokinetic parameters C max , AUC 0-24 and C min,av was performed using an ANOVA model according to Ciminera et al (1987) extended with the factor gender.…”

Section: Statistical Methodologymentioning

confidence: 99%

Mirtazapine in combination with amitriptyline: a drug–drug interaction study in healthy subjects

Sennef¹,

Timmer²,

Sitsen³

2003

Human Psychopharmacology

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“…Pharmacokinetics. The statistical analysis of the log-transformed pharmacokinetic parameters C max , AUC 0±24 , en-C max (extent normalized-C max C max AUC ) C av , DF and C min,av was performed using an ANOVA model (Ciminera et al, 1987), extended with gender as a factor. When a gender effect was found, analysis was done separately for each sex.…”

Section: Statistical Methodologymentioning

confidence: 99%

Mirtazapine and paroxetine: a drug‐drug interaction study in healthy subjects

Ruwe¹,

Smulders²,

Kleijn³

et al. 2001

Human Psychopharmacology

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Paroxetine inhibits cytochrome P(450) 2D6, which is involved in the metabolism of mirtazapine. The possible drug-drug interaction between two pharmacologically distinct antidepressants, mirtazapine and paroxetine, has been investigated in a randomized, three-way crossover study in 24 healthy male and female subjects. After a titration phase of 3 days, each subject received single daily doses of 30 mg mirtazapine, 40 mg paroxetine or the combination for 6 days. Assessments included serial blood sampling for pharmacokinetics at steady state, cognitive testing using the test battery of CDR Ltd, a visual analogue mood rating scale (Bond and Lader) and the Leeds Sleep Evaluation Questionnaire. Paroxetine inhibits the metabolism of mirtazapine, as shown by increases of approximately 17% and 25% of the 24 h AUC's of mirtazapine and its demethyl metabolite, respectively. Mirtazapine did not alter the pharmacokinetics of paroxetine. The combined administration of mirtazapine and paroxetine probably does not alter cognitive functioning or result in major changes on the visual analogue mood rating scale and Sleep Evaluation Questionnaire, compared with the administration of either drug alone. The incidence of adverse events was lower during combined administration of mirtazapine and paroxetine than during administration of either drug alone. Fatigue, dizziness, headache, nausea, anxiety and somnolence were the most common adverse events during combined administration. These data suggest that the combination of mirtazapine and paroxetine is unlikely to lead to clinically relevant drug-drug interactions and can be used without dose adjustment of either drug. The combination may even be better tolerated than either drug alone. Copyright 2001 John Wiley & Sons, Ltd.

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The Statistical Evaluation of a Three-Period Two-Treatment Crossover Pharmacokinetic Drug Interaction Study

Cited by 9 publications

References 6 publications

Indinavir and Rifabutin Drug Interactions in Healthy Volunteers

Indinavir and Rifabutin Drug Interactions in Healthy Volunteers

Mirtazapine in combination with amitriptyline: a drug–drug interaction study in healthy subjects

Mirtazapine and paroxetine: a drug‐drug interaction study in healthy subjects

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