Who Needs Individual Bioequivalence Studies for Narrow Therapeutic Index Drugs? A Case for Warfarin

Yacobi, Avraham; Masson, Éric; Moros, Daniel A.; Ganes, Derek; Lapointe, Claude; Abolfathi, Zohreh; LeBel, Marc; Golander, Yechiel; Doepner, Darlene; Blumberg, Tamar; Cohen, Yoram; Levitt, Barrie

doi:10.1177/00912700022009558

Cited by 15 publications

(13 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The sample size for the proof‐of‐concept study ( n = 12 evaluable subjects) was calculated based on 80% power to detect a 25% change in the primary endpoints with a type I error of 0.05; the primary endpoints were the treatment/control ratios of log‐transformed AUC 0–48 (( S )‐warfarin) or AUC 0–inf (midazolam) and C max (( S )‐warfarin and midazolam), and the predefined no effect range was 0.75–1.33 5 , 6 . Intraindividual variability in midazolam and warfarin AUC and C max were assumed to be ~20% 46 – 48 . Secondary outcomes, t 1/2 and t max , were evaluated using a paired two‐tailed Student's t ‐test on log‐transformed data or Wilcoxon signed‐rank test as appropriate, with 90% confidence intervals and ranges reported for t 1/2 and t max , respectively.…”

Section: Methodsmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction

Brantley

Gufford

Dua

et al. 2014

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

Herb–drug interaction predictions remain challenging. Physiologically based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb–drug interactions using the semipurified milk thistle preparation, silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and (S)-warfarin AUC by 5% and 4%, respectively. A proof-of-concept clinical study confirmed minimal interaction between high-dose silibinin and both midazolam and (S)-warfarin (9 and 13% increase in AUC, respectively). Unexpectedly, (R)-warfarin AUC decreased (by 15%), but this is unlikely to be clinically important. Application of this PBPK modeling framework to other herb–drug interactions could facilitate development of guidelines for quantitative prediction of clinically relevant interactions.

show abstract

Section: Methodsmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction

Brantley

Gufford

Dua

et al. 2014

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

show abstract

“…Significant differences were noted in the t ½ between the present and previous studies. The t ½ of warfarin was first reported as 36.3 hours, followed with the range of 30 to 60 hours in the continuous studies . After analysis of these literature data, we found that the elimination rate of warfarin would change with different administered dosages, which directly affects the concentration of warfarin.…”

Section: Discussionmentioning

confidence: 90%

Bioequivalence Study of Warfarin in Healthy Chinese Volunteers With a Validated High‐Performance Liquid Chromatography‐Mass Spectrometry Method

et al. 2017

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

This study was designed to investigate the pharmacokinetics of an innovative film-coated warfarin sodium tablet and to compare it with the marketed sugar-coated warfarin sodium tablet in humans. A single-dose, open-label, randomized, two-way crossover study was performed in 24 healthy Chinese male volunteers. They were administered 2.5 mg of innovative film-coated warfarin sodium tablets or the marketed sugar-coated warfarin sodium tablets. Blood samples were collected at different time points after dosing for investigation of the pharmacokinetics of warfarin in human plasma. A sensitive liquid chromatography mass spectrometry method was established to determine warfarin in plasma. Drug and Statistics 2.1.1 was applied to calculate the pharmacokinetics parameters. The main pharmacokinetic parameters for film-coated and sugar-coated warfarin were the following: t , 103.5 ± 18.8 and 105.8 ± 21.3 hours; T , 0.7 ± 0.5 and 1.3 ± 0.8 hours; C , 347.8 ± 74.8 and 322.9 ± 75.7 ng/mL; AUC , 16,024.2 ± 3713.9 and 15,586.6 ± 3477.0 ng·mL ·h; AUC , 17,335.7 ± 4089.1 and 16,912.0 ± 3911.2 ng·mL ·h, respectively. The human pharmacokinetics of film-coated and sugar-coated warfarin were slightly different. The oral absorption and bioavailability of innovative film-coated warfarin were slightly higher than those of the sugar-coated warfarin. This study is vital to clinical usage of warfarin not only because of the pharmacokinetic parameters of the 2 pharmaceutical dosage forms of warfarin but also to obtain data on the prevalence of CYP2C9 and VKORC1 genes and their influence on the concentration of warfarin.

show abstract

“…In the study of Schumaker and Metzler (1998), phenytoin did not appear to be a highly variable drug (the relative standard deviation, RSD, was \20% for C max , and drugs are considered highly variable if RSD C30% (Endrenyi and Midha 1998)) and, since no subject-by-formulation interaction was found, bioequivalence was concluded between the tested formulations both by the average and individual approaches. Although experimentally obtained data on IBE studies do not abound, probably due to the fact that no health authority require IBE studies, other examples of the described situation can be found for other drugs (Yacobi et al 2000;Joukhadar et al 2003;Christians et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Is saliva suitable as a biological fluid in relative bioavailability studies? Analysis of its performance in a 4 × 2 replicate crossover design

Ruiz

Fagiolino

Buschiazzo

et al. 2011

Eur J Drug Metab Pharmacokinet

View full text Add to dashboard Cite

The aim of the present study was to evaluate the suitability of saliva as a biological fluid in relative bioavailability (RBA) studies, with the focus on the statistical design and data variability. A randomized, open-label, four periods and two sequences (4 × 2) crossover RBA study in saliva of two phenytoin (PHT) 100 mg immediate-release capsules was performed. PHT is a narrow therapeutic index drug that has been widely used for epilepsy treatment for many years. Published information regarding its bioavailability is available, but plasma assessed. This study was designed and performed using saliva as the biological fluid and the simplest conditions that produce coherent results with previously published plasma studies. Pharmacokinetic parameters (C (max), T (max), AUC(0-t ), AUC(0-inf), C (max)/AUC(0-t ), K (e), and t (1/2)) for each volunteer at each period were calculated. Four different BE calculations were performed: individual bioequivalence, by the method of moments, and three average bioequivalence with data averaged over the two administrations and with data of periods 1-2 and 3-4. ANOVA calculation showed no significant subject-by-formulation interaction, period and sequence effects. The intra-subject variabilities were at least 20-fold lower than the inter-subject ones for C (max), AUC(0-t ) and AUC(0-inf). In all four BE calculations, the 90% CIs for the T/R ratios of studied pharmacokinetics parameters fell within the 80-125% range proposed by most regulatory agencies.

show abstract

Who Needs Individual Bioequivalence Studies for Narrow Therapeutic Index Drugs? A Case for Warfarin

Cited by 15 publications

References 8 publications

Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction

Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction

Bioequivalence Study of Warfarin in Healthy Chinese Volunteers With a Validated High‐Performance Liquid Chromatography‐Mass Spectrometry Method

Is saliva suitable as a biological fluid in relative bioavailability studies? Analysis of its performance in a 4 × 2 replicate crossover design

Contact Info

Product

Resources

About