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Relative bioavailability of rifampicin in four Chinese fixed-dose combinations compared with rifampicin in free combinations.

Zhu H, Guo SC, Hao LH, Liu CC, Wang B, Fu L, Chen MT, Zhou L, Chi JY, Yang W, Nie WJ, Lu Y - Chin. Med. J. (2015)

Bottom Line: Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (C max ), 91.43 ± 30.82 μg·h-1·ml-1 , 55.49 ± 37.58 μg·h-1·ml-1 , 96.50 ± 47.24 μg·h-1·ml-1 , 101.47 ± 33.07 μg·h-1·ml-1 , respectively, for area under the concentration-time curve (AUC 0-24 h ).Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumour Research Institute, Beijing 101149, China.

ABSTRACT

Background: Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure. Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.

Methods: Eighteen and twenty healthy Chinese male volunteers participated in two open-label, randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study, respectively. The washout period between treatments was 7 days. Bioequivalence was assessed based on 90% confidence intervals, according to two one-sided t-tests. All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China, Shanghai, China).

Results: Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (C max ), 91.43 ± 30.82 μg·h-1·ml-1 , 55.49 ± 37.58 μg·h-1·ml-1 , 96.50 ± 47.24 μg·h-1·ml-1 , 101.47 ± 33.07 μg·h-1·ml-1 , respectively, for area under the concentration-time curve (AUC 0-24 h ).

Conclusions: Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product. The three two-drug FDCs (formulations B, C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451).

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Dissolution profiles of RFP from 4 FDCs (A, B, C, D) and free combination (Reference) in PBS solution. Dissolution profiles are presented as the mean of six tablets/capsule ± SD. FDC: Fixed-dose combination; RFP: Rifampicin; SD: Standard deviation; PBS: Phosphate buffer saline.
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Figure 1: Dissolution profiles of RFP from 4 FDCs (A, B, C, D) and free combination (Reference) in PBS solution. Dissolution profiles are presented as the mean of six tablets/capsule ± SD. FDC: Fixed-dose combination; RFP: Rifampicin; SD: Standard deviation; PBS: Phosphate buffer saline.

Mentions: The dissolution profiles are shown in Figure 1. For the reference, the percentage of RFP dissolved after 30 min was 84.9% ± 1.32%, while for formulations A and C it was above 80% (96.2% ± 0.50% and 97.2% ± 1.64%, respectively), and for formulation B and D it was 33.7% ± 0.48% and 65.8% ± 1.05%. Formulation B and D did not meet the requirement of the dissolution test.[10]


Relative bioavailability of rifampicin in four Chinese fixed-dose combinations compared with rifampicin in free combinations.

Zhu H, Guo SC, Hao LH, Liu CC, Wang B, Fu L, Chen MT, Zhou L, Chi JY, Yang W, Nie WJ, Lu Y - Chin. Med. J. (2015)

Dissolution profiles of RFP from 4 FDCs (A, B, C, D) and free combination (Reference) in PBS solution. Dissolution profiles are presented as the mean of six tablets/capsule ± SD. FDC: Fixed-dose combination; RFP: Rifampicin; SD: Standard deviation; PBS: Phosphate buffer saline.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836242&req=5

Figure 1: Dissolution profiles of RFP from 4 FDCs (A, B, C, D) and free combination (Reference) in PBS solution. Dissolution profiles are presented as the mean of six tablets/capsule ± SD. FDC: Fixed-dose combination; RFP: Rifampicin; SD: Standard deviation; PBS: Phosphate buffer saline.
Mentions: The dissolution profiles are shown in Figure 1. For the reference, the percentage of RFP dissolved after 30 min was 84.9% ± 1.32%, while for formulations A and C it was above 80% (96.2% ± 0.50% and 97.2% ± 1.64%, respectively), and for formulation B and D it was 33.7% ± 0.48% and 65.8% ± 1.05%. Formulation B and D did not meet the requirement of the dissolution test.[10]

Bottom Line: Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (C max ), 91.43 ± 30.82 μg·h-1·ml-1 , 55.49 ± 37.58 μg·h-1·ml-1 , 96.50 ± 47.24 μg·h-1·ml-1 , 101.47 ± 33.07 μg·h-1·ml-1 , respectively, for area under the concentration-time curve (AUC 0-24 h ).Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumour Research Institute, Beijing 101149, China.

ABSTRACT

Background: Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure. Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.

Methods: Eighteen and twenty healthy Chinese male volunteers participated in two open-label, randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study, respectively. The washout period between treatments was 7 days. Bioequivalence was assessed based on 90% confidence intervals, according to two one-sided t-tests. All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China, Shanghai, China).

Results: Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (C max ), 91.43 ± 30.82 μg·h-1·ml-1 , 55.49 ± 37.58 μg·h-1·ml-1 , 96.50 ± 47.24 μg·h-1·ml-1 , 101.47 ± 33.07 μg·h-1·ml-1 , respectively, for area under the concentration-time curve (AUC 0-24 h ).

Conclusions: Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product. The three two-drug FDCs (formulations B, C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451).

Show MeSH
Related in: MedlinePlus