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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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Mean concentration-time profiles of RFP after administration of free combination and FDCs in three bioequivalence trials (Formulation a–d). Y-error bars indicate SD (for sample sizes refer to Table 1). FDC: Fixed-dose combination; RFP: Rifampicin; SD: Standard deviation.
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Figure 2: Mean concentration-time profiles of RFP after administration of free combination and FDCs in three bioequivalence trials (Formulation a–d). Y-error bars indicate SD (for sample sizes refer to Table 1). FDC: Fixed-dose combination; RFP: Rifampicin; SD: Standard deviation.

Mentions: Mean concentration-time profiles of RFP for the four FDC formulations are presented in Figure 2. The PK parameters (AUC0−24 h, Cmax, Tmax and t½) of RFP are given in Table 2. The primary estimates of bioequivalence are shown in Table 3. All of these PK parameters were compared for both the FDCs and free combinations. Out of four FDC formulations tested, only one, FDC A, had comparable AUC0−24 h and Cmax values of RFP to those for the corresponding free combinations and hence passed the bioequivalence test. For both the FDC and free combination, a 600-mg dose of RFP produced AUC0−24 h values of 55.5–108.3 μg·h−1 ·ml−1 and Cmax values of 7.9–16.2 μg/ml.


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)

Mean concentration-time profiles of RFP after administration of free combination and FDCs in three bioequivalence trials (Formulation a–d). Y-error bars indicate SD (for sample sizes refer to Table 1). FDC: Fixed-dose combination; RFP: Rifampicin; SD: Standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Mean concentration-time profiles of RFP after administration of free combination and FDCs in three bioequivalence trials (Formulation a–d). Y-error bars indicate SD (for sample sizes refer to Table 1). FDC: Fixed-dose combination; RFP: Rifampicin; SD: Standard deviation.
Mentions: Mean concentration-time profiles of RFP for the four FDC formulations are presented in Figure 2. The PK parameters (AUC0−24 h, Cmax, Tmax and t½) of RFP are given in Table 2. The primary estimates of bioequivalence are shown in Table 3. All of these PK parameters were compared for both the FDCs and free combinations. Out of four FDC formulations tested, only one, FDC A, had comparable AUC0−24 h and Cmax values of RFP to those for the corresponding free combinations and hence passed the bioequivalence test. For both the FDC and free combination, a 600-mg dose of RFP produced AUC0−24 h values of 55.5–108.3 μg·h−1 ·ml−1 and Cmax values of 7.9–16.2 μg/ml.

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