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A randomized single-dose, two-period crossover bioequivalence study of two fixed-dose Paracetamol/Orphenadrine combination preparations in healthy volunteers under fasted condition.
BMC Pharmacol Toxicol. 2020 Jun 23; 21(1):45.BP

Abstract

BACKGROUND

Paracetamol/Orphenadrine is a fixed dose combination containing 35 mg orphenadrine and 450 mg paracetamol. It has analgesic and muscle relaxant properties and is widely available as generics. This study is conducted to investigate the relative bioavailability and bioequivalence between one fixed dose paracetamol/orphenadrine combination test preparation and one fixed dose paracetamol/orphenadrine combination reference preparation in healthy volunteers under fasted condition for marketing authorization in Malaysia.

METHOD

This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2-period crossover study with a washout period of 7 days. Paracetamol/Orphenadrine tablets were administered after a 10-h fast. Blood samples for pharmacokinetic analysis were collected at scheduled time intervals prior to and up to 72 h after dosing. Blood samples were centrifuged, and separated plasma were kept frozen (- 15 °C to - 25 °C) until analysis. Plasma concentrations of orphenadrine and paracetamol were quantified using liquid-chromatography-tandem mass spectrometer using diphenhydramine as internal standard. The pharmacokinetic parameters AUC0-∞, AUC0-t and Cmax were determined using plasma concentration time profile for both preparations. Bioequivalence was assessed according to the ASEAN guideline acceptance criteria for bioequivalence which is the 90% confidence intervals of AUC0-∞, AUC0-t and Cmax ratio must be within the range of 80.00-125.00%.

RESULTS

There were 28 healthy subjects enrolled, and 27 subjects completed this trial. There were no significant differences observed between the AUC0-∞, AUC0-t and Cmax of both test and reference preparations in fasted condition. The 90% confidence intervals for the ratio of AUC0-t (100.92-111.27%), AUC0-∞ (96.94-108.08%) and Cmax (100.11-112.50%) for orphenadrine (n = 25); and AUC0-t (94.29-101.83%), AUC0-∞ (94.77-101.68%) and Cmax (87.12-101.20%) for paracetamol (n = 27) for test preparation over reference preparation were all within acceptable bioequivalence range of 80.00-125.00%.

CONCLUSION

The test preparation is bioequivalent to the reference preparation and can be used interchangeably.

TRIAL REGISTRATION

NMRR- 17-1266-36,001; registered and approved on 12 September 2017.

Authors+Show Affiliations

Clinical Research Ward, Clinical Trial Unit, Institute for Clinical Research, National Institutes of Health, Ministry of Health Malaysia, Hospital Ampang, Ampang, Selangor, Malaysia. kityeecheah@hotmail.com.Clinical Research Ward, Clinical Trial Unit, Institute for Clinical Research, National Institutes of Health, Ministry of Health Malaysia, Hospital Ampang, Ampang, Selangor, Malaysia.Clinical Research Ward, Clinical Trial Unit, Institute for Clinical Research, National Institutes of Health, Ministry of Health Malaysia, Hospital Ampang, Ampang, Selangor, Malaysia.Clinical Research Ward, Clinical Trial Unit, Institute for Clinical Research, National Institutes of Health, Ministry of Health Malaysia, Hospital Ampang, Ampang, Selangor, Malaysia.Pharmacy-Attest Research Sdn Bhd BA/BE Centre, George Town, Pulau Pinang, Malaysia.Pharmacy-Attest Research Sdn Bhd BA/BE Centre, George Town, Pulau Pinang, Malaysia.Pharmacy-Attest Research Sdn Bhd BA/BE Centre, George Town, Pulau Pinang, Malaysia.Pharmacy-Attest Research Sdn Bhd BA/BE Centre, George Town, Pulau Pinang, Malaysia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32576287

Citation

Cheah, Kit Yee, et al. "A Randomized Single-dose, Two-period Crossover Bioequivalence Study of Two Fixed-dose Paracetamol/Orphenadrine Combination Preparations in Healthy Volunteers Under Fasted Condition." BMC Pharmacology & Toxicology, vol. 21, no. 1, 2020, p. 45.
Cheah KY, Mah KY, Pang LH, et al. A randomized single-dose, two-period crossover bioequivalence study of two fixed-dose Paracetamol/Orphenadrine combination preparations in healthy volunteers under fasted condition. BMC Pharmacol Toxicol. 2020;21(1):45.
Cheah, K. Y., Mah, K. Y., Pang, L. H., Ng, S. M., Wong, J. W., Tan, S. S., Tan, H. Z., & Yuen, K. H. (2020). A randomized single-dose, two-period crossover bioequivalence study of two fixed-dose Paracetamol/Orphenadrine combination preparations in healthy volunteers under fasted condition. BMC Pharmacology & Toxicology, 21(1), 45. https://doi.org/10.1186/s40360-020-00416-3
Cheah KY, et al. A Randomized Single-dose, Two-period Crossover Bioequivalence Study of Two Fixed-dose Paracetamol/Orphenadrine Combination Preparations in Healthy Volunteers Under Fasted Condition. BMC Pharmacol Toxicol. 2020 Jun 23;21(1):45. PubMed PMID: 32576287.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A randomized single-dose, two-period crossover bioequivalence study of two fixed-dose Paracetamol/Orphenadrine combination preparations in healthy volunteers under fasted condition. AU - Cheah,Kit Yee, AU - Mah,Kar Yee, AU - Pang,Lai Hui, AU - Ng,Shi Min, AU - Wong,Jia Woei, AU - Tan,Siew Siew, AU - Tan,Hong Zhe, AU - Yuen,Kah Hay, Y1 - 2020/06/23/ PY - 2019/03/25/received PY - 2020/05/19/accepted PY - 2020/6/25/entrez PY - 2020/6/25/pubmed PY - 2020/6/25/medline KW - Bioequivalence KW - Fasted KW - Orphenadrine KW - Paracetamol SP - 45 EP - 45 JF - BMC pharmacology & toxicology JO - BMC Pharmacol Toxicol VL - 21 IS - 1 N2 - BACKGROUND: Paracetamol/Orphenadrine is a fixed dose combination containing 35 mg orphenadrine and 450 mg paracetamol. It has analgesic and muscle relaxant properties and is widely available as generics. This study is conducted to investigate the relative bioavailability and bioequivalence between one fixed dose paracetamol/orphenadrine combination test preparation and one fixed dose paracetamol/orphenadrine combination reference preparation in healthy volunteers under fasted condition for marketing authorization in Malaysia. METHOD: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2-period crossover study with a washout period of 7 days. Paracetamol/Orphenadrine tablets were administered after a 10-h fast. Blood samples for pharmacokinetic analysis were collected at scheduled time intervals prior to and up to 72 h after dosing. Blood samples were centrifuged, and separated plasma were kept frozen (- 15 °C to - 25 °C) until analysis. Plasma concentrations of orphenadrine and paracetamol were quantified using liquid-chromatography-tandem mass spectrometer using diphenhydramine as internal standard. The pharmacokinetic parameters AUC0-∞, AUC0-t and Cmax were determined using plasma concentration time profile for both preparations. Bioequivalence was assessed according to the ASEAN guideline acceptance criteria for bioequivalence which is the 90% confidence intervals of AUC0-∞, AUC0-t and Cmax ratio must be within the range of 80.00-125.00%. RESULTS: There were 28 healthy subjects enrolled, and 27 subjects completed this trial. There were no significant differences observed between the AUC0-∞, AUC0-t and Cmax of both test and reference preparations in fasted condition. The 90% confidence intervals for the ratio of AUC0-t (100.92-111.27%), AUC0-∞ (96.94-108.08%) and Cmax (100.11-112.50%) for orphenadrine (n = 25); and AUC0-t (94.29-101.83%), AUC0-∞ (94.77-101.68%) and Cmax (87.12-101.20%) for paracetamol (n = 27) for test preparation over reference preparation were all within acceptable bioequivalence range of 80.00-125.00%. CONCLUSION: The test preparation is bioequivalent to the reference preparation and can be used interchangeably. TRIAL REGISTRATION: NMRR- 17-1266-36,001; registered and approved on 12 September 2017. SN - 2050-6511 UR - https://www.unboundmedicine.com/medline/citation/32576287/A_randomized_single-dose,_two-period_crossover_bioequivalence_study_of_two_fixed-dose_Paracetamol/Orphenadrine_combination_preparations_in_healthy_volunteers_under_fasted_condition L2 - https://bmcpharmacoltoxicol.biomedcentral.com/articles/10.1186/s40360-020-00416-3 DB - PRIME DP - Unbound Medicine ER -
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