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Fixed Dose Combination Tablets of Aripiprazole and Divalproex Sodium: a Pilot Pharmacokinetic Study in Human Volunteers

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Abstract

A combination product of aripiprazole (antipsychotic) and divalproex sodium (mood stabilizer) was recently developed to establish their tolerability and safety in fixed dose combination (FDC). A pilot pharmacokinetic (PK) open-labeled parallel study on healthy human volunteers was carried out to assess the PK of FDC of aripiprazole/divalproex sodium in comparison with its individual components with a view to rationalize therapeutic regimen and potentially improve compliance of bipolar patients in future. A total of 24 volunteers were randomized to aripiprazole 5mg, divalproex sodium 500mg, and FDC (aripiprazole/divalproex sodium 5/500 mg) enteric-coated tablets. Peak plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax) of aripiprazole increased, Cmax of valproic acid increased, and Tmax decreased. Half-life (t1/2) of both aripiprazole and valproic acid decreased. Area under the curve (AUC) of both aripiprazole and valproic acid increased while volume of distribution (Vd) and clearance (Cl) decreased when used in fixed combination. Increase in the AUC and decrease in the Vd of aripiprazole in the presence of valproic acid were found statistically significant while rest of the parameters were insignificant at level 0.05. Although not adequately powered, this pilot study gives an idea that FDC of aripiprazole and divalproex sodium has a PK profile comparable to its mono-component products. Thus, concomitant use of aripiprazole and valproate in FDC is possible which may prove to be a cost-effective and result-oriented substitute for conventional individual tablets to improve patients’ compliance; however, further evaluation with positive control is required.

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Data Availability

The datasets (Supporting Information) generated during the current study is freely available any time from the corresponding authors on reasonable request.

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Acknowledgments

Authors are grateful to Qazi Abdur Rashid and the owners of Genome Pharmaceutical Industry (Pvt) limited, Hattar Industrial estate Haripur, Khyber Phaktunkhawa, Pakistan for providing research platform and their technical assistance to accomplish this research work. Likewise, Dr. Zia Ahmed is also obliged to Miss Lubna Ahmed (MA English) and Prof. Dr. Saeed Farooq (Psychiatrist) for their help in the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Abbottabad University of Science & Technology, Havelian, Abbottabad, Khyber Pakhtunkhawa (KP), Pakistan

    Zia Ahmed

  2. Department of Pharmacy, University of Peshawar, Peshawar, KP, Pakistan

    Zia Ahmed & Fazal Subhan

  3. Department of Pharmacy, CECOS University of IT and Emerging Sciences, Phase 6 Hayatabad, Peshawar, KP, 25120, Pakistan

    Fazal Subhan

  4. COMSATS Institute of Information Technology, Abbottabad, KP, Pakistan

    Saba Ahmed

Authors
  1. Zia Ahmed
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  2. Fazal Subhan
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  3. Saba Ahmed
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Contributions

Dr. Zia Ahmed: designed and performed all the experiments mentioned in the manuscript, and is a major contributor in writing the manuscript. Prof. Dr. Fazal Subhan: supervised the whole study. Ms. Saba Ahmed: involved in the HPLC analyses and citation.

Corresponding authors

Correspondence to Zia Ahmed or Fazal Subhan.

Ethics declarations

Ethics Approval

Experiments were carried out in accordance with the accepted guidelines approved by the institutional “Committee for Research Ethics,” Department of Pharmacy, University of Peshawar, Peshawar, Pakistan under license number “UOP/03/EC-14/PHARM, 06, 04, 2014.”

Conflict of Interest

The authors declare no competing interests.

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Additional information

Novelty statement

1. Pharmaceutically stable FDC product of aripiprazole and divalproex is expected to be better substitute for conventional individual tablets in terms of patients’ compliance by reducing the daily load of tablets.

2. Development of this FDC product may reduce the production and administrative costs so that medicines become cheaper and large population of bipolar patients may have an easy access to the medicines especially in resource poor countries.

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Ahmed, Z., Subhan, F. & Ahmed, S. Fixed Dose Combination Tablets of Aripiprazole and Divalproex Sodium: a Pilot Pharmacokinetic Study in Human Volunteers. AAPS PharmSciTech 23, 232 (2022). https://doi.org/10.1208/s12249-022-02378-7

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