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A randomized, double-blind, placebo-controlled, pharmacokinetic and pharmacodynamic study of a fixed-dose combination of phentermine/topiramate in adolescents with obesity.
Diabetes Obes Metab. 2020 Apr; 22(4):480-491.DO

Abstract

AIMS

To assess the pharmacokinetic (PK) and pharmacodynamic characteristics of VI-0521, a fixed-dose combination of immediate-release phentermine (PHEN) and extended-release topiramate (TPM) in adolescents aged 12 to 17 years with obesity, and to report weight loss and adverse events using this drug combination.

MATERIALS AND METHODS

This was a multicentre, randomized, double-blind, parallel-design, placebo-controlled study in adolescents with obesity. A total of 42 adolescents were randomly assigned in a 1:1:1 ratio to placebo, or to a mid-dose (PHEN/TPM 7.5 mg/46 mg), or a top-dose (PHEN/TPM 15 mg/92 mg) of VI-0521. A total of 26 adolescents were included in the PK analysis (14 from the mid-dose group and 12 from the top-dose group).

RESULTS

On day 56, arithmetic means of terminal elimination half-life, apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) were consistent across dose levels for both PHEN and TPM. Arithmetic means of CL/F and Vc/F for PHEN and TPM administered as a combination in adolescents with obesity were within 10% to 30% of those previously assessed in adults with obesity enrolled in phase II and III studies. A higher proportion of adolescents in both the mid- and top-dose groups (13.3% and 50.0%, respectively) compared with placebo (0.0%) reached ≥5% weight loss at day 56. The least squares (LS) mean change in systolic blood pressure from baseline to day 56 was -5.2 mmHg for the placebo group, -2.5 mmHg for the mid-dose group, and - 5.5 mmHg for the top-dose group. The LS mean change in diastolic blood pressure from baseline to day 56 was -2.4 mmHg for the placebo group, +3.8 mmHg for the mid-dose group, and + 2.0 mmHg for the top-dose group. Participants in the top-dose group had increases in heart rate from baseline of 4.1 bpm, while participants in the mid-dose group experienced a mean decrease in heart rate of 4.5 bpm at day 56. Both PHEN/TPM dose combinations were safe and well tolerated.

CONCLUSIONS

Treatment of adolescents with obesity using a fixed-dose combination of PHEN/TPM for 8 weeks resulted in exposure to PHEN and TPM that was comparable to that observed in adults, statistically significant weight loss, and a tolerable safety profile. These data indicate that both mid- and top-dose levels are appropriate for longer-term safety and efficacy studies in adolescents.

Authors+Show Affiliations

Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States.Certara USA, Inc, Princeton, New Jersey.Cincinnati Children's Hospital/University of Cincinnati, Cincinnati, Ohio, United States.Certara USA, Inc, Princeton, New Jersey.Certara USA, Inc, Princeton, New Jersey.Vivus, Inc, Campbell, California.Vivus, Inc, Campbell, California.Cincinnati Children's Hospital/University of Cincinnati, Cincinnati, Ohio, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31696603

Citation

Hsia, Daniel S., et al. "A Randomized, Double-blind, Placebo-controlled, Pharmacokinetic and Pharmacodynamic Study of a Fixed-dose Combination of Phentermine/topiramate in Adolescents With Obesity." Diabetes, Obesity & Metabolism, vol. 22, no. 4, 2020, pp. 480-491.
Hsia DS, Gosselin NH, Williams J, et al. A randomized, double-blind, placebo-controlled, pharmacokinetic and pharmacodynamic study of a fixed-dose combination of phentermine/topiramate in adolescents with obesity. Diabetes Obes Metab. 2020;22(4):480-491.
Hsia, D. S., Gosselin, N. H., Williams, J., Farhat, N., Marier, J. F., Shih, W., Peterson, C., & Siegel, R. (2020). A randomized, double-blind, placebo-controlled, pharmacokinetic and pharmacodynamic study of a fixed-dose combination of phentermine/topiramate in adolescents with obesity. Diabetes, Obesity & Metabolism, 22(4), 480-491. https://doi.org/10.1111/dom.13910
Hsia DS, et al. A Randomized, Double-blind, Placebo-controlled, Pharmacokinetic and Pharmacodynamic Study of a Fixed-dose Combination of Phentermine/topiramate in Adolescents With Obesity. Diabetes Obes Metab. 2020;22(4):480-491. PubMed PMID: 31696603.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A randomized, double-blind, placebo-controlled, pharmacokinetic and pharmacodynamic study of a fixed-dose combination of phentermine/topiramate in adolescents with obesity. AU - Hsia,Daniel S, AU - Gosselin,Nathalie H, AU - Williams,Jenna, AU - Farhat,Nada, AU - Marier,J F, AU - Shih,Winnie, AU - Peterson,Craig, AU - Siegel,Robert, Y1 - 2019/12/18/ PY - 2019/08/01/received PY - 2019/10/19/revised PY - 2019/10/31/accepted PY - 2019/11/7/pubmed PY - 2019/11/7/medline PY - 2019/11/8/entrez KW - antiobesity drug KW - obesity therapy KW - pharmacodynamics KW - pharmacokinetics SP - 480 EP - 491 JF - Diabetes, obesity & metabolism JO - Diabetes Obes Metab VL - 22 IS - 4 N2 - AIMS: To assess the pharmacokinetic (PK) and pharmacodynamic characteristics of VI-0521, a fixed-dose combination of immediate-release phentermine (PHEN) and extended-release topiramate (TPM) in adolescents aged 12 to 17 years with obesity, and to report weight loss and adverse events using this drug combination. MATERIALS AND METHODS: This was a multicentre, randomized, double-blind, parallel-design, placebo-controlled study in adolescents with obesity. A total of 42 adolescents were randomly assigned in a 1:1:1 ratio to placebo, or to a mid-dose (PHEN/TPM 7.5 mg/46 mg), or a top-dose (PHEN/TPM 15 mg/92 mg) of VI-0521. A total of 26 adolescents were included in the PK analysis (14 from the mid-dose group and 12 from the top-dose group). RESULTS: On day 56, arithmetic means of terminal elimination half-life, apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) were consistent across dose levels for both PHEN and TPM. Arithmetic means of CL/F and Vc/F for PHEN and TPM administered as a combination in adolescents with obesity were within 10% to 30% of those previously assessed in adults with obesity enrolled in phase II and III studies. A higher proportion of adolescents in both the mid- and top-dose groups (13.3% and 50.0%, respectively) compared with placebo (0.0%) reached ≥5% weight loss at day 56. The least squares (LS) mean change in systolic blood pressure from baseline to day 56 was -5.2 mmHg for the placebo group, -2.5 mmHg for the mid-dose group, and - 5.5 mmHg for the top-dose group. The LS mean change in diastolic blood pressure from baseline to day 56 was -2.4 mmHg for the placebo group, +3.8 mmHg for the mid-dose group, and + 2.0 mmHg for the top-dose group. Participants in the top-dose group had increases in heart rate from baseline of 4.1 bpm, while participants in the mid-dose group experienced a mean decrease in heart rate of 4.5 bpm at day 56. Both PHEN/TPM dose combinations were safe and well tolerated. CONCLUSIONS: Treatment of adolescents with obesity using a fixed-dose combination of PHEN/TPM for 8 weeks resulted in exposure to PHEN and TPM that was comparable to that observed in adults, statistically significant weight loss, and a tolerable safety profile. These data indicate that both mid- and top-dose levels are appropriate for longer-term safety and efficacy studies in adolescents. SN - 1463-1326 UR - https://www.unboundmedicine.com/medline/citation/31696603/A_randomized,_double-blind,_placebo-controlled,_pharmacokinetic_and_pharmacodynamic_study_of_a_fixed-dose_combination_of_phentermine/topiramate_in_adolescents_with_obesity L2 - https://doi.org/10.1111/dom.13910 DB - PRIME DP - Unbound Medicine ER -
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