A randomized, double‐blind, placebo‐controlled, pharmacokinetic and pharmacodynamic study of a fixed‐dose combination of phentermine/topiramate in adolescents with obesity. Issue 4 (18th December 2019)

• Record Type: Journal Article
• Authors: Hsia, Daniel S.; Gosselin, Nathalie H.; Williams, Jenna; Farhat, Nada; Marier, J. F.; Shih, Winnie; Peterson, Craig; Siegel, Robert
• Is Part Of: Diabetes, obesity & metabolism. Volume 22:Issue 4(2020)
• Page Start: 480
• Page End: 491
• Publication Date: 2019-12-18
• Subjects: antiobesity drug -- obesity therapy -- pharmacodynamics -- pharmacokinetics; Diabetes -- Periodicals; Obesity -- Periodicals; Metabolism -- Disorders -- Periodicals; Clinical pharmacology -- Periodicals; 616.462
• DOI: 10.1111/dom.13910
• Languages: English
• ISSNs: 1462-8902

Abstract

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.