What is Qsymia?Qsymia= Phentermine + Topiramate extended-releasePhentermine, Sympathomimetic amine anorecticTopiramate extended-release, Antiepileptic drug
Phentermine• An appetite suppressant to help reduce weight in obese patients – used short-term and combined with exercise• A psycho-stimulant drug of the phenethylamine class, with pharmacology similar to Amphetamine
Topiramate extended-release• An anticonvulsant (antiepilepsy) drug – Topiramate was first approved by the FDA in 1996 – The last patent for topiramate in the U.S. was for pediatric use; this patent expired on February 28, 2009• Extended-release: – allowing a twofold or greater reduction in frequency of administration of a drug in comparison with the frequency required by a conventional dosage form.
Phentermine• Target organ: Hypothalamus portion of the brain• Effect: Stimulate the adrenal glands to release norepinephrine• Peripheral Effect: Release epinephrine or adrenaline, causing fat cells to break down stored fat – Epinephrine(adrenaline)& Norepinephrine: fight-or- flight response
Topiramate• blockage of voltage-dependent sodium channels• an augmentation of gamma-aminobutyrate (GABA) acid activity at some subtypes of the GABA- α receptors• antagonism of AMPA/kainate subtype of the glutamate receptor• inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV
Topiramate (continued)• The exact mechanism of action is unknown• Weight loss was initially seen as a side effect – effect on taste
Clinical Trials Phase 0 study Phase I Study Phase II Study Phase III study Phase IV study
Phase 0 Study• Exploratory study involving very limited human exposure to the drug, with no therapeutic or diagnostic goals• Pharmacodynamics and Pharmacokinetics – Pharmacodynamics: what dose Drug do to Person? – Pharmacokinetics: what dose person do to Drugs?
Pharmacodynamics of QysmiaCentral Nervous System stimulation andelevation of blood pressure
Pharmacokinetics for Phentermine Maximum concentration (Cmax) 49.1 ng/mL 6 hr time to Cmax (Tmax) area under the concentration curve from time zero to the last 1990 ng⋅hr/mL time with measureable concentration (AUC0-t) Fig.1.1 Pharmacokinetics descriptive values for Phentermine – Approximately dose-proportional – 6 hours to reach the peak blood concentration – A high fat meal does not affect phentermine pharmacokinetics, 17.5% plasma protein bound
Pharmacokinetics for Topiramate Maximum concentration (Cmax) 1020.0 ng/mL 9 hr time to Cmax (Tmax) area under the concentration curve from time zero to the last 61600 ng⋅hr/mL time with measureable concentration (AUC0-t) Fig.1.2 Pharmacokinetics descriptive values for Topiramte – approximately dose-proportional – 9 hours to reach the peak blood concentration – 15-41% plasma protein bound
Phase I Study ---- Screening for safetyStudies that are usually conducted with healthyvolunteers and that emphasize safety. The goalis to find out what the drugs most frequent andserious adverse events are and, often, how thedrug is metabolized and excreted
• A Phase I, Open-Label, Parallel-Group, Single Dose, Non- Randomized Study To Compare The Pharmacokinetics Of Each Individual Component ( Topiramate And Phentermine) Of The Combination Product VI-0521 In Subjects With Mild, Moderate And Severe Renal Impairment To Subjects With Normal Renal Function Reporting Groups Description Placebo No text entered Top Dose PHEN/TPM 15mg/92mg Fig.1.3 Upper Level for Phen/Tpm dosage
Phase II StudyStudies that gather preliminary data on effectiveness(whether the drug works in people who have a certaindisease or condition). For example, participantsreceiving the drug may be compared with similarparticipants receiving a different treatment, usually aninactive substance (called a placebo) or a different drug.Safety continues to be evaluated, and short-termadverse events are studied
Phase II Study provided by VIVUS: Values Enrollment number 80 Ages Eligible for Study 21 Years to 45 Years Genders Eligible for Study Both Condition ICMJE Overweight Obesity Intervention ICMJE Drug: VI-0521* Drug: Placebo** Other: Alcohol or fruit juice Fig.2.1 Phase II Study of Drug VI-0521 and Placebo descriptive values*Phentermine 3.75 mg and topiramate 23 mg daily for the 1st week; Phentermine 7.5 mg and topiramate 46 mg daily for the 2nd week; Phentermine 11.25 mg and topiramate 69 mg daily for the 3rd week; Phentermine 15 mg and topiramate 92 mg daily for the 4th week**Placebo daily for 4 weeks
EffectivenessFor the Treatment of Obstructive Sleep Apnea HypopneaSyndrome in Obese AdultsStudy Type: Interventional Allocation: Randomized; Endpoint Classif ication: Safety/Efficacy Study; InterventiStudy Design: on Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Pri mary Purpose: TreatmentCondition: Sleep Apnea Drug: VI-0521Interventions: Drug: placeboFig.2.2 Results for the effectiveness of VI-0521 in Phase II Study
Effectiveness(continued) Placebo Top DoseNumber of Participants 23 22AnalyzedPercent Change in WeightFrom Baseline to Week -10.26 ± 1.17 -4.21 ± 1.1528*Fig.2.3 Results for the effectiveness of VI-0521 on weight change in Phase II Study Placebo Top DoseNumber of Participants 23 22AnalyzedChange in theApnea/Hypopnea Index -16.6 ± 4.15 -31.46 ± 4.25Between Baseline andWeek 28/Early Term**Fig.2.4 Results for the effectiveness of VI-0521 on Apnea/hypopnea Change in Phase II Study *[units: percent change] Least Squares Mean ± Standard Error **[units: events/hour] Least Squares Mean ± Standard Error
Phase III StudyStudies that gather more information about safety andeffectiveness by studying different populations anddifferent dosages and by using the drug in combinationwith other drugs.
#1 A Safety and Efficacy Study of VI-0521 to Evaluatethe Long Term Treatment of Obesity in Adults WithObesity-Related Co-Morbid Conditions. DescriptionPlacebo PlaceboVI-0521 Mid VI-0521 7.5 mg PHEN/46 mg TPMVI-0521 Top VI-0521 15 mg PHEN/92 mg TPMFig.3.1 Phase III Study of Drug VI-0521 and Placebo descriptive dosage in Experiment 1
Effectiveness Measured Values Placebo VI-0521 Mid VI-0521 Top Number of Participants Analyzed 227 153 295 Percent Weight Change at End of -1.8 ± 0.55 -9.32 ± 0.67 -10.5 ± 0.5 Treatment, Week 108. Fig.3.2 Results for the effectiveness of VI-0521 on weight change in Experiment 1 of Phase III Study Placebo VI-0521 Mid VI-0521 Top Number of Participants Analyzed 227 153 295 Percentage of Subjects With at Least 5% Weight Loss at End of 30 75.2 79.3 Treatment, Week 108. Fig.3.3 Results for the effectiveness of VI-0521 on Percentage of Subjects With at Least 5% Weight Loss in Experiment 1 of Phase III Study *[units: percent weight loss] Least Squares Mean ± Standard Error **[units: percent participants]
Adverse ReactionSerious Adverse Events Total, serious Placebo VI-0521 Mid VI-0521 Top adverse events# participants 9/227 (3.96%) 4/153 (2.61%) 13/295 (4.41%)affected / at risk Fig.3.4 Results for the adverse reaction of VI-0521 in Experiment 1 of Phase III Study
#2 A Study Comparing Multiple Doses of VI-0521 WithPlacebo and Their Single-agent Constituents for Treatment ofObesity in Adults Description Placebo Placebo PHEN 7.5 mg 7.5 mg phentermine TPM 46 mg 46 mg topiramate VI-0521 Mid 7.5 mg/46 mg phentermine/topiramate PHEN 15 mg 15 mg phentermine TPM 92 mg 92 mg topiramate VI-0521 Top 15 mg/92 mg phentermine/topiramate Fig.3.5 Phase III Study of Drug VI-0521 and Placebo descriptive dosage in Experiment 2
Effectiveness PHEN 7.5 VI-0521 PHEN 15 Placebo TPM 46 mg TPM 92 mg VI-0521 Top mg Mid mg# of 103 104 102 103 106 105 103ParticipantsPercentWeight Loss 1.7 5.5 5.1 8.5 6.1 6.4 9.2From ± 0.61 ± 0.61 ± 0.61 ± 0.62 ± 0.61 ± 0.62 ± 0.61Baseline toWeek 28Fig.3.6 Results for the effectiveness of VI-0521 on weight change in Experiment 2 of Phase III Study PHEN 7.5 VI-0521 TPM 92 Placebo TPM 46 mg PHEN 15 mg VI-0521 Top mg Mid mg# of 103 104 102 103 106 105 103ParticipantsPercentage ofSubjects Withat Least 5% 15.5 43.3 39.2 62.1 46.2 48.6 66.0Weight Loss atWeek 28Fig.3.7 Results for the effectiveness of VI-0521 on Percentage of Subjects With at Least 5% Weight Loss inExperiment 1 of Phase III Study*[units: participants] [units: percent weight loss]**Least Squares Mean ± Standard Error
Adverse Reaction PHEN 7.5 VI-0521 PHEN 15 Placebo TPM 46 mg TPM 92 mg VI-0521 Top mg Mid mg#participan 0/109 2/109 0/106 1/106 1/108 1/107 2/108ts affected (0.00%) (1.83%) (0.00%) (0.94%) (0.93%) (0.93%) (1.85%)/ at risk Fig.3.8 Results for the adverse reaction of VI-0521 in Experiment 1 of Phase III Study
Phase IV StudyStudies occurring after FDA has approved a drugfor marketing. These including postmarketrequirement and commitment studies that arerequired of or agreed to by the sponsor. Thesestudies gather additional information about adrugs safety, efficacy, or optimal use.
Phase IV Study Status: Active, not Recruitinghttp://www.clinicaltrials.gov
Potential Side Effect• Fetal Toxicity• Increase in Heart Rate• Suicidal Behavior and Ideation• Acute Myopia and Secondary Angle Closure Glaucoma• Mood and Sleep Disorders• Cognitive Impairment• Metabolic Acidosis• Elevation in Creatinine