CLINICAL PHARMACOLOGY
Mechanism of Action
Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and d/l-amphetamine). Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics." The effect of phentermine on chronic weight management is likely mediated by release of catecholamines in the hypothalamus, resulting in reduced appetite and decreased food consumption, but other metabolic effects may also be involved. The exact mechanism of action is not known.
The precise mechanism of action of topiramate on chronic weight management is not known. Topiramate's effect on chronic weight management may be due to its effects on both appetite suppression and satiety enhancement, induced by a combination of pharmacologic effects including augmenting the activity of the neurotransmitter gamma-aminobutyrate, modulation of voltage-gated ion channels, inhibition of AMPA/kainite excitatory glutamate receptors, or inhibition of carbonic anhydrase.
Pharmacodynamics
Typical actions of amphetamines include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for.
Cardiac Electrophysiology
The effect of Qsymia on the QTc interval was evaluated in a randomized, double-blind, placebo- and active-controlled (400 mg moxifloxacin), parallel group/crossover thorough QT/QTc study. A total of 54 healthy subjects were administered Qsymia 7.5 mg/46 mg at steady state and then titrated to Qsymia 22.5 mg/138 mg at steady state. Qsymia 22.5 mg/138 mg [a supra-therapeutic dose resulting in a phentermine and topiramate maximum concentration (Cmax) of 4- and 3- times higher than those at Qsymia 7.5 mg/46 mg, respectively] did not affect cardiac repolarization as measured by the change from baseline in QTc.
Pharmacokinetics
Phentermine
Upon oral administration of a single Qsymia 15 mg/92 mg, the resulting mean plasma phentermine maximum concentration (Cmax), time to Cmax (Tmax), area under the concentration curve from time zero to the last time with measureable concentration (AUC0-t), and area under the concentration curve from time zero to infinity (AUC0-
∞) are 49.1 ng/mL, 6 hr, 1990 ng∙hr/mL, and 2000 ng∙hr/mL, respectively. A high fat meal does not affect phentermine pharmacokinetics for Qsymia 15 mg/92 mg. Phentermine pharmacokinetics is approximately dose-proportional from Qsymia 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine/topiramate 15/100 mg fixed dose combination capsule to steady state, the mean phentermine accumulation ratios for AUC and Cmax are both approximately 2.5.
Topiramate
Upon oral administration of a single Qsymia 15 mg/92 mg, the resulting mean plasma topiramate Cmax, Tmax, AUC0-t, and AUC0-
∞, are 1020 ng/mL, 9 hr, 61600 ng∙hr/mL, and 68000 ng∙hr/mL, respectively. A high fat meal does not affect topiramate pharmacokinetics for Qsymia 15 mg/92 mg. Topiramate pharmacokinetics is approximately dose-proportional from Qsymia 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine 15 mg/topiramate 100 mg fixed dose combination capsule to steady state, the mean topiramate accumulation ratios for AUC and Cmax are both approximately 4.0.
Distribution
Phentermine
Phentermine is 17.5% plasma protein bound. The estimated phentermine apparent volume of distribution (Vd/F) is 348 L via population pharmacokinetic analysis.
Topiramate
Topiramate is 15 - 41% plasma protein bound over the blood concentration range of 0.5 to 250 µg/mL. The fraction bound decreased as blood topiramate increased. The estimated topiramate Vc/F (volume of the central compartment), and Vp/F (volume of the peripheral compartment) are 50.8 L, and 13.1 L, respectively, via population pharmacokinetic analysis.
Metabolism and Excretion
Phentermine
Phentermine has two metabolic pathways, namely p-hydroxylation on the aromatic ring and N-oxidation on the alipthatic side chain. Cytochrome P450 (CYP) 3A4 primarily metabolizes phentermine but does not show extensive metabolism. Monoamine oxidase (MAO)-A and MAO-B do not metabolize phentermine. Seventy to 80% of a dose exists as unchanged phentermine in urine when administered alone. The mean phentermine terminal half-life is about 20 hours. The estimated phentermine oral clearance (CL/F) is 8.79 L/h via population pharmacokinetic analysis.
Topiramate
Topiramate does not show extensive metabolism. Six topiramate metabolites (via hydroxylation, hydrolysis, and glucuronidation) exist, none of which constitutes more than 5% of an administered dose. About 70% of a dose exists as unchanged topiramate in urine when administered alone. The mean topiramate terminal half-life is about 65 hours. The estimated topiramate CL/F is 1.17 L/h via population pharmacokinetic analysis.
Specific Populations
Renal Impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of Qsymia 15 mg/92 mg in patients with varying degrees of chronic renal impairment compared to healthy volunteers with normal renal function. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (greater or equal to 50 and less than 80 mL/min), moderate (greater than or equal to 30 and less than 50 mL/min), and severe (less than 30 mL/min). Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault equation.
Compared to healthy volunteers, phentermine AUC0-inf was 91%, 45%, and 22% higher in patients with severe, moderate, and mild renal impairment, respectively; phentermine Cmax was 2% to 15% higher. Compared to healthy volunteers, topiramate AUC0-inf was 126%, 85%, and 25% higher for patients with severe, moderate, and mild renal impairment, respectively; topiramate Cmax was 6% to 17% higher. An inverse relationship between phentermine or topiramate Cmax or AUC and creatinine clearance was observed.
Qsymia has not been studied in patients with end-stage renal disease on dialysis [see Dosage and Administration, Warnings and Precautions, and Use in Specific Populations].
Hepatic Impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of Qsymia 15 mg/92 mg in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh score 5 - 6) and moderate (Child-Pugh score 7 - 9) hepatic impairment. In patients with mild and moderate hepatic impairment, phentermine AUC was 37% and 60% higher compared to healthy volunteers. Pharmacokinetics of topiramate was not affected in patients with mild and moderate hepatic impairment when compared with healthy volunteers. Qsymia has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15) [see Dosage and Administration, Warnings and Precautions, and Use in Specific Populations].
Drug Interactions
In Vitro Assessment of Drug Interactions
Phentermine
Phentermine is not an inhibitor of CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, and is not an inhibitor of monoamine oxidases. Phentermine is not an inducer of CYP1A2, CYP2B6, and CYP3A4. Phentermine is not a P-glycoprotein substrate.
Topiramate
Topiramate is not an inhibitor of CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5. However, topiramate is a mild inhibitor of CYP2C19. Topiramate is a mild inducer of CYP3A4. Topiramate is not a P-glycoprotein substrate.
Effects of Phentermine/Topiramate on Other Drugs
Table 6. Effect of Phentermine/Topiramate on the Pharmacokinetics of Co-administered Drugs
| Phentermine/Topiramate |
Co-administered Drug and Dosing Regimen |
| Drug and Dose (mg) |
Change in AUC |
Change in Cmax
|
|
15 mg/92 mg dose QD for 16 days |
Metformin 500 mg BID for 5 days |
↑ 23% |
↑ 16% |
|
15 mg/92 mg dose QD for 21 days |
Sitagliptin 100 mg QD for 5 days |
↓ 3% |
↓ 9% |
| 15 mg/92 mg dose QD for 15 days |
Oral contraceptive single dose
norethindrone 1 mg
ethinyl estradiol 35 mcg |
↑ 16%
↓ 16% |
↑ 22%
↓ 8% |
Effect of Other Drugs on Phentermine/Topiramate
Table 7. Effect of Co-administered Drugs on the Pharmacokinetics of Phentermine/Topiramate
| Co-administered Drug and Dosing Regimen |
Phentermine/Topiramate |
| Dose (mg) |
Change in AUC |
Change in Cmax
|
| Topiramate 92 mg single dose |
15 mg phentermine single dose |
↑ 42% |
↑ 13% |
| Phentermine 15 mg single dose |
92 mg topiramate single dose |
↑ 6% |
↑ 2% |
|
Metformin 500 mg BID for 5 days |
15 mg/92 mg dose QD for 16 days
phentermine
topiramate |
↑ 5%
↓ 5% |
↑ 7%
↓ 4% |
|
Sitagliptin 100 mg QD for 5 days |
15 mg/92 mg dose QD for 21 days
phentermine
topiramate |
↑ 9%
↓ 2% |
↑ 10%
↓ 2% |
|
Probenecid 2 g QD |
15 mg/92 mg dose QD for 11 days
phentermine
topiramate |
↓ 0.3%
↑ 0.7% |
↑ 4%
↑ 3% |
Effects of Topiramate Alone on Other Drugs and Effects of Other Drugs on Topiramate
Antiepileptic Drugs
Potential interactions between topiramate and standard antiepileptic (AED) drugs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 8.
In Table 8, the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when topiramate was given alone.
Table 8. Summary of AED Interactions with Topiramate
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| NC = Less than 10% change in plasma concentration; NE = Not Evaluated; TPM = topiramate |
| Phenytoin |
NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideIs not administered but is an active metabolite of carbamazepine.
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
Digoxin
In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established.
Hydrochlorothiazide
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.
Pioglitazone
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the area under the concentration-time curve during a dosage interval at steady state (AUCÏ„,ss) of pioglitazone with no alteration in maximum steady-state plasma drug concentration during a dosage interval (Cmax,ss) was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUCÏ„,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCÏ„,ss of the active keto-metabolite. The clinical significance of these findings is not known. When topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Glyburide
A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in Cmax and a 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxyglyburide (M1) and 3- cis -hydroxyglyburide (M2), was reduced by 13% and 15%, and Cmax was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.
Lithium
In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses up to 600 mg/day. Lithium levels should be monitored when co-administered with high-dose topiramate.
Haloperidol
The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hours) in 13 healthy adults (6 males, 7 females).
Amitriptyline
There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.
Sumatriptan
Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).
Risperidone
When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Co-administration of topiramate 400 mg/day with risperidone resulted in a 14% increase in Cmax and a 12% increase in AUC12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance.
Propranolol
Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg/day of topiramate.
Dihydroergotamine
Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study.
Diltiazem
Co-administration of diltiazem (240 mg Cardizem CD®) with topiramate (150 mg/day) resulted in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC12 of topiramate.
Venlafaxine
Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg extended release) did not affect the pharmacokinetics of topiramate.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Phentermine/Topiramate
No animal studies have been conducted with phentermine/topiramate, the combined products in Qsymia, to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on findings in studies performed individually with phentermine or topiramate, Qsymia's two active ingredients.
Phentermine
Phentermine was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in Chinese hamster lung (CHL-K1) cells, or an in vivo micronucleus assay.
Rats were administered oral doses of 3, 10, and 30 mg/kg/day phentermine for 2 years. There was no evidence of carcinogenicity at the highest dose of phentermine (30 mg/kg) which is approximately 11 to 15 times the maximum recommended clinical dose of Qsymia 15 mg/92 mg based on AUC exposure.
No animal studies have been conducted with phentermine to determine the potential for impairment of fertility.
Topiramate
Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.
An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 2 to 4 times steady-state exposures measured in patients receiving topiramate monotherapy at the MRHD of Qsymia 15 mg/92 mg. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 4 to 10 times the MRHD of Qsymia based on AUC estimates).
No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg or approximately 4 to 8 times male and female MRHD exposures of Qsymia based on AUC.
Reproductive and Developmental Toxicology
Topiramate
Topiramate, a component of Qsymia, causes developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses.
When oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose of topiramate in this study (20 mg/kg) is approximately 2 times the MRHD of topiramate in Qsymia 15 mg/92 mg on a mg/m2 basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.
In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (34 times the MRHD of Qsymia based on AUC estimates) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (2 times the MRHD of Qsymia based on estimated AUC). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.
In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the MRHD based on estimated AUC) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the MRHD of Qsymia based on estimated AUC). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.
When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (16 times the MRHD of Qsymia based on estimated AUC) and reductions in pre-and/or post-weaning body weight gain at 2 mg/kg (2 times the MRHD of Qsymia based on estimated AUC) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.
In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (34 times the MRHD of Qsymia based on estimated AUC) and persistent reductions in body weight gain at 30 mg/kg (2 times the MRHD of Qsymia based on estimated AUC) and higher.
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