*2.2.2. Zonisamide (Zonegran®)*

approved anti-obesity drugs, the safety of monotherapy of phentermine is relatively scarce due to the long history of combination products, most notably phentermine/fenfluramine (Phen-Fen), which was removed from the market due to serious and potentially fatal cardio‐ vascular effects [30, 31]. More recently a combination product containing phentermine and topiramate has been investigated (see *Topiramate* below) and is currently under review by the

Because of the similarity in activity and mechanism of action, drug interactions with phenter‐ mine are similar to those for diethylpropion (see *Diethylpropion* above) including avoidance of alcohol, potential changes to antidiabetic agent therapy, and avoidance of coadministration of MAOIs [28]. There is one case report of a female patient experiencing two penropative hypertensive crises, which were attributed to an interaction between phentermine and

Several antiepileptic agents are known to have an effect on weight gain [33]. However, two newer antiepileptic agents, topiramate and zonisamide, have shown an associated decrease in weight in patients taking these medications [34]. Therefore, these two drugs are being looked

Topiramate is a carbonic anhydrase inhibitor (Figure 1c) that is typically used in the treatment of migraines and as an anticonvulsant [35]. Topiramate is proposed to exert its antiepileptic activity via gamma-aminobutyric acid (GABA)-A-mediated inhibition via a benzodiazepine insensitive pathway, although the drug also blocks voltage dependent sodium channels [35-37]. Weight loss has been a commonly reported adverse effect of topiramate; therefore, the drug has recently come into focus as a potential anorectic agent [38-42]. Topiramate has shown promise as a combination low-dose therapy with phentermine (Qsymia(R) (originally Qnexa(R), Vivus Pharmaceuticals, Mountain View, CA, USA) for long term treatment of obesity [43-46]. Despite, safety concerns related to teratogenicity and cardiovascular effects,

the product has recently been approved by the U.S. Food and Drug Administration."

Drug interactions with topiramate include coadministration with other antiepileptic agents. Although no changes in carbamazepine or phenytoin levels were seen, topiramate levels decreased by 40% or 48%, respectively [35]. However, there have been two case reports of antiepileptic drug intoxications in patients initiated on topiramate who were already taking the maximum carbamazepine dose [47]. Decrease in carbamazepine dosage resolved the interaction. Hyperammonemia, hypothermia and potentially encephalopathy can result from a synergistic interaction between topiramate, valproic acid, and phenobarbital, although the exact mechanism of this interaction is unknown [35, 48-50]. Levels of ethinyl estradiol can be significantly decreased in patients taking topiramate as an adjunctive therapy with valproic acid [35]. As a carbonic anhydrase inhibitor, topiramate can cause metabolic acidosis, and therefore is contraindicated in patients taking metformin, while patients taking other carbonic

US Food and Drug Administration (FDA).

anesthetic agents [32].

110 Drug Discovery

**2.2. Antiepileptic agents**

at as potential anorectic agents.

*2.2.1. Topiramate (Topamax®)*

Zonisamide (Figure 1d), a methanesulfonamide, is an antiepileptic agent which has broad spectrum activity and has proven to be useful in patients not responding to other antiepileptic treatments [57]. The drug blocks sustained and repetitive neuronal firing by blocking voltage sensitive sodium channels and decreasing voltage sensitive T-type calcium channels [58, 59]. Additionally, it was found that zonisamide has dopaminergic and serotonergic activity, which contributes to the anorectic effects of the drug [60, 61]. In one randomized placebo-controlled trial, 30 subjects were administered zonisamide 100 mg daily along with a low calorie diet (500 kcal/day) for a period of 16 weeks. Dosage was increased to up to 600 mg/day for patients not losing >5% of their initial body weight within the first 12 weeks. The zonisamide group lost significantly more body weight at the end of the trial compared to the placebo group (approx. 6% loss vs. 1% loss) [62].

Zonisamide is metabolized by the cytochrome P450 3A4 system and therefore can potentially interact with other drugs metabolized via this route. In one study, the half-life of zonisamide (t½ = 60 h) was decreased in patients receiving both zonisamide and phenytoin (t½ = 27 h), carbamazepine (t½ = 38 h, and sodium valproate (t½ = 46 h) [57, 63]. Another study in the dog demonstrated decreased plasma levels of zonisamide during administration of phenobarbital [64]. However, any associated decrease in levels of other antiepileptic drugs was not found to be clinically significant [65, 66]. Cigarette smoking may alter the pharmacokinetics of zonisa‐ mide. Coadministration of carbonic anhydrase inhibitors may increase risk of metabolic acidosis and kidney stone formation, therefore monitoring is recommended in this patient population [66]. One study on the effects of cigarette smoke on zonisamide concentrations in rats suggests that cigarette smoke may decrease plasma levels of the drug due to decreased oral absorption [67]. Brain, but not plasma levels of zonisamide may be affected by chronic ethanol consumption. In one study inbred EL mice were administered zonisamide 75 mg/kg for 1 – 4 weeks along with 10% ethanol *ad libidum*. In groups with 4 week coadministration, representing chronic use of alcohol, a decrease in zonisamide brain concentrations, but not serum concentration were observed [68].

### **2.3. Orlistat (Xenical®, Alli®)**

Orlistat (Figure 1e) is a gastrointestinal lipase inhibitor approved both as a prescription (Xenical®) and over-the-counter (Alli®) weight loss aid in the long term treatment of obesity [69]. The drug exhibits antiobesity activity by inhibiting the absorption of dietary fat from the lumen of the stomach and small intestine through covalent binding with gastric and pancreatic lipase active serine residues [70]. Multiple randomized controlled trials have reported significant weight loss in patients taking orlistat compared to placebo controlled groups. One meta-analysis cites mean weight loss compared to control of -2.59 kg [95%CI, -3.46 to -1.74] or -2.9 kg [95%CI, -3.2 to -2.5] over 6 or 12 months, respectively, with a corresponding decrease in waist circumference, blood pressure, and blood glucose and lipid profiles [71-73].

adverse events, especially related to increased risk of suicide, caused the Agency to rescind the approval in 2009. Although rimonabant is not available in most major markets, ongoing investigations surrounding the development of the drug continue, while the drug has been approved in other markets [97-100]. Additionally, the drug appears to be available readily via online pharmacy services and has been identified as an adulterant in dietary supplements

Interactions with Drugs and Dietary Supplements Used For Weight Loss

http://dx.doi.org/10.5772/51145

113

Given the limited and short-lived approval status of rimonabant, there is little information regarding potential drug-drug and herb-drug interactions available. According to package insert data submitted to the EMEA, rimonabant is known to be eliminated hepatically and into the bile by amidohydrolase and CYP3A4, with a 104% increase in rimonabant AUC (95% CI 40 – 197%) upon coadministration of ketoconazole [92, 96, 104, 105]. Therefore, the manufac‐ turer indicated potential interactions with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, telithromycin, clarithromycin, and nefazodone) and inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, and St. John's Wort). Because rimona‐ bant can decrease levels of fasting insulin and blood sugar, use of rimonabant in diabetic

Sibutramine hydrocholoride (Figure 1g), and its active primary (M1) and secondary (M2) metabolites, is a selective serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor [106-110]. Clinical data supported the efficacy of sibutramine as a weight loss agent, reporting significant weight loss compared to placebo for patients taking at least 10 mg/day for up to one year [107, 110-114]. The drug was approved as an anti-obesity agent in 1997 by the U.S. FDA and in 2002 by the EMEA, despite evidence of increased risk of hypertension and tachycardia, with a requirement that additional post-marketing safety data be collected relative to cardiotoxicity. As a result, the SCOUT (Sibutramine Cardiovascular OUTcomes) trial was implemented, which enrolled 10,000 overweight or obese patients aged 55 and older with coexisting diabetes and/or heart disease in a randomized controlled trial with a 6-month lead in period [115-118]. At the end of the six year study period, data showed a significant decrease in body weight compared to placebo but increased cardiovascular morbidity in the randomized sibutramine group [115-118]. Following publication of the SCOUT trial results in 2010, the EMEA and most other major markets pulled sibutramine while the United States and Australia required stricter labeling. By 2011 sibutramine was pulled from all major markets globally. However, as with the case of rimonabant (see above), sibutramine is of note since it is the primary contaminant found in dietary weight loss supplements (see

Sibutramine is known to be metabolized by CYP 3A4 into two active metabolites (M1 and M2). Data reported by the manufacturer in limited clinical trials (n = 12 – 27 patients) suggest potential pharmacokinetic changes in AUC and Cmax for sibutramine when taken in combina‐ tion with CYP 3A4 inhibitors such as cimetidine, ketoconazole, erythromycin, simvastatin, and omeprazole; while sibutramine does not generally have a significant impact on the levels of these drugs in return [106]. Because of the role of CYP 3A4 in sibutramine elimination, use of

marketed for weight loss (see *Adulteration of Dietary Supplements* below) [101-103].

patients taking anti-diabetic agents is cautioned [92, 96, 104, 105].

**2.5. Sibutramine (Meridia®, Reductil®)**

*Adulteration of Dietary Supplements* below).

A large number of preclinical and clinical studies and case reports related to potential drug interactions with orlistat have been published. There have been several cases of orlistat interaction with cyclosporine [74-79]. In all cases, significant decreases in plasma cyclosporine levels were observed following adjunct treatment with orlistat for cyclosporine-associated weight gain. Although one proposed mechanism for the reduction in plasma cyclosporine is a decrease in drug absorption, decreased levels may be due to rapid gastrointestinal transit time resulting from contraindicated high fat diets rather than a true drug-drug interaction [80]. Because orlistat is designed to inhibit gastrointestinal lipases, theoretically absorption of lipophilic molecules would also be inhibited [81-83]. In one open-label, placebo-controlled randomized two-way crossover study, orlistat (120 mg) was administered to 12 healthy subjects three times daily for 9 days followed by administration of Vitamin A (25,000 IU) or Vitamin E (400 IU) [82]. Although no effect was seen on Vitamin A levels, a significant reduction in Cmax (approx. 43%) and AUC (approx. 60%) were observed for Vitamin E, suggesting impaired absorption of Vitamin E by orlistat. In another study, approximately a 30% reduction in beta-carotene levels was observed after administration of orlistat (120 mg) for four days followed by administration of 0 – 120 mg of beta-carotene three times a day for six days [83]. Absorption of lipophilic drugs such as the CNS agent lamotrigene can also be affected by orlistat. In one report, increased frequency of seizures was reported in an 18 year old female taking lamotrigene following initiation of an orlistat regimen [84]. One case of hypothyroidism in thyroid carcinoma was reported, presumably due to decreased absorption of thyroxine [85]. Although orlistat was not found to alter warfarin kinetics *per se*, but the drug may alter absorption of the fat soluble vitamin K which can have an effect warfarin levels and therefore these patients should be monitored for changes in coagulation parameters [86].

#### **2.4. Rimonabant (Acomplia®, Zumulti®)**

Rimonabant (Figure 1f) is a cannabanoid receptor antagonist that suppresses appetite by preventing activation of CB1 receptors by the endogenous cannabanoids anandamide and 2 arachidonoyl-glycerol [87]. In clinical trials the drug resulted in improvement of multiple endpoints associated with obesity and metabolic syndrome compared to control groups including significant weight loss, reduction in waist circumference, decreased triglycerides, blood glucose, fasting insulin, and leptin levels with increased HDL cholesterol and adipo‐ nectin levels [88-96]. Although rimonabant proved a potentially successful drug in the treatment of obesity, especially given lack of cardiovascular risks compared to other weight loss drugs (see *Sibutramine* below), the drug has not been approved by the U.S. Food and Drug Administration (FDA). Additionally, although the drug was initially approved in 2006 by the European Medicines Agency (EMEA), later studies indicating serious neuropsychiatric adverse events, especially related to increased risk of suicide, caused the Agency to rescind the approval in 2009. Although rimonabant is not available in most major markets, ongoing investigations surrounding the development of the drug continue, while the drug has been approved in other markets [97-100]. Additionally, the drug appears to be available readily via online pharmacy services and has been identified as an adulterant in dietary supplements marketed for weight loss (see *Adulteration of Dietary Supplements* below) [101-103].

Given the limited and short-lived approval status of rimonabant, there is little information regarding potential drug-drug and herb-drug interactions available. According to package insert data submitted to the EMEA, rimonabant is known to be eliminated hepatically and into the bile by amidohydrolase and CYP3A4, with a 104% increase in rimonabant AUC (95% CI 40 – 197%) upon coadministration of ketoconazole [92, 96, 104, 105]. Therefore, the manufac‐ turer indicated potential interactions with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, telithromycin, clarithromycin, and nefazodone) and inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, and St. John's Wort). Because rimona‐ bant can decrease levels of fasting insulin and blood sugar, use of rimonabant in diabetic patients taking anti-diabetic agents is cautioned [92, 96, 104, 105].
