DRUG EVALUATION Effi cacy, safety and tolerability of orlistat, a lipase inhibitor, in the treatment of adolescent weight excess The treatment of childhood and adolescent obesity is diffi cult and the outcome of behavioral interventions remains unsatisfactory. Several pharmacological approaches, used in conjunction with comprehensive behavioral interventions designed to improve diet and decrease inactivity have been developed and extensively studied, mainly in adults. Orlistat is a lipase inhibitor that reduces dietary fat absorption by a third. It is the only pharmacological agent approved in the pediatric age group for the treatment of obesity. The goal of this article is to review the effi cacy and safety of orlistat in adolescents, with emphasis on its effects on weight and body mass index, body composition and liposoluble vitamins during growth. KEYWORDS: adolescent obesity, fat absorption, lipase inhibitor, liposoluble, Roberto Bogarin1 & vitamins, weight loss Jean-Pierre Chanoine2,† †Author for correspondence: Adolescent obesity is one of the most refractory and adolescents, and there is a need for new 1Division of Endocrinology, health problems facing the health professional effective pharmaco logical agents that will Costa Rica’s NaƟ onal Children’s today. Long-term follow-up studies indicate promote long-term weight loss in adolescents, Hospital, Paseo Colon, that obese children have a 15-fold greater risk while offering a reassuring safety profi le. Only San Jose, 10103, Costa Rica of becoming obese adults compared with those three drugs have received extensive attention Tel.: +506 2222 0122 children and adolescents who are not obese [1] . It in the pediatric age group: sibutramine, met- Fax: +506 2221 6897 is a chronic condition that can affect emotional formin and orlistat. In addition, rimonabant, [email protected] and physical quality-of-life [2]. It is also the sin- a specifi c inhibitor on cannabinoid receptor 1 2Endocrinology and Diabetes gle most signifi cant risk factor for complications that reduces food intake, is approved for the Unit, Room K4–212, BriƟ sh such as Type 2 diabetes and cardiovascular dis- treatment of obesity in adults [8], but has to Columbia’s Children’s Hospital, ease. The prevalence of obesity in the pediatric our knowledge not been investigated in adoles- 4480 Oak Street, Vancouver, age group is increasing at an alarming rate world- cents. Rimonabant has not received US FDA BC, V6H 3V4, Canada wide. In the USA, the proportion of obese ado- approval and is not marketed in North America Tel.: +1 604 875 2624 lescents aged 12–19 years was 15.5% in 1999– for adults or adolescents. Sibutramine is a Fax: +1 604 875 3231 2000, compared with 10.5% in 1988–1994. centrally-acting serotonin–norepinephrine [email protected] This increase is even more pronounced in ethnic reuptake inhibitor that decreases appetite and minorities [3]. A similar increase was observed in was shown to cause a signifi cant weight loss in European countries and the prevalence of over- young subjects. In a prospective, randomized, weight adolescents is now 10–20% in northern placebo-controlled, 52-week study, Berkowitz European countries and 20–35% in southern et al. observed that administration of 10–15 mg European countries [4]. Despite constant media sibutramine in obese adolescents caused a body focus on this ‘obesity epidemic’, and awareness mass index (BMI) decrease of 2.9 kg/m2, com- of the effects of excess body fat on health, the pared with 0.3 kg/m2 in the placebo group [9]. existing preventative and therapeutic measures All subjects took part in a comprehensive behav- have not succeeded in curbing the prevalence of ioral program. However, changes in blood pres- adolescent obesity. sure and heart rate were statistically signifi cantly Treatment of pediatric obesity remains a different in the sibutramine compared with the diffi cult process. Recommended approaches placebo group, raising the possibility of adverse classically include improved diet, decreased long-term consequences on the cardiovascular inactivity and long-term changes in behavior system, and sibutramine is presently not indi- together with family involvement. However, the cated in pediatrics. Metformin is an antidiabetic outcome of these interventions remains poor agent that inhibits hepatic glucose production, [5], and health professionals are turning towards increases insulin sensitivity and may decrease adjuvant measures such as pharmacotherapy appetite. It is considered as a fi rst-line approach [6] and bariatric surgery [7]. Pharmacological for the treatment of Type 2 diabetes in youth. options are presently limited in obese children Recently, attention has focused on its potential 10.2217/14750708.6.1.23 © 2009 Future Medicine Ltd Therapy (2009) 6(1), 23–30 ISSN 1475-0708 23 DRUG EVALUATION Bogarin & Chanoine as an adjuvant to behavioral weight loss inter- in adolescents. Zhi et al. investigated 32 male ventions [10] . To date, the results are confl icting, and female obese adolescents from Caucasian, and metformin is not presently approved for the Black or Hispanic ethnicity [18] . Compared treatment of obesity in youths [11] . Orlistat is a with the placebo group, orlistat given at the gastrointestinal lipase inhibitor that decreases dose of 120 mg three-times daily for 7 days, the absorption of dietary fat. Data on the use increased fat excretion from 4.1 (6.1%) to of orlistat in adults have been reviewed in detail 15.9 g/day (27.1%). elsewhere [12] . The goal of this article is to pro- vide an overview on the pediatric aspects of the Pharmacokinetics effi cacy, safety and tolerability of orlistat. The pharmacokinetics of orlistat in adults has been described in detail elsewhere [19] . More Competitors than 97% of the drug is excreted in the feces, Orlistat (Xenical®, Roche, Basel, Switzerland) mostly as the parent compound (83%). Systemic is the only drug that acts locally in the gastro- absorption of orlistat is minimal. In the cir- intestinal tract by inhibiting intestinal lipases culation, orlistat is mostly bound to proteins and that is currently approved for the treatment (>99%) and is partially metabolized into two of obesity in adults and adolescents. Another pharmacologically inactive metabolites, M1, inhibitor of gastrointestinal lipases, cetilistat which results from hydrolysis of a β-lactone (Alizyme, Cambridge, UK), is presently under ring and M3, which results from the cleavage development [13] . To our knowledge, there is only of the N-formyl leucine side chain of M1. In one adult study published in abstract form that obese adolescents, mean plasma concentrations compares the effi cacy and tolerability of orlistat of orlistat measured at weekly intervals 4 h fol- and cetilistat in patients with Type 2 diabetes [14], lowing administration of the dose, a time cor- and no data on cetilistat in adolescents. responding to the expected peak concentration, ranged from 0.4 to 0.9 ng/ml. These values were Methods 24 to 33 ng/ml for M1 and 45 to 117 ng/ml Articles were identifi ed using the PubMed data- for M3 [18], and are similar to those observed base [101] . The keyword used was orlistat, and the in adults during continuous administration of search was limited to an age group of 0–18 years. orlistat at the recommended dose of 120 mg All published or in press articles listed in the three-times daily [20]. search until 1 September 2008 and written in English (n = 58) were screened for relevance to Clinical effi cacy the topic of this review. Additional reports were Orlistat has been studied extensively in adults, identifi ed from a review of references listed in and was shown to be more effective than placebo the reports. in promoting weight loss, as well as in improv- ing obesity-related risk factors in obese patients Pharmacological profi le with and without metabolic complications [12,21] . Mechanism of action By contrast, the number of studies assessing the Orlistat is a chemically synthesized derivative effi cacy of orlistat in children and adolescents is of lipstatin, a natural product of Streptomyces small. To our knowledge, no Phase I or II tri- toxytricini. Its empirical formula is C29H53NO5, als were performed in the pediatric age group. and its molecular weight is 495.7. Orlistat exerts Several Phase III trials were performed in chil- its therapeutic activity in the lumen of the stom- dren and adolescents, although only two were ach and small intestine by forming a covalent randomized and placebo-controlled. All pediat- bond with the active serine residue site of gastric ric studies used a dose of orlistat that was iden- and pancreatic lipases. This prevents hydrolysis tical to the adult recommendations (120 mg of the dietary triglycerides into absorbable free three-times daily). fatty acids and monoglycerides [15,16] . The calo- rie defi cit caused by decreased fat absorption is Anthropometry & thought to be the main mechanism by which body composition orlistat causes weight loss. Therefore, systemic Chanoine et al. performed a 52-week random- absorption of the drug is not needed for activ- ized, double-blind, placebo-controlled trial in ity. At the recommended therapeutic dose 539 adolescents with uncomplicated obesity of 120 mg three-times daily, orlistat inhibits (TABLE 1) [22]. Statistical analysis was performed dietary fat absorption by approximately 30% in on 533 patients who received at least one dose adults [17] . Similar fi ndings have been reported of the medication. A total of 76% of subjects 24 Therapy (2009) 6(1) future science group in 0.1 kg/m 0.1 in BMI had kg/m decreased by0.55 baseline with placebo. At the the of study, end the orlistat increased but group, back beyond in stable remained weeks, BMI After 12 group. maximal weeks by12 and greater in the orlistat weight in both treatment groups, which was mentation. There was adecrease in BMI and cation and weregiven amultivitamin supple- a mildly hypocaloric diet, behavioral modifi Caucasianwere of origin.