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Journal of the American College of Nutrition, Vol. 22, No. 5, 357-362 (2003)
Published by the American College of Nutrition

Original Research

The Effect of Short-Term (21-Day) Orlistat Treatment on the Physiologic Balance of Six Selected Macrominerals and Microminerals in Obese Adolescents

Jianguo Zhi, PhD, Rema Moore and Linda Kanitra

Hoffmann-La Roche Inc., Nutley, New Jersey

Address reprint requests to: Jianguo Zhi, Ph.D., Department of Clinical Pharmacology, Hoffmann-La Roche, Inc., 340 Kingsland St., Nutley, NJ 07110-1199. E-mail: jianguo.zhi{at}roche.com


   ABSTRACT
TOP
 FOOTNOTES
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Objectives: Orlistat is a gastrointestinal lipase inhibitor used to reduce dietary fat absorption and could be used to treat overweight and obesity in adolescents. The primary objective was to assess whether orlistat has an effect on the physiologic balance of three macrominerals (calcium, phosphorus and magnesium) and three microminerals (iron, zinc and copper).

Methods: This was a 21-day, double-blind, randomized, parallel-group, placebo-controlled mineral balance study conducted in adolescent obese volunteers (BMI >= 85th percentile, adjusted for age and gender). Subjects were maintained on a hypocaloric diet with a normal daily mineral content in both treatment groups and received oral treatment with orlistat 120 mg (n = 16) or placebo (n = 16) three times daily for 21 days. Following a 14-day equilibration period, balances for calcium, phosphorus, magnesium, iron, copper and zinc were measured for days 15–21. Serum and urine electrolytes were also measured at baseline and at the end of treatment.

Results: On average, orlistat inhibited dietary fat absorption by ~27%. This degree of dietary fat inhibition caused no significant changes in mineral balance between orlistat and placebo groups. In addition, serum and urine electrolytes (sodium and potassium) as well as urinary creatinine excretion were not affected by orlistat treatment. Orlistat was well tolerated; adverse events occurred mainly in the gastrointestinal tract and were of mild or moderate intensities.

Conclusions: Administration of orlistat had no significant effect on the balance of six selected minerals in adolescent obese patients.

Key words: dietary fat inhibition, orlistat, mineral absorption, adolescents


   INTRODUCTION
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Childhood overweight, defined by at least the 85th percentile of body mass index (BMI), continues to increase, particularly among Hispanics and African Americans and the present prevalence estimate is 22% in the US [1–2]. Childhood obesity is now recognized as a chronic health problem that predisposes to obesity in adulthood. It is also associated with hypertension, dyslipidemias, abnormal insulin and other risk factors commonly associated with adult obesity [3]. Treatment of childhood obesity may prevent or ameliorate adult obesity and associated health risks. Unfortunately, currently there is no therapeutic agent approved for treatment of childhood obesity.

Orlistat is a novel nonsystemically acting antiobesity agent that inhibits the activity of gastrointestinal lipases and has been shown to reduce the absorption of dietary fats by ~30% [4]. By effectively limiting dietary fat absorption, it promotes weight loss and maintenance of lost weight in overweight and obese patients. Unlike other medications previously approved for the treatment of adult obesity, orlistat does not act on the central nervous system, and it is not significantly absorbed into the systemic circulation. Major adverse events reported with orlistat are predominantly gastrointestinal and related to the mechanism of action of the drug (increasing fecal fat excretion). By balancing a benefit-risk ratio, it is potentially advantageous to the treatment of childhood obesity with orlistat.

Minerals have many essential roles, some of which are also involved in the growth process. Although human gastrointestinal functional development is generally complete by the time of weaning in early childhood [5] and functionality is expected to be similar to adult in the age group proposed for this study (12 to 16 years of age), adolescents incorporate twice the amount of essential minerals such as calcium, iron, zinc and magnesium into their bodies during the years of their growth spurt than at other times. It is therefore important to confirm that mineral balance is maintained, even though there is no plausible mechanism for a mineral imbalance during orlistat treatment in adolescents. The inhibition of dietary fat absorption caused by orlistat increases fecal fat excretion of triacylglycerol and other glycerol-based lipid with esterified long chain fatty acid, which could not theoretically promote the formation of insoluble mineral soaps (only with free fatty acids) and adversely affect mineral absorption and balance. It has recently been demonstrated that orlistat did not affect the extent of mineral absorption in adults [6].

Therefore, the primary aim of this study was to assess the effect of orlistat (120 mg tid) treatment on the balance (dietary intake minus urinary and fecal excretion) of selected minerals in obese adolescents, 12 to 16 years of age. Secondary objectives were to 1) assess the effect of orlistat treatment on plasma and urine sodium and potassium, 2) evaluate the extent of fecal fat excretion induced by orlistat and 3) measure the plasma levels of orlistat and its degradation metabolites in this population.

Due to the variation in transit time through the gut, a method is required to make no assumptions about day to day variations in bowel habit, is easy to perform and is practical and accurate. The continuous administration of radio-opaque pellets satisfies these criteria, and the method of Cummings et al. [7–9] was used in this study to correct mineral fecal excretions by fecal recovery of radio markers.


   MATERIALS AND METHODS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects and Ethics
This double-blind, randomized, parallel-group, placebo-controlled study was conducted at one research center in the United States (PPD Development, Inc., Austin, TX) in June of 2000. Thirty-two obese (BMI >= 85th percentile, adjusted for age and gender), otherwise healthy, male and female volunteers, 12 to 16 years of age were recruited into the study. Every attempt was made to include female subjects of childbearing potential, who were not menstruating nor expected to menstruate during any part of the sample collection period (days 15 to 21). This was due to the fact that in this study, days 15 through 22 were critical for the mineral balance segment of the assessment. Samples (urine and fecal) collected over that period were analyzed for mineral content including iron that could be affected by menstruation.

The protocol was approved by the local ethics committee and the trial was conducted in accordance with the Declaration of Helsinki (as amended in Tokyo, Venice and Hong Kong). All volunteers provided written informed consent prior to study participation.

Procedures
A pre-study medical history was taken and a physical examination (also repeated on day 22) was performed within three week before the study. Volunteers who met the inclusion criteria were randomly assigned to receive either 120 mg orlistat (n = 16) or matching placebo (n = 16) three times a day for 21 days in conjunction with a daily menu that repeated every three days. All subjects stayed at the CPU under supervision of center’s staff, and they followed the same daily routine throughout the 21-day period. The standardized three-day menu cycle of the hypocaloric diet (~18% and 28–40% lower than average energy allowance for female and male adolescents, respectively) was based on a food composition table (Table 1) and prepared by a dietitian of the clinical research center. Approximately 30% of energy was from fat.


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  		Table 1. Calories, total fat, and minerals of the diet (three daily menus)1

 
The dietary content of the minerals under consideration in this study (calcium, phosphorous, magnesium, iron, copper and zinc) was provided to meet the US Dietary Reference Intakes for children [10]. However, further differentiation of age and gender was not considered due to potential complexity for the trial and data analysis. Subjects were permitted to drink deionized water ad libitum between meals.

To allow calculation of fecal recovery of minerals all subjects received quantitative fecal markers consisting of one capsule containing 10 small radiopaque cylindrical pellets (Konsyl Pharmaceuticals Inc., Fort Worth, TX) concomitant with the test medication (orlistat 120 mg or placebo three times a day). Orlistat (Xenical®) and matching placebo capsules were manufactured by Hoffmann-La Roche, Nutley, NJ. The test medication was administered with 100 mL of water with the three main meals. Use of any other medication or alcohol was prohibited during the study, with the exception of medication required to treat adverse events or intercurrent illness.

Adverse events were monitored throughout the trial. Vital signs and standard laboratory tests (hematology, clinical chemistry and urinalysis) were performed at screening, before study entry on day 1 and at the end of the study (follow-up).

Sample Collections
The initial 14 days of the study were considered to be an equilibration period that allowed gastrointestinal clearance of unabsorbed minerals from the prestudy diet, homogeneous distribution of radiopaque markers in the gastrointestinal tract and steady-state fecal fat excretion by orlistat. Mineral balance was assessed on days 15–21 (the balance period).

Fecal collection commenced on the morning of day 10 and continued through to the morning of day 22, over 24-hour periods. At the end of the 24-hour period, all fecal samples collected within that time were frozen immediately and stored at -20°C or lower. Commencing on the morning of day 10 until the morning of day 22, all urine passed was collected in 24-hour intervals. The samples were collected and refrigerated at 4°C until the end of the collection interval. The entire 24-hour sample was then frozen in an upright position at -20°C or lower. Fecal and urine samples from days 15–21 were stored for subsequent analysis of minerals, urine creatinine, and fecal fat.

Pre-dose on the morning of days 1 and 22, a urine sample was collected from fasted subjects for the determination of sodium and potassium. Blood samples for determination of plasma concentrations of orlistat and its metabolites (M1, the ß-lactone ring hydrolysis product and M3, the subsequent metabolite after cleavage of the N-formyl leucine side chain) were taken four hours (expected peak time) after the second drug administration (mid-meal during lunch) on days 1, 7, 14 and 21.

Assays
Each daily fecal collection (days 10–22) sample was examined by flat plate X-ray to determine the number of radio-opaque markers present. The fecal content of mineral and fat was normalized using the method of Cummings et al. to accurately determine mineral balance [7–9] and fecal fat excretion collected on a 24-hour interval.

All fecal samples were assayed for mineral and fat content by titrimetry (Medi-Lab BioProfil, Copenhagen, Denmark). For each mineral, the assay for mineral content was similar for meals, urine and fecal samples. With the exception of phosphorus that required UV-photometry after wet-ashing, all other five minerals were measured by flame atomic absorption spectroscopy [11]. Meal and fecal samples were subject to destruction before assay. For copper in meal and fecal samples, the assay required slight modification called electrothermal atomic absorption spectroscopy. The accuracy and precision of measurements for minerals and biochemical anylates were determined; precision ranged from 2% to 20%.

Fecal fat was determined using a standard approach [12]. Sodium, potassium and creatinine were determined by standard methods used for safety assessments. Serum sodium and potassium were analyzed with ion selective electrodes. Urinary sodium and potassium were analyzed by flame photometry; urine creatinine was assayed by Central Lab, LabCorp.

Plasma concentrations of orlistat and its metabolites (M1 and M3) were measured with a validated high pressure liquid chromatography method. The limit of quantitation was 0.2 ng/mL for orlistat, 0.32 ng/mL for M1 (Ro 42-3988) and 10 ng/mL for M3 (Ro 42-2556).

Statistical Analyses
Mineral balance was calculated by subtracting fecal and urinary mineral content from dietary mineral intake. The fecal mineral content was normalized by the ratio of the actual number of radio-opaque markers counted in fecal samples to the expected number excreted. No correction in mineral balance was made for unaccounted miscellaneous mineral losses from sweat, semen, menses and so on.

Mineral balance parameters were calculated separately for each subject using the average of the last seven days (days 15–22) of treatment. Descriptive statistics were calculated for each treatment group, and 95% confidence intervals were used to estimate differences between treatment groups separately for each of the six minerals. For sodium, potassium, creatinine and fecal fat, as well as plasma concentrations of orlistat and its metabolites M1 and M3, summary statistics are provided.

A sample size of 32 was initially chosen based on an anticipated dropout rate of 15% to ensure 26 subjects were evaluable.


   RESULTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
Thirty-two subjects, 16 in orlistat and 16 in placebo treatment groups, were enrolled in the study. The two treatment groups were balanced with respect to demographics (Table 2). Overall, 44% and 63% of subjects were non-Caucasian in the placebo and orlistat treatment groups, respectively. Mean BMI was 34 kg/m2 in both treatment groups; seven and three subjects in placebo and orlistat treatment groups, respectively, had a BMI < 30 kg/m2. At the end of trial (three weeks treatment), weight loss was 7.0% and 7.8% of the initial body weight for orlistat and placebo groups, respectively.


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  		Table 2. Summary of demographic data at baseline

 
Two subjects, one from each treatment group, were discontinued prior to study completion. Of the 30 subjects who completed the study, three did not have their fecal samples available during the balance period, and, thus, they were excluded from further analysis of fecal sample related parameters. In the remaining 27 subjects who had at least 10% fecal radio-markers recovered, no significant difference between the placebo and orlistat groups (0.69 and 0.70, respectively) was seen in the observed-to-expected radiopaque marker ratio during the balance period.

During the balance period, days 15–21, average dietary fat intake was ~59 g/day in both groups (Table 3). Mean fecal fat content was ~16 g/day in the orlistat-treated group and ~4 g/day in the placebo-treated group; fat was excreted fourfold more in the orlistat-treated group than that in the placebo-treated group.


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  		Table 3. Dietary fat excretion during seven days of treatment with orlistat (120 mg) or placebo three times daily1

 
This magnitude of dietary fat inhibition yielded no significant effect on apparent balance for most of the minerals studied (calcium, phosphorus, magnesium, zinc and copper), which was expected to be neutral (Table 4). Regarding iron, both treatment groups had a slight decrease in mean iron balance, which appeared to be consistent with those seen in a previous orlistat mineral balance study conducted in adult subjects [6]. However, between the two treatment groups, the decrease in mean iron balance was similar: placebo, -40.4 µmol/24 hour or 2.2 mg/day; orlistat, -43.3 µmol/24 hour (excluding an outlier at -299) or 2.4 mg/day, about 11% to 12% of daily dietary intake, respectively.


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  		Table 4. Mineral balance during seven days of treatment with orlistat (120 mg) or placebo three times daily

 
In an attempt to interpret the decrease with respect to iron balance, an ad hoc analysis of variance for the association of menstrual cycles and iron balance was performed in 1) male (N = 11) versus female (N = 16) and 2) females menstruating (N = 4) versus non-menstruating (N = 12). There was no apparent association between gender and iron balance. Unfortunately, a test of the potential difference between female subjects with and without menstruation could not be made due to small sample size, even when the orlistat and placebo treatment groups were combined. Therefore, the likely explanation for slight negative iron balance in both treatment groups can be attributed to 1) intrinsically low bioavailability of iron absorption (5%–15%) from food intake by subjects without iron deficiency, 2) variable biliary excretion (only route for iron excretion), 3) assay variability (10% for both diet content and fecal content) and 4) error in calculation of food content (a twofold day-to-day variation shown in Table 1).

During the balance period, urinary creatinine excretion was unaffected by orlistat treatment. Daily mean +/- SE (95% CI) urinary creatinine excretion was 1378 ± 96 (1182–1575) and 1480 ± 95 (1284–1575) mg/day in the placebo and orlistat treatment groups, respectively. Likewise, electrolytes were not affected by orlistat treatment. At the end-of-treatment, serum and urine sodium and potassium did not differ between treatment groups (Table 5).


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  		Table 5. Effect of treatment with orlistat (120 mg) or placebo three times daily with a hypocaloric diet for 21 days on serum and urine electrolytes in obese adolescents1

 
Mean four-hour plasma concentrations (Cmax) for orlistat ranged from 0.428 to 0.869 ng/mL during the study, while mean Cmax for M1 and M3 ranged from 24.2 to 32.7 ng/mL and from 44.8 to 117 ng/mL, respectively (Table 6). Not every subject had measurable orlistat in all four plasma samples.


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  		Table 6. Plasma concentrations (Cmax) for orlistat and its degradation metabolites M1 and M3

 
Orlistat was well tolerated during the 21-day study period. Fifteen orlistat-treated subjects and 13 placebo-treated subjects reported at least one adverse with a total of 47 events reported with placebo and 66 reported with orlistat. The incidence of adverse events was similar in orlistat and placebo groups for most body systems. However, a higher proportion of patients in the orlistat group had adverse events in the gastrointestinal system (orlistat, 25 events in 13 patients; placebo, 13 events in 9 patients). The only significant difference between the two treatment groups was the incidence of fatty/oily stool (44% of the orlistat subjects and no placebo subjects), a known commonly occurring side effect of orlistat. Adverse events (such as abdominal pain and fatty/oily stool) were of mild or moderate intensity and resolved without any subject’s discontinuing treatment. No serious adverse events were reported, and no clinically significant findings were noted in vital signs and in laboratory tests parameters.


   DISCUSSION
 
Presented here is a mineral balance study that was conducted as part of the orlistat pediatric program. The goal of this study was to clarify any potential effects that orlistat might have on growth and development in the adolescent population. Towards this end, whether orlistat has any negative effects on key measures of mineral balance including calcium, magnesium, iron, phosphorus, zinc and copper was examined. A total of 32 subjects (enrolled in the hope of obtaining 26 evaluable subjects) to be treated with orlistat or placebo for 21 days in an in-patient metabolic ward setting was planned. Thirty adolescent subjects completed the 21-day study; 27 subjects were evaluable for mineral balance, meeting the objective of 26 evaluable subjects.

The study also replicates an adult mineral balance study [6] where the no-effect conclusion was based on 95% CIs. The study in adults had 14 subjects per treatment group and a fecal marker recovery of observed to expected ratio with a mean of 0.92 (range 0.50–1.28) for placebo-treated subjects and mean of 0.95 (range 0.49–1.37) for orlistat-treated subjects. Mean fecal marker recovery in this study was slightly lower with 0.70 for placebo-treated subjects and 0.69 for orlistat-treated subjects. However, this lower recovery was balanced between the treatment groups and is likely to be due to the difficulty of conducting this type of study in an adolescent population.

As is similar to that found from previous studies in adults [4], the amount of fecal fat in this study was significantly increased during treatment with orlistat, resulting in a reduction of dietary fat absorption efficiency by ~30%. This magnitude of inhibition of dietary fat absorption by orlistat administered for 21 days did not alter mineral balance in comparison with placebo treatment. However, it remains to be seen whether a longer time span may affect the mineral balance (e.g., calcium, phosphorus) negatively. It is possible that an impairment of the vitamin D absorption and metabolism due to the fat malabsorption may over time induce a secondary hyperparathyreoidism and pre-osteomalacia.

Due to the limitation of study complexity, this study did not measure the calcium and vitamin D metabolism such as measurement of serum PTH, 25-OH-Vitamin D and markers of bone resorption and bone formation (osteocalcin, pyridinolin cross links). Furthermore, DXA measurements of bone density would have added further data. These aspects are being investigated in a long-term (one-year) efficacy study in adolescent obese patients. In a completed adult study, one year of treatment with orlistat induced a relative increase in bone turnover in favor of resorption, possibly due to malabsorption of vitamin D and/or calcium. However, no changes in bone mass or density were seen after one year of orlistat treatment apart from those explained from the weight loss itself. Thus a one year orlistat treatment seems safe from a "bone preserving" point of view [13].

There were no changes in serum concentrations as well as urinary excretion of sodium and potassium during the 21-day course of the study in either treatment group. In addition, there was no clinically significant difference between the two treatment groups in urinary creatinine excretion during the study. Plasma concentrations of orlistat and metabolites were variable and somewhat lower than those found in adults at the same dose level [14]. This suggests that orlistat systemic exposure is not enhanced in the adolescent population.

Orlistat was well tolerated; adverse events were of a mild or moderate intensity, and the majority of these events were gastrointestinal. The only noted difference between the two treatment groups was the incidence of fatty/oily stool (placebo, no subjects; orlistat, 44%), a known, commonly occurring side effect of orlistat treatment.

In summary, this study provides evidence that in obese adolescents, orlistat has low systemic exposure, significantly inhibits dietary fat absorption, has no significant effects on either mineral absorption or mineral balance and is well tolerated. These results are consistent with those seen in obese adults [4,6,14].


   ACKNOWLEDGMENTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors would like to gratefully acknowledge the contributions of Dr. A. L. Laurent for overseeing the conduct of this study at CPU, and G. Smoluk, K. Klamerus and R. Guerciolini, for the design and execution of the protocol.


   FOOTNOTES
TOP
 FOOTNOTES
ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
This study was fully funded by Hoffmann-La Roche Inc., Nutley, New Jersey.

Received June 19, 2002. Accepted February 7, 2003.


   REFERENCES
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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  3. Deckelbaum RJ, Williams CL: Childhood obesity: the health issue.Obes Res4(Suppl) :239S –243S,2001 .
  4. Zhi J, Melia AT, Guerciolini R, Chung J, Kinberg J, Hauptman JB, Patel IH: Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers.Clin Pharmacol Ther56 :82 –85,1994 .[Medline]
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  6. Pace DG, Blotner S, Guerciolini R: Short-term orlistat treatment does not affect mineral balance and bone turnover in obese men.J Nutr131 :1694 –1699,2001 .[Abstract/Free Full Text]
  7. Cummings JH, Jenkins DJ, Wiggins HS: Measurement of the mean transit time of dietary residue through the human gut.Gut17 :210 –218,1976 .[Abstract/Free Full Text]
  8. Andersson H, Navert B, Bingham SA, Englyst HN, Cummings JH: The effects of breads containing similar amounts of phytate but different amounts of wheat bran on calcium, zinc and iron balance in man.Brit J Nutr50 :503 –510,1983 .[Medline]
  9. Cummings JH, Beatty ER, Kingman SM, Bingham SA, Englyst HN: Digestion and physiological properties of resistant starch in the human large bowel.Brit J Nutr75 :733 –747,1996 .[Medline]
  10. Food and Nutrition Board: "Dietary Reference Intakes: Elements ." Washington DC: National Academy Press,2001 .
  11. Schelkop GM, Milne DB: Wet microwave digestion of diet and fecal samples for inductively coupled plasma analysis.Anal Chem60 :2060 –2062,1988 .[Medline]
  12. Van de Kramer JH, et al.: Titrimetri.J Biol Chem177 :347 ,1949 .[Free Full Text]
  13. Gotfredsen A, Westergren Hendel H, Andersen T: Influence of orlistat on bone turnover and body composition.Int J Obes Relat Metab Disord25 :1154 –1160,2001 .[Medline]
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