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PHARMACOKINETICS

Food Does Not Affect the Pharmacokinetics of Tesaglitazar, a Novel Dual Peroxisome Proliferator-Activated Receptor {alpha}/{gamma} Agonist

S. Samuelsson, MSc, S. Johansson, MSc, S. Halldórsdóttir, MSc, H. Stenhoff, MSc and K. P. Öhman, MD, PhD

From AstraZeneca R&D Mölndal, Mölndal, Sweden.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Tesaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) {alpha}/{gamma} agonist in development to treat lipid and glucose abnormalities associated with type 2 diabetes. This study evaluated the effects of food on tesaglitazar pharmacokinetics. In an open, randomized, 2-way crossover study, 20 healthy men received tesaglitazar 1 mg during fasting and after a high-fat, high-calorie breakfast. Blood samples were taken to assess pharmacokinetic variables. Systemic exposure to tesaglitazar was unaffected by food intake. Estimated ratios were 0.99 (90% confidence interval [CI], 0.94-1.04) for fed/fasted area under plasma concentration-time curve and 0.82 (90% CI, 0.78-0.86) for fed/fasted maximum plasma concentration (Cmax). Mean Cmax was ~18% lower (0.41 [95% CI, 0.38-0.43] versus 0.50 [95% CI, 0.47-0.53] µmol/L), and median time to Cmax was increased (2.00 vs 0.75 h) in fed versus fasted state. The median difference of tmax was 1.25 h (P = .0001, signed-rank test). Tesaglitazar was well tolerated. Tesaglitazar pharmacokinetics is unaffected by food intake, allowing once-daily administration of tesaglitazar with or without food in clinical practice.

Key Words: Tesaglitazar • PPAR • type 2 diabetes • food • pharmacokinetics

The prevalence of type 2 diabetes is increasing dramatically: approximately 200 million people are affected worldwide. Epidemiologic studies predict that 366 million will be affected by 2030.1 Although there is a genetic predisposition to type 2 diabetes, it is clear that a high-fat diet, sedentary lifestyle, and rising obesity rates have led to the increased prevalence of type 2 diabetes, metabolic syndrome, and other conditions associated with insulin resistance.

Diabetes is a major cause of cardiovascular disease, renal disease, blindness, and limb amputation. Although tight glycemic control alone can reduce the risk of many diabetic complications,2,3 it produces only modest reductions in the risk of coronary heart disease and stroke,3 which are the main causes of type 2 diabetes morbidity and mortality.4 These cardiovascular diseases are closely linked to the dyslipidemia that is characteristic of type 2 diabetes and the metabolic syndrome–low high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, and abnormalities in low-density lipoprotein (LDL) particle size.5 Although statin treatment can reduce the risk of cardiovascular disease in diabetic patients, even in the absence of elevated LDL cholesterol,6 statins have only modest effects on hypertriglyceridemia. As a result, many statin-treated diabetic patients fail to meet recommended lipid targets and remain at high risk of developing cardiovascular disease.7 Given the clear vascular benefits associated with tight control of glucose, cholesterol, and triglycerides, treatments that target all these abnormalities could be important in the management of type 2 diabetes and other conditions associated with insulin resistance.

Tesaglitazar is a novel, dual peroxisome proliferator-activated receptor (PPAR) {alpha}/{gamma} agonist being developed to target the lipid and glucose abnormalities associated with type 2 diabetes and metabolic syndrome.8 PPAR{alpha} activation promotes fatty acid catabolism in the liver and skeletal muscle, whereas PPAR{gamma} activation regulates fatty acid storage and improves glucose homeostasis in liver and pancreatic ß-cells.9 In a phase II clinical study with insulin-resistant, nondiabetic, dyslipidemic patients, tesaglitazar produced significant improvements in both lipid and glucose values and was well tolerated.10 In addition, the study showed a significant change in the distribution of lipoprotein particle sizes toward a larger, less atherogenic phenotype.

Pharmacokinetic evaluation of single oral doses of a liquid formulation of tesaglitazar in healthy male subjects has shown that the drug is rapidly absorbed (maximum plasma concentration reached within 1 hour) and that the bioavailability is complete, suggesting no, or negligible, first-pass metabolism.11 Tesaglitazar has been found to be a typical low-clearance drug with a small volume of distribution, a mean plasma clearance in healthy male subjects of 0.16 L/h, and a volume of distribution at steady state of 9.1 L. Excretion is mainly via urine, with an elimination half-life of approximately 40 to 60 hours. The excreted product is almost entirely the acyl glucuronide conjugate, which is the main tesaglitazar metabolite. The immediate-release tablet formulation used in this study dissolves rapidly and exhibits a similar pharmacokinetic profile to the oral solution (data on file; SH-SBC-0004).

The absorption of drugs may be affected by physiologic changes that occur in the gastrointestinal tract during fed and fasted states, such as changes in pH, gastric emptying, motility, intestinal transit time, and splanchnic blood flow.12,13 The interaction of these factors can result in decreases, increases, or delays in drug absorption, all of which can affect efficacy and safety. Fatty, high-calorie meals in particular are associated with decreased transit times and reduced absorption.14

The objective of this study was to evaluate the effect of food on the pharmacokinetics of single oral dose administration of tesaglitazar in healthy male subjects. The safety and tolerability of a single oral dose of tesaglitazar were also assessed.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Healthy, male subjects aged 20 to 50 years with clinically normal physical findings and laboratory values, a body mass index between 19 and 27 kg/m2, and who gave written, informed consent prior to enrollment, were eligible to participate in the study. Exclusion criteria included history of significant clinical illness in the 2 weeks preceding the study; history of a major systemic disorder; use of prescription or over-the-counter medicines (except paracetamol) in the preceding 2 weeks or 1 week, respectively; exposure to any other investigational drug or a change in smoking habit in the preceding 8 weeks; a history of drug or alcohol abuse; and blood donation within the 12 weeks preceding the study.

Study Design
This study (SH-SBC-0006) had a randomized, open, crossover design consisting of 2 study periods separated by a washout period of at least 12 days. Eligible subjects were randomized to 1 of 2 treatment sequences: fed-fasted or fasted-fed. During each study period, subjects received a single oral dose of tesaglitazar (GALIDA, AstraZeneca, Mölndal, Sweden) at approximately 8:00 AM. The first day in each period was spent at the clinic. Based on the plasma elimination half-life of tesaglitazar, the 2 doses were separated by at least 12 days. The study was approved by the ethics committee of the University of Gothenburg and by the Swedish Medical Product Agency and was conducted according to the Declaration of Helsinki and Good Clinical Practice.

All subjects were instructed to fast for 10 hours before their 2 clinic visits. On arrival at the clinic, an indwelling plastic cannula was inserted into a forearm vein for blood sampling. Blood samples were taken for routine laboratory tests, an electrocardiogram (ECG) was performed, and vital signs were recorded. Under fed conditions, the subjects received a high-fat, high-calorie breakfast consisting of 2 slices toast, 20 g butter, 2 eggs fried in butter, 2 slices bacon, a 120-g potato cake, 240 mL whole milk, and 175 mL orange juice.15 The meal contained about 150 kcal protein, 250 kcal carbohydrate, and 500 kcal fat and had to be consumed within 30 minutes. The subjects received two 0.5-mg immediate-release tesaglitazar tablets with 180 mL water within 5 minutes of completing the meal. Under fasted conditions, subjects received the same tesaglitazar dose without any food. No food was allowed for at least 4 hours postdose.

Blood (5 mL) was taken via the indwelling cannula 15, 30, and 45 minutes, and 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after administration of tesaglitazar, after which the cannula was removed. Further blood samples were taken by venipuncture at 24, 48, 72, 96, 120, 144, and 168 hours after administration of tesaglitazar. In both study periods, an ECG was performed and vital signs were recorded predose and at 1 hour and 72 hours postdose. A follow-up examination that included ECG, vital signs, and routine laboratory tests was performed on all subjects 11 to 14 days after the second tesaglitazar dose.

The safety and tolerability of tesaglitazar were assessed for all subjects who received at least 1 dose of assigned treatment. Adverse events were recorded from the first study day until the follow-up visit 11 to 14 days after the second dose of tesaglitazar. They were reported by subjects spontaneously and in response to an open question asked by the study personnel or were observed directly by study personnel.

Bioanalysis
Blood samples were centrifuged and the plasma stored at –18°C until analysis. The plasma concentration of tesaglitazar was determined using liquid-liquid extraction and reversed-phase liquid chromatography. After addition of the internal standard, AR-H045166XX-D5, extraction of the samples was performed at pH 2.0 using dichloromethane-hexane (45:55, volume/volume). After evaporation of the organic phase and redissolution, 60 µL was injected onto a chromatographic system consisting of an autosampler (Perkins-Elmer 200, Norwalk, Conn) equipped with a 200-µL loop and a quadrapole mass spectrometer (Applied Biosystem API-365, Concord, Ontario, Canada) with turbo ion-spray interface. The mobile phase was a mixture of 600 mL acetonitrile, 1.0 mL formic acid, 0.50 mL aqueous sodium acetate (0.044 M), and 20 mL aqueous ammonium acetate (0.10 mol/L), diluted to 1000 mL with water. Analytes were separated on a Zorbax SB-CN 3.5 µM 50 x 4.6-mm column (Agilent Technologies, Palo Alto, Calif) maintained at room temperature with a mobile phase flow rate of 0.75 mL/min. A guard column (Optiguard CN 15 x 1 mm; Optimize Technologies, Oregon City, Ore) was used to protect the analytical column.16

The absolute recovery (accuracy) for tesaglitazar was 96%, 101%, and 99% at 5000, 620, and 10 nmol/L, respectively. The intraday precision (CV%) was 1.5%, 1.2%, and 5.2% (n = 8) at 5000, 620, and 10 nmol/L, respectively. The lower limit of quantification was 3.0 nmol/L (CV <20%), and the upper limit of quantification was 5000 nmol/L. The absolute recovery for the internal standard, AR-H045166XX-D5, was 96%. The between-day precision (CV%) for tesaglitazar was 2.7% (n = 30) with an accuracy of 98%.

The multiple reaction monitoring transitions between the disodium precursor and disodium product ions of tesaglitazar (mass-to-charge ratio [m/z] 453-> m/z 267) and AR-H040156XX-D5 (m/z 458 -> m/z 272) are used for quantification, respectively.

Pharmacokinetic Analysis
Pharmacokinetic variables were estimated by noncompartmental methods using WinNonlin Professional software (version 3.1, Pharsight Corp, Mountain View, Calif). The following pharmacokinetic variables were calculated for each subject: the observed maximum plasma concentration (Cmax); the time to reach the observed maximum plasma concentration (tmax); the area under the plasma concentration-time curve (AUCt) from time zero to the last quantifiable concentration (Clast), calculated by the log-linear trapezoidal method; the total area under the plasma concentration-time curve (AUC), calculated by AUCt + AUCt-{infty}, where AUCt-{infty} is the residual area under the plasma concentration-time curve extrapolated by Clast, predicted/{lambda}z (/{lambda}z is the elimination rate constant estimated from individual linear regression of the terminal part of the log-concentration versus time curve); and the apparent terminal half-life (t1/2), calculated by ln2/{lambda}z. The actual sampling times were used in the calculations.

Statistical Analysis
Twenty subjects were included to ensure that at least 16 provided evaluable data. This sample size calculation was based on a standard deviation for the log-transformed AUC of 0.18 and assumed a food effect of less than 5%.

Only subjects who completed both study periods per protocol were included in the pharmacokinetic analysis. Descriptive statistics were calculated for all pharmacokinetic variables. The pharmacokinetic variables AUC and Cmax were log-transformed and then analyzed using a mixed model analysis of variance (ANOVA) with fixed effects for sequence, period, and treatment (fed or fasted) and a random effect for subject. Estimates and 90% confidence intervals (CIs) of the true ratio of geometric means were determined for AUC(fed)/AUC(fasted) and Cmax(fed)/Cmax(fasted). The 2 regimens were considered equivalent if the CI fell within 0.80 to 1.25 for AUC and 0.70 to 1.43 for Cmax. These CIs were based on those recommended by the Food and Drug Administration at the time the study was designed.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Demographics
Twenty healthy, male, white subjects between the ages of 19 and 35 years were randomized into the study. Demographic data, including body mass index, height, and weight, were similar in the 2 groups defined by treatment sequence (Table I).


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  		Table I Demographic Characteristics of the Study Population

 

Two subjects were excluded from the pharmacokinetic evaluation: 1 subject because of a protocol violation (not fasted during the fasting period), and 1 subject discontinued the study because of a common cold after receiving 1 dose of tesaglitazar.

Pharmacokinetics
The mean plasma concentrations of tesaglitazar versus time following administration of tesaglitazar 1 mg are shown in Figure 1 (0-168 hours postdose) and Figure 2 (0-24 hours postdose). There were no apparent differences in the plasma profiles between the fed and fasted states, with similar absorption and disposition. tmax was reached slightly later in the fed state (2.0 vs 0.75 hours in the fasted state). The median difference of tmax was 1.25 hours (P = .0001, signed-rank test).


Figure 1
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  		Figure 1. Mean plasma tesaglitazar concentration versus time profiles from healthy male subjects up to 168 hours following 1-mg single-dose administration.

 

Figure 2
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  		Figure 2. Mean plasma tesaglitazar concentration versus time profiles in healthy male subjects up to 24 hours following 1-mg single-dose administration.

 
The exposure to tesaglitazar was similar after administration under fed and fasted conditions (AUC: 13.1 [95% CI, 11.8-14.5] vs 13.2 µmol·h/L [95% CI, 11.9-14.6]; AUCt: 12.5 [95% CI, 11.4-13.8] vs 12.6 µmol·h/L [95% CI, 11.4-13.8], respectively) (Table II). Compared with the fasted state, the Cmax of tesaglitazar in the fed state was 18% lower (0.41 [95% CI, 0.38-0.43] vs 0.50 [95% CI, 0.47-0.53] µmol/L). The elimination half-life of tesaglitazar was similar under both fasted and fed conditions (~37 hours; range, 25.1-53.3 hours).


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  		Table II Tesaglitazar Pharmacokinetic Variables in Healthy Male Subjects After 1-mg Single-Dose Administration (n = 18)

 

The estimated fed/fasted ratios of AUC and Cmax showed that there were no clinically significant differences between the 2 regimens (Table II). The fed/fasted ratios for AUC and AUCt were 0.99 (90% CI, 0.94-1.04) and 1.00 (90% CI, 0.95-1.04), respectively, both well contained within the prespecified equivalence interval of 0.80 to 1.25. Although the Cmax for tesaglitazar was slightly lower in the fed state than in the fasted state, the estimated fed/fasted ratio for Cmax was 0.82 (90% CI, 0.78-0.86), which also fell within the prespecified equivalence interval of 0.70 to 1.43. There was no sequence effect (fed-fasted vs fasted-fed) on any of the pharmacokinetic variables.

Safety Evaluation
Tesaglitazar (1 mg) was well tolerated, and there were only few adverse events reported, including respiratory infection and headache. No serious adverse events were reported. No clinically significant abnormalities in laboratory values, vital signs, or physical examinations were observed.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
This crossover study compared the pharmacokinetics of a single oral dose of tesaglitazar in healthy male subjects when administered after a high-fat, high-calorie breakfast and when given in a fasted state. The fat and calorie composition of the break-fast administered was typical of food interaction studies and was used to provide maximal stress to gastric emptying. The overall systemic exposure to tesaglitazar, as assessed by AUC and AUCt, was not affected by food intake, although absorption was slower in fed subjects; tmax was delayed, and Cmax was reduced by approximately 18% compared with the fasted state. The differences in tmax and Cmax are not considered to be of clinical significance. The elimination half-life of approximately 37 hours was similar under both fed and fasted conditions.

In this study, the delayed absorption of tesaglitazar in fed subjects did not influence the amount of drug being absorbed; the overall exposure was the same under both fed and fasted conditions. Similar delays in absorption are very common when drugs of any class are taken with food and are mostly associated with the gastric emptying process. For example, delayed absorption has been described for the thiazolidinediones (PPAR{gamma} agonists), rosiglitazone17 and pioglitazone.18 These absorption delays have been attributed to delayed gastric emptying and changes in gastric and intestinal pH,17 both of which have been well described.12-14

In most cases in which concomitant food intake delays drug absorption but does not affect the total amount of drug absorbed, the delay is not clinically significant. Clinical significance is only likely when high plasma concentrations of the drug are required quickly, such as with antibiotic treatment, or if the drug has a narrow therapeutic index and a high plasma concentration peak could pose a safety problem.13 For the thiazolidinediones, however, the maximal therapeutic effect is reached after several weeks of chronic treatment,19 thus reducing the likelihood that the delayed absorption with a flatter plasma concentration profile is relevant. Similarly, the pharmacodynamic effects of tesaglitazar on blood glucose and the plasma lipid profile are based on normalization of insulin resistance at the receptor level, and long-term treatment is therefore required to produce a therapeutic effect. As the extent of absorption of tesaglitazar was not affected by concomitant food intake and only a minor delay in absorption after food intake was observed, tablets can be taken with or without food, thus simplifying drug administration.

Tesaglitazar was well tolerated in this study. The adverse events reported (headache and respiratory infection) were typical of those reported by healthy subjects. There were no clinically relevant changes in pulse rate, blood pressure, or ECG variables during the study.

In conclusion, the pharmacokinetics of tesaglitazar was unaffected by food. When tesaglitazar was administered with a high-fat, high-calorie breakfast, absorption was slower and Cmax decreased approximately 18% compared to the fasted state. Tesaglitazar was well tolerated under both fed and fasted conditions in healthy male subjects. A previous study has suggested that tesaglitazar is suitable for once-daily dosing during long-term treatment,11 and this study shows that the drug can be taken independently of food.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors thank principal investigator Dr Kajs-Marie Schützer. This study was approved by the ethics committee of the University of Gothenburg and the Swedish Medical Product Agency.

DOI: 10.1177/0091270006290335


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27: 1047-1053.[Abstract/Free Full Text]

2. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352: 854-865.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352: 837-853.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

4. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339: 229-234.[Abstract/Free Full Text]

5. Grundy SM. Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation. 1997;95: 1-4.[Free Full Text]

6. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364: 685-696.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

7. Pearson TA, Laurora I, Chu H, Kafonek S. The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med. 2000;160: 459-467.[Abstract/Free Full Text]

8. Cronet P, Petersen JF, Folmer R, et al. Structure of the PPAR alpha and gamma ligand binding domain in complex with AZ 242: ligand selectivity and agonist activation in the PPAR family. Structure (Camb). 2001;9: 699-706.

9. Ferre P. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes. 2004;53(suppl 1): S43-S50.[Abstract/Free Full Text]

10. Fagerberg B, Edwards S, Halmos T, et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia. 2005;48: 1716-1725.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Ericsson H, Hamren B, Bergstrand S, et al. Pharmacokinetics and metabolism of tesaglitazar, a novel dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, after a single oral and intravenous dose in humans. Drug Metab Dispos. 2004;32: 923-929.[Abstract/Free Full Text]

12. Anderson KE. Influences of diet and nutrition on clinical pharmacokinetics. Clin Pharmacokinet. 1988;14: 325-346.[Web of Science][Medline] [Order article via Infotrieve]

13. Williams L, Hill DP Jr, Davis JA, Lowenthal DT. The influence of food on the absorption and metabolism of drugs: an update. Eur J Drug Metab Pharmacokinet. 1996;21: 201-211.[Web of Science][Medline] [Order article via Infotrieve]

14. Williams L, Davis JA, Lowenthal DT. The influence of food on the absorption and metabolism of drugs. Med Clin North Am. 1993;77: 815-829.[Web of Science][Medline] [Order article via Infotrieve]

15. Guidance for Industry. Food-effect bioavailability and bioequivalence studies. Available at: http://www.geocities.com/HotSprings/Spa/6896/1719dft.pdf. Accessed April 19, 2006.

16. Svennberg H, Bergh S, Stenhoff H. Factorial design for the development of automated solid-phase extraction in the 96-well format for determination of tesaglitazar, in plasma, by liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2003;787: 231-241.[Web of Science][Medline] [Order article via Infotrieve]

17. Freed MI, Allen A, Jorkasky DK, DiCicco RA. Systemic exposure to rosiglitazone is unaltered by food. Eur J Clin Pharmacol. 1999;55: 53-56.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

18. Hanefeld M. Pharmacokinetics and clinical efficacy of pioglitazone. Int J Clin Pract Suppl. 2001; 19-25.

19. Diamant M, Heine RJ. Thiazolidinediones in type 2 diabetes mellitus: current clinical evidence. Drugs. 2003;63: 1373-1405.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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