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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland.
Address for reprints: Paul L. M. van Giersbergen, PhD, Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Gewerbestrasse 18, 4123 Allschwil, Switzerland.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Bosentan • endothelin receptor antagonist • Caucasian and Japanese subjects • pharmacokinetics
The single-dose pharmacokinetics of bosentan have been described previously and were recently reviewed.6 In brief, bosentan shows dose-proportional pharmacokinetics up to single oral doses of 600 mg and an oral bioavailability of 50%. After intravenous administration of a 250-mg dose, a volume of distribution of 18 L and a clearance of 8.2 L/h were determined.7 The apparent half-life after oral administration of 125 mg was 5.4 hours.8 Bosentan is metabolized by CYP2C9 and CYP3A4 to 3 metabolites,9 of which only Ro 48-5033 binds to endothelin receptors, albeit with a 2-fold lower affinity than bosentan (Actelion Pharmaceuticals, data on file). Biliary excretion of the metabolites is the main route of elimination.9
The pharmacokinetics of bosentan have mainly been investigated in Caucasian subjects. However, it is well known that drug disposition and response may differ between ethnic groups. The molecular basis for these differences is not always well understood but may include genetic variations in drug-metabolizing enzymes, drug transporters, drug receptors or other proteins.10 We investigated the pharmacokinetics of 4 different single doses of bosentan in both Caucasian and Japanese subjects in support of the clinical development of bosentan in Japan. Because PAH is a disease that is more frequent in females, both male and female subjects were included. Placebo was included to avoid bias in the assessment of tolerability and safety of bosentan in the 2 ethnic groups.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study Design
This was a monocenter, double-blind, placebo-controlled, single-ascending dose, 5-way crossover study in 2 groups of 10 subjects. Each subject was given 4 different doses of bosentan (Tracleer; Ro 47-0203) and placebo during 5 consecutive treatment periods with a washout of 4 to 14 days between periods. The doses of bosentan investigated were 31.25, 62.5, 125, and 250 mg, and these were given in an ascending order. Placebo was randomized in between. On all days, the meals were standardized, and throughout the 5 treatment periods, the meals were of the same composition. Japanese subjects received typical Japanese food, whereas European food was served to the Caucasian subjects. In each period, blood samples of 4 mL were collected into EDTA-containing tubes by venipuncture just before drug administration and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hours thereafter. Plasma was separated and stored at -20°C pending analysis.
Tolerability and safety were evaluated by a physical examination, adverse events, vital signs, electrocardiogram (ECG), and clinical laboratory tests at screening as well as during and at the end of the study.
Bioanalytical Methods
Plasma samples obtained were analyzed for bosentan and Ro 48-5033. A liquid chromatography assay method with tandem mass spectrometry detection was used, the details of which have been described previously.11 The limit of quantification was 1.0 ng/mL for bosentan and 2.0 ng/mL for the hydroxy metabolite. The day-to-day coefficients of variation varied between 3.8% and 7.1% for bosentan and Ro 48-5033, and inaccuracy was <8%.
Pharmacokinetic and Statistical Evaluations
The pharmacokinetic evaluation for bosentan and Ro 48-5033 was performed with model-independent methods12 using the WinNonlin software (version 3.3; Pharsight Corp., Mountain View, Calif). The peak plasma concentration (Cmax) and the time to Cmax (tmax) were read directly from the concentration-time data. The area under the plasma concentration-time curve (AUC) was estimated with use of the linear trapezoidal rule and extrapolation to infinity with the terminal elimination rate constant 
z. The latter was determined by log-linear regression analysis of the terminal phase. The apparent half-life, t1/2, was calculated by division of ln2 by z. Pharmacokinetic parameters were analyzed descriptively, calculating geometric mean and 95% confidence intervals or, for tmax, median and range. Plasma concentrations in figures are expressed as arithmetic mean values (±SEM).
The study was powered to detect with 90% power a difference of 50% in AUC0-
between the 2 ethnic groups. Differences between Caucasian and Japanese subjects for bosentan and metabolite pharmacokinetic parameters were explored using the 2-sample t test on logarithmically transformed Cmax, AUC0-, and t1/2 values, as well as the 2-sample Wilcoxon signed rank test for tmax. Prior to the t test, the Shapiro-Wilk test for normality was performed on the logarithmically transformed data.
To explore dose proportionality of bosentan pharmacokinetics, the values for AUC0- were corrected for dose, log transformed, and compared with ANOVA using subject and dose as factors.13 Furthermore, dose-normalized individual AUC0- values were plotted and subjected to linear regression. The statistical analysis was performed using SAS (version 8.2; SAS Institute, Cary, NC).
Tolerability and safety were analyzed by descriptive statistics only.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The mean plasma concentration-time curves of bosentan and Ro 48-5033 following the different treatments are presented in Figures 1 and 2, respectively. The derived pharmacokinetic parameters of bosentan are presented in Table II, whereas those of Ro 48-5033 are given in Table III. The 2-sample t test did not yield any statistically significant differences between the 2 ethnic groups regarding the pharmacokinetics of bosentan. In contrast, consistently higher and statistically significant (P < .05) Cmax values of Ro 48-5033 were found in Japanese subjects. This difference in Cmax persisted after correction for body weight (data not shown). Exposure to the metabolite also tended to be greater in Japanese subjects, but this did not reach statistical significance. Maximum plasma concentrations of bosentan were attained after 4 hours in Caucasian and after 3 to 4 hours in Japanese subjects (Table II). Median tmax values of Ro 48-5033 were more variable but, in general, were greater than those of bosentan in both ethnic groups (Table III). The Wilcoxon signed rank test indicated shorter tmax values for bosentan and the metabolite in Japanese subjects in the higher dose groups.
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The slope of the linear regression line through the individual dose-normalized AUC0- values did not deviate significantly from 0. A graphical presentation of the linear regression for both ethnic groups is shown in Figure 3. Furthermore, ANOVA of these dose-normalized values indicated a lack of an effect of dose (P = .97 and .07 for Caucasian and Japanese subjects, respectively). Thus, both tests concluded dose-proportional pharmacokinetics in both ethnic groups.
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In both ethnic groups, bosentan and Ro 48-5033 plasma concentrations tended to be higher in females than in males, although no statistically significant differences in AUC0- were observed. After correction for body weight, these differences largely disappeared. There were no differences in tmax and t1/2 between male and female subjects (data not shown).
Of the 24 adverse events that occurred during the study, 14 were reported by Caucasian and 10 by Japanese subjects. Two adverse events, one in each ethnic group, were reported after placebo administration. In the dose range tested, no dose relationship for any adverse event could be discerned. Headache of mild to moderate intensity was the most frequently reported adverse event in both ethnic groups. No clinically relevant changes or differences in ECG parameters/morphology, clinical laboratory variables, and vital signs between Caucasian and Japanese subjects were observed in this study.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Ethnic differences in drug disposition exist but are difficult to predict, probably because a multitude of both genetic and environmental factors play a role.14,15 Therefore, for compounds in clinical development intended to be marketed globally, possible ethnic differences need to be investigated, even if compounds with similar structure, activity, and/or metabolism have not shown such differences. For example, no interethnic differences could be demonstrated for nimodipine between Caucasians and Japanese,16 whereas in South Asians, the exposure to nifedipine was double that in Caucasians.17 Both compounds are calcium channel blockers, are metabolized by CYP3A4, and do not differ markedly in their structure. Although differences in CYP3A4 liver content exist between Asian and Caucasian subjects,18 the activity of this enzyme was not different when using midazolam as a model substrate.19 Thus, assuming that drug disposition of nimodipine and nifedipine is similar in South Asians and Japanese, other factors than CP3A4 activity are to explain the apparent differences between these 2 calcium channel blockers.
The underlying mechanism for the higher Cmax values of Ro 48-5033 in Japanese subjects is unknown. This metabolite is either excreted into the bile or further metabolized by CYP2C9 and/or 3A4 to a hydroxy phenol metabolite.9 It is unlikely that differences in CYP isoenzyme activity play a role because these would have affected the exposure to bosentan as well. The excretion into the bile is possibly mediated by 1 or more drug transporter proteins.20 Changed drug transporter protein function could possibly explain the observed higher Cmax of Ro 48-5033 in Japanese subjects. So far, drug transporter protein function has been poorly investigated in the context of ethnic differences in drug disposition.10
Limitations of the present study include that only single doses were given and that pharmacodynamics were not investigated. Bosentan is a mild to moderate inducer of CYP2C9 and 3A4 and induces its own metabolism, leading to lower plasma concentrations at steady state when compared to the first dose.6 To the best of our knowledge, no study has been published comparing the inducing potential of enzyme inducers between different ethnic groups. Although the present study shows that the single-dose pharmacokinetics of bosentan are similar in Caucasian and Japanese subjects, it remains to be demonstrated that bosentan at the doses currently used in Caucasian patients has a similar efficacy and safety profile in Japanese patients. The lack of a clinically relevant pharmacodynamic variable that can be measured in healthy subjects precluded the investigation of the responsiveness of the endothelin system in the present study.
In conclusion, the results suggest that, based on pharmacokinetic grounds, no dose adjustment of bosentan is necessary when used to treat Japanese patients in comparison to Caucasian patients. However, this needs to be verified in a patient trial.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication February 3, 2004; Revised version accepted September 7, 2004.
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REFERENCES |
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1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336: 111-117.
2. Barst RJ. Primary pulmonary hypertension in children. In: Rubin LJ, Rich S, eds. Primary Pulmonary Hypertension. New York: Marcel Dekker; 1987: 179-225.
3. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334: 296-302.
4. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358: 1119-1123.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346: 896-903.
6. Dingemanse J, van Giersbergen PLM. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. In press.
7. Weber C, Schmitt R, Birnboeck H, et al. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther. 1996;60: 124-137.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Dingemanse J, Bodin F, Weidekamm E, Kutz K, van Giersbergen P. Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. J Clin Pharmacol. 2002;42: 283-289.[Abstract]
9. Weber C, Gasser R, Hopfgartner G. Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects. Drug Metab Disp. 1999;27: 810-815.
10. Xie H-G, Kim RB, Wood AJJ, Stein CM. Molecular basis of ethnic differences in dug disposition and response. Annu Rev Pharmacol Toxicol. 2001;41: 815-850.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Dell D, Lausecker B, Hopfgartner G, van Giersbergen PLM, Dingemanse J. Evolving bioanalytical methods for the cardiovascular drug bosentan. Chromatographia. 2002;55(suppl): S115-S119.[CrossRef]
12. Gibaldi M, Perrier D: Pharmacokinetics. 2nd ed. New York: Marcel Dekker; 1982.
13. Gough K, Hutchison M, Keene O, et al. Assessment of dose proportionality: report from the statisticians in the pharmaceutical industry/pharmacokinetics UK joint working party. Drug Info J. 1995;29: 1039-1048.
14. Johnson JA. Predictability of the effects of race or ethnicity on pharmacokinetics of drugs. Int J Clin Pharmacol Ther. 2000;38: 53-60.[Web of Science][Medline] [Order article via Infotrieve]
15. Bjornsson TD, Wagner JA, Donahue SR, et al. A review and assessment of potential sources of ethnic differences in drug responsiveness. J Clin Pharmacol. 2003;43: 943-967.
16. Muck W, Tanaka T, Ahr G, Kuhlmann J. No interethnic differences in stereoselective disposition of oral nimodipine between Caucasian and Japanese subjects. Int J Clin Pharmacol Ther. 1996;34: 163-171.[Web of Science][Medline] [Order article via Infotrieve]
17. Rashid TJ, Martin U, Clarke H, Waller DG, Renwick AG, George CF. Factors affecting the absolute bioavailability of nifedipine. Br J Clin Pharmacol. 1995;40: 51-58.[Web of Science][Medline] [Order article via Infotrieve]
18. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994;270: 414-423.
19. Tateishi T, Watanabe M, Nakura H, et al. CYP3A activity in European American and Japanese men using midazolam as an in vivo probe. Clin Pharmacol Ther. 2001;69: 333-339.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Hooiveld GJEJ, van Montfoort JE, Meijer DKF, Müller M. Function and regulation of ATP-binding cassette transport proteins involved in hepatobiliary transport. Eur J Pharmaceut Sci. 2000;12: 13-30.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
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