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Similarity of Insulin Detemir Pharmacokinetics, Safety, and Tolerability Profiles in Healthy Caucasian and Japanese American Subjects

From California Clinical Trials, Beverly Hills, California (Dr. Jhee, Dr. Leibowitz, Dr. Zarotsky); Novo Nordisk Pharmaceuticals, Inc., Princeton, New Jersey (Dr. Lyness, Dr. Rojas); and Novo Nordisk Pharmaceuticals, A/S, Bagsvaerd, Denmark (Ms. Jacobsen).

Address for reprints: Stanford S. Jhee, PharmD, Director of Research, California Clinical Trials, 8501 Wilshire Blvd., Beverly Hills, CA 90211.

	ABSTRACT

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The objective of this study was to compare the pharmacokinetics of insulin detemir in three ascending doses in healthy Japanese and Caucasian subjects. This was an open-label, single-center, parallel-group design evaluating 30 subjects (15 Japanese and 15 Caucasians). Subjects received a total of three subcutaneous injections (one injection per visit) of insulin detemir (0.19, 0.38, 0.75 U/kg [1 U = 24 nmol]) in ascending order. Following drug administration, subjects received intravenous glucose in 0.5-mg/kg/min increments every 30 minutes, followed by a constant rate of 2.0 mg/kg/min for up to 12 hours. For pharmacokinetic evaluations, serial blood sampling was performed over a period of 30 hours after dosing. Of the subjects, 36 were enrolled, and 30 completed the study. There was a linear dose-response relationship between the three ascending insulin detemir doses and serum insulin detemir AUC values for both the Japanese and Caucasian subjects. The two dose-response regression lines had equivalent slopes but slightly different intercepts (although not statistically significant). This difference may be due to variation in AUC, body weight differences, or chance. Six subjects discontinued the study, 2 as a result of adverse events (blood draw-related ecchymosis and hypoglycemia). The most frequent treatment-emergent adverse events (TEAE) were headache, dizziness, and reactions related to blood draws/infusion sites. All TEAEs were mild to moderate in severity. The results show that an increase in insulin detemir dose will result in a similar increase in insulin detemir concentration in the two ethnic groups. Therefore, therapeutic dosing of insulin detemir is expected to be similar in both ethnic groups, with no special dose adjustment or algorithm based on race. Insulin detemir at 0.19, 0.38, and 0.75 U/kg was generally well tolerated in both Japanese and Caucasian subjects.

Key Words: Insulin detemir • Japanese • pharmacokinetics

Clinical trials have confirmed that insulin detemir has a sustained blood glucose-lowering effect in both healthy subjects and subjects with type 1 and type 2 diabetes.^4-6 It has been demonstrated that a higher molar dose of insulin detemir than of NPH insulin is needed to achieve comparable glycemic control, and the glucose-lowering effect of 0.3 IU/kg (1 IU = 6 nmol) NPH insulin was between 0.2 and 0.4 U/kg insulin detemir.⁷

In general, patients' response to medications is affected by many factors, including racial or ethnic origin. Dosing sometimes needs to be adjusted for different racial subgroups.⁸ The current clinical trial compared the pharmacokinetics of insulin detemir in Japanese and Caucasian populations, using three ascending therapeutic doses (0.19, 0.38, and 0.75 U/kg). The results of this study will clarify whether insulin detemir can be dosed in Japanese patients using a similar algorithm as in Caucasian patients.

	METHODS

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Subjects
Healthy male or female subjects between the ages of 18 and 50 years inclusive, of Japanese American (both parents born in Japan of Japanese ancestry) or Caucasian American origin, were eligible to be enrolled in the study. The subjects had to have a body mass index (BMI) of less than or equal to 30 kg/m², a fasting blood glucose level between 4.4 and 6 mmol/L (80-108 mg/dL), and a HbA_1C value within the normal range ( 6.4%).

Subjects were excluded if there were clinically significant abnormalities in laboratory tests. Subjects with a history of diabetes, cancer, or cardiac, respiratory, metabolic, gastrointestinal, renal, hepatic, neurological, or psychiatric diseases were excluded. Subjects with a history of multiple and/or severe allergies to drugs or foods were also excluded. All subjects provided written informed consent prior to trial-related activities. This study was conducted at California Clinical Trials Medical Group in accordance with the Declaration of Helsinki⁹ and good clinical practice, and the protocol was approved by an independent institutional review board (California IRB, Inc.).

The study had a planned enrollment of 30 subjects, with equal numbers of Japanese and Caucasian Americans (15 in each group). If a withdrawal occurred following dosing, the subject would be replaced. The study required that 15 subjects per group would receive three insulin detemir doses.

Design
This was an open-label, single-center, parallel-group study evaluating three doses (4.5, 9.0, and 18.0 nmol/kg, corresponding to 0.19, 0.38, and 0.75 U/kg, where 1 U equals 24 nmol) of insulin detemir in healthy subjects, administered on three separate visits. Insulin detemir (2400 nmol/mL) was administered by subcutaneous injection into the thigh using a NovoPen-3® injection device fitted with a NovoFine® 30 (30-gauge) x 8-mm needle. Body weight on the evening before the first dose was used to calculate all three doses.

The study consisted of a screening visit, three dosing visits, and a posttreatment visit. Subjects reported to the screening visit in a fasting state and underwent a physical examination, including vital signs and a laboratory work-up (including hematology, chemistry panel, urine drug screen, HIV and hepatitis B and C screen, and pregnancy test). Subjects reported to the clinical research center approximately 1 week on the morning after an overnight fast for rechecking of inclusion/exclusion criteria. Subjects returned to the clinic the following day for dosing. Subjects were fasting (except for water) from the previous midnight until 12 hours after each dose of insulin detemir. After insulin detemir administration, infused glucose was the only source of calories.

At the three dosing visits, the subjects were injected subcutaneously with one single dose of insulin detemir in ascending order. Immediately following the injection of the insulin detemir dose, and intravenous infusion of 10% dextrose in water was started in 0.5-mg/kg/min increments every 30 minutes, followed by a constant rate of 2.0 mg/kg/min for up to 12 hours. The following procedures were carried out during the dosing visits: vital signs (four times per visit), blood chemistry and complete blood cell count (CBC), serial blood samples for pharmacokinetic evaluation, and monitoring of adverse events, including hypoglycemic episodes. The dosing visits were separated by 4- to 14-day washout periods. The posttreatment visit consisted of a physical examination, vitals signs, ECG, blood chemistry/hematology panel, urine screen, pregnancy test, and monitoring of any adverse events.

Pharmacokinetic assessments were made by collection of blood via an 18- to 20-gauge short cannula inserted into the arm vein of subjects. Sampling occurred at baseline and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 12, 15, 18, 24, and 30 hours after dosing (visits 2, 3, and 4) for the determination of serum insulin detemir concentrations. Pharmacokinetic parameters of area under the curve from 0 to 30 hours (AUC_{(0-30 h)}), maximum serum concentration (C_max), and time to C_max (t_max) were estimated from the serum insulin detemir profiles (see Statistics section for the calculation of these parameters).

Serum insulin detemir was measured by an insulin detemir enzyme-linked immunosorbent assay (ELISA) developed by NovoNordisk A/S using monoclonal antibodies recognizing the acylation site of insulin detemir.¹⁰ This insulin detemir ELISA does not cross-react with human insulin, pro-insulin, or anti-insulin antibodies.

Safety assessments consisted of monitoring adverse events during every site visit. Clinical laboratory tests included a chemistry panel performed at visits 1, 3, and 5; hematology; complete blood cell count performed at every visit; HbA_1c at visit 1 only; urine screen and pregnancy test at visits 1 and 5; and drug and alcohol screen at visits 1 through 4. Other safety parameters included a physical examination, vital signs, ECG monitoring, weight, height, BMI, and bedside determinations of blood glucose prior to blood draws and at any time hypoglycemia was suspected.

	STATISTICS

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The primary endpoints comparing the dose-linearity relationship of insulin detemir AUC_{(0-30 h)} in three ascending doses between Japanese and Caucasian Americans were analyzed in a linear regression model of log (AUC_{(0-30 h)}) on log dose. The model included population and interaction between population and log insulin detemir dose as fixed effects, as well as subject as a random effect. The equations for the linear regression model are as follows:

In this model, ethnicity has value 0 for Japanese Americans and value 1 for Caucasian Americans. This model generates two models according to ethnicity:

The AUC_{(0-30 h)} was log transformed before analysis, in which case equivalence would be declared if the 90% confidence interval (CI) for the estimated ratio (of slopes or intercepts) was within the interval of (0.80, 1.25).^11,12

The serum insulin detemir AUC_{(0-30 h)} was also analyzed using an analysis of variance (ANOVA) model with repeated measurements over dose. The ANOVA model had the following terms: ethnic group, subject within group, dose, and Group x Dose. Other parameters, including insulin detemir C_max and t_max, were analyzed in the same way as AUC_{(0-30 h)}. The 90% confidence intervals for the geometric mean ratio were calculated using bootstrap methods, and the Fieller method was used for calculation of the 90% confidence intervals of the arithmetic mean ratio.¹³

A sample size of 15 subjects per group would give an 80% probability of declaring equivalence when the average pharmacokinetic response in the two populations was actually equal. All subjects exposed to at least one dose were included in the safety analysis.

	RESULTS

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Six of the 36 subjects discontinued the study; 2 withdrawals were due to adverse events. One Japanese female withdrew as a result of blood draw-related ecchymosis, and 1 Caucasian male experienced a hypoglycemic episode resulting in dizziness, flushing, and increased sweating. All other discontinuations were due to noncompliance or other reasons (difficulty with blood draws, withdrawn consent, etc.). One subject had no data collected due to difficulties in obtaining blood samples and was not included in pharmacokinetic/pharmacodynamic analyses. Demographic and baseline characteristics are listed in Table I. The two ethnic groups were different in height, weight, and BMI. Japanese subjects were also younger and had a higher percentage of smokers than Caucasian subjects.

Pharmacokinetic Analysis
The serum insulin detemir profiles for the three doses are presented in Figure 1. A dose-response regression for log insulin AUC_{(0-30 h)} values was performed, and the best-fit line was created for the three ascending doses (total dose) of each ethnic group (Figure 2). There was a clear dose-response relationship between the three ascending insulin detemir doses and serum insulin detemir AUC_{(0-30 h)} values, and the relationship was linear in both populations. The linear regression model was fitted to the data with reasonable success (R² = 78% and overall F-test with p < 0.001). Based on the estimation of the parameters in the model, ß₂ and ß₃ are not significantly different from zero (p = 0.783 and 0.993, respectively), and their effects can therefore be neglected. The equations for the Caucasian and Japanese population can be expressed as follows:

View larger version (27K): [in this window] [in a new window]   Figure 1. Mean serum detemir concentrations over time.

View larger version (16K): [in this window] [in a new window]   Figure 2. Log of AUC for insulin detemir by log of (total dose).

The ratio of the slopes is 0.991, and the ratio of the intercepts is 1.053. The 95% confidence intervals of the slopes for the two ethnic groups both encompassed 1.00 (Table II), indicating that the increase in insulin detemir AUC was in proportion to the increase in the dose of insulin detemir administered in both ethnic groups. The 90% CI for the slope ratio fell within the equivalence ranges (0.8-1.25), while the intercept ratio fell slightly out of the equivalence range (Table II). The two regression lines were parallel, indicating that the two ethnic groups had similar increases in log AUC_{(0-30 h)} values in response to increases in log dose.

When log (dose/body weight) was used in the linear regression model instead of log (total dose), the mean values of log AUC for the three different dose levels (0.19, 0.38, and 0.75 U/kg) for Japanese subjects were 9.69, 10.47, and 11.18, respectively, and they were significantly different from each other (p < 0.0001). The mean values of log AUC for Caucasian subjects were 9.71, 10.59, and 11.26, respectively, and they were also significantly different from each other (p < 0.0001). When the values from the Japanese model were compared with the values from the Caucasian model, no significant differences were found between the two models (p = 0.157). These results are consistent with the result comparing the intercepts and slopes between the two models, indicating that the pharmacokinetic response to insulin detemir was not significantly different between Japanese and Caucasians.

Secondary pharmacokinetic parameter estimates from the insulin detemir curves are summarized in Table III. AUC_{(0-30 h)} and C_max values increased in proportion to dose administered; t_max values were between 5 and 7 hours, with slight delays when the insulin detemir dose was increased. No significant differences between the two ethnic groups were observed for any pharmacokinetic parameters at any dose level.

Safety
Twenty-six subjects reported a total of 81 adverse events (12 Japanese with 26 events and 14 Caucasians with 55 events). The most frequents adverse events were headache, dizziness, and reactions related to infusion sites or blood-sampling sites. All adverse events were mild (68 events) to moderate (14 events) in severity. Forty-two adverse events (5 from the Japanese group and 37 from the Caucasian group) were deemed as possibly related to study medication. The most frequently reported adverse event possibly related to study medication was headache (13 events), dizziness (12 events), fatigue (3 events), and tremor (3 events).

Eighteen subjects (7 Japanese and 11 Caucasians) reported a total of 69 hypoglycemic events. All hypoglycemic events were deemed to be minor (blood glucose [BG] < 50 mg/dL [2.8 mmol/L], with or without symptoms). Caucasian subjects experienced a greater number of hypoglycemic events than the Japanese subjects. The incidence of hypoglycemia increased with increasing dose of insulin detemir in both groups.

Overall, Caucasians reported more adverse events than Japanese subjects. There was no association between the number of adverse events and the insulin detemir dose. No serious adverse events were reported. There were no clinically relevant changes in vital signs, physical examinations, ECGs, or laboratory tests.

	DISCUSSION

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This study was designed to compare the pharmacokinetic response to insulin detemir between Japanese and Caucasian populations. Japanese and Caucasian populations may differ in some body mass parameters, with smaller stature and lighter body weight among Japanese Americans. These groups might also have differences in drug metabolism that could be associated with ethnic differences in cytochrome P450 enzymes or other metabolic processes.^14,15 A study evaluating repaglinide noted that following a single fixed oral dose of repaglinide (0.5, 1.0, or 2.0 mg), subjects of Japanese origin had significantly higher AUC and C_max values than Caucasian subjects at each dose level (p = 0.0038 for C_max, p = 0.023 for AUC). The discrepancies in body weight and BMI between Caucasian and Japanese subjects could not explain these differences, indicating potential differences in metabolic pathways (e.g., CYP 450). The results indicated that within the recommended dose range (0.5-4.0 mg) for repaglinide, a lower dose might be needed to achieve glycemic control in Japanese patients in comparison to Caucasian patients.^16,17 Other researchers compared the results of pharmacokinetic studies with similar designs conducted separately in European and Japanese populations and found that absorption of insulin aspart was higher in Japanese than in Caucasian subjects, even when the administered dose was based on body weight (0.025, 0.05, and 0.075 U/kg). At the 0.05-U/kg dose level, mean and AUC_{(0-6 h)} were 28% higher, and C_max was 55% higher in Japanese compared to Caucasians.^18,19 It was therefore a question of possible clinical interest to compare the pharmacokinetics of insulin detemir in Japanese and Caucasian populations.

According to guidelines from the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA), bioequivalence is defined to correspond to a 90% CI for the ratio of compared parameters falling in the range between 0.8 and 1.25.^11,12 The results of this study indicate that the ratio of insulin detemir AUC slopes meets this definition of equivalence. Such equivalence indicates that a given increase in insulin detemir dose will result in a similar increase in serum insulin detemir concentration for the two ethnic groups. A direct comparison of a series of pharmacokinetic parameters confirmed this conclusion. The 90% CI for the ratio of insulin detemir AUC intercepts (0.7-1.28) fell slightly beyond the equivalence range. However, the two intercepts were not significantly different. The wider distribution of the intercept was probably caused by a combination of random variation and the fact that the sample size was powered to show equivalence for the slopes and not for the intercepts. Although the two regression lines were separated by a small difference in intercept, the observed difference is too small to be clinically significant. The observed difference in intercepts would not be great enough to justify any adjustment of insulin detemir starting dose based on race, especially since the insulin detemir starting dosage is based on individual body weight. No statistically significant differences were detected for any pharmacokinetic parameters.

In terms of safety profiles, the Japanese group reported fewer adverse events than the Caucasian group. They also experienced fewer hypoglycemic events as compared to Caucasian subjects, even though the two groups had a similar reduction of serum glucose values. Such observations may be due to chance or related to the differences in body composition between the two groups, which might affect insulin detemir distribution. There were no clinically relevant changes in vital signs, physical examinations, ECGs, or laboratory tests in either group.

	CONCLUSIONS

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The results of this study indicate that there is a linear dose-response relationship in the three ascending insulin detemir doses for both Japanese and Caucasian subjects. The slopes of the dose-response regression lines of log AUC_{(0-30 h)} were equivalent in the two ethnic groups. The observed nonequivalence of the intercepts of the dose-response regression lines of log AUC_{(0-30 h)} was found to be neither statistically nor clinically significant. There were no statistically significant differences found in any pharmacokinetic parameters at any dose level, and all doses evaluated were generally well tolerated in both Japanese and Caucasian subjects.

Taken together, the results show that an increase in insulin detemir dose will result in the same increase in insulin detemir concentration in the two ethnic groups. Therefore, therapeutic dosing of insulin detemir is expected to be similar in both ethnic groups, with no special dose adjustment or algorithm based on race. Insulin detemir at 0.19, 0.38, and 0.75 U/kg was generally well tolerated in both Japanese and Caucasian subjects.

	FOOTNOTES

 
DOI: 10.1177/0091270003262949

Submitted for publication April 30, 2003; Revised version accepted December 20, 2003.

	REFERENCES

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Jhee, S. S. Articles by Jacobsen, L. V. Search for Related Content PubMed PubMed Citation Articles by Jhee, S. S. Articles by Jacobsen, L. V. Social Bookmarking                   What's this?