Pharmacokinetics Of Levothyroxine Treatment In Athyreotic Patients Biology Essay

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Hypothyroid has still be a problem in Thailand. Lack of pharmacokinetics information of levothyroxine in athyreotic patients for modify dosing. Therefore, the aim of this study was to investigate the pharmacokinetic parameters of 2 doses of levothyroxine (50 mg and 100 mg) in such group of patients. The 24 athyreotic patients were recruited and randomly assigned to receive 50 mg or 100 mg of levothyroxine. The pharmacokinetic parameters (Cmax, Tmax, AUC0-8, ke, T1/2 and Vd) of FT4 and TSH were calculated by non-compartment model. The parameters of 2 doses were compared. From the results found that, by monitoring FT4, there were no statistically significant difference (p>0.05) of almost all pharmacokinetic parameters between 2 doses except Cmax which has significant greater in 100 mg of levothyroxine. While all pharmacokinetics parameters of TSH were not statistically significant difference. The use of non-compartment model seems appropriate for calculation of pharmacokinetic parameters of FT4 (R2 = 0.81) while it has poor predictive capacity in terms of TSH (R2 = 0.24). In conclusion, administration of 50 mg and 100 mg of leveothyroxine to athyreotic patients have similar pharmacokinetic in term of FT4 (non-significant different in Tmax, AUC) and TSH. Further study of these parameters in more subjects is needed.

Key word: Pharmacokinetics, Athyreotic patients, Levothyroxine

Introduction

Hypothyroid is the condition that mostly found in athyreotic patients. The incidence of low free T4 (FT4) and high Thyroid Stimulating Hormone (TSH) is about 0.3% while the incidence of low thyroid hormone is found to 4.3%[1-3] The general treatment of hypothyroid should gradually modified drug dosing. American Association of Clinical Endocrinologists recommended Levothyroxine (L-T4) 1.6 mcg/kg/day by begin with 12.5 mcg/day and then increase dose gradually depends on age, weight, cardiovascular status and duration of hypothyroid[4, 5]

In Thailand, the endocrine specialist recommended high dose oral levothyroxine 1000 µg for single dose. Currently there have not been studied of efficacy and side effects of high doses regimen.

However, there are several studies in high doses of levothyroxin in patients with hypothyroid [6, 7] , the study found that myxedema coma or myxedema ileus , Levothyroxine oral route has variable absorption but patients had better response after administration. Intravenous levothyroxine can make higher level of thyroid hormone. However, it can not conclude that, which appropriate dose should be administered in severe hypothyroidism.

Vicky Blakesley et al [8] reported Bioequivalence of Levothyroxine oral 400, 450 and 600 mg in healthy volunteer and measured thyroid hormone to determine Cmax (maximum serum concentration), time to Cmax , and AUC (area under the serum concentration-time curve) and suggested that the bioequivalence study of levothyroxine should use endogenoud T4 in the calculation and the serious adverse effects were not found in high dose levothyroxine. In Thailand, there is lack of pharmacokinetic information of levothyroxine pharmacokinetics in hypothyroid patients. Therefore, this study aimed to investigate the pharmacokinetic parameters of 2 doses levothyroxine in such patients.

Materials and methods

Patients

Twenty four primary hypothyroidism patients with underlying well-differentiated thyroid cancer were recruited. Patients had Total or Near-total thyroidectomy and stop levothyroxine for 6 weeks and had 131I radiation therapy which is available as standard treatment.

Inclusion criteria

Males or females whose ages between 15-60 years old

TSH > 30mIU/mL

No underlying diseases such as Cardiovascular diseases, Liver insufficiency (AST and/or ALT >3 times UL), renal insufficiency (Scr>1.5 mg/dL)

No receiving other drugs that effect levothyroxine absorption such as calcium containing drugs, anticonvulsants, estrogens, and proton pump inhibitors or H2 blockers.

Exclusion criteria

Patients were excluded if they

were poor compliance with drug regimens

were pregnancy or lactation

had hypersensitivity or intolerate to thyroxine

had infectious or liver diseases

were considered by physician as inappropriate to be included in this study.

Drug administration

Patients were administered levothyroxine 50 mg (50mg) 1 tablets or Levothyroxine 100 mg (50mg 2 tablets) single dose .

Pharmacokinetic study

Pharmacokinetic analysis

Levothyroxine plasma concentrations were analyzed as a function of time and the following pharmacokinetic parameters were obtained for each subject ; the maximum plasma concentration (Cmax), Area under the concentration versus time curve for 8 hours (AUC0-8), Elimination rate constatnt (ke), and volume of distribution (Vd). All pharmacokinetic parameters of free T4 (FT4) and Thyroid Stimulation hormone (TSH) were assessed by Win-nonlin professional software (version1, Pharsight corporation,Pato Alta,California) and non-compartment methods was used.

Data analysis

Student t-test statistic was used to test the different of pharmacokinetic parameters between 2 groups of different regimens. The statistical significant difference was considered when p value was less than 0.05.

Results

The pharmacokinetic parameters that found in 24 hypothyroid subjects was presented in Table 1 and Table 2 respectively

Table 1 Pharmacokinetics parameters of FT4 in 24 hypothyroid subjects

Average R2 = 0.81

Table 2 Pharmacokinetics parameters of TSH in 24 hypothyroid subjects

Average R2 = 0.24

Discussion

According to the results, the pharmacokinetic parameters of levothyroxine 50 mg and 100 mg which measure by monitor FT4 have not significant difference except peak concentration (Cmax) is higher in levothyroxine 100 mg, while all pharmacokinetic parameters in terms of TSH were not significant difference. It seems that may be the pharmacokinetic of levothyroxine may have non-linear behavior.

When comparison of these parameters with previous study found that, the tmax and average half life were similar to this study.[9-11] The much variations is Cmax and AUC when compare to previous studies since due to the hypothyroid status of patients in this study which may had lower T4 base line and 50-100 mg single dose can not make FT4 reach for normal range and it implied that non-compartmental method can be used in calculation of pharmacokinetic parameters of LT4 with good R 2 (average = 0.8), while is not appropriate use for TSH because R 2 is quite low (average =0.2). More over the sensitivity of TSH is less than FT4.

This study leads to persuaded establishing the use of pharmacokinetic model for monitoring FT4 in athreotic patients which is useful in levothyroxine dose adjustment.

However, this study had some limitations, because of small number of subjects, the pharmacokinetics parameters may be not generalized for every patient, further study with more number of subjects are needed. The second point is there is no repeated study for application of this model to another group of patients for proving about the accuracy of the model. Using this model for levothyroxine dose adjustment in another group of athyreotic patients for measuring the accuracy may help to prove about generalization of this proposed model.

In conclusion, administration of levothyroxine (50 mg) and levothyroxine (100 mg) have similar pharmacokinetic in term of FT4 (non-significant different in Tmax, AUC) and TSH. Further study of these parameters in more subjects is needed.

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