Evaluation of renal adverse effects of combination anti-retroviral therapy including tenofovir in HIV-infected patients.

PURPOSE: In order to maintain plasma HIV-RNA concentration in HIV-infected patients, below the detection limit combination anti-retroviral therapy (cART) are used. Although the nucleoside/nucleotide reverse transcriptase inhibitor, tenofovir disoproxil fumarate (TDF) is a first-line drug commonly used, it is associated with renal dysfunction. Nevertheless, only few clinical studies have focused on TDF in combination with new anti-HIV drugs, including the protease inhibitor (PI) darunavir (DRV), or the integrase strand transfer inhibitor (INSTI) raltegravir (RAL). Here we report the influence of such cART involving TDF on renal function. METHODS: We retrospectively investigated 68 patients under cART that included TDF between November 2004 and May 2012. We used hospital records to establish each patient's background and characteristics, CD4 cell count, plasma HIV-RNA concentration, drug combinations, renal function, and anti-retrovial therapy history. RESULTS: In all patients who had received cART, the plasma HIV-RNA concentration had fallen to less than 40 copies/mL by week 24 after the start of the therapy, and an increase in the CD4 cell count was observed. For each drug used in combination with TDF, the plasma HIV-RNA concentration and CD4 cell count showed a similar trend. After week 12, the estimated glomerular filtration rate (eGFR) had significantly decreased in all patients. The eGFR was significantly lower in those received PI on week 24 and in those received INSTI on week 12. The eGFR was significantly reduced in PI group who received atazanavir + ritonavir (ATV/RTV) on week 60. The eGFR in the DRV/RTV group tended to decrease. The eGFR in the PI and ATV/RTV group was significantly lower than in the efavirenz (EFV) group on week 96. CONCLUSION: It selecting drugs to include in combination therapy of HIV-infected patients, consideration should be given to the risk of renal dysfunction. There is a need to monitor renal function when TDF is combined with ATV/RTV, DRV/RTV or RAL.

Tissue concentrations of antibiotics given prophylactically during colorectal cancer surgery.

BACKGROUND/AIMS: This study was designed to clarify the pharmacokinetics of prophylactically administered cefmetazole in serum, intestinal tissue, and subcutaneous adipose tissue in patients who underwent surgery for colorectal cancer. METHODOLOGY: Cefmetazole sodium (1 g) was given intravenously during the induction of anesthesia, followed by a 1-g dose after 3 hours. Blood samples were taken at the start of surgery, immediately before administration of the additional dose of cefmetazole, at the time of lesion resection, and at the time of wound closure. Tissue samples were obtained immediately after lesion resection and at the time of wound closure. Concentrations of cefmetazole in serum and tissue were measured by high performance liquid chromatography using an internal standard for calibration. Minimum inhibitory concentrations (MIC80) of cefmetazole for Escherichia coli, Klebsiella pneumoniae, and Bacteroides fragilis were measured, and pharmacokinetics were evaluated. RESULTS: In subcutaneous adipose tissue, cefmetazole concentrations were maintained higher than the MIC80's for E. coli and K. pneumoniae, but were low in all patients regardless of the time of measurement. CONCLUSIONS: The low transition rate of cefmetazole into subcutaneous adipose tissue indicates the need for additional measures, such as high-pressure washing of the subcutaneous wound tissue.

Epinephrine administered with lidocaine solution does not worsen intrathecal lidocaine neurotoxicity in rats.

BACKGROUND: Epinephrine can potentially worsen the neurotoxic effects of local anesthetics when used for spinal or epidural anesthesia. The vasoconstrictive property of epinephrine reduces dural blood flow, which in turn reduces the clearance of local anesthetics from the subarachnoid space. This study examined the histological and neurofunctional effects of intrathecally administered lidocaine combined with epinephrine in rats. METHODS: Sixty-two rats were divided into 9 treatment groups: 5% or 7.5% lidocaine in 10% glucose solution with or without 0.1 or 0.5 mg/mL epinephrine, or epinephrine alone at 0.1 or 0.5 mg/mL in 10% glucose, or 10% glucose alone. Hind-limb motor function was evaluated immediately after drug injection by walking behavior. Sensory function was assessed by the response to radiant heat stimulation at just before and 1 week after the injection. Seven days after the injection, L3 spinal cord with anterior and posterior roots, the dorsal ganglion, and cauda equina were harvested and examined histologically. RESULTS: Histological lesions were limited to the posterior root just at entry into the spinal cord in rats injected with 7.5% lidocaine, with and without epinephrine. No histological abnormalities were noted in other areas or other groups. There was no significant change in sensory threshold in all groups. Significantly, prolongation of gait recovery time was noted in 5% and 7.5% lidocaine with epinephrine groups compared with 5% or 7.5% lidocaine alone. CONCLUSIONS: Intrathecal epinephrine prolonged the action of intrathecal lidocaine but did not worsen lidocaine-induced histological damage and functional impairment.

Evaluation of arbekacin anti-MRSA agents for adult in Japan.

There are a limited number of reports that compare the clinical efficacy of anti-MRSA agents such as arbekacin (ABK), vancomycin (VCM), teicoplanin (TEIC) and linezolid (LZD). There is a tendency for these four agents to show variation in the inflammatory response parameters, in C-reactive protein (CRP) and in white blood cell count (WBC), depending on the administration period. There was no significant difference among the agents in analysis of variance (ANOVA) in the group of days 1-3 (p = 0.0536) but there was some significant difference in the group of days 4-7, as well as days 8-14 (p < 0.001, p < 0.01) in relative variation rate of CRP. Furthermore, we compared in more detail the groups of LZD, VCM and ABK, with a significant decrease of CRP, each of which showed more decrease in comparison with the group of TEIC in the period days 4-7 (p < 0.01). We took 1-hr serum level after days 3-4, with the ABK treatment as the peak concentration (C(peak)). Having made nonlinear logistic regression analysis of CRP and C(peak)/MIC, we concluded that the decrease rate estimable by early inflammatory effect could be decreased to some 40%, assuming that C(peak)/MIC shows the high value within 4 days after ABK treatment.

Population pharmacokinetics of oxycodone in patients with cancer-related pain.

Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 - Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

Population pharmacokinetics of transdermal fentanyl in patients with cancer-related pain.

Determining the appropriate dose of transdermal fentanyl (TDF) for the alleviation of cancer pain requires determining the factors causing variations in serum fentanyl concentration after TDF treatment. The objective of this study was to identify these factors and incorporate them into a formula that can be used to predict serum fentanyl concentration after application of a TDF patch. Blood samples of cancer patients treated with a TDF patch for the alleviation of pain were collected at 24, 48, and 72 hours after application to evaluate population pharmacokinetics using the nonlinear mixed-effect model (NONMEM). Based upon this evaluation, Child-Pugh Score and use of a cytochrome P450 3A4 (CYP3A4) inducer were identified as the most significant factors in variations in serum fentanyl concentration and incorporated into the following Final Model formula: CL(fenta) (L/h) = 3.53 × (15 - Child-Pugh Score) × (1 + 1.38 × use or no use of CYP3A4 inducer). Bootstrap evaluation of the Final Model revealed a high convergence rate, suggesting that the model formula is a reliable and useful tool for determining TDF dose for the alleviation of cancer pain.

Effects of tamsulosin and silodosin on isolated albino and pigmented rabbit iris dilators: possible mechanism of intraoperative floppy-iris syndrome.

PURPOSE: To determine the mechanism of intraoperative floppy-iris syndrome (IFIS) by examining the binding affinity of tamsulosin and silodosin to α-receptors and melanin pigment using control and α(2)-blocker chronically administered in rabbit models. SETTING: Department of Ophthalmology, Kitasato University School of Medicine, Kanagawa, Japan. DESIGN: Experimental study. METHODS: The study was performed in isolated albino and pigmented rabbit iris dilators using pharmacologic and morphologic examinations. RESULTS: For pharmacologic examinations, the mean pK(B) values (pK(B) = -log K(B), where -log K(B) is the equilibrium dissociation constant of the antagonist-receptor complex) of tamsulosin in albino and pigmented rabbits were 9.10 and 8.08 and those of silodosin, 10.3 and 8.11, respectively. The pK(B) values of tamsulosin and silodosin in albino rabbits were significantly higher than in pigmented rabbits. In the isolated rabbit iris dilator, the maximum contraction evoked by 10(-3) mol/L phenylephrine gradually decreased by repetitive application in the chronic α-blocker-administered models. For morphologic examinations, the sizes of the pigment granules of pigment epitheliums for the α-blocker-administered models were irregular. The shape of shared nucleus of dilator muscles and pigment epitheliums changed to lobular, and the dilator muscle layer was thinner than in the control. CONCLUSIONS: The high affinity of α-blockers for α(1)-adrenoreceptors is important in the analysis of the mechanism of IFIS. However, IFIS should not be attributed to long-term binding with receptors alone; the drug-melanin interaction causing dilator muscle atrophy is probably the other important factor in the mechanism of IFIS.

Investigation and threshold of optimum blood concentration of voriconazole: a descriptive statistical meta-analysis.

Voriconazole (VRCZ) reportedly possesses a broad spectrum of antifungal activity against Aspergillus spp. and Candida spp., and the blood concentration of VRCZ is correlated with both the efficacy and the adverse effects of this drug. Monitoring of the blood concentration target level of VRCZ has not yet been widely adopted in the medical field, and no evidence concerning this target level has been reported. Accordingly, we used a meta-analysis to investigate the optimal blood concentration of VRCZ. Using data from 12 reports, we found that the success rate for fungal infection treatment increased significantly at VRCZ levels greater than 1.0 µg/ml when a graded cutoff value within the range of 1.0-3.0 µg/ml was used as the VRCZ trough blood concentration [odds ratio (OR) 7.23, 95% confidence interval (CI) 2.84-18.37, P < 0.0001]. Concerning the safety evaluation, the incidence of adverse neurological effects increased significantly at a cutoff value of 4.0 µg/ml when a graded cutoff value within the range of 3.0-6.0 µg/ml was used (OR 2.23, 95% CI 1.12-4.46, P = 0.02). However, in all 12 literature sources, an increasing incidence of liver dysfunction was reported at higher blood concentrations, and no accurate cutoff values were obtained. Consequently, a VRCZ trough blood concentration more than 1.0 µg/ml from the perspective of efficacy and less than 4.0 µg/ml from the perspective of safety is recommended.

Clinical efficacy of arbekacin for Gram-negative bacteria.

In an analysis of methicillin-resistant Staphylococcus aureus (MRSA) infected patients treated with arbekacin (ABK) only, Gram-negative bacteria (GNB) that were inhibited by low minimal inhibitory concentrations (MICs) of amikacin (AMK) or gentamycin (GM) were eradicated by the end of the ABK treatment. On the other hand, GNB that were only inhibited by high MICs of AMK or GM persisted until the end of treatment with ABK only. Thus, ABK can be expected to be effective even in cases of mixed infection with GNB and MRSA.

[Solutions for the clinical problems of analgesics for cancer pain treatment in Japan].

The pain experienced by cancer patients can be managed in 70-90% of cases by the World Health Organisation protocol for cancer pain. However, cancer pain treatment in Japan is not sufficiently effective. To use medicine safely and effectively, various problems must be solved. Therefore, in this study, appropriate usage of cancer pain treatment was examined. We were able to use acetaminophen suppositories (800 mg each) in cancer pain patients. It was suggested that high serum concentrations of oxycodone and hydrocotarnine might be observed in geriatric patients or in the state of decreased hepatic blood flow, making dose adjustment is necessary for such patients. We also clarified that the conversion ratio from oral oxycodone to intravenous ocycodone/hydrocotarnine was 0.71±0.12. In addition, we clarified the pharmacokinetics of controlled-release oxycodone in patients with cancer pain. Moreover, the findings of our study indicate that in the steady state, the serum concentrations of fentanyl are not maintained at a constant level for 3 days following the use of transdermal fentanyl. We established a method of appropriately passing a nasal duct for sustained release of fine granules of morphine sulfate. Resolution of the clinical problems associated with cancer pain treatments is anticipated to allow the proper use of cancer pain treatments in Japan.

[Liposomal-amphotericin B efficacy and safety].

Liposomal amphotericin B (L-AMB), a lipid-based amphotericin B formulation, has been used in Japan since June 2006 to treat fungal infection. In the 3 years since L-AMB was launched, few reports have been made on its status. To ensure its appropriate use, we restrospectively reviewed its efficacy and safety in treating fungal infections. 25 subjects with fungal infection treated with L-AMB from April 2007 until February 2008. Of those, 16 showed clinical improvement. Elevated serum creatinine occurred in 1 and decreased serum potassium in 6. We found a positive relationship between the serum potassium decrease and L-AMB dose. Logistic regression analysis of this relationship showed that serum potassium tended to fall on day 5 to 6 of L-AMB administration. While L-AMB appears highly effective in fungal infection, it requires serum potassium monitoring to ensure patient safety.

[Selection of an optimum solvent for administration of oxinorm powder through a tube].

Oxinorm powder is a rapid-release preparation of oxycodone hydrochloride for oral administration recently marketed for the first time in Japan. Administration of a powdered drug through a nasal tube is known to involve the risk of tube obstruction by the drug. For narcotic preparations like oxinorm powder, it is desirable from the perspective of drug control, that the drug administered be unlikely to remain in the cup, syringe or catheter used, and that the drug be dispensable in precise amounts. The present study was undertaken to identify problems associated with administration of oxinorm powder through a nasal tube and to determine an appropriate method for its administration. First, the solubility of the powder in various solvents was evaluated macroscopically to select initially appropriate solvents. Then, the drug dissolved in each of these solvents was administered through 3 types of catheters with different raw materials and forms, to simulate drug administration through a nasal tube. Percent residual drug remaining on/within the cup, syringe, and catheter was measured by HPLC, to evaluate the adhesiveness of the drug. When dissolved in distilled water, black vinegar, or milk, the drug was easy to administer through the catheter, with a low percentage of drug remaining on the cup, syringe, and catheter, suggesting that these fluids can be used as solvents for oxinorm powder. Semidigested nutrients such as Ensure.H were found to be unsuitable solvents for oxinorm powder.

[Evaluation of the 2.5 mg fentanyl patch, applied using the half-side application procedure in patients with cancer pain].

Occasionally, pain control with the fentanyl patch may lead to overdose at an initial dose of 2.5 mg, as well as during dose increase from 2.5 to 5.0 mg. Respiratory depression and other adverse drug reactions associated with fentanyl overdose have been observed in several of our patients. We developed a procedure for applying one-half of the fentanyl patch formulations and evaluated the new mode of application by examining the fentanyl concentration in 32 patients with cancer-related pain who had been using the fentanyl patch for pain control. While some patients were treated with the full-sized 2.5-, 5.0-, or 7.5-mg formulations, others were treated with the half-sized 2.5-mg formulation. The fentanyl patch was equally divided by drawing a line on the side on which the product name and dose were written. Tegaderm was applied to the patient's skin, and after detaching from the protective liner, half of the patch was applied to overlap Tegaderm along the line and the other half applied directly to the skin. Blood samples were collected 48-72 h after patch application. The mean serum concentration of fentanyl given in the half-sized 2.5-mg formulation was 0.286 ng/ml, which was approximately one-half of the concentration of the full-sized 2.5-mg formulation, 0.544 ng/ml. Therefore the 2.5-mg fentanyl patch, applied using the one-half procedure we developed, is clinically useful.

[Conversion ratio between intravenous oxycodone/hydrocotarnine and sustained-release oral oxycodone in patients with cancer pain].

The demand for oxycodone increases in the treatment of patients with cancer pain, but there is no injection formulation containing oxycodone as a single ingredient in Japan. Instead, we have an oxycodone/hydrocotarnine compound product. Long ago, hydrocotarnine was added to enhance the analgesic effect of oxycodone. However, the mechanism of hydrocotarnine is unclear, and few studies have mentioned the conversion ratio between intravenous and oral oxycodone. In the present study, in order to define the conversion ratio between them, we investigated 18 patients treated by intravenous or oral oxycodone and changed to another administration route during their treatment. We surveyed the change in pain level and adverse effects before and after changing the administration route. The conversion ratio from oral oxycodone to intravenous oxycodone/hydrocotarnine was 0.71+/-0.12 (mean+/-S. D.), and no obvious change in adverse effect was observed.

Pharmacokinetics and variation in the clearance of oxycodone and hydrocotarnine in patients with cancer pain.

Compound injections of oxycodone and hydrocotarnine are currently used as one of the treatment options for some cases with cancer pain. However, there have been no reports examining the factors that influence oxycodone and hydrocotarnine clearance, so detailed examination is necessary. As for hydrocotarnine, there have been no reports examining the pharmacokinetics. Therefore in this study, we determined the pharmacokinetics of oxycodone and hydrocotarnine in patients with cancer pain. The study was conducted on 19 patients, in whom pain control was attempted by using the compound injections of oxycodone and hydrocotarnine. We used HPLC-electrochemical detector (ECD) to determine oxycodone and hydrocotarnine serum concentrations, and used the nonlinear least-squares method (MULTI) for calculation of the pharmacokinetic parameters. Furthermore, we examined the factors that influence the clearance of oxycodone and hydrocotarnine by multiple regression analysis (step wise method). The pharmacokinetic parameters were as follows: Oxycodone; V(d)=226.7+/-105.5 l (mean+/-S.D.), CL=37.9+/-25.1 l/h, t(1/2)=4.1+/-1.9 h. Hydrocotarnine; V(d)=276.8+/-237.2 l, CL=95.1+/-64.3 l/h, t(1/2)=2.0+/-0.7 h. The clearance of oxycodone represented by a regression formula was significantly correlated to the age, the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance of hydrocotarnine represented by a regression formula was significantly correlated to the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance also indicated that oxycodone concentration in the blood was likely to be higher in patients having these factors. Oxycodone/hydrocotarnine compound injections should be used with caution and dose reduction may be necessary in such populations.

[Pharmacokinetics of controlled-release oxycodone in patients with cancer pain].

Oxycodone is a useful analgesic for cancer patients in pain. However, its pharmacokinetics have not been sufficiently examined and there is a lack of information, with very few reports on pharmacokinetics concerning the absorption process in particular. With this in mind, we studied the pharmacokinetics of controlled-release oxycodone (Oxy contin). We measured its serum concentration in patients with cancer pain, and calculated parameters derived using the nonlinear least-squared method program (MULTI). In the result, pharmacokinetic parameters calculated at CL/F were: 45.6+/-22.0 L/hr (Mean+/-SD), Vd/F: 473.0+/-19 6.7 L, t(1/2): 7.2+/- 6.2 hr, kel: 0.103+/-0.034, kal: 1.082+/-0.604, Lag time: 0.9 9+/-0.40 hr. In addition, the serum oxycodone concentration hardly rose until 1 hour after and just before medication, whereupon a rapid increase was evident after 1 hour. The pharmacokinetics of controlled-release oxycodone in patients with cancer pain were clarified in this study. Especially during the absorption process, the lag time was calculated specifically at about 1 hour, making it approximately equal to MS contin.

[Appropriate usage of antibiotics by therapeutic drug monitoring].

Aminoglycosides are mainly distributed in the extracellular fluid, so when they are given to neonates who have a large amount of extracellular fluid, their distribution is increased. In our data, the volume of distribution (Vd) of Arbekacin in the neonates was twice that of the adults, 0.54 l/kg. Therefore, the dose per weight of aminoglycosides to the neonates should be increased more than to the adults. In the renal function of the neonates, differentiation of the nephron is completed within 36 weeks after conception, but it is functionally immature. In our data, renal drug excretion increased rapidly in the post-conceptional ages (PCAs) of 34-35 weeks. Consequently, we based the Arbekacin administration schedule for the neonates on the PCAs. There is excellent correlation between serum level of vancomicin (VCM) and dose x serum creatinine (Scr)/weight in the haemodialysis patients, suggesting that we can use weight and Scr to set the VCM administration schedule for these patients. We also established on administration schedule of Teicoplanin for the haemodialysis patients. In this article, we present the TDM analysis result of the antibiotics in our hospital.

Phase II study of radiation therapy combined with weekly nedaplatin in locally advanced uterine cervical carcinoma: Kitasato Gynecologic Radiation Oncology Group (KGROG 0501).

In order to evaluate the safety and efficacy of chemoradiotherapy using nedaplatin for locally advanced uterine cervical carcinoma in Japanese patients, we have started a single-institute phase II trial. Eligibility criteria include: (i) pathologically proven squamous cell carcinoma or adenocarcinoma, (ii) clinical FIGO stage Ib, IIa, or IIb with bulky tumor (> 40 mm) or pelvic lymph node swelling, or (iii) clinical FIGO stage IIIa, IIIb and IVa, (iv) no para-aortic lymph node swelling. A combination of external beam radiation and high dose rate intracavitary irradiation is given. Nedaplatin (30 mg/m2) is intravenously infused on a weekly basis for five times. The primary endpoint is 3-year overall survival, and the secondary endpoints are tumor response, 2-year overall survival, 3-year progression-free survival, acute adverse events, protocol treatment compliance, and late adverse events. We plan to recruit 45 patients within 3 years.

Liver abscess that responded well to pazufloxacin therapy.

Pazufloxacin (PZFX), an injectable, new quinolone antibacterial drug, has strong antibacterial activity against gram-negative bacteria (which often account for liver abscess) and transfers well to liver tissue, gallbladder tissue, and bile. Therefore, it is probable that PZFX could be extremely useful for patients with liver abscess. Here, we report two cases of liver abscess that resolved with PZFX. PZFX was intravenously administered to patients who had undergone abscess drainage, at a dose level of 500 mg x 2/day. PZFX therapy thereby allowed the patients to shorten the period of hospital stay. Liver abscess has been considered as a poor-prognosis disorder, due to delay in diagnosis of the disorder and the high incidence of septicemia that subsequently occurs. However, now, appropriate antibacterial drug therapy in combination with abscess drainage successfully allows excellent prognosis of patients with liver abscess without the reduction in the activities of daily living (ADL) that accompanies hepatic artery injection.

Evaluation of AUC(0-4) predictive methods for cyclosporine in kidney transplant patients.

Cyclosporine (CyA) is the most commonly used immunosuppressive agent in patients who undergo kidney transplantation. Dosage adjustment of CyA is usually based on trough levels. Recently, trough levels have been replacing the area under the concentration-time curve during the first 4 h after CyA administration (AUC(0-4)). The aim of this study was to compare the predictive values obtained using three different methods of AUC(0-4) monitoring. AUC(0-4) was calculated from 0 to 4 h in early and stable renal transplant patients using the trapezoidal rule. The predicted AUC(0-4) was calculated using three different methods: the multiple regression equation reported by Uchida et al.; Bayesian estimation for modified population pharmacokinetic parameters reported by Yoshida et al.; and modified population pharmacokinetic parameters reported by Cremers et al. The predicted AUC(0-4) was assessed on the basis of predictive bias, precision, and correlation coefficient. The predicted AUC(0-4) values obtained using three methods through measurement of three blood samples showed small differences in predictive bias, precision, and correlation coefficient. In the prediction of AUC(0-4) measurement of one blood sample from stable renal transplant patients, the performance of the regression equation reported by Uchida depended on sampling time. On the other hand, the performance of Bayesian estimation with modified pharmacokinetic parameters reported by Yoshida through measurement of one blood sample, which is not dependent on sampling time, showed a small difference in the correlation coefficient. The prediction of AUC(0-4) using a regression equation required accurate sampling time. In this study, the prediction of AUC(0-4) using Bayesian estimation did not require accurate sampling time in the AUC(0-4) monitoring of CyA. Thus Bayesian estimation is assumed to be clinically useful in the dosage adjustment of CyA.