Population Pharmacokinetic Approach to the Use of Low Dose Cyclosporine in Patients with Connective Tissue Diseases.

This study describes the population pharmacokinetics and dose personalization of cyclosporine in 36 patients with connective tissue diseases. A one-compartment open model with absorption was adopted as a pharmacokinetic model, and a nonlinear mixed effects model was used to analyze the population pharmacokinetic models. In the final model, age (AGE) and total body weight (TBW) were influential covariates on clearance (CL/F), which was expressed as CL/F (L/h)=17.8×(AGE/60)(-0.269)×(TBW/46.9)(0.408), in addition to the volume of distribution (Vd/F), (L)=98.0 and absorption rate constant (Ka) (h(-1))=0.67 (fixed). The results of the present study provide novel insights into factors involved in determining the most suitable dose and dosing strategy for individual patients with connective tissue disease.

Population pharmacokinetics of doxapram in low-birth-weight Japanese infants with apnea.

UNLABELLED: This study aimed to determine the population pharmacokinetics of doxapram in low-birth-weight (LBW) infants. A total of 92 serum concentration measurements that were obtained from 34 Japanese neonates were analyzed using nonlinear mixed-effect modeling (NONMEM). Estimates generated by NONMEM indicated that clearance of doxapram (CL; L/kg/h) was affected by postmenstrual age (PMA; weeks), body weight (BW; g), and aspartate aminotransferase (AST; IU/L). In addition, the volume of distribution (Vd; L/kg) was affected by gestational age (GA; weeks). The final pharmacokinetic model was as follows: CL = BW / PMA × 0.0453 × serum AST(-0.373); Vd = 2.54 (if GA >28 weeks) and Vd = 2.54 × 2.11 (if GA ≤28 weeks). The interindividual variabilities in CL and Vd were 39.9 and 83.0 %, respectively, and the residual variability was 20.9 %. To clarify the reasons for large interindividual variations, the enzymes involved in the metabolic pathway of doxapram were also determined. We found that doxapram was metabolized by CYP3A4/5. CONCLUSION: We report the population pharmacokinetics of doxapram in neonates and the involvement of CYP3A4/5 in its metabolism. The final model of population pharmacokinetics may be useful for formulating a safe and effective dosage regimen and for predicting serum doxapram concentrations in neonates.

Population pharmacokinetic analysis of linezolid in low body weight patients with renal dysfunction.

Linezolid has antibacterial activity against aerobic Gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA). Adjustment of the dose of linezolid has been proposed to be unnecessary in patients with reduced renal function. However, platelet counts and hemoglobin levels were shown to be significantly lower in such patients than in patients with normal renal function. The population pharmacokinetic (PPK) of linezolid was investigated in MRSA infected patients with renal dysfunction. Linezolid concentrations in serum were measured by high-performance liquid chromatography. PPK analysis was performed in the nonlinear mixed effects model (NONMEM) computer program. In the final PPK model, total body weight (TBW), estimated glomerular filtration rate (eGFR), hemoglobin (HB), and alanine amino transferase (ALT) were influential covariates on total body clearance (CL), and the volume of distribution (Vd) was affected by TBW, which was expressed as CL (L/h) = 0.00327 × TBW × eGFR(0.428) × HB(0.502) × 0.283 (ALT ≥ 100 IU/L) and CL (L/h) = 0.00327 × TBW × eGFR(0.428) × HB(0.502) (ALT < 100 IU/L), Vd (L) = 1.310 × TBW. The PPK parameters of linezolid obtained here are useful for the optimal use of linezolid with similar patient population characteristics.

Pharmacokinetics of linezolid in the mediastinum and pleural space.

The purpose of this study was to investigate the penetration of linezolid into the mediastinum and pleural space by comparing its concentration in the serum, mediastinum, and pleural space. The linezolid area under the concentration-versus-time curve from zero to 12h (AUC)(mediastinum fluid/serum) and AUC(pleural fluid/serum) ratio were 1.32 and 1.64, respectively. The results suggest that the linezolid concentration in the mediastinum varies as in the serum, and that the concentration in the mediastinum is the same as or greater than that in the serum.

Incompatibility between propericiazine oral solution and tea-based drink.

Here, we studied the incompatibility between an oral solution of propericiazine (PCZ), an antipsychotic drug, and various commercially available bottled tea-based drinks. When 0.5 mL of the PCZ oral solution (10 mg/mL) was mixed with 16.5 mL of a tea-based drink (such as green tea, oolong tea, and black tea), the residual PCZ content declined to approximately 50% in some mixed solutions. After mixing with other tea-based drinks, the residual PCZ content declined to approximately 30%, while in others, it changed very little. The residual PCZ content declined immediately after mixing with tea-based drinks, but the rate remained almost unchanged for the next 24 h. Furthermore, the pH of the mixture increased to 4.5-5.1 after the oral solution of PCZ (original pH 3.8) was diluted with various tea-based drinks. Afterwards, the pH did not change for 24 h. The mixture became cloudy immediately after diluting PCZ oral solution with tea-based drinks, and the insoluble substance gradually precipitated. In order to elucidate factors responsible for the decline in the content of PCZ, a (-)-epigallocatechin gallate solution, which is a main ingredient of green tea polyphenol, was mixed with the PCZ oral solution. After mixing, the residual PCZ content declined to approximately 60-75%. On the other hand, the content of PCZ did not decline when a (-)-epigallocatechin solution was mixed with the PCZ oral solution. The results from this study demonstrated that PCZ content was reduced after dilution in tea-based drinks because of the interaction between PCZ and polyphenol with a galloyl group in tea-based drinks.

Evaluation of the pharmacokinetics of linezolid in an obese Japanese patient.

We evaluated the pharmacokinetics of linezolid in the case of an obese Japanese patient (body weight 116 kg; body mass index 37 kg/m(2)). Linezolid was administered at a dose of 600 mg by intravenous drip infusion for 60-90 min at 12-h intervals. The results showed increased clearance of linezolid and a reduced serum concentration compared to population pharmacokinetic parameters, with trough levels below the 90% minimum inhibitory concentration. However, linezolid was effective for improving lung infection and inflammation in our patient, which may be due to its particularly effective transfer into lung tissues. Linezolid undergoes slow non-enzymatic oxidation in vivo that may be increased in obese patients, and this may account for the greater clearance. Our findings are useful for the planning of linezolid therapy in obese patients.

[Mechanism of interaction between risperidone and tea catechin (2) influence of presence of galloyl group in catechin on insoluble complex formation with risperidone].

The influence of the presence of a galloyl group in catechin on complexation with risperidone (RISP) was examined using (--)-epigallocatechin gallate (EGCg) and (--)-epigallocatechin (EGC), which are present in green tea as tea catechins. By quantitative analysis using HPLC, it was found that EGCg formed an insoluble complex with RISP for concentration dependence, whereas EGC did not. The large contribution of the galloyl group of catechin to form an insoluble complex with RISP was recognized in this study. In a molecular modeling study, it was found that the EGCg-R complex (EGCg with RISP) formed three hydrogen bonds between the hydroxyl groups of EGCg and the two N atoms and an O atom of RISP. The hydrogen bond between the hydroxyl group of the galloyl ring in EGCg and the N atom of the piperidine ring in RISP stabilized EGCg-R more energetically. The EGC-R complex (EGC with RISP) also formed three hydrogen bonds, but the N atom of the piperidine ring in RISP did not participate in hydrogen bond formation. According to the calculation using the COSMO-RS method, the water solubility of the EGCg-R complex was 1/26 that of the EGC-R complex. Therefore, the EGCg-R complex was difficult to dissolve in water. In the (1)H-NMR spectra of RISP in DMSO-d(6), although chemical shifts of protons near the N atom on the piperidine ring moved downfield on the addition of EGCg, no change in chemical shifts of these protons was observed on the addition of EGC. Therefore, based on these results, the galloyl group of EGCg contributes to the formation of an insoluble complex between tea catechin and RISP, and this insoluble complex is stabilized by the hydrogen bond between the hydroxyl group of the galloyl ring in EGCg and the N atom of the piperidine ring in RISP.

Population pharmacokinetic investigation for optimization of amiodarone therapy in Japanese patients.

BACKGROUND: Optimal use of amiodarone (AMD) requires information regarding the drug's pharmacokinetics and the influence of various factors on the drug's disposition. This study was conducted to establish the role of patient characteristic in estimating doses of AMD using nonlinear mixed effects modeling in Japanese patients treated with oral therapy. METHODS: Serum concentrations of AMD were determined by high-performance liquid chromatography. The 151 serum trough concentrations from 23 patients receiving repetitive oral AMD were collected. Analysis of the pharmacokinetics of AMD was accomplished using a 1-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on AMD disposition was investigated. RESULTS: Estimates generated by nonlinear mixed effects modeling indicated that the clearance of AMD was influenced by the demographic variables: total body weight (TBW), daily dosage of AMD (DD), body mass index (BMI), gender (GEN), duration of AMD dosing (DUR), and patient clearance factor (Conc(θ); Conc = serum trough concentration of AMD). The final pharmacokinetic parameters were CL/F (L/h) = 0.072·TBW·Conc(-1.01)·1.95(DD≥200)·0.931(BMI≥25)·1.37(GEN)·DUR(-0.016), and Vd/F (L) = 78.4·TBW, where CL is total body clearance and Vd is volume of distribution. As all doses were given orally, it was impossible to assess the bioavailability (F). DD ≧200 is an indicator variable that has a value of 1 if the patient is receiving more than 200 mg daily dosage of AMD, and 0 otherwise. BMI ≧25 is an indicator variable that has a value of 1 if the BMI is 25 kg/m² and over, and 0 otherwise. GEN is an indicator variable that has a value of 1 if the patient is woman, and 0 otherwise. CONCLUSIONS: The authors developed new population pharmacokinetic parameters. Clinical application of the findings in the present study to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect.

Determination of digoxin clearance in Japanese elderly patients for optimization of drug therapy: a population pharmacokinetics analysis using nonlinear mixed-effects modelling.

BACKGROUND: Optimal use of digoxin in the elderly population requires information about the drug's pharmacokinetics and the influence of various factors on the drug's disposition. However, because of sampling restrictions, it is often difficult to perform traditional pharmacokinetic studies in elderly patients. OBJECTIVE: This study was conducted to determine the apparent total clearance of digoxin from serum after oral administration (CL/F) and to establish the role of patient characteristics in estimating doses of digoxin for elderly patients (age ≥65 years), using routine therapeutic drug monitoring data. METHODS: Analyses of the pharmacokinetics of digoxin were conducted using the nonlinear mixed-effects modelling (NONMEM®) software, a computer program designed to analyse pharmacokinetics in study populations by allowing pooling of data. Steady-state data (140 observations) obtained by routine therapeutic drug monitoring following repeated oral administration of digoxin in 94 hospitalized elderly patients (age ≥65 years) were analysed to establish the role of patient characteristics in estimating doses of digoxin for elderly patients. RESULTS: Estimates generated by NONMEM® indicated that digoxin CL/F was influenced by the demographic variables of total bodyweight (TBW), serum creatinine (SCr), age (AGE), presence of congestive heart failure (CHF), concomitant administration of the calcium channel antagonists (calcium channel blockers [CCBs]: verapamil, diltiazem or nifedipine), sex (SEX) and elderly clearance factor (trough serum concentration of digoxin; [C(trough)] θ). The full version of the final NONMEM® model was where CCB is 1 for concomitant administration of a CCB and is 0 otherwise; CHF is 1 for patients with CHF and is 0 otherwise; SEX is 0 for male and is 1 for female; and the elderly clearance factor C(trough)-0.180 is 1 for digoxin C(trough) <1.7 ng/mL. CONCLUSIONS: We developed a new model for elderly patient dosing of digoxin with good predictive performance. Clinical application of the findings of the present study to patient care may permit selection of an appropriate initial digoxin maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect. However, the digoxin dosage regimen should be based on an appraisal of the individual patient's clinical need for the drug.

Evaluation of the vancomycin dosage regimen based on serum creatinine used in the neonatal intensive care unit.

BACKGROUND: Vancomycin is frequently used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections; however, determining the optimal dosage for neonates is difficult because of their immature renal function. METHODS: Serum creatinine-based dosing was introduced in Kumamoto City Hospital Neonatal Medical Center. Serum trough concentration and therapeutic efficacy of vancomycin were evaluated before and after the introduction of the creatinine-based dosing. RESULTS: When the therapeutic range of serum trough concentration of vancomycin at steady state was set to 5-15 µg/mL, 20 trough concentrations (48.8%) were within the therapeutic range and 21 trough concentrations were outside the therapeutic range before the introduction of the serum creatinine-based dosing. After the introduction of serum creatinine-based dosing, 18 trough concentrations (81.8%) were within the therapeutic range and 4 trough concentrations were not, and there was an increase in the number of patients with trough concentrations in the therapeutic range (P= 0.01; Fisher's exact test). CONCLUSIONS: The serum creatinine-based dosing of vancomycin is useful in maintaining the appropriate serum level of vancomycin in neonates.

Population pharmacokinetic investigation of digoxin in Japanese infants and young children.

To establish the role of patient characteristics in estimating doses of digoxin for infants and young children using routine therapeutic drug monitoring data, the steady-state blood-level data (n = 245) after repetitive oral administration in 117 hospitalized infants and young children were analyzed using nonlinear mixed effects modeling (NONMEM), a computer program designed for analyzing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a 1-compartment pharmacokinetic model. Estimates generated by NONMEM indicated that the clearance of digoxin (CL/F; L/h) was influenced by the following demographic variables: total body weight (TBW), presence of congestive heart failure (CHF), and infant-young children clearance factor (trough serum concentration of digoxin; Conc). These influences could be modeled by the equation CL/F (L/h) = 0.302 · TBW (kg)¹·¹7 · 0.905(CHF) · Conc (trough serum digoxin concentration >1.7 ng/mL)⁻°·54°; F = 0.754, where CHF is 1 for presence of congestive heart failure, 0 otherwise; F is bioavailability, 1 for elixirs, 0.754 for powders; and Conc⁻°·54° is 1 for digoxin concentration <1.7 ng/mL. Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of his or her clinical need for the drug.

Population pharmacokinetic study of a test dose oral busulfan in Japanese adult patients undergoing hematopoietic stem cell transplantation.

PURPOSE: The aim of this study is to determine the population pharmacokinetics of oral busulfan in Japanese adults. METHODS: We previously underwent a clinical trial involving the dose adjustment of oral busulfan depending on the individual pharmacokinetics using a test dose in hematopoietic stem cell transplantation recipients. Seventy-one Japanese patients aged from 16 to 67 years were enrolled. After taking oral busulfan 0.5 mg/kg as a test dose, blood samples were collected at five time points from each patient. Busulfan concentrations were measured by high-performance liquid chromatography, and the individual parameters were estimated by using the nonlinear mixed effects model computer program. A one-compartment model with first-order absorption was sufficient to describe the concentration-time profile. RESULTS: The final pharmacokinetic parameter were the clearance (CL/F) = 0.153 L/h/kg, distribution volume (Vd/F) = 0.695 L/kg, and absorption rate constant (ka) = 2.39 h(-1). The inter-individual variabilities in CL/F, Vd/F and ka were 25.9, 26.2, and 111.8%, respectively, and the residual variability was 12.1% as the coefficient of variation. CONCLUSION: We developed a population pharmacokinetic model of oral busulfan in Japanese adults. The final population model was implemented into the program excel, leading to an easy and proper therapeutic monitoring of oral BU by using small number of samples.

Population pharmacokinetics of pranlukast hydrate dry syrup in children with allergic rhinitis and bronchial asthma.

This study aimed to assess the steady-state pharmacokinetics of pranlukast, a leukotriene receptor antagonist, in children with allergic rhinitis and bronchial asthma, and to clarify factors affecting apparent clearance (CL/F). A total of 192 plasma samples were obtained from 98 children (rhinitis 64, asthma 13, complications 21), aged 3-14 years in 2 clinical trials. Plasma concentration of pranlukast was determined by liquid chromatography connected with a tandem mass spectrometer and analyzed by a population approach using NONMEM program. The plasma concentration-time course of pranlukast was described by using a one-compartment model with the first-order absorption and lag time. The robustness of the population pharmacokinetic model was evaluated by using 200 bootstrap samples. The results of population pharmacokinetic analysis showed that only age was a factor affecting the CL/F per body weight, with CL/F decreasing with increasing age. No significant variation was seen in the CL/F between rhinitis and asthma. The interindividual variability in the CL/F and the residual variability were 19.7% and 48.4%, respectively. All the parameters fell within 10% of the bootstrapped mean. In conclusion, the results show that age is the most influential factor for explaining interindividual variability in CL/F, and the difference in diseases does not affect CL/F.

Lithium concentration correlates with QTc in patients with psychosis.

QT prolongation induced by antipsychotics has been reported to be a determinant for the development of torsade de pointes and sudden death. However, the effect of lithium on QT interval has not been fully clarified. The aim of the present study was to elucidate the relationship between serum lithium concentration and QT interval in patients treated with lithium. We examined serum lithium concentrations and electrocardiographic features in 39 inpatients with bipolar affective disorder or schizophrenia. The longest QT interval in the 12 electrocardiographic leads was measured using GE Marquette QT guard System Software, and Bazett formula was used for heart rate correction. The longest QTc was positively correlated with lithium concentration ( r = 0.46, P = .003). Multiple regression analysis revealed that sex (female, P = .037), lower serum K + concentration ( P = .029), and especially, higher serum lithium concentration ( P = .009) were determinants for the prolongation of the QTc.

Chronopharmacology of melatonin in mice to maximize the antitumor effect and minimize the rhythm disturbance effect.

The influence of dosing time on the antitumor effect and the rhythm disturbance effect of melatonin (MLT) was investigated in ICR male mice under a light/dark (12:12) cycle. In tumor-bearing mice, the antitumor effect of MLT (1 mg/kg intraperitoneal) was most effective in the dark phase; and the rhythm disturbance effect of MLT on the locomotor activity was more serious in the light phase than in the dark phase. The antitumor effect and the rhythm disturbance effect of MLT increased when the specific binding of MLT receptor in target tissues, tumor or suprachiasmatic nucleus, increased and they decreased when the level decreased. Furthermore, because luzindole, an MT1 and MT2 blocker, caused the antitumor effect or rhythm disturbance effect of MLT to decrease, it is suggested that the time-dependent change of the pharmacological effects of MLT were influenced by that of MLT receptor(s) function. On the other hand, there was no significant dosing time-dependent change of MLT concentration in tumor or brain after injection. Thus, the pharmacokinetic factor does not seem to contribute to the dosing time-dependent effect of MLT. These results suggest that by choosing the most suitable dosing time for MLT, the efficacy of the drug can be increased, and the toxicity of the drug can be decreased in certain experimental and clinical situations.

Dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity in rats.

Cardiac toxicity caused by doxorubicin (adriamycin) is a serious dose-limiting factor in the clinical situation. However, the influence of doxorubicin dosing time has not been clarified from the viewpoints of cardiotoxic development and its mechanism. In this study, we have investigated the dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity after repeated administration of doxorubicin in rats. When doxorubicin (5 mg kg(-1), i.p.) was administered every seven days (total of 30 mg kg(-1)) at 3, 9, 15 or 21 h after the light was turned on (HALO), toxic death was significantly higher in the 9 HALO treated group than the other groups. When doxorubicin was injected every seven days for 28 days at 9 or 21 HALO, we measured the levels of creatine kinase, malondialdehyde (MDA; an index of lipid peroxide), and glutathione peroxidase (GPx) as markers of cardiotoxicity. On days 14 and 28, creatine kinase levels were significantly higher in the 9-HALO group compared with the 21-HALO group (P< 0.01, respectively). On day 14, MDA levels increased significantly in the 9 HALO group compared with the 21 HALO group (P< 0.01). A single dose of doxorubicin was administered at 9-h or 21-h after the light was turned on to investigate the dosing-time-dependent difference of the pharmacokinetics. The area under the plasma time-concentration curve showed a significant increase at 9 HALO compared with 21 HALO (P< 0.05). These results suggested that the dosing-time-dependent difference of cardiotoxicity induced by doxorubicin was closely related to the daily variation of doxorubicin pharmacokinetics. In conclusion, the choice of optimal dosing time based on the chronopharmacokinetics of doxorubicin may decrease the cardiotoxicity and enable the practice of effective and safe chemotherapy of doxorubicin.

Chronopharmacology of analgesic effect and its tolerance induced by morphine in mice.

The influence of morphine dosing time on analgesic effect after acute or chronic treatment, recovery of analgesic effect after once developed tolerance, and their pharmacological mechanisms were investigated in ICR male mice under a 12-h light/dark cycle (light on from 7:00 AM to 7:00 PM). There was a significant 24-h rhythm in the latency of thermal response at 30 min after morphine injection. The analgesic effect was significantly greater at the dark phase than at the light phase. The rhythmic pattern resembled overall the rhythm occurring in the latency of thermal response under non-drugged state. The absolute value of morphine analgesic effect (the real time spent on the hot-plate) on days 1 and 2 after morphine daily injection was significantly larger after morphine injection at 9:00 PM than after saline injection at 9:00 PM or after morphine injection at 9:00 AM. The recovery from tolerance of analgesic effect was significantly faster at the dark phase than at the light phase. The time-dependent difference in the analgesic effect after chronic treatment or recovery from tolerance is closely related to that in the expression of mu-opioid receptor. The present study suggests that 24-h rhythm of morphine analgesic effect is consistent with 24-h rhythm of mu-opioid receptor expression.

Cell kinetics-dependent antitumor effect of irinotecan hydrochloride induced by the synchronizing effect of hydroxyurea: cell kinetics and dosing time.

Influence of hydroxyurea (HU) on the antitumor effect of irinotecan hydrochloride (CPT-11) was investigated in ICR male mice transplanted with sarcoma 180 cells (S-180). A single dose of CPT-11 (100 mg/kg) was injected at various times after a single dose of HU (300 mg/kg). The relative tumor weight varied significantly depending on the timing of CPT-11 injection after HU injection (P < 0.01). The higher antitumor effect of CPT-11 was observed when DNA synthesis of S-180 cells increased (20 hr), and the lower effect was observed when the DNA synthesis decreased (0 hr). The loss of body weight also varied significantly depending on the timing of CPT-11 injection after HU injection (P < 0.01). The toxicity of CPT-11 was higher when the inhibitory effect of HU on DNA synthesis of bone marrow cells was stronger (15 hr), and the lower toxicity was observed when the inhibitory effect was not observed (0 hr). The plasma SN-38 concentration at 2 hr after CPT-11 injection was higher at 20 hr after HU injection than at 0 hr after HU injection. The difference in plasma esterase activity between 0 hr and 20 hr after HU injection was regarded as the mechanism underlying the dosing time-dependent difference of the SN-38 concentration. These experiments suggest that HU can produce a different phase of cell cycle between tumor cells and normal cells. This leads to increase the antitumor effect of CPT-11 without increasing the adverse effect of the drug. It is essential to consider the dosing time in the two-drug combination therapy.

Relationship between 24-hour rhythm in antiviral effect of interferon-beta and interferon-alpha/beta receptor expression in mice.

The influence of interferon-beta (IFN-beta) dosing time on antiviral activity was investigated in ICR male mice under light-dark cycle conditions (lights on at 07:00, off at 19:00) with food and water available ad libitum. There was a significant dosing time-dependent change in 2',5'-oligoadenylate synthetase (2',5'-OAS) activities, as an index of antiviral activity, in liver at 12 h after IFN-beta (15 MIU/kg, i.v.) injection. IFN-beta-induced 2',5'-OAS activity was more potent after the drug injection during the late dark phase. The higher antiviral effect of IFN-beta was observed when the interferon-alpha/beta receptor (IFNAR) expression in the liver increased, and the lower effect was observed when its expression decreased. IFN-beta-induced fever was more serious after IFN-beta injection from the late dark phase to the early light phase. A significant dosing time-dependent change was demonstrated for plasma IFN-beta concentrations, which showed a higher level during the light phase and a lower level during the dark phase. The dosing time-dependent change of plasma IFN-beta concentrations was not associated with that of the antiviral effect or fever induced by IFN-beta. These results suggest that selecting the most suitable dosing time of IFN-beta, associated with the 24-h rhythm of IFNAR expression in the liver, may be important to increase effectively the antiviral activity of the drug in experimental and clinical situations.