Dose-normalized Plasma Concentration Research Articles

Characterization of plasma daptomycin in patients with serum highly glycated albumin and obesity

PurposePlasma daptomycin has not been fully characterized in diabetic and obese patients. This study aimed to evaluate the associations of plasma daptomycin with glycation of serum albumin and obesity. MethodsInfectious patients (n = 70) receiving intravenous daptomycin were enrolled. The plasma concentration of total and free daptomycin were determined using liquid chromatograph-tandem mass spectrometer. The associations of the plasma concentrations of daptomycin with clinical factors including serum albumin fractionations and physical status (obese including overweight, body mass index ≥ 25.0) were investigated. Daptomycin doses were adjusted using total body-weight. ResultsThe serum albumin level was positively and negatively correlated with the plasma concentration of total daptomycin and its free fraction proportion, respectively. The serum non-glycated albumin was negatively correlated with the free fraction proportion. The dose-normalized plasma concentration of total daptomycin was higher in the obese patients than in non-obese patients when the body-weight was corrected with total and adjusted values. For the dose adjustment with lean body-weight, no difference was observed in the dose-normalized plasma concentration of total daptomycin between the physical statuses. For each body-weight correction method, physical status did not affect the dose-normalized plasma concentration of free daptomycin. ConclusionThe glycation of serum albumin and obesity did not associate with dose-normalized plasma free daptomycin. In obese patients, daptomycin dosage adjustment with total body-weight and adjusted body-weight may lead to an apparent excessive exposure resulting in overdosage compared to lean body-weight.

Monitoring Simvastatin Adherence in Patients With Coronary Heart Disease: A Proof-of-Concept Study Based on Pharmacokinetic Measurements in Blood Plasma.

Poor statin adherence remains a public health concern associated with adverse outcomes. We evaluated the use of pharmacokinetic measurements to monitor adherence to simvastatin in patients with coronary heart disease (CHD). Eighteen patients with CHD taking an evening dose of simvastatin 20 mg (n = 7), 40 mg (n = 5), or 80 mg (n = 6) were examined at steady-state pharmacokinetics. Ten patients were instructed to interrupt simvastatin dosing and return for blood sampling for the subsequent 3 days. Dose-normalized plasma concentrations of simvastatin lactone and simvastatin acid and the sum of the 2 were evaluated to discriminate between adherent dosing and dose omission. Bioanalytical quantification was performed using liquid chromatography-tandem mass spectrometry. A simvastatin acid cutoff of 1.0 × 10 -2 nmol -1 ·L -1 ·mg -1 identified 100% of those omitting 2 doses and 60% of those omitting a single dose. Simvastatin acid showed superior ability to discriminate dose omission, as well as the best agreement between samples handled at ambient and cool temperatures (median deviation 3.5%; interquartile range -2.5% to 13%). The cutoff for a morning dose schedule, with a similar ability to discriminate, was estimated at 2.0 × 10 -3 nmol -1 ·L -1 ·mg -1 . The present method discriminated between adherence and reduced adherence to simvastatin therapy in patients with CHD. Sample handling is feasible for routine practice, and the assessment of adherence can be performed by direct measurement of simvastatin acid in a blood sample, according to defined cutoff values. Further studies validating the cutoff value and utility for clinical application are encouraged.

Effects of Corticosteroid Treatment on Mycophenolic Acid Exposure in Renal Transplant Patients-Results From the SAILOR Study.

Background: Mycophenolic acid (MPA) is a potent immunosuppressive agent used in solid organ transplantation. MPA exhibits large interindividual variation in dose-normalized plasma concentrations but is nevertheless usually prescribed as a fixed dose without use of therapeutic drug monitoring (TDM). Data on the effect of corticosteroid (CS) treatment on MPA concentrations during concomitant tacrolimus treatment remains sparse.Methods: Data is based on TDM of MPA area under the concentration curve (AUC) in 210 renal transplant recipients participating in the prospective, randomized, controlled, multi-center trial (SAILOR) where a steroid-free immunosuppressive regimen with mycophenolate mofetil (MMF) and low-dose tacrolimus was compared with a conventional prednisolone-based treatment regimen. Multilevel mixed-effects linear regression post-hoc analyses of MPA AUC was performed.Results: Median MPA AUC at baseline (within the first 2 weeks post-transplant) in patients taking 2 g MMF daily was 53 mg*h/L (interquartile range: 43–69 mg*h/L, min: 24—max: 117 mg*h/L). Between-patient variation in MPA AUC was up to 5-fold on the same MMF dose. Patients in the steroid-free group had 12.5% lower (95% CI; 3.2–20.9%, p = 0.01) MPA AUC levels at baseline compared to the steroid treated group. During follow-up (14 days–2 years post-transplant) there were no significant differences in MPA AUC between the groups with MPA AUC being 4.2% lower (95% CI: −4.8%−12,5%, p = 0.35) in the steroid-free vs standard treatment group in restricted analysis after multivariate adjustment for tacrolimus trough level, body weight, time after transplantation and MMF dose. MMF dose was positively correlated with MPA AUC (p < 0.001) whereas body weight was negatively correlated with MPA AUC (p < 0.001). MPA AUC was 0.4% (95% CI: 0.2–0.6%, p < 0.001) lower per 1 kg increase in weight. Tacrolimus trough levels had no significant effect on MPA AUC.Conclusion: Immunosuppression with CS during concomitant tacrolimus treatment was shortly after transplantation associated with a significantly higher MPA exposure but the effect was small and not maintained during follow-up. Low body weight was associated with higher MPA exposure, which suggests a potential for weight adjusted MMF dosing.

A novel direct method to determine adherence to simvastatin therapy in patients with coronary heart disease

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): National Association of Health OnBehalf NORCOR Background Poor adherence to statin therapy remains a public health concern associated with adverse clinical outcome. Reliable classification and detection of statin adherence is needed in clinical practice and for clinical studies with overall aim to improve the lipid management. Simvastatin is a frequently used statin in cardiovascular disease prevention. Purpose To develop a feasible test based on spot blood samples to monitor the adherence to simvastatin therapy in coronary heart disease (CHD) patients. Methods Eighteen CHD patients on an evening dose of simvastatin 20 mg (n = 7), 40 mg (n = 5) and 80 mg (n = 6) were studied at steady-state pharmacokinetics. Ten patients were instructed to avoid simvastatin dosing and return for blood sampling the subsequent three days. Dose-normalized plasma concentrations of simvastatin lactone, simvastatin acid and the sum of the two were evaluated as discriminators between adherent dosing and dose avoidance. Bioanalytical quantifications were performed with liquid chromatography tandem mass spectrometry. Results The dose-normalized plasma concentrations at steady-state demonstrated 23-fold and 39-fold interindividual variabilities for simvastatin lactone and simvastatin acid. A simvastatin acid cut-off at 1.0·10^-2 nmol/L/mg identified 100% of those omitting 2 doses and 60% of those omitting a single dose (Figure 1). Simvastatin acid showed superior ability to discriminate dose avoidance from adherence, and also the best agreement between samples handled at ambient and cool temperature (median deviation 3.5%, interquartile range -2.5 to 13%). A cut-off for morning dose schedule, with similar ability to discriminate, was estimated at 2.0·10^-3 nmol/L/mg. Conclusion A novel method discriminating between good and poor adherence to simvastatin therapy in CHD patients has been developed. The sample handling is feasible for routine practice, and the assessment of adherence can be performed by direct measurements in spot blood samples, according to specific cut-off values. Abstract Figure 1 Drug levels vs dose avoidance

Anti-Lymphocyte Antigen 6 Complex, Locus E-Seco-Cyclopropabenzindol-4-One-Dimer Antibody-Drug Conjugate That Forms Adduct with α1-Microglobulin Demonstrates Slower Systemic Antibody Clearance and Reduced Tumor Distribution in Animals.

Anti-Ly6E-seco-cyclopropabenzindol-4-one dimer antibody-drug conjugate (ADC) has been reported to form an adduct with α1-microglobulin (A1M) in animal plasma, but with unknown impact on ADC PK and tissue distribution. In this study, we compared the PK and tissue distribution of anti-Ly6E ADC with unconjugated anti-Ly6E mAb in rodents and monkeys. For PK studies, animals received an intravenous administration of anti-Ly6E ADC or unconjugated anti-Ly6E mAb. Plasma samples were analyzed for total antibody (Tab) levels and A1M adduct formation. PK parameters were generated from dose-normalized plasma concentrations. Tissue distribution was determined in tumor-bearing mice after a single intravenous dosing of radiolabeled ADC or mAb. Tissue radioactivity levels were analyzed using a gamma counter. The impact of A1M adduct formation on target cell binding was assessed in an in vitro cell binding assay. The results show that ADC Tab clearance was slower than that of mAb in mice and rats but faster than mAb in monkeys. Correspondingly, the formation of A1M adduct appeared to be faster and higher in mice, followed by rats, and slowest in monkeys. Although ADC tended to show an overall lower distribution to normal tissues, it had a strikingly reduced distribution to tumors compared with mAb, likely due to A1M adduct formation interfering with target binding, as demonstrated by the in vitro cell binding assay. Together, these data 1) demonstrate that anti-Ly6E ADC that forms A1M adduct had slower systemic clearance with strikingly reduced tumor distribution and 2) highlight the importance of selecting an appropriate linker-drug for successful ADC development. SIGNIFICANCE STATEMENT: Anti-lymphocyte antigen 6 complex, locus E, ADC with seco-cyclopropabenzindol-4-one-dimer payload formed adduct with A1M, which led to a decrease in systemic clearance but also attenuated tumor distribution. These findings demonstrate the importance of selecting an appropriate linker-drug for ADC development and also highlight the value of a mechanistic understanding of ADC biotransformation, which could provide insight into ADC molecule design, optimization, and selection.

Risk of Prolonged Corrected QT Interval With Amisulpride Therapy for Renal Function Management in Patients With Schizophrenia.

Amisulpride (AMI) is a popular antipsychotic drug prescribed for the management of schizophrenia. However, patients may experience prolonged corrected QT (QTc) interval. We therefore aimed to assess the risk factors for QTc prolongation during AMI therapy in patients with schizophrenia. This study retrospectively enrolled 271 patients with schizophrenia. Continuous variables were analyzed with a t test or analysis of variance, and categorical variables were analyzed with a χ test. Patients with and without QTc prolongation were compared using a backward stepwise logistic regression analysis to identify the important variables. Comedication of AMI with clozapine (odds ratio, 3.5 [95% confidence interval, 1.3-9.7]) and decreased renal function (mildly decrease, 3.4 [1.2-10.1]; mild to moderately decreased, 4.8 [1.3-17.3]; moderately decreased, 13.6 [2.0-90.6]) were identified as the independent risk factors of QTc prolongation. The dose-normalized plasma concentration of AMI (plasma concentration per dose) was significantly higher in the QTc prolongation group (z = -1.735, P = 0.015) and renal dysfunction group (F = 16.002, P < 0.001). Renal function should be monitored in patients prescribed with AMI, particularly in those taking clozapine. Plasma concentration per dose values can be considered as a risk factor of QTc interval prolongation. The founding help clinicians to analyze the risk of QTc prolongation before prescribing AMI and to monitor QTc prolongation during AMI therapy.

Dose-adjusted plasma concentrations of sublingual buprenorphine are lower during than after pregnancy

Buprenorphine is a Food and Drug Administration-approved maintenance therapy for opioid use disorders and is increasingly being used in pregnant women with opioid use disorders as an alternative to methadone. Dosing of buprenorphine in pregnant women is based on the regimen recommended for nonpregnant females and males. Limited data are available defining the pharmacokinetic properties of sublingual buprenorphine administered during pregnancy. This study evaluated the impact of physiological changes associated with pregnancy on the pharmacokinetics of sublingual buprenorphine during and after pregnancy. Pregnant women (n= 13), between 180/7 and 376/7 weeks' singleton gestation, receiving sublingual buprenorphine twice daily for opioid use disorders were studied. Pharmacokinetic-2 studies were performed between 18 and 25 weeks (n= 7), pharmacokinetic-3 studies were performed between 31 and 37 weeks (n= 11), and pharmacokinetic-P was performed 4-18 weeks postpartum (n= 10). On the day of the study, blood was withdrawn prior to the daily morning dose of buprenorphine and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, and 12 hours after the dose. Buprenorphine plasma concentrations were analyzed by liquid chromatography tandem mass spectrometric detection. All pharmacokinetic parameters were observed or estimated using Microsoft Excel. Statistical analyses were performed to identify significant changes in study participants' buprenorphine pharmacokinetic parameter estimates over the duration of the study. Univariate linear and generalized linear mixed models were used to investigate changes in these measures over time, some of which were log transformed for normality. Dose-normalized (plasma concentration per dose) buprenorphine plasma concentrations were significantly lower during pregnancy (pharmacokinetic-2 plus pharmacokinetic-3) than during the postpartum period (pharmacokinetic-P). Specific pharmacokinetic parameters (and level of significance) were as follows: the area under the buprenorphine plasma concentration-time curves (P < .003), maximum buprenorphine concentrations (P < .018), buprenorphine concentrations at 0 hour (P < .002), and buprenorphine concentrations at 12 hours (P < .001). None of these parameters differed significantly during pregnancy (ie, pharmacokinetic-2 vs pharmacokinetic-3). The time to maximum buprenorphine concentrations did not differ significantly between groups. The dose-normalized plasma concentrations during a dosing interval and the overall exposure of buprenorphine (area under the buprenorphine plasma concentration-time curves) are lower throughout pregnancy compared with the postpartum period. This indicates an increase in apparent clearance of buprenorphine during pregnancy. These data suggest that pregnant women may need a higher dose of sublingual buprenorphine compared with postpartum individuals. The dose of buprenorphine should be assessed after delivery to maintain similar buprenorphine exposure during the postpartum period.

CYP3A activity based on plasma 4β-hydroxycholesterol during the early postpartum period has an effect on the plasma disposition of amlodipine

This study aimed to evaluate plasma 4β-hydroxycholesterol as an endogenous marker of CYP3A4/5 activity in early postpartum women and its impact on the plasma disposition of amlodipine. Twenty-seven early postpartum women treated with amlodipine for pregnancy-induced hypertension were enrolled. The plasma concentration of 4β-hydroxycholesterol and its ratio to cholesterol in postpartum and in non-perinatal women were evaluated. The predose plasma concentration of amlodipine was determined at steady state. The medians of the plasma 4β-hydroxycholesterol concentration at day 0–3 and 8–21 after delivery were 146 and 161 ng/mL, respectively. No significant difference was observed in the plasma concentration of 4β-hydroxycholesterol between the postpartum periods. The plasma concentration of 4β-hydroxycholesterol and its ratio to cholesterol in postpartum women were significantly higher than those in non-perinatal women. A large individual variability was observed in the dose-normalized plasma concentration of amlodipine in early postpartum women. A weak negative correlation was observed between the dose-normalized plasma concentration of amlodipine and the plasma concentration of 4β-hydroxycholesterol. In conclusion, early postpartum women possessed higher CYP3A activity based on plasma 4β-hydroxycholesterol and had a large pharmacokinetic variability in amlodipine. CYP3A activity during the early postpartum period had an effect on the plasma disposition of amlodipine.

Impact of inflammation and concomitant glucocorticoid administration on plasma concentration of triazole antifungals in immunocompromised patients

BackgroundThe expression of hepatic CYP3A decreases with inflammatory response but increases with glucocorticoid administration. The aim of this study was to evaluate the plasma concentration of voriconazole and itraconazole under inflammatory conditions and glucocorticoid therapy. MethodsForty-one voriconazole- and 42 itraconazole-treated immunocompromised patients were enrolled in this study. Plasma concentrations of triazoles and their major metabolites at 12h after dosing were determined. The relationships between C-reactive protein (CRP), prednisolone dose, and plasma exposure parameters of triazole were evaluated. ResultsPlasma concentration of voriconazole was not correlated with that of its N-oxide. A higher CRP was correlated with a higher dose-normalized plasma concentration of voriconazole and a lower plasma concentration ratio of N-oxide to voriconazole. Prednisolone dose was weakly correlated with the plasma concentration ratio of N-oxide to voriconazole. Plasma concentration of itraconazole had a good correlation with that of its hydroxide. Parameters of itraconazole were not associated with CRP and prednisolone dose. ConclusionsAn inflammatory state raised the plasma concentration of voriconazole through its metabolic reduction, while it did not have an effect on plasma concentration of itraconazole. Concomitant glucocorticoid administration slightly elevated the voriconazole metabolism, although it did not affect the plasma concentration of triazoles.

Influence of ABCC2, SLCO1B1, and ABCG2 Polymorphisms on the Pharmacokinetics of Olmesartan

This study was designed to determine whether genetic polymorphisms of multidrug-resistant protein 2 (ABCC2), organic anion transporting polypeptide 1B1 (SLCO1B1), and breast cancer resistance protein (ABCG2) have an effect on olmesartan pharmacokinetics in Korean subjects. Sixty-eight healthy male volunteers who participated in previous pharmacokinetics studies of olmesartan medoxomil (single dose, 20 mg or 40 mg) were enrolled. All subjects were analyzed and grouped according to the genotypes of ABCC2, SLCO1B1, and ABCG2. The dose-normalized peak plasma concentration (C(max)) and area under the plasma concentration-time curve (AUCt) values were analyzed. The dose-normalized mean C(max) and AUC(t) in the ABCC2 -24CT genotype group were higher than those in the -24CC genotype group [C(max,dn): CT 26.1 ± 6.5 (ng/mL)/mg versus CC 22.1 ± 6.7 (ng/mL)/mg, P = 0.010, AUC(t,dn): CT 178.7 ± 45.6 (hr·ng(-1)·mL(-1))/mg versus CC 149.9 ± 39.8 (hr·ng(-1)·mL(-1))/mg, P = 0.010]. The difference in AUC(t,dn) between the ABCC2 -1549GG and -1549GA genotype groups was statistically significant [GG 149.0 ± 41.0 (hr·ng(-1)·mL(-1))/mg versus GA 174.1 ± 43.3 (hr·ng(-1)·mL(-1))/mg, P = 0.019]. No significant differences were observed for any other single nucleotide polymorphism in ABCC2, SLCO1B1, or ABCG2. The ABCC2 -24CC genotype group exhibited lower systemic exposure of olmesartan than the -24CT genotype group, whereas no significant differences were observed in the other transporter genotype groups.

Impact of Concentrative Nucleoside Transporter 1 Gene Polymorphism on Oral Bioavailability of Mizoribine in Stable Kidney Transplant Recipients

Mizoribine, an immunosuppressive anti-metabolite, is largely excreted into urine in its unchanged form, and its pharmacokinetics has been considered to be dependent on the glomerular filtration rate. However, the pharmacokinetic disposition of mizoribine has not been fully clarified. The aim of this study was to evaluate the pharmacokinetic disposition of mizoribine based on polymorphism of concentrative nucleoside transporter (CNT) 1 gene in kidney transplant recipients. Thirty-four Japanese stable recipients receiving an immunosuppressive regimen containing mizoribine for more than four months after transplantation were enrolled. Each recipient had been receiving a fixed dose of mizoribine for at least one month before enrolment. Oral bioavailability of mizoribine was obtained by dividing its amount in 24-hr urine by the daily dose. The median and interquartile range of the dose-normalized plasma concentration of mizoribine at 12 hr (C(12)) were 6.11 and 3.47-10.9 ng/ml per mg, respectively. The median bioavailability of mizoribine was 44.8%, and interindividual variability was also observed (interquartile range, 37.8-61.5%). The correlation coefficient between creatinine clearance and substitute renal clearance (CL(MZ)) estimated from the mizoribine C(12) was 0.65. The CNT1 G565A allele frequency was 51.5%. The mizoribine bioavailability was significantly lower in 565GA and AA than that in GG (median, 42.0%, 41.4% and 62.4%, respectively). No significant differences were observed in the dose-normalized C(12) of mizoribine and substitute CL(MZ) between the G565A genotypes. The mizoribine bioavailability was affected by CNT1 G565A in kidney transplant recipients. CNT1 G565A would contribute to interindividual differences in plasma disposition of mizoribine.

Comparison of Steady-State Plasma Concentrations of Armodafinil and Modafinil Late in the Day Following Morning Administration

Armodafinil, the R- and longer-lasting isomer of modafinil, may maintain higher plasma drug concentrations compared with racemic modafinil because of stereospecific differences in elimination of its isomers. This analysis set out to compare the steady-state pharmacokinetic profiles of armodafinil and modafinil on a milligram-to-milligram basis following once-daily administration. A post hoc analysis of two multiple-dose pharmacokinetic studies in healthy male subjects aged 18-50 years was conducted to compare dose-normalized (200 mg/day) plasma drug concentration and pharmacokinetic data for subjects in each study who completed 7 days of once-daily (morning) administration of armodafinil (n = 34) or modafinil (n = 18). Dose-normalized plasma concentrations of armodafinil on day 7 were higher than those of modafinil, with the greatest differences being observed later in the day. Across the 24-hour dose interval, plasma drug concentration fluctuation and swing were 28% and 42% less, respectively, with armodafinil than with modafinil. In addition, average late-day (3 pm to 7 pm after an 8 am dosing) plasma drug concentrations and partial values for the area under the plasma concentration versus time curve for 7-11 hours after dosing were both 44% higher with armodafinil. At steady state, armodafinil produces consistently higher plasma drug concentrations late in the day than modafinil when compared on a milligram-to-milligram basis. The distinct pharmacokinetic profile of armodafinil compared with that of the racemate may result in fundamentally different durations of action. These differences between the two medications cannot be made equivalent by increasing the dose of the racemate without introducing potential safety concerns.

Effects of CYP2D6 and CYP3A5 Genotypes on the Plasma Concentrations of Risperidone and 9-Hydroxyrisperidone in Korean Schizophrenic Patients

This study was conducted to evaluate the effects of the CYP2D6 and CYP3A5 genotypes on the steady-state plasma levels of risperidone (RIS), 9-hydroxyrisperidone (9-OH-RIS), and the active moiety (RIS plus 9-OH-RIS) in Korean schizophrenic patients. Sixty-four Korean schizophrenic patients were enrolled. CYP2D6 and CYP3A5 genotypes were determined, and the plasma levels of RIS and 9-OH-RIS were measured using high-performance liquid chromatography. The dose-normalized plasma concentrations of RIS, 9-OH-RIS, and the active moiety were compared according to the CYP2D6 and CYP3A5 genotypes. Among the patients, 57 were CYP2D6 extensive metabolizers (EMs; CYP2D6*1/*1, *1/*10, and *10/*10) and 7 were CYP2D6 poor metabolizers (PMs; CYP2D6*1/*5 and *10/*5). For the CYP3A5 genotype, 30 patients were CYP3A5*1 expressors (*1/*1 [n = 1] and *1/*3 [n = 29]) and 34 patients were CYP3A5 nonexpressors (*3/*3). The plasma levels of RIS (2.03 ng/mL per milligram for EMs vs 5.57 ng/mL per milligram for PMs, P < 0.001) and 9-OH-RIS (5.06 ng/mL per milligram for EMs vs 0.22 ng/mL per milligram for PMs, P < 0.001) were significantly different among CYP2D6 genotype groups, but the CYP2D6 EMs (7.09 ng/mL per milligram) and PMs (5.79 ng/mL per milligram) did not show no difference in the levels of the active moiety (P = 0.470). CYP3A5 nonexpressors exhibited higher plasma concentrations of both RIS and 9-OH-RIS than its expressors. In the case of 9-OH-RIS, CYP3A5 nonexpressors exhibited significantly higher concentrations than CYP3A5 expressors (5.42 vs 3.51 ng/mL per milligram, P = 0.022). In addition, concentrations of the active moiety were also significantly different between the CYP3A5 nonexpressors (8.39 ng/mL per milligram) and expressors (5.30 ng/mL per milligram, P = 0.005). In conclusion, both CYP2D6 and CYP3A5 genotypes affected plasma levels of RIS and 9-OH-RIS, whereas the active moiety levels were influenced only by the CYP3A5 genotype but not by the CYP2D6 genotype.

Pharmacokinetics and Bioavailability of the Flavonoid 7,8-Benzoflavone in Rats

The flavonoid 7,8-benzoflavone was recently identified as one of the most potent inhibitors of breast cancer resistance protein (BCRP); however, little is known of the in vivo disposition of 7,8-benzoflavone. The objective of this study was to investigate the pharmacokinetics and bioavailability of 7,8-benzoflavone in rats. Three intravenous (5, 10, and 25 mg/kg) and three oral (12.5, 25, and 50 mg/kg) doses were administered to female Sprague-Dawley rats. Plasma samples were analyzed by high-performance liquid chromatography. Pharmacokinetic analysis was conducted by WinNonlin and ADAPT II. The dose-normalized plasma concentration versus time curves did not superimpose with each other, indicating the nonlinear pharmacokinetics of 7,8-benzoflavone. 7,8-benzoflavone exhibited a large volume of distribution (V(ss) approximately 1.5 L/kg) and rapid oral absorption (t(max) < 30 min). The bioavailability of 7,8-benzoflavone was low (0.61-13.2%) and dose-dependent. A pharmacokinetic model with dose-dependent bioavailability, linear absorption and nonlinear elimination best described the pharmacokinetic profiles of 7,8-benzoflavone. Using a 50 mg/kg oral dose of 7,8-benzoflavone, we could significantly increase the AUC for the BCRP substrate nitrofurantoin, demonstrating the potential for BCRP-mediated drug interactions.

Effect of liver and kidney function on migafungin disposition in patients with hematologic malignancies

The plasma concentration of micafungin (MCFG) after intravenous infusion of MCFG at 150 or 300 mg/day over 1 hour to 49 patients with hematologic malignancies were determined, and the relationship between the plasma concentrations and the patients' laboratory parameters of liver and kidney function was analyzed. Plasma samples were obtained at the end of the initial administration of MCFG, 5 to 6 hours after the start of the initial administration, immediately before the second dosing, immediately before the fourth dosing, and the end of the fourth dosing. The plasma concentration of MCFG was measured by high performance liquid chromatography. The plasma concentration of MCFG was correlated with the doses of MCFG per kilogram body weight. The peak concentration after the initial administration was 3.8 times higher than the trough level after the initial administration. The steady-state peak and trough levels were 1.4-1.5 times higher than those after the initial administration. There was no correlation between the laboratory parameters of liver/kidney function and the dose-normalized plasma concentration of MCFG. These results suggest that MCFG can be administered safely to patients with liver or kidney dysfunction without adjusting the dose.

Therapeutic Drug Monitoring of Quetiapine: Effect of Coadministration with Antiepileptic Drugs in Patients with Psychiatric Disorders

Antiepileptic agents, particularly those with mood-stabilizing properties, are increasingly used in the manage- ment of psychiatric disorders and may be prescribed in combination with antipsychotics. Aim of the present study was to evaluate the pharmacokinetic interaction between various antiepileptics and quetiapine, a second-generation antipsychotic, in psychiatric patients, by using data from a therapeutic drug monitoring service. Steady-state plasma concentrations of quetiapine were compared in patients treated with quetiapine alone (controls, n=35) and in patients comedicated with val- proic acid (n=19), lamotrigine (n=16), carbamazepine (n=6), topiramate (n=6) and oxcarbazepine (n=5). The six groups were matched for sex, age and daily dose of quetiapine. Dose-normalized plasma concentrations of quetiapine were sig- nificantly lower in the carbamazepine group than in the control group (p<0.001), while there were no differences in plasma quetiapine concentrations between the valproic acid, lamotrigine, topiramate or oxcarbazepine groups and the con- trol group. In 5 patients assessed on and off carbamazepine comedication, dose-normalized plasma concentrations of quetiapine were significantly lower during combination therapy than on quetiapine alone (p<0.01). By contrast, no appre- ciable changes in plasma levels of quetiapine were found in the 8 and 6 patients assessed on and off valproic acid or lamo- trigine comedication, respectively. These findings confirm that carbamazepine decreases markedly steady-state plasma concentrations of quetiapine, presumably by inducing its CYP3A4-mediated biotransformation. Conversely, concomitant administration of therapeutic doses of valproic acid, lamotrigine, topiramate or oxcarbazepine does not appear to affect significantly plasma levels of quetiapine.

Drug Concentration Monitoring with Tolerability and Efficacy Assessments during Open-Label, Long-Term Sertraline Treatment of Children and Adolescents

The aim of this study was to evaluate the long-term pharmacokinetics, safety, and efficacy of sertraline in children and adolescents with obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). After 42-day initial treatment and 9-day withdrawal phases, children (6-12 years, n = 16) and adolescents (13-18 years, n = 27) entered a 24-week open-label phase, with sertraline titrated to 200 mg/day. Blood samples for plasma sertraline and N-desmethylsertraline levels were taken at the beginning of the 24-week phase and at weeks 1, 4, 8, 12, and 24. Efficacy and safety data were also collected. Mean maximum daily dose at endpoint was 157 +/- 49 mg. For female and male children, mean sertraline/N-desmethylsertraline concentrations normalized to a 200-mg dose were 85.0/160 ng/mL (n = 8) and 79.3/134 ng/mL (n = 8), respectively, and for female and male adolescents, 70.5/109 ng/mL (n = 16) and 76.3/120 ng/mL (n = 8). No significant age or gender effects or age-by-gender interactions were observed in sertraline values. Mean sertraline plasma concentrations normalized for dose and body weight did not differ significantly by age or gender. Three (3) patients (7%) discontinued owing to adverse events. In patients with OCD (n = 10), improvements were observed in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (p = 0.029) and National Institute of Mental Health (NIMH) Global Obsessive Compulsive Scale (OCS) (p = 0.01). In MDD patients (n = 32), Clinical Global Impression (CGI) Severity (p = 0.002) and Improvement (p = 0.011) improved. Long-term treatment of MDD and OCD with sertraline up to 200 mg/day in children and adolescents results in dose-normalized plasma concentrations comparable to those seen in adults. Sertraline was generally well tolerated, and patients demonstrated clinical improvement over 24 weeks of treatment.

Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients

Despite the belief that cytochrome P450 (CYP) 2D6 alone is responsible for the metabolism of risperidone, several studies suggest that CYP3A may be involved. The aim of this study was to evaluate the effect of itraconazole, a CYP3A inhibitor, on the plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients in relation to CYP2D6 genotype. Nineteen schizophrenic patients treated with 2 to 8 mg/d of risperidone received 200 mg/d of itraconazole for a week. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured immediately before and after itraconazole treatment, as well as at 1 week after itraconazole treatment was stopped, together with clinical assessment by use of the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale and the Brief Psychiatric Rating Scale. Dose-normalized plasma concentrations of risperidone and 9-hydroxyrisperidone before itraconazole treatment (0.9 +/- 0.8 ng.mL(-1).mg(-1) and 6.9 +/- 3.3 ng.mL(-1).mg(-1), respectively) were significantly elevated after itraconazole treatment (1.6 +/- 1.3 ng.mL(-1).mg(-1) and 11.3 +/- 4.5 ng.mL(-1).mg(-1)) and decreased 1 week after its discontinuation (1.0 +/- 0.8 ng.mL(-1).mg(-1) and 7.2 +/- 3.7 ng.mL(-1).mg(-1)) (P < .01). However, the ratio of risperidone/9-hydroxyrisperidone, an index of CYP2D6 activity, did not differ before itraconazole treatment (0.14 +/- 0.13), after itraconazole treatment (0.15 +/- 0.13), and 1 week after discontinuation (0.14 +/- 0.13) (P > .05). Itraconazole increased the concentrations of risperidone by 69% (P < .001) and 75% (P < .01) in CYP2D6 extensive and poor metabolizers, respectively. In addition, the active moiety (risperidone plus 9-hydroxyrisperidone) also increased similarly, by 71% (P < .001) and 73% (P < .05), respectively, with itraconazole, without a significant difference between CYP2D6 genotypes. The scores on the Brief Psychiatric Rating Scale decreased significantly but only by 6% after itraconazole treatment (P < .05); however, the scores on the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale were not changed. Our results provide in vivo evidence of the involvement of CYP3A in the disposition of risperidone and 9-hydroxyrisperidone. In addition to CYP2D6, treatment with CYP3A inhibitor(s) including itraconazole may influence clinical symptoms and risperidone side effects.

Dose‐Proportional and Stereospecific Pharmacokinetics of Methylphenidate Delivered Using an Osmotic, Controlled‐Release Oral Delivery System

Methylphenidate hydrochloride (HCl) is frequently used for the treatment of attention deficit/hyperactivity disorder (ADHD). A study was conducted in healthy subjects to evaluate the dose-ranging pharmacokinetics of 18, 36, and 54 mg methylphenidate HCl delivered using an oral, osmotic, controlled-release formulation (OROS). Plasma concentrations of l-methylphenidate were 40-fold lower than those of d-methylphenidate, whereas plasma concentrations of d-alpha-phenyl-2-piperidine acetic acid (d-PPA) and l-PPA, the major metabolite of methylphenidate, were comparable. Mean AUCinf values for d-methylphenidate were 42.2, 80.9, and 120 ng.h/mL for the 18, 36, and 54 mg doses, respectively, increasing dose proportionally. AUCinf values for l-methylphenidate were only approximately 1% of d-methylphenidate (0.43, 0.96, and 1.82 ng.h/mL for the 18, 36, and 54 mg dose groups, respectively). In contrast, AUCinf values of d- and l-PPA were comparable. The dose-normalized d- and l-methylphenidate plasma concentration-time profiles for the three treatment groups were superimposable. Similarly, dose-normalized plasma concentrations of d- and l-PPA were superimposable. Methylphenidate metabolism, measured as the ratio of d-methylphenidate AUCinf to d-PPA AUCinf and as l-methylphenidate AUCinf to l-PPA AUCinf, was similar for the three dose groups, indicating that methylphenidate metabolism was not affected by increasing dose. OROS (methylphenidate HCl) exhibits dose-proportional and linear pharmacokinetics.

Pharmacokinetics of navelbine after oral administration in cancer patients

The pharmacokinetic behavior of navelbine was investigated in 19 patients presenting with advanced cancers (mainly women with breast cancer). Navelbine was given orally at seven dose levels of up to 200 mg/week. For a given dose, patients received four successive weekly treatments. Five subjects also received two different doses. After drug administration, plasma was collected for 48 or 72 h and monitored for navelbine concentration by radioimmunoassay. Absorption of navelbine was very rapid after oral administration: maximal drug concentrations were reached within the first 1 or 2 h (Tmax, 0.9-1.75 h; cmax, 70.9-832.6 ng/ml), with absorption constants ranging from 0.85 to 2.42 l/h. A comparison of dose-normalised plasma concentration profiles revealed significant time dependence in six evaluable patients (P less than 0.001). Only four subjects who received low doses (less than or equal to 100 mg/week) exhibited time-independent kinetics. All of the five patients who were treated at different doses displayed apparent dose dependence (P less than 0.001). No individual profile was characterised by both time- and dose-independent pharmacokinetics. In all, 18 patients presented biphasic plasma concentration-decay patterns, and only 1 subject exhibited monophasic decay kinetics. The navelbine pharmacokinetic parameters obtained following oral administration were similar to those observed after i.v. bolus injection and were characterised by high oral clearance (0.43-1.45 1 h-1 kg-1), a large apparent volume of distribution (27.4-45.9 1/kg), and a long terminal half-life (24.2-56.5 h). Large intra- and inter-individual variations in pharmacokinetic parameters were observed. Moreover, after a high dose of 200 mg, an enterohepatic cycle and/or a delay in navelbine's absorption at a distal intestinal site as evidenced by a marked plasma level rebound was observed.