Pharmacokinetics Of Single Oral Dose Research Articles

Pharmacokinetics of single and multiple oral doses of arbidol in healthy Chinese volunteers

Arbidol is licensed in Russia and China for prophylaxis and treatment of influenza A and B. This study was to assess the pharmacokinetics of single and multiple doses of arbidol in healthy Chinese volunteers. This was a single-center, open-label, two-phase study conducted in 12 subjects. In single-dose phase, subjects were randomized to receive single doses of 0.2, 0.4 and 0.8 g of arbidol in a crossover design with a 7-day washout period between administration. In the multiple-dose phase, subjects received 0.2 g 3 times a day for 7 days. Serial blood samples were collected at predefined time points. Plasma concentrations were determined with a validated HPLC method. Safety assessments were conducted throughout the study. After administration of single doses of 0.2, 0.4 and 0.8 g, geometric mean estimates for arbidol Cmax were 0.70, 1.24, and 2.16 mg/l and the mean of AUClast were 3.27, 5.81 and 12.72 mg×h/l, respectively. The AUClast and Cmax showed dose proportionality. After administration of multiple doses, the mean of Cmax,ss of arbidol was 0.41 mg/l and the mean accumulation ratio is ~ 1.12. Compared with single-dose phase, arbidol exhibited lower Cmax and prolonged plasma concentration profiles. In healthy Chinese subjects, single dosing of arbidol resulted in linear plasma pharmacokinetics. Arbidol exhibited little accumulation with repeated administration. Compared with single doses, multiple oral doses showed somewhat different pharmacokinetics and tissue distribution patterns. Sex did not appear to affect the pharmacokinetic properties of arbidol.

Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers

Dietary sodium, the main determinant of the pharmacodynamic response to renin-angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin-angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC0-∞: 0.74; [90% CI, 0.66-0.82] and 0.69 [90% CI, 0.54-0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin-angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC0-24 of plasma drug concentration explained <1% and 21% of the variance of the AUC0-24 of delta plasma renin concentration for candesartan (P=0.8882/P=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.

Single Oral Dose Pharmacokinetics of Decursin, Decursinol Angelate, and Decursinol in Rats

Decursin and decursinol angelate are the major components in the alcoholic extract of the root of Angelica gigas Nakai. Our previous work convincingly demonstrated that both decursin and decursinol angelate were rapidly converted to decursinol in mice after administration by either oral gavage or i. p. injection. In the current study, we compared for the first time the plasma profiles of decursinol, when equal moles of decursin/decursinol angelate or decursinol were given to rats by oral gavage, and investigated the effect of different formulas and other chemicals in Angelica gigas extract on the bioavailability of decursinol. Our results show that gavage of decursinol led to a faster attainment of plasma decursinol peak (Tmax ~ 0.7 h) and much higher peak levels than an equal molar amount administered as decursin/decursinol angelate mixture or as Angelica gigas ethanol extract, resulting in 2-3 fold higher bioavailability as estimated by the area under the curve of the respective regimens (65 012 vs. 27 033 h · ng/mL for decursinol and decursin/decursinol angelate treatment groups, respectively). Compared to a formula based on ethanol-PEG400-Tween80, carboxyl methyl cellulose was a less optimized vehicle. In addition, we detected peak levels of decursin and decursinol angelate in the plasma of rats administered with decursin/decursinol angelate or Angelica gigas extract in the nM range (Tmax ~ 0.5 h) with a newly established sensitive UHPLC-MS/MS method. Furthermore, our data support the liver, instead of intestine, as a major organ site where decursin and decursinol angelate were hydrolyzed to decursinol with a S9 microsomal in vitro metabolism assay. Taken together, our study provided important PK, LC-MS/MS methodology, formulation and metabolism insights in a rodent model for the rational design of in vivo efficacy studies of the corresponding chemicals in the future.

Pharmacokinetics of single and multiple oral doses of 5 mg linagliptin in healthy Chinese volunteers

To investigate the pharmacokinetic and safety profile of linagliptin after single and multiple doses in healthy Chinese volunteers. Men and women (n = 12) aged 18 - 45 years with body mass index 19 - 24 kg/m2 received a single 5-mg dose of linagliptin on Day 1, followed by 7-day washout and 6 consecutive days of once-daily administration. Vital signs, electrocardiogram, routine laboratory tests, urinalysis, and adverse events were recorded. Blood and urine analytes were measured by HPLC/MS/MS. Linagliptin was rapidly absorbed; median time to maximum concentration was 1.75 h for single dose and 1.5 h at steady-state. Maximum plasma drug concentration (Cmax) after single dose was 4.9 ng/ml (10.4 nM), with a geometric coefficient of variation (gCV) 46%. The corresponding geometric mean area under the plasma concentrationtime curve (AUC) was 71 ng×h ml-1 (150 nmol×h l-1, gCV 25%). At steady-state, Cmax and AUC were 6.7 ng/ml (14.1 nM, gCV 49%) and 96 nmol×h l-1 (204 nmol×h l-1, gCV 25%). An accumulation half-life of ~ 11.5 h (gCV 46.9%) was calculated. Renal excretion of linagliptin was low and < 8% of administered dose at steady-state (< 2% at Day 1). Single and multiple daily oral doses of 5 mg linagliptin were safe and well tolerated. No adverse events or clinically significant changes in laboratory tests, vital signs, or physical examination were reported. Linagliptin demonstrated a favorable safety profile in healthy Chinese volunteers, with a pharmacokinetic profile that was similar to that observed previously in subjects of Japanese, Caucasian, or African American origin.

Differences in the In Vitro and In Vivo Pharmacokinetic Profiles of Once-Daily Modified-Release Methylphenidate Formulations in Canada: Examination of Current Bioequivalence Criteria

BackgroundCurrent Canadian bioequivalence criteria rely on rate and extent of drug exposure, that is, Cmax and AUC. In the case of complex modified-release formulations, these criteria may not address pharmacokinetic differences with potential therapeutic and tolerability implications. ObjectiveThis study was performed to characterize in vitro dissolution and in vivo pharmacokinetic profiles of three modified-release formulations of methylphenidate (MPH) marketed in Canada, two of which meet the criteria for assuming bioequivalence as defined by Health Canada: MPH extended-release (ER-C) and osmotic controlled-release oral-delivery-system (OROS-MPH). MethodsIn vitro dissolution tests were performed using 54-mg OROS-MPH, 54-mg MPH ER-C, and 20-mg MPH sustained-release (SR) tablets. In vivo pharmacokinetics of single oral doses of 54 mg OROS-MPH, 54 mg MPH ER-C, and 60 mg MPH-SR were evaluated in an open-label, randomized, crossover study in healthy subjects. Plasma samples were collected up to 24 hours after administration of the drug. ResultsIn vitro dose-corrected release profiles of MPH ER-C and MPH-SR tablets were similar (<10% difference), whereas OROS-MPH exhibited a profile distinct from that of the other formulations. Twenty-four subjects completed the pharmacokinetic study and were included in the analyses. Analysis of Cmax and AUC of MPH showed that OROS-MPH and MPH ER-C met the criteria for assumed bioequivalence according to Health Canada guidelines. However, partial AUCs exhibited significant differences between the two formulations, which were supported by ratios of MPH concentrations over time. Comparison of MPH ER-C with MPH-SR (dose corrected) also satisfied bioequivalence criteria. ConclusionsThe pharmacokinetic data suggest that in vitro and in vivo profiles of OROS-MPH and MPH ER-C are distinct. However, using traditional criteria for bioequivalence, MPH ER-C would be assumed bioequivalent to both OROS-MPH and MPH-SR. Inclusion of partial AUCs as additional criteria could aid in ensuring therapeutic equivalence. ClinicalTrials.gov identifier: NCT01118702.

Pharmacokinetics of single and multiple oral doses of valsartan/amlodipine (80/5 mg) in healthy Chinese subjects

The efficacy and safety of valsartan/amlodipine combination have been demonstrated for the treatment of hypertension. In China, where the prevalence of hypertension is increasing the pharmacokinetic study of valsartan, amlodipine assumes significance. The aim of this study was to characterize the pharmacokinetics (PK) of valsartan and amlodipine following single- and multiple-dose oral administrations of valsartan/ amlodipine 80/5 mg fixed-dose combination in healthy Chinese subjects. This was an open-label, two-period (single-dose treatment followed by a multiple-dose (once-daily for 9 days), with a 7-day intertreatment washout period) study conducted in 18 subjects. Serial blood samples were collected at pre-defined time points, and the plasma concentrations of valsartan and amlodipine were measured using LC-MS/MS. Safety was evaluated after single- and multiple-dose drug administration. Following the single-dose oral administration of valsartan/amlodipine 80/5 mg, valsartan and amlodipine plasma concentrations reached peak levels at median tmax of 3 and 6 h, respectively. These concentrations declined thereafter, with mean elimination half-lives of 7.7 h (single dose) and 8.6 h (multiple dose) for valsartan, and 47 h (single dose) and 45 h (multiple dose) for amlodipine. After a 9-day multiple-dose treatment (at steady state), accumulation of valsartan and amlodipine was consistent with their half-lives. The single- and multiple-dose administration of valsartan/amlodipine 80/5 mg was associated with asymptomatic hypotension, consistent with the pharmacological activity of the combination of these two blood pressure-lowering drugs when co-administered in healthy subjects. The PK of valsartan and amlodipine are linear following oral administration of valsartan/amlodipine fixed-dose combination.

2.244 PHARMACOKINETICS, PHARMACODYNAMICS AND TOLERABILITY OF OPICAPONE, A NOVEL COMT INHIBITOR, DURING FIRST ADMINISTRATION TO HEALTHY MALE SUBJECTS

Aim: Opicapone was developed to fulfill the need for more potent, safer and longer acting catechol-O-methyltransferase (COMT) inhibitors [1]. This study was aimed to assess the tolerability, pharmacodynamics, and pharmacokinetics of single oral doses of opicapone in healthy male subjects. Design: Single rising oral doses of 10mg to 1200mg of opicapone were studied under a double-blind, randomised, placebo-controlled design. Eight sequential groups of 8 subjects were enrolled. Within each group, 6 subjects were randomised to receive opicapone and 2 subjects to receive placebo. Opicapone/placebo was administered after a 10h overnight fasting. Results: The extent and rate of systemic exposure (AUC and Cmax) to opicapone increased in an approximately dose-proportional manner. Despite the relatively short half-life of opicapone (1 to 4h), inhibition of soluble COMT (S-COMT) activity in erythrocytes was long-lasting, ranging from 6% (10mg) to 55% (1200mg) at 72h postdose. Maximum S-COMT inhibition (Emax) occurred between 1 and 6h post-dose (tEmax), and was 34.5%, 71.7%, 93.8%, 96.3%, 100%, 100%, 100% and 100% with the doses of 10, 25, 50, 100, 200, 400, 800 and 1200mg, respectively. Urine levels of opicapone and its metabolites usually remained below the limit of quantification, showing that kidney is not the primary route of excretion. Opicapone was well tolerated at all doses tested. Conclusion: Opicapone was well tolerated at oral single doses of 10mg to 1200mg, presented a dose-proportional kinetics and effectively inhibited erythrocyte soluble COMT activity.

2.245 PHARMACOKINETICS, PHARMACODYNAMICS AND TOLERABILITY OF OPICAPONE, A NOVEL COMT INHIBITOR, DURING MULTIPLE RISING DOSE REGIMENS IN HEALTHY MALE SUBJECTS

Aim: Opicapone was developed to fulfill the need for more potent, safer and longer acting catechol-O-methyltransferase (COMT) inhibitors [1]. This study was aimed to assess the tolerability, pharmacodynamics, and pharmacokinetics of single oral doses of opicapone in healthy male subjects. Design: Single rising oral doses of 10mg to 1200mg of opicapone were studied under a double-blind, randomised, placebo-controlled design. Eight sequential groups of 8 subjects were enrolled. Within each group, 6 subjects were randomised to receive opicapone and 2 subjects to receive placebo. Opicapone/placebo was administered after a 10h overnight fasting. Results: The extent and rate of systemic exposure (AUC and Cmax) to opicapone increased in an approximately dose-proportional manner. Despite the relatively short half-life of opicapone (1 to 4h), inhibition of soluble COMT (S-COMT) activity in erythrocytes was long-lasting, ranging from 6% (10mg) to 55% (1200mg) at 72h postdose. Maximum S-COMT inhibition (Emax) occurred between 1 and 6h post-dose (tEmax), and was 34.5%, 71.7%, 93.8%, 96.3%, 100%, 100%, 100% and 100% with the doses of 10, 25, 50, 100, 200, 400, 800 and 1200mg, respectively. Urine levels of opicapone and its metabolites usually remained below the limit of quantification, showing that kidney is not the primary route of excretion. Opicapone was well tolerated at all doses tested. Conclusion: Opicapone was well tolerated at oral single doses of 10mg to 1200mg, presented a dose-proportional kinetics and effectively inhibited erythrocyte soluble COMT activity.

Single-dose and multiple-dose pharmacokinetics of zaltoprofen after oral administration in healthy Chinese volunteers

Zaltoprofen, a propionic acid derivative of non-steroidal anti-inflammatory drugs, has strong inhibitory effects on actue and chronic inflammation. A randomized, dose-escalating study was conducted to evaluate the pharma-cokinetics of single and multiple oral doses of zaltoprofen in 12 healthy Chinese volunteers. Pharmacokinetics was determined from serial blood samples obtained up to 24 h after administration of a single dose of zaltoprofen at 80, 160 or 240 mg and after multiple doses of zaltqorofen at 80 mg 3 times daily. The Cmax and AUC0–24 of zaltoprofen were found to be proportional to drug dose. Zaltoprofen was rapidly absorbed (tmax =1.46±0.83 h) and cleared (t1/2 =4.96±2.97 h). Pharmacokinetic parameters after multiple doses were similar to those after single doses. Zaltoprofen was well tolerated. These results support a tid regimen of zaltoprofen for the management of acute and chronic inflammation.

The influence of Nifadin®, Niprisan® and Niprd/92/001/1-1 (AM-1) on the pharmacokinetics of metronidazole in rats

The single oral dose pharmacokinetics of metronidazole was studied alone and after co-administration with phytomedicines, Nifadin, Niprisan and Niprd/92/001/1-1 (AM-1), in rats. Plasma metronidazole concentrations were measured using high-performance liquid chromatography method developed earlier in our laboratory. The data were fitted into a WinNonlin standard non-compartmental programme. The co-administration of the herbal medicines with metronidazole produced an increase in the serum concentration of metronidazole at each sampling time. The highest increase of 184% occurring at the time of peak concentration (1 h) was obtained with AM-1, followed by 145% with Niprisan, the least was 131% with Nifadin. Significant increase was also observed in some other parameters, such as area under the serum concentration-time curve (AUC0-24) and maximum serum concentration (Cmax), while the apparent volume of distribution (Vd) and plasma clearance (C1) reduced significantly (P < 0.05). It was concluded that the gastric presence of the herbal medicines impaired the absorption and elimination Niadin alone) of metronidazole in rats significantly (P < 0.05).

A single-dose, three-period, six-sequence crossover study comparing the bioavailability of solution, suspension, and enteric-coated tablets of magnesium valproate in healthy Mexican volunteers under fasting conditions

Background: Valproic acid has been associated with a highly variable intersubject absorptive phase; therefore, magnesium salt (magnesium valproate [MgV]) was developed to diminish variation during enteric absorption. Objectives: The aims of this study were to assess the pharmacokinetics of single oral doses of MgV 500-mg solution, suspension, and enteric-coated tablets in a healthy Mexican population, and to compare formulation-related differences. Methods: This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy Mexican volunteers aged 18 to 45 years. In each period, subjects received single oral doses of 500-mg MgV solution, suspension, and enteric-coated tablet formulations, with a 7-day washout period between each dosing period. Serial blood samples were collected at 0 hour (prior to MgV administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 24, 48, and 72 hours after dosing. Valproate was measured by a new method of ultraperformance liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters of interest were C max, T max, AUC 0–72, AUC 0−∞, t½, V d/F, CL/F, and mean residence time (MRT). Formulation-related differences were assayed in accordance with the Mexican regulatory bioequivalence criteria. Log-transformed values of C max and AUC were used to construct a classic 90% CI. Bioequivalence was established if the 90% CI for the mean test:reference ratio of log-transformed C max and AUC were within the range of 0.80 to 1.25. Tolerability was assessed based on subject interview, vital sign monitoring, and clinical assessment. Results: A total of 24 healthy volunteers (12 women and 12 men; mean [SD] age, 28.79 [6.5] years; height, 164 [9.8] cm; weight, 65.42 [8.95] kg; and body mass index, 24.28 [2.11] kg/m 2) were included. For the MgV solution, the mean (SD) pharmacokinetic parameters of C max, T max, AUC 0–72, AUC 0–∞, t½, V d/F, CL/F, and MRT were 59.75 (8.24) μg/mL, 0.542 (0.14) hours, 1099.67 (241.70) μg · h/mL, 1156.30 (264.01) μg · h/mL, 16.19 (2.36) hours, 9633.68 (1892.70) mL, 418.35 (92.01) mL/h, and 18.36 (1.44) hours, respectively. For the MgV suspension, the mean (SD) pharmacokinetic parameters of C max, T max, AUC 0–72, AUC 0−∞, t½, V d/F, CL/F, and MRT were 55.04 (7.72) μg/mL, 0.773 (0.51) hour, 1057.76 (223.37) μg · h/mL, 1111.09 (245.07) μg · h/mL, 16.32 (2.20) hours, 1069.05 (1775.64) mL, 435.43 (99.59) mL/h,\\ and 18.41 (1.43) hours, respectively. For the MgV entericcoated tablets, the mean (SD) pharmacokinetic parameters of C max, T max, AUC 0–72, AUC 0−∞, t½, V d/F, CL/F, and MRT were 54.88 (6.73) μg/mL, 2.79 (0.89) hours, 1100.79 (216.70) μg · h/mL, 1163.61 (238.36) μg · h/mL, 16.48 (2.10) hours, 9675.15 (1659.36) mL, 412.36 (85.24) mL/h, and 19.95 (1.53) hours, respectively. The 90% CIs for the tablets:solution ratio were 82.15 to 95.44, 94.60 to 105.39, and 95.43 to 105.95 for C max, AUC 0–72, and AUC 0−∞, respectively. The 90% CIs for the suspension:solution ratio were 84.79 to 98.50, 88.89 to 99.02, and 89.15 to 98.97, respectively. The 90% CIs for the tablets:suspension ratio were 89.90 to 104.43, 100.84 to 112.34, and 101.60 to 112.80, respectively. Conclusion: This single-dose study found that the 3 formulations (solution, suspension, and enteric-coated tablets) of MgV met the regulatory criteria for bioequivalence in these healthy, fasting, Mexican volunteers.

Effect of phytomedicines, AM-1, niprisan® and nifadin on the pharmacokinetics of chloroquine in rats

The single oral dose pharmacokinetics of chloroquine was studied alone and after coadministration with phytomedicines NIPRID\92\001\1-1 (AM-1), Niprisan, and Nifadin in rats. Plasma chloroquine concentrations were measured using High performance liquid chromatography (HPLC) method developed earlier in our laboratory. The data were fitted into a WinNonlin standard non-compartmental programme. The co-administration of the herbal medicines with chloroquine produced decrease in the serum concentration of chloroquine at each sampling time. The highest decrease of 85% occurring at the time of peak concentration (1 h) was recorded with Nifadin, followed by 75% with Niprisan the least was 50% with AM-1. Significant reduction was also observed in some other parameters, such as area under the serum concentration- time curve (AUC(0-24)) and maximum serum concentration (Cmax) while the apparent volume of distribution (Vd) and elimination half-life (t 1/2beta) increased significantly (P< 0.05). It was concluded that the gastric presence of the herbal medicines significantly impaired the absorption of chloroquine in rats.

Nilotinib for imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase, accelerated phase, or blast crisis: A single- and multiple-dose, open-label pharmacokinetic study in Chinese patients

Background: Nilotinib, an oral second-generation Bcr-Abi tyrosine kinase inhibitor, is approved in the United States and European Union for the treatment of Philadelphia chromosome-positive (Ph+), chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) resistant to or intolerant of prior therapy, including imatinib. Information on the pharmacokinetics of nilotinib in Chinese patients with CML is lacking, and regulatory requirements for registration of this drug are needed in China. Objectives: This study assessed the pharmacokinet-ics of single and multiple oral doses of nilotinib in Chinese patients with CML and compared the pharmacokinetic profiles of nilotinib between the Chinese patients and a subgroup of white patients with CML. Methods: Chinese patients aged ≥18 years with Ph+ CML-CP, CML-AP, or CML-BC (blast crisis) resistant to or intolerant of imatinib were eligible. Patients were administered oral nilotinib 400 mg BID for 15 days. Serial blood samples were collected before and at 1, 2, 3, 5, 8, and 12 hours after the administration of a single dose (day 1) and multiple doses (day 15, steady state). Serum nilotinib concentrations were determined using a validated liquid chromatography-tandem mass spectrometry assay, and pharmacokinetic parameters of nilotinib were calculated using a noncompartmental method. Tolerability was assessed using cardiac assessments; laboratory analysis (hematology, blood chemistry, and urinalysis); and physical examination, including vital signs. Results: Twenty-three patients were enrolled (18 men, 5 women; mean age, 40.0 years; mean weight, 68.3 kg; CML-CP, 22 patients; CML-AP, 1). All 23 patients were included in the tolerability analysis. Two patients withdrew consent and discontinued after administration of the first dose; thus, 21 patients were included in the pharmacokinetic analysis. Median T max was ~2 hours after administration of single and multiple doses. At steady state, C min was 1025.4 ng/mL and C max was 2160.7 ng/mL. Mean AUCs from time 0 to the end of the dosing interval τ (AUC 0-τ) were 5076.3 and 17,751.3 ng · h/mL at days 1 and 15, respectively, representing an accumulation factor of 3.92. Apparent oral clearance (CL/F) was 0.39 L/h/kg (range, 0.12–0.74 L/h/ kg) at steady state. The study found a 42% intersubject variability in nilotinib pharmacokinetics. Steady-state C max, C min, AUC 0-τ, and CL/F were not significantly different from those previously reported in a subgroup of white patients with CML who received the same 400-mg BID dose. Rash (11/23 patients [47.8%]) and elevated bilirubin, headache, and muscle pain (4 patients each [17.4%]) were the most frequently reported nonhematologic adverse events. Conclusions: In this pharmacokinetic study in Chinese patients with CML resistant to or intolerant of imatinib, nilotinib 400 mg BID was rapidly absorbed after a single dose and multiple doses. The steady-state pharmacokinetic properties in this population were consistent with those reported previously in white patients with CML.

Validated LC–MS–MS Method for Quantitative Determination of Batifiban in Human Plasma and Its Application to a Pharmacokinetic Study

Batifiban is a new platelet GPIIb/IIIa receptor antagonist. In this work, an analytical method based on liquid chromatography and electrospray ionization tandem mass spectrometry has been firstly developed and validated for the quantitative measurement of batifiban in human plasma to support the investigation of this compound. Separation of analyte and the internal standard eptifibatide was performed on a Thermo HyPURITY C18 column (150 × 2.1 mm, 5 μm) with a mobile phase consisting of formic acid 0.1% (v/v)–acetonitrile (40:60, v/v) at a flow rate of 0.25 mL min−1. The Waters QuattroMicro API triple quadrupole mass spectrometer was operated in multiple reaction monitoring mode via positive electrospray ionization interface using the transition m/z 819.2 → m/z (623.9 + 159.4) for batifiban and m/z 833.4 → m/z (645.7 + 159.3) for IS. The method was linear over the concentration range of 2.45–5,000 μg L−1. The intra- and inter- day precisions were less than 15% in terms of relative standard deviation, and the accuracy was within 8.5% in terms of relative error (RE). The lower limit of quantification (LLOQ) was identifiable and reproducible at 2.45 μg L−1 with acceptable precision and accuracy. The validated method offered sensitivity and wide linear concentration range. This method was successfully applied for the evaluation of pharmacokinetics of batifiban afer single oral doses of 55, 110 and 220 μg kg−1 batifiban to 36 Chinese healthy volunteers.

Single‐Dose Pharmacokinetics of Oral and Intravenous Pantoprazole in Children and Adolescents

The primary objective was to determine the pharmacokinetics of single oral and intravenous doses of pantoprazole in children 2 to 16 years of age. The secondary objective was to assess the safety and tolerability of these doses. Male and female hospitalized and nonhospitalized patients from ages 5 to 16 years received single oral doses (20 mg or 40 mg), and those from ages 2 to 16 years received single intravenous doses (0.8 mg/kg or 1.6 mg/kg) of pantoprazole. The plasma concentration-time data for each patient were analyzed using noncompartmental methods. Routine safety and tolerability assessments were also obtained. The mean values for peak plasma concentration and total area under the plasma concentration-time curve increased with increasing dose. Pharmacokinetic values were similar in patients from ages 2 to 16 years and to those previously obtained in adults. Statistically significant differences were observed for dose-normalized pantoprazole area under the plasma concentration-time curve when compared between CYP2C19 extensive metabolizers with 1 versus 2 functional alleles. All adverse events were mild in severity and considered to be unrelated to study drug. The pharmacokinetic profile of oral and intravenous pantoprazole was similar in children ages 2 to 16 years. The doses used here were safe and well tolerated in this population.

Single‐ and Multiple‐Dose Pharmacokinetics of Pirfenidone, an Antifibrotic Agent, in Healthy Chinese Volunteers

A randomized, dose-escalating study evaluated the pharmacokinetics of single and multiple oral doses of pirfenidone, a promising antifibrotic agent, in 48 healthy Chinese volunteers. The effects of sex and food on the pharmacokinetics of pirfenidone were also evaluated. Pharmacokinetics was determined from serial blood samples obtained up to 12 hours after administration of single 200-, 400-, or 600-mg doses of pirfenidone and after multiple doses of 400 mg administrated 3 times daily (tid). Plasma levels of pirfenidone and areas under the curve were found to be proportional to dose. Pirfenidone was rapidly absorbed (t(max) = 0.33-1 hours) and cleared (t((1/2)) = 2-2.5 hours). Pharmacokinetic parameters after multiple doses were similar to those after single doses. Food had a significant effect (P < .01) on the extent of absorption (AUC(0-infinity) = 37.4 +/- 15.4 mg x h/L [fed] vs 46.6 +/- 16.8 mg x h/L [fasted]), rate of absorption was considerably (P < .001) prolonged (t(max) = 1.5 +/- 0.4 hours [fed] vs 0.7 +/- 0.2 hours [fasted]), and peak concentrations were significantly (P < .001) decreased (C(max) = 9.2 +/- 2.9 mg/L [fed] vs 13.0 +/- 1.8 mg/L [fasted]). No significant sex differences were noted for pharmacokinetic variables. Pirfenidone was well tolerated. These results support a tid regimen of pirfenidone for the management of idiopathic pulmonary fibrosis. Concomitant intake of food will reduce the rate and extent (about 20%) of absorption, which is associated with better tolerability of pirfenidone.

Induction of the metabolism of etizolam by carbamazepine in humans

To examine the effect of carbamazepine on the single oral dose pharmacokinetics of etizolam. Eleven healthy male volunteers received carbamazepine 200 mg/day or placebo for 6 days in a double-blind, randomized, crossover manner, and on the sixth day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured using high-performance liquid chromatography. Carbamazepine treatment significantly decreased the peak plasma concentration (17.5±4.1 ng/ml versus 13.9±4.1 ng/ml; P<0.05), total area under the plasma concentration–time curve (194.8±88.9 ng h/ml versus 105.9±33.0 ng h/ml; P<0.001), and elimination half-life (11.1±4.6 h versus 6.8±2.8 h; P<0.01) of etizolam. No significant change was induced by carbamazepine in the two pharmacodynamic parameters. The present study suggests that carbamazepine induces the metabolism of etizolam.

Rifampicin Markedly Decreases Plasma Concentration and Hypnotic Effect of Brotizolam

The purpose of the present study was to examine the effects of rifampicin on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam. Thirteen healthy male volunteers received rifampicin 450 mg/day, or matched placebo, for 7 days in a double-blind randomized crossover manner. On the sixth day they received a single oral 0.5-mg dose of brotizolam, and blood sampling was performed for 24 hours, together with an assessment of psychomotor function using the Digit Symbol Substitution Test and the Stanford Sleepiness Scale. Rifampicin treatment significantly (P<0.001) decreased the peak plasma concentration (69%), total area under the plasma concentration-time curve (90%) and elimination half-life (79%) of brotizolam. Rifampicin significantly increased the area under the score-time curve of the Digit Symbol Substitution Test (P<0.01), and decreased that of the Stanford Sleepiness Scale (P<0.05). The present study suggests that rifampicin markedly decreases plasma concentration and hypnotic effect of brotizolam and, therefore, this combination is not recommended in clinical practice.

Effect of carbamazepine on the single oral dose pharmacokinetics of perospirone and its active metabolite

Perospirone is a serotonin 5-HT 2A and dopamine D 2 receptor antagonist which originated in Japan. It has been shown that perospirone is metabolized to ID-15036 mainly by CYP3A4 based on an in vitro study. To investigate the metabolism of perospirone in humans, the authors measured the concentration of perospirone and ID-15036 after a single oral dose of perospirone (8 mg) in 10 healthy male subjects, before and during coadministration of carbamazepine, known as a potent inducer of CYP3A4. Before carbamazepine coadministration, the peak plasma concentrations ± SD of perospirone and ID-15036 were 4.0 ± 4.3 and 11.7 ± 7.1 ng/ml, respectively. During carbamazepine coadministration, the concentration of perospirone was decreased below the detection limit, and that of ID-15036 was 6.0 ± 1.7 ng/ml. The concentrations of perospirone and ID-15036 were influenced significantly by the treatment with carbamazepine, and this was probably attributable to the induction of CYP3A4. This study provided an in vivo evidence of involvement of CYP3A4 in the metabolism of perospirone.

Effects of Itraconazole and Tandospirone on the Pharmacokinetics of Perospirone

Perospirone is an atypical antipsychotic agent originated and clinically used in Japan. Based on an in vitro study, it is reported that perospirone is mainly metabolized to ID-15036 by cytochrome P450 (CYP) 3A4. In this study, the authors investigated the effects of itraconazole, which is a specific inhibitor of CYP3A4, or tandospirone, which is mainly metabolized by CYP3A4 and is expected to competitively inhibit the activity of this enzyme, on single oral dose pharmacokinetics of perospirone. After pretreatment with 200 mg daily of itraconazole or 10 mg daily of tandospirone for 5 days, 9 healthy male subjects received 8 mg of perospirone. Plasma concentrations of perospirone and ID-15036 up to 10 hours after perospirone dosing were measured by high-performance liquid chromatography (HPLC). The metabolism of perospirone was significantly inhibited by treatment with itraconazole but not by tandospirone. The present study suggests that CYP3A4 is significantly involved in metabolism of perospirone in humans.